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Kezic, Aleksandra, Marko Baralic, Djina Tomasevic, Sasa Kadija, and Radmila Sparic. "Various faces of the same disease: membranous nephropathy in pregnancy - A case series." Srpski arhiv za celokupno lekarstvo 147, no. 9-10 (2019): 632–35. http://dx.doi.org/10.2298/sarh190221076k.
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Introduction. Pregnancies in women with membranous nephropathy (MN) are usually complicated by increased proteinuria and superimposed preeclampsia, and this frequently results in poor pregnancy outcomes. The aim of this paper is to present case series of pregnant women with MN and different fetal and maternal outcomes. Outline of cases. Case 1 presents a 25-year-old woman with MN, who had relapsed nephrotic syndrome in early pregnancy with proteinuria of 4.14 g/day and serum albumin of 30 g/L accompanied by hypertension. Due to a missed abortion, the pregnancy was terminated. Three months later her proteinuria was still increased, measuring 3 g/day. Case 2 presents a 29-year-old woman with a history of diffuse proliferative glomerulonephritis, who conceived with proteinuria below 0.5 g/day. The proteinuria ranged between 1 and 2 g/day from the 32nd until the 38th gestational week, when she delivered a healthy neonate. After delivery, the woman underwent a kidney biopsy, which revealed MN. Case 3 presents a 25-year-old woman with MN, whose proteinuria was 1 g/day at the time of conception, but in the 35th gestational week proteinuria of 4.2 g/day was noticed. In the 36th gestational week, increased proteinuria was detected, and a cesarean section was performed with favorable neonatal outcome. After two weeks her proteinuria dropped to 0.6 g/day. Conclusion. Pregnancies in women with MN associated with low-grade proteinuria at the time of conception may have a favorable perinatal outcome. Such pregnancies require multidisciplinary management by both obstetricians and nephrologists, and team decision regarding the best timing of delivery.
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Ghani, Afroza, Aftabun Nahar, Nasrin Sultana, Ashiya Khatun, Rifat Sultana, Md Abdullah Yusuf, and Rooh E. Zakaria. "Prediction of Gestational age by Last Menstrual Period (LMP) in Comparison to Ultrasonography (USG)." Journal of Shaheed Suhrawardy Medical College 6, no. 2 (March 7, 2017): 82–86. http://dx.doi.org/10.3329/jssmc.v6i2.31776.
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Background: Accurate dating is cardinally important for good pregnancy care. USG provides accurate dating of GA and has now days become an essential part maternal antenatal care.Objective: The purpose of the present study was to identify LMP as a better method for predicting the day of delivery than the USG measurement.Methodology: This was a Hospital-Based prospective, comparative study conducted at both inpatient and outpatient Department of Obstetrics and Gynaecology at Chittagong Medical College Hospital, Chittagong from October 2007 to September 2008 for a period of one year. The study populations were pregnant women with certain LMP and had dating USG at Nuclear Medicine Centre, Chittagong performed in first or early second trimester 12 - 14 weeks.Result: Among the 112 patients, 61 patients delivered within i 7 days of EDD based on LMP; whereas 82 patients delivered within 1 7 days of EDD based on USG. Of these, actual day of delivery of 49 patients correlated with the same gestational week determined by both LMP and USG. Actual day of delivery of 18 among these 112 patients did not correlate with the EDD determined either by LMP or USG and they all delivered beyond i 7 days of EDD based on either LMP or USG.Conclusion: USG dating during the estimated GA range of 12 to 14 weeks gave a more accurate prediction of delivery date than the estimate based on LMP.J Shaheed Suhrawardy Med Coll, 2014; 6(2):82-86
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Janssen, Anna B., Katrina A. Savory, Samantha M. Garay, Lorna Sumption, William Watkins, Isabel Garcia-Martin, Nicola A. Savory, et al. "Persistence of anxiety symptoms after elective caesarean delivery." BJPsych Open 4, no. 5 (August 17, 2018): 354–60. http://dx.doi.org/10.1192/bjo.2018.48.
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BackgroundIn the UK, 11.8% of expectant mothers undergo an elective caesarean section (ELCS) representing 92 000 births per annum. It is not known to what extent this procedure has an impact on mental well-being in the longer term.AimsTo determine the prevalence and postpartum progression of anxiety and depression symptoms in women undergoing ELCS in Wales.MethodPrevalence of depression and anxiety were determined in women at University Hospital Wales (2015–16; n = 308) through completion of the Edinburgh Postnatal Depression Scale (EPDS; ≥13) and State-Trait Anxiety Inventory (STAI; ≥40) questionnaires 1 day prior to ELCS, and three postpartum time points for 1 year. Maternal characteristics were determined from questionnaires and, where possible, confirmed from National Health Service maternity records.ResultsUsing these criteria the prevalence of reported depression symptoms was 14.3% (95% CI 10.9–18.3) 1 day prior to ELCS, 8.0% (95% CI 4.2–12.5) within 1 week, 8.7% (95% CI 4.2–13.8) at 10 weeks and 12.4% (95% CI 6.4–18.4) 1 year postpartum. Prevalence of reported anxiety symptoms was 27.3% (95% CI 22.5–32.4), 21.7% (95% CI 15.8–28.0), 25.3% (95% CI 18.5–32.7) and 35.1% (95% CI 26.3–44.2) at these same stages. Prenatal anxiety was not resolved after ELCS more than 1 year after delivery.ConclusionsWomen undergoing ELCS experience prolonged anxiety postpartum that merits focused clinical attention.Declaration of interestNone.
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Singh, Lucky, Ritam Dubey, Prashant Kumar Singh, Saritha Nair, M. Vishnu Vardhana Rao, and Shalini Singh. "Association between timing and type of postnatal care provided with neonatal mortality: A large scale study from India." PLOS ONE 17, no. 9 (September 16, 2022): e0272734. http://dx.doi.org/10.1371/journal.pone.0272734.
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Objectives This study examines the association between quality Postnatal Care (PNC) considering timing and providers’ type on neonatal mortality. The aim extends to account for regional disparities in service delivery and mortality including high and non-high focus states. Methods Ever-married women aged 15–49 years (1,87,702) who had delivered at least one child in five years preceding the survey date surveyed in National Family Health Survey (2015–16) were included in the study. Neonatal deaths between day two and seven and neonatal deaths between day two and twenty-eight were considered dependent variables. Descriptive statistics and multivariate regression analysis were conducted. Results Chances of early neonatal mortality were 29% (OR = 0.71; 95%CI: 0.59–0.84) among newborns receiving PNC within a day compared to ones devoid of it while 40% (OR: 0.60; 95%CI: 0.51–0.71) likelihood for the same was noted if PNC was delivered within a week. Likelihood of neonatal mortality decreased by 24% (OR: 0.76; 95%CI: 0.65–0.88) when skilled PNC was delivered within 24 hours. Receiving quality PNC by skilled providers within a day in a non-high focus state decreased the chances of neonatal mortality by 26% (OR: 0.74; 95%CI: 0.59–0.92) compared to ones who did not receive any PNC. Conclusions Neonatal deaths were significantly associated with socioeconomic and contextual characteristics including age, education, household wealth, social group and region. Timing of PNC delivered and by a skilled healthcare provider was found significant in reducing neonatal mortality.
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Simister, Robert, Georgia B. Black, Mariya Melnychuk, Angus IG Ramsay, Abigail Baim-Lance, David L. Cohen, Jeannie Eng, et al. "Temporal variations in quality of acute stroke care and outcomes in London hyperacute stroke units: a mixed-methods study." Health Services and Delivery Research 8, no. 34 (August 2020): 1–98. http://dx.doi.org/10.3310/hsdr08340.
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Background Seven-day working in hospitals is a current priority of international health research and policy. Previous research has shown variability in delivering evidence-based clinical interventions across different times of the day and week. We aimed to identify factors influencing such variations in London hyperacute stroke units. Objectives To investigate variations in quality of acute stroke care and outcomes by day and time of admission in London hyperacute stroke units, and to identify factors influencing such variations. Design This was a prospective cohort study using anonymised patient-level data from the Sentinel Stroke National Audit Programme. Factors influencing variations in care and outcomes were studied through interview and observation data. Setting The setting was acute stroke services in London hyperacute stroke units. Participants A total of 7094 patients with a primary diagnosis of stroke took part. We interviewed hyperacute stroke unit staff (n = 76), including doctors, nurses, therapists and administrators, and 31 patients and carers. We also conducted non-participant observations of delivery of care at different times of the day and week (n = 45, ≈102 hours). Intervention Hub-and-spoke model for care of suspected acute stroke patients in London with performance standards was designed to deliver uniform access to high-quality hyperacute stroke unit care across the week. Main outcome measures Indicators of quality of acute stroke care, mortality at 3 days after admission, disability at the end of the inpatient spell and length of stay. Data sources Sentinel Stroke National Audit Programme data for all patients in London hyperacute stroke units with a primary diagnosis of stroke between 1 January and 31 December 2014, and nurse staffing data for all eight London hyperacute stroke units for the same period. Results We found no variation in quality of care by day and time of admission across the week in terms of stroke nursing assessment, brain scanning and thrombolysis in London hyperacute stroke units, nor in 3-day mortality nor disability at hospital discharge. Other quality-of-care measures significantly varied by day and time of admission. Quality of care was better if the nurse in charge was at a higher band and/or there were more nurses on duty. Staff deliver ‘front-door’ interventions consistently by taking on additional responsibilities out of hours, creating continuities between day and night, building trusting relationships and prioritising ‘front-door’ interventions. Limitations We were unable to measure long-term outcomes as our request to the Sentinel Stroke National Audit Programme, the Healthcare Quality Improvement Partnership and NHS Digital for Sentinel Stroke National Audit Programme data linked with patient mortality status was not fulfilled. Conclusions Organisational factors influence 24 hours a day, 7 days a week (24/7), provision of stroke care, creating temporal patterns of provision reflected in patient outcomes, including mortality, length of stay and functional independence. Future work Further research would help to explore 24/7 stroke systems in other contexts. We need a clearer understanding of variations by looking at absolute time intervals, rather than achievement of targets. Research is needed with longer-term mortality and modified Rankin Scale data, and a more meaningful range of outcomes. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 34. See the NIHR Journals Library website for further project information.
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AlShamsi, Abdullatif, Jihad Mohaidat, Noura Al Hinai, and Ahmed Samy. "Instructional and Business Continuity Amid and Beyond COVID-19 Outbreak: A Case Study from the Higher Colleges of Technology." International Journal of Higher Education 9, no. 6 (September 18, 2020): 118. http://dx.doi.org/10.5430/ijhe.v9n6p118.
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With the announcement of COVID-19 as pandemic, and the call for social distancing, academic institutions reacted by shutting campuses and calling for the shift to virtual online delivery. In HCT, we conducted this study in an effort to sustain success in these global challenging times of crisis that is informed by strategic foresight.HCT called for an all-online delivery starting March 22, 2020 after a two-day pilot in the preceding week. HCT readiness is a result of orchestrating: an ecosystem perspective on digital transformation, a forth-looking institutional strategy that has technology utilization as a major pillar, an education technology strategy, and a comprehensive set of intelligent learning tools.Forward-looking scenarios were designed based on two critical uncertainties: (1) COVID-19 longevity and (2) socio-economic disruption. These scenarios are: Divine Mercy, Recovery Mode, New Norm, and Survival of the Fittest. Subsequently, the features of each scenario are assessed for implications on HCT’s business and support operations, and the proactive strategies are documented to cope with these implications.During the full online delivery mode period, HCT recorded 86% satisfaction amongst its faculty and 54% amongst its student body, delivered 234,000 hours through 61,000 online classes, and delivered over 21,000 hours of online professional development (PD). Over the same period, more than 1900 non-faculty employees have been running business as usual from home.Envisioning future scenarios and preparing the organization for them is a practice that should be deployed in parallel to emergency response efforts to ensure successful business continuity.
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Darrow, Lyndsey A., Mengjiao Huang, Joshua L. Warren, Matthew J. Strickland, Heather A. Holmes, Andrew J. Newman, and Howard H. Chang. "Preterm and Early-Term Delivery After Heat Waves in 50 US Metropolitan Areas." JAMA Network Open 7, no. 5 (May 24, 2024): e2412055. http://dx.doi.org/10.1001/jamanetworkopen.2024.12055.
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ImportanceHeat waves are increasing in frequency, intensity, and duration and may be acutely associated with pregnancy outcomes.ObjectiveTo examine changes in daily rates of preterm and early-term birth after heat waves in a 25-year nationwide study.Design, Setting, and ParticipantsThis cohort study of singleton births used birth records from 1993 to 2017 from the 50 most populous US metropolitan statistical areas (MSAs). The study included 53 million births, covering 52.8% of US births over the period. Data were analyzed between October 2022 and March 2023 at the National Center for Health Statistics.ExposuresDaily temperature data from Daymet at 1-km2 resolution were averaged over each MSA using population weighting. Heat waves were defined in the 4 days (lag, 0-3 days) or 7 days (lag, 0-6 days) preceding birth.Main Outcomes and MeasuresDaily counts of preterm birth (28 to <37 weeks), early-term birth (37 to <39 weeks), and ongoing pregnancies in each gestational week on each day were enumerated in each MSA. Rate ratios for heat wave metrics were obtained from time-series models restricted to the warm season (May to September) adjusting for MSA, year, day of season, and day of week, and offset by pregnancies at risk.ResultsThere were 53 154 816 eligible births in the 50 MSAs from 1993 to 2017; 2 153 609 preterm births and 5 795 313 early-term births occurring in the warm season were analyzed. A total of 30.0% of mothers were younger than 25 years, 53.8% were 25 to 34 years, and 16.3% were 35 years or older. Heat waves were positively associated with daily rates of preterm and early-term births, showing a dose-response association with heat wave duration and temperatures and stronger associations in the more acute 4-day window. After 4 consecutive days of mean temperatures exceeding the local 97.5th percentile, the rate ratio for preterm birth was 1.02 (95% CI, 1.00-1.03), and the rate ratio for early-term birth was 1.01 (95% CI, 1.01-1.02). For the same exposure, among those who were 29 years of age or younger, had a high school education or less, and belonged to a racial or ethnic minority group, the rate ratios were 1.04 (95% CI, 1.02-1.06) for preterm birth and 1.03 (95% CI, 1.02-1.05) for early-term birth. Results were robust to alternative heat wave definitions, excluding medically induced deliveries, and alternative statistical model specifications.Conclusions and RelevanceIn this cohort study, preterm and early-term birth rates increased after heat waves, particularly among socioeconomically disadvantaged subgroups. Extreme heat events have implications for perinatal health.
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Ende, Holly B., Ruth Landau, Naida M. Cole, Sara M. Burns, Brian T. Bateman, Melissa E. Bauer, Jessica L. Booth, et al. "Labor prior to cesarean delivery associated with higher post-discharge opioid consumption." PLOS ONE 16, no. 7 (July 9, 2021): e0253990. http://dx.doi.org/10.1371/journal.pone.0253990.
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Background Severe acute post-cesarean delivery (CD) pain has been associated with an increased risk for persistent pain and postpartum depression. Identification of women at increased risk for pain can be used to optimize post-cesarean analgesia. The impact of labor prior to CD (intrapartum CD) on acute post-operative pain and opioid use is unclear. We hypothesized that intrapartum CD, which has been associated with both increased inflammation and affective distress related to an unexpected surgical procedure, would result in higher postoperative pain scores and increased opioid intake. Methods This is a secondary analysis of a prospective cohort study examining opioid use up to 2 weeks following CD. Women undergoing CD at six academic medical centers in the United States 9/2014-3/2016 were contacted by phone two weeks following discharge. Participants completed a structured interview that included questions about postoperative pain scores and opioid utilization. They were asked to retrospectively estimate their maximal pain score on an 11-point numeric rating scale at multiple time points, including day of surgery, during hospitalization, immediately after discharge, 1st week, and 2nd week following discharge. Pain scores over time were assessed utilizing a generalized linear mixed-effects model with the patient identifier being a random effect, adjusting for an a priori defined set of confounders. A multivariate negative binomial model was utilized to assess the association between intrapartum CD and opioid utilization after discharge, also adjusting for the same confounders. In the context of non-random prescription distribution, this model was constructed with an offset for the number of tablets dispensed. Results A total of 720 women were enrolled, 392 with and 328 without labor prior to CD. Patients with intrapartum CD were younger, less likely to undergo repeat CD or additional surgical procedures, and more likely to experience a complication of CD. Women with intrapartum CD consumed more opioid tablets following discharge than women without labor (median 20, IQR 10–30 versus 17, IQR 6–30; p = 0.005). This association persisted after adjustment for confounders (incidence rate ratio 1.16, 95% CI 1.05–1.29; p = 0.004). Pain scores on the day of surgery were higher in women with intrapartum CD (difference 0.91, 95% CI 0.52–1.30; adj. p = <0.001) even after adjustment for confounders. Pain scores at other time points were not meaningfully different between the two groups. Conclusion Intrapartum CD is associated with worse pain on the day of surgery but not other time points. Opioid requirements following discharge were modestly increased following intrapartum CD.
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Kucuk, Izzet Goker, and Ebru Aladag. "Young Maternal Death Caused by COVID-19." Eurasian Journal of Family Medicine 10, no. 3 (September 30, 2021): 158–62. http://dx.doi.org/10.33880/ejfm.2021100307.
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Maternal death refers to the death of a woman during pregnancy, during delivery, or within 42 days after the termination of pregnancy, and for any reason exaggerated by the pregnancy condition or pregnancy process regardless of the duration and location of the pregnancy. Starting on 11 March 2020 in Turkey, the COVID-19 pandemic resulted in a total of 5,638,178 confirmed cases and 51,048 deaths. Our case aged 24 years was a young mother having severe weight loss since the beginning of pregnancy because of malnutrition due to depression, smoking, and nausea. The weight loss of the patient, who was infected by COVID-19 in a short while after the last visit in family healthcare, became more severe, the general appearance became worse, and she gave preterm birth in the 30th gestational week. The cardiopulmonary arrest occurred during the delivery. Although necessary interventions were made, the patient was lost on the same day. Since it is a rare case, this case is presented together with a literature review. Keywords: COVID-19, pandemics, maternal mortality
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De Carvalho, Cleginaldo Pereira, Marcela Aparecida Guerreiro Machado, Herlandí de Souza Andrade, Fabrício Maciel Gomes, Nilo Antônio de Souza Sampaio, and Ícaro da Silva Vieira. "Improving the delivery performance: a case study applying statistical approaches for brasilian fast food." Revista de Gestão e Secretariado 14, no. 12 (December 27, 2023): 22069–99. http://dx.doi.org/10.7769/gesec.v14i12.3298.
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Purpose - Brazilian demand for a faster way of food feeding is growing and delays in delivery time impair customer satisfaction. Although food delivery apps are popular, the work aims to find the root causes of delays at a popular pizzeria in the Brazilian State of São Paulo, highlighting that the pizza manufacturing processes are the same as in past years. Design/methodology/approach - An anonymous survey conducted with the customers showed the key points of improvement for pizzerias in the city where the pizzeria was located. Data was collected from the pizzeria in question, so its non-compliances could be identified and further investigated using statistical analysis. Findings - The results showed a strong correlation between delivery time and the hour of order. Deliveries were faster on Monday compared to the other days of the week, possibly due to a reduced number of orders on this day, but it doesn’t explain the fact that Tuesday, Wednesday, and Thursday, which also had low numbers of orders, had high delivery times. This research work intends also to show that the process of the coming order is standard by apps, but the pizza manufacturing process is not. It means the concept of service quality is not reached during a period. Originality/value - This work has shown that applying quality tools and statistical analysis can bring advantages even for small food service companies. Other establishments that suffer from similar problems could also use the strategies for solving the delays.
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Lalloo, Aadila, Bazo Raheem, Giovanni Cocco, Ana Guzman, Michael Rose, Flavia Niccolini, and Eli Silber. "WED 028 One person can make a difference: our experience in a busy london dgh." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 10 (September 13, 2018): A5.1—A5. http://dx.doi.org/10.1136/jnnp-2018-abn.17.
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Our Neurology unit is in a busy district general hospital; serving a deprived inner London community, providing a ward consultation service 5 days a week. The unit consists of 5 consultant Neurologists, a consultant Neuroradiologist and 2 specialist nurses. In 2016, a junior doctor was appointed. By analysing data from 10 months in 2015 and 2017; we assessed the impact on the delivery of Neurological care, before and after the appointment. The unit saw a 157% increase in number of patients seen, including a significant proportion now seen in ED and ambulatory care. This is equivalent to a minimum of 2 more patients each working day (n=872 vs. 1317). The percentage of patients seen on same day of referral (<12 hours) increased from 47% to 77%. The proportion of inpatients reviewed who were then followed up on the ward during their stay, increased from 13.9% to 35.5%, representing increased availability of continuing Neurology advice. The percentage of patients who waited more than 24 hours for Neurology input decreased from 14.9% to 5.83%. Our results support the appointment of a full time junior colleague to allow rapid, safe and ongoing Neurological input to patients and to support ED and admitting colleagues.
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Leviton, Alan, Elizabeth N. Allred, Raina N. Fichorova, Deborah K. VanderVeen, T. Michael O'Shea, Karl Kuban, and Olaf Dammann. "Early Postnatal IGF-1 and IGFBP-1 Blood Levels in Extremely Preterm Infants: Relationships with Indicators of Placental Insufficiency and with Systemic Inflammation." American Journal of Perinatology 36, no. 14 (January 27, 2019): 1442–52. http://dx.doi.org/10.1055/s-0038-1677472.
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Objective To evaluate to what extent indicators of placenta insufficiency are associated with low concentrations of insulin-like growth factor 1 (IGF-1) and IGF-1–binding protein-1 (IGFBP-1) in neonatal blood, and to what extent the concentrations of these growth factors are associated with concentrations of proteins with inflammatory, neurotrophic, or angiogenic properties. Study Design Using multiplex immunoassays, we measured the concentrations of IGF-1 and IGFBP-1, as well as 25 other proteins in blood spots collected weekly from ≥ 880 infants born before the 28th week of gestation, and sought correlates of concentrations in the top and bottom quartiles for gestational age and day the specimen was collected. Results Medically indicated delivery and severe fetal growth restriction (sFGR) were associated with low concentrations of IGF-1 on the first postnatal day and with high concentrations of IGFBP-1 on almost all days. Elevated concentrations of IGF-1 and IGFBP-1 were accompanied by elevated concentrations of many other proteins with inflammatory, neurotrophic, or angiogenic properties. Conclusion Disorders associated with impaired placenta implantation and sFGR appear to account for a relative paucity of IGF-1 on the first postnatal day. Elevated concentrations of IGF-1 and especially IGFBP-1 were associated with same-day elevated concentrations of inflammatory, neurotrophic, and angiogenic proteins.
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Grinberg, Amy S., Olivia Datre, Daniel G. Rogers, Sarah W. Clark, Stanley C. Takagishi, John P. Ney, Elizabeth K. Seng, Brenda T. Fenton, and Jason J. Sico. "Interactive CBT for headache and relaxation training (iCHART): Study protocol of a single-arm trial of interactive voice response technology delivery of cognitive-behavioral therapy for Veterans with post-traumatic headache." Cephalalgia Reports 6 (January 1, 2023): 251581632311724. http://dx.doi.org/10.1177/25158163231172418.
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Background: Post-traumatic headache (PTH) is persistent and highly disabling. Cognitive-behavioral therapy for headache (CBT-HA) reduces headache frequency and severity and improves people’s quality of life, yet it is underutilized and inaccessible to many. Leveraging technology to deliver evidence-based psychological treatments for headache may address barriers to treatment engagement. Methods/design: This single-arm, single-site pilot trial aims to test the feasibility, acceptability, clinical signal, and cost of a five-session CBT-HA intervention delivered via interactive voice response technology (IVR). Participants will include 35 Veterans with PTH receiving care within VA Connecticut Healthcare System. Participants will complete an intake interview and a 9-item, 30-day electronic headache diary during a baseline run-in period. The same diary will be done again by participants immediately after treatment completion. Following the baseline assessment period, eligible participants will receive CBT-HA via IVR for 10 weeks, including an automated daily assessment of patient-reported outcomes and retrieval of biweekly tailored feedback from a study therapist. In addition, participants will access an electronic patient workbook, and study therapists will visualize patient-reported data through a secure provider dashboard. Participants will complete validated and reliable assessment measures at baseline, immediately post-treatment completion (week 10), and 1-month post-treatment completion (week 14). The primary clinical signal outcome is the change in self-reported headache days from the 30-day baseline run-in period before treatment (weeks −4 to 0) to the 30-day post-treatment completion (weeks 10–14). Paired-samples t-tests will explore changes in outcomes from baseline. All cost analyses will be exploratory and will use micro-costing techniques. Trial Registration: Clinical Trials.gov: NCT05093556. Registered October 26, 2021.
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Geller, Melissa Ann, Sarah A. Cooley, Mark Wallet, Bahram Valamehr, Deanna Gek Koon Teoh, Todd E. DeFor, Martin Felices, and Jeffrey Miller. "APOLLO: A phase I study of adaptive memory natural killer (NK) cells in recurrent ovarian cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 6044. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.6044.
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6044 Background: Human cytomegalovirus (CMV) infection induces a subset of long-lived CD57+NKG2C+ adaptive NK cells that exhibit enhanced antibody-dependent cellular cytotoxicity and resistance to tumor-suppressive mechanisms. We developed a 7-day culture process using a GSK3 inhibitor and IL-15 to manufacture modulated adaptive NK cells (FATE-NK100) from CMV+ haploidentical donors for adoptive transfer. The phase I Apollo trial tests the maximum tolerated dose/maximum feasible dose (MTD/MFD) of FATE-NK100 administered intraperitoneally (IP) to treat platinum-sensitive or -resistant recurrent ovarian, fallopian tube, and primary peritoneal cancer. Methods: FATE-NK100 via IP port was tested using 3 dose cohorts ([DC]; 1 × 107 cells/kg; >1 × 107 cells/kg to ≤3 × 107 cells/kg; or >3 × 107 to ≤10 × 107 cells/kg) after lympho-conditioning with fludarabine 25 mg/m2 IV and cyclophosphamide 300 mg/m2 IV on days −6 and −5. After FATE-NK100 infusion on day 0, rhIL-2 at 6 million IU was given IP 3 times a week for 6 doses for in vivo NK activation. IP fluid and peripheral blood were collected regularly until response assessment (day 28). Patients with stable disease or better were eligible for retreatment. Pre- and post-treatment tumor biopsies were collected. Results: Nine patients were treated with no dose-limiting toxicities (DLTs) to date. Retreatment based on clinical benefit was performed on 3 patients (33%), 2 following stable disease (DC 2) and 1 with partial remission (48% tumor reduction, DC 3). IP samples were collected for PK and functional analysis. FATE-NK100 product was detected by flow cytometry in 5 of 6 patients with evaluable samples (range 4.8%–91.2% donor NK cells at day +5-7). Retreatment samples were available in 1 patient, where FATE-NK100 persisted to day +21, demonstrating that repeated IP dosing did not accelerate clearance of the donor NK cells. In that same patient, measurement of NK cell CD107a degranulation or IFNg production in response to K562 targets demonstrated sustained enhanced in vivo function of FATE-NK100 compared to endogenous patient NK cells (e.g. at Day +12 CD107a+ NK were 39.0% vs. 22.5% cycle 1, and 40.3% vs. 18.2% retreatment cycle 2, and IFNg+ NK were 12.3% vs. 5.9% cycle 1, and 2.4% vs. 0.2% retreatment cycle 2). Conclusions: IP delivery of FATE-NK100 is safe, with clinical benefit in 3/9 patients treated. The allogeneic product cells persist and have enhanced function compared to patient NK cells for up to 21 days, even after retreatment. This phase I study in recurrent/refractory ovarian cancer shows promise for IP NK cell delivery. Clinical trial information: NCT00652899.
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Ibrahim, Khalid, Mohsen Al-Mutary, Amel Bakhiet, and Haseeb Khan. "Histopathology of the Liver, Kidney, and Spleen of Mice Exposed to Gold Nanoparticles." Molecules 23, no. 8 (July 25, 2018): 1848. http://dx.doi.org/10.3390/molecules23081848.
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Gold nanoparticles (GNPs) are biocompatible nanomaterials that are currently researched for biomedical applications such as imaging and targeted drug delivery. In this investigation, we studied the effects of a single dose (injected on day 1) as well as a priming dose (two injections with a gap of one week) of 5 nm, 20 nm, and 50 nm diameter GNPs on the structural and biochemical changes in the liver, kidney, and spleen of mice. The results showed that small sized GNPs (5 nm) produced significant pathological changes in the liver on day 2 that gradually reduced on day 8. The medium (20 nm) and large (50 nm) sized GNPs preferentially targeted the spleen and caused significant pathological changes to the spleen architecture on day 2 that persisted on day 8 as well. There were minimal and insignificant pathological changes to the kidneys irrespective of the GNPs size. The animals that were primed with the pre-exposure of GNPs did not show any aggravation of histological changes after the second dose of the same GNPs. None of the dose regimens of the GNPs were able to significantly affect the markers of oxidative stress including glutathione (GSH) and malondialdehyde (MDA) in all of the organs that were studied. In conclusion, the size of GNPs plays an important role in their pathological effects on different organs of mice. Moreover, the primed animals become refractory to further pathological changes after the second dose of GNPs, suggesting the importance of a priming dose in medical applications of GNPs.
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Moodabagil, Nikil V., Sarah Scheiderich Osmundson, Christian Cepeda, and Colleen Morton. "Delayed Diagnosis of Anemia in Late Pregnancy: Consequences at Delivery and Unintended Effects of Third Trimester HIV Screening Policy." Blood 134, Supplement_1 (November 13, 2019): 4675. http://dx.doi.org/10.1182/blood-2019-124910.
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Background/Objective: The World Health Organization, Centers for Disease Control, and the American College of Obstetricians and Gynecologists recommend screening for anemia in pregnancy. While screening is commonly performed in the second half of pregnancy to prevent anemia at delivery, few guidelines specify a gestational age when screening should occur. Our primary study objective was to examine whether gestational age (GA) at anemia diagnosis is associated with anemia at delivery. Secondarily, as Tennessee is one of 17 states with statues requiring third trimester HIV screening, we also assessed whether bundling of common screening labs, especially state-mandated third trimester HIV screening, is associated with later anemia screening in pregnancy. Study Design: We performed a retrospective cohort study of all outpatient pregnant women who had a CBC done at >=24 weeks, delivered at >= 32 weeks, and had a CBC within 7 days of delivery between 1/1/19 and 1/31/19. Anemia was defined as a hemoglobin (hg) <10.5g/dL between 24-27 weeks and <11g/dL at >=28 weeks. The primary exposure was gestational age when anemia was first diagnosed. Relevant covariates included maternal age, race/ethnicity, and comorbidities associated with anemia such as hemoglobinopathies and malabsorptive disorders. The primary outcome was anemia at delivery and secondary outcome was mean Hg at delivery. Anemia screening was defined as the first CBC performed >=24 weeks and anemia diagnosis was defined by the earliest GA at >= 24 weeks when anemia was diagnosed. Bundling of screening tests was defined as performing HIV and/or glucose tolerance testing (GTT) on the same day as the CBC versus testing on different days. We constructed logistic and linear regression models to examine the association between both anemia at delivery and hg at delivery, and gestational age of anemia diagnosis, adjusted for covariates. Results: Of 208 women meeting inclusion criteria, 53 (26%) women were anemic at delivery with a mean Hg of 10.0+1.0 g/dL. Later anemia diagnosis (in weeks) was associated both an increased odds for anemia at delivery (aOR 1.06, 95% CI 1.04-1.09) and a decreased Hg level at delivery. Specifically, each week later that anemia was diagnosed resulted in a 0.04 decrease in Hg at delivery (-0.04, 95% CI -0.06 to -0.03). These findings were unchanged after adjusting for maternal age, race, and comorbidities. The timing of anemia screening and frequencies of anemia are displayed in Figure 1. The majority (58%) of anemia screening occurred between 28-31 weeks and anemia screening was frequently done either in conjunction with HIV (73%), GTT (36%), or both (29%). Anemia screening was more likely to occur in conjunction with HIV screening at 28-31 weeks (OR 3.47, 95% CI 1.39-8.63) compared to 24-28 weeks. Conclusions: One quarter of pregnant women are anemic at delivery, which is associated with later diagnosis of anemia in pregnancy. Bundling of screening labs, particularly state-mandated HIV testing, may impact timing of anemia screening in Tennessee, which suggests unintended consequences of well-intended health policies. Figure 1 Disclosures No relevant conflicts of interest to declare.
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Murad, Hussam, Osama Ahmed, Tawfik Ghabrah, and Mamdooh Gari. "Telmisartan Self-Nanoemulsifying Drug Delivery System, Compared With Standard Telmisartan, More Effectively Improves Hepatic Fibrosis in Rats." Dose-Response 18, no. 4 (October 1, 2020): 155932582098219. http://dx.doi.org/10.1177/1559325820982190.
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Background: This study was designed to examine effects of telmisartan; an angiotensin receptor blocker; self-nanoemulsifying drug delivery system (SNEDDS) in reversing already-established hepatic fibrosis. Method: Forty rats were given thioacetamide (200 mg/kg, intraperitoneally) twice/week for 8 weeks then divided into 5 groups (n = 8), PC and 4 treated groups. Treatments were given orally for another 2 months as follows: telmisartan low and high doses (TL and TH: 1.8 and 3.6 mg/kg/day) and telmisartan SNEDDS at the same doses (TLS and THS). At end of treatment, blood was obtained and liver was isolated. Results: Rats showed significant elevations of plasma ALT and AST and hepatic IL-6, TNF-α, and MDA, significant reductions of plasma albumin, hepatic GSH, and body weight, and hepatic histopathological damage. All treatments except for TL significantly reversed these thioacetamide-induced changes. THS group showed significant differences from all groups. Regarding ratio of free telmisartan concentration in hepatic homogenate to that of plasma, TH and TLS groups showed non-significant variation between each other while THS group showed significant differences from them. No significant changes were detected in blood pressure, hemoglobin, white blood cells, and platelets. Conclusion: Telmisartan SNEDDS, compared with telmisartan, more effectively reversed chronic hepatic fibrosis with good safety profile.
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Wee, Christopher E., Jilan Kubusek, Irbaz Riaz, Robert Wolf, Julian R. Molina, and Naseema Gangat. "Risk Factors for Increased Length of Stay (LOS) in Patients with Hematological Malignancies Electively Admitted for Chemotherapy." Blood 134, Supplement_1 (November 13, 2019): 2138. http://dx.doi.org/10.1182/blood-2019-127367.
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Introduction Despite more robust attempts to deliver chemotherapy in the outpatient setting, certain regimens for hematologic malignancies require inpatient hospitalization for treatment and monitoring clinical status. Increased length of stay (LOS) for planned chemotherapy admissions leads to increased healthcare utilization and decreased patient satisfaction. We sought to identify potentially modifiable risk factors for increased LOS. Methods Planned chemotherapy admissions to the inpatient hematology services at Mayo Clinic (Rochester, MN) from October 2018 through March 2019 were reviewed. We included patients who had treatment plans based on four pre-specified common regimens for acute myeloid leukemia, relapsed non-Hodgkins lymphoma and multiple myeloma. Patients who remained in the hospital for lack of caregiver support were excluded. Patient characteristics, including age, malignancy type, and chemotherapy regimen were recorded. Encounter characteristics included day of week of admission, time of admission, time chemotherapy plan initiated, and whether or not all necessary procedures (labs, vascular access, chemo orders) were completed prior to admission. Primary outcome was LOS. Secondary outcome was time to treatment initiation (TTI) after admission. Results There were 100 planned admissions for patients receiving four regimens: cytarabine consolidation, EPOCH, ICE, VDT-PACE, during the six month review period. Thirty-six admissions did not occur as planned (regimen changed, rescheduled, or disease progression). Of the remaining 66 admissions, 11 outliers were excluded from primary analysis. Baseline characteristics are summarized in Table 1. Univariate analysis with independent t-test found no difference in LOS for patients who had physician chemotherapy orders in place prior to admission. To the contrary, we detected a non-significant trend toward longer mean length of stay for patients that were not seen in clinic on day of admission (Table 2). On ANOVA, there was a statistically significant difference in LOS when comparing Monday admissions 3.93 days (95% CI 3.07 to 4.79) vs Friday 5.25 days (95% CI, 4.86 to 5.64), but not between any other days. There were no statistically significant differences in TTI when comparing by day of week, physician order status, or chemotherapy regimen. Again, a non-significant trend toward increased TTI was observed for patients not seen in clinic on the same day as admission. Conclusions This study serves as a starting point towards identifying modifiable factors that are essential to delivery of safe, satisfying inpatient care to our hematological malignancy patients.Our noteworthy finding regarding patients who were admitted on Friday having a longer LOS than those admitted on Monday requires further exploration. This study is ongoing with mature data to be presented at the meeting. Disclosures No relevant conflicts of interest to declare.
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Milankovic, Jasna. "Retrospective analysis of perinatal mortality in Belgrade in 1996." Stanovnistvo 38, no. 1-4 (2000): 119–50. http://dx.doi.org/10.2298/stnv0004119m.
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Through the set hypotheses and presented results of statistical analysis it was attempted to answer the question of what more could be done in our country, especially in the health sector, to decrease perinatal mortality, so as to achieve the level which some northwest European countries already have. On the basis of data of official statistics, there is still insufficient cooperation in Belgrade between departments in the same health institution, as well as between certain levels of health care, without appropriate transfer of information on the women who have just given birth, namely the new-born (pregnancy card). A lack of uniformity in the level of equipment and insufficient usage of genetic counseling offices is present. About 62% of pregnant women reports to the counseling offices for pregnant women for the first time in the first trimester, which is not sufficient. The standardization of the application of doctrinal standpoints should be achieved, especially in the diagnosis of risk factors and the provision of adequate medical documentation for transfer of information during pregnancy, labor and the condition of the newborn. Within that, it is necessary to continually provide expert advanced training of health workers in the future, in the organization of the relevant institution. The research results of biological variables of women who have just given birth, such as average age, parity, abortion and illness in her reproductive history, as well as the most common complications during delivery, showed that no significant deviation as regards this risk factor within control and risk groups. The stated data indicated that in the risk group there were somewhat more primipara, which might present an increased factor of risk for the outcome of the delivery, while there were almost the same percentage less than in the control group of the women who bore their second child. On the other hand, there were less women who previously had an abortion in the sample. Biological variables of newborns showed that in the risk group, out of the total infant deaths, 41.6% were stillborn, and 57.3% died during the first week, namely 22.6% during the first day of life. The ratio between sexes was almost identical: 44.8% of dead newborns were male and 44.4% were female sex. In the first twentyfour hours, namely in the first five hours upon birth, the mortality of male newborns was greater by about 10%. The mortality of female newborns was greater in the second day of life, by about 7% of the mortality of the male newborns of the same age. Upon reception into the maternity hospital already, normal state of the fetus was noted in only one third of the cases with these deliveries, while in two thirds death had already occurred or suffering of the fetus was present. As many as 198 or 71% of newborns were prematurely delivered. Not a single delivery was noted after term. 3.9% of the newborns had weight upto 499 grams, as many as 29.4% had exceptionally small weight (500-999 g), and another 20.8% small weight at birth (1000-1499 g). In 19.4% cases, the fetus was completely immature, while in 60.6% of the cases the delivery came between the 28th and 36th gestation weeks. As early as the first minute of birth, the lives of over 60% of the liveborn children were endangered (low apgar score). Over one half of the newborns which received the mark one or two in the first minute upon birth, died in the first seventy-two hours of life. The most critical were the first five hours upon birth, as well as the second day of life. The knowledge of the samples of seminatal mortality in Belgrade also represents a basis for further programming of health care for the mother and child on the city level. A dominant mortality sample is severe asphyxia (60%). In 13.8% of the cases, the cause of death is registered as unmarked or unknown, so the second place according to intensity is present as respiratory distress (6.9%). Multiple deliveries with seminatal mortality were present in 26.9% cases. Most of the deliveries were carried out with the "normal" position of the fetus, while 15.1% of the deliveries were pelvic, and 17.3% were carried out by some childbearing operation technique.
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Lee, Shaoying Nikki, Cheryl Stork, Ghesal Razag, Nelson Quintana, Chris Wahl, and Sharat Singh. "POTENTIAL EFFECTS OF FOOD ON A NOVEL DRUG DELIVERY SYSTEM (DDS) TO DELIVER A THERAPEUTIC COMPOUND IN THE COLON." Inflammatory Bowel Diseases 29, Supplement_1 (January 26, 2023): S11. http://dx.doi.org/10.1093/ibd/izac247.022.
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Abstract The clinical remission rate in moderate to severe ulcerative colitis (UC) and Crohn’s disease (CD) has plateaued at ~15-20% despite the approval of multiple therapeutics. Research has shown that an inadequate amount of drug at the disease site in the colon may be responsible for limited clinical benefit. The Drug Delivery System (DDS) is an ingestible electronic targeted delivery device containing a localization system to autonomously identify colon entry based on gastrointestinal (GI) anatomy, independent of the variable GI physiological conditions, and deliver a bolus of a liquid drug formulation to the colon mucosa to improve efficacy and reduce systemic toxicity. In this study, we aim to evaluate the safety, tolerability, and functionality of the DDS devices in fasted and fed states in normal healthy volunteers (NHV). NHV were enrolled and administered a single DDS device at each week in either the fasted state or in 1 of 3 possible fed schedules over ~ 4 weeks. Subjects were fasted overnight and were dosed in the morning (fasted schedule) or fasted overnight and consumed a light breakfast with equivalent calories and protein/fat content of egg-beater meal either immediately before administration of DDS device (fed schedule #1), 30 minutes post-dose (fed schedule #2), or 2 hours pre-dose (fed schedule #3). Devices were recovered from the feces, and data were extracted from the capsule to confirm the function of the colon entry call and activation of payload release. A total of twelve NHV (N=12) were enrolled in this study. Eleven subjects completed all four fasted/fed dosing schedules over 4 weeks, while one subject was withdrawn due to non-compliance with device recovery. Overall, the DDS device was well-tolerated in all enrolled subjects with a total of 46 devices dosed in this study. Mild AEs were reported as possibly related to the device in two subjects, including vomiting (N=1) and nausea (N=1) following device administration which was resolved on the same day. No other device-related AEs were reported in this study. Out of 44 devices administered to 11 subjects, 43 were successfully recovered, and device data was successfully recovered from 39 devices for device function evaluation. Thirty-nine devices for which data was recovered (100%) had successfully identified colon entry calls (S4) and activated H2 gas cells for delivery in all fasted/fed schedules (Table 1). Thirty-eight (38) out of 39 recovered devices (97.4%) had successfully activated the payload release function, and one did not (Table 1). The results from this study demonstrated that the DDS device was well-tolerated and functioned as intended in NHV subjects in these four fasted/fed dosing schedules and confirmed that the potential food effect of a light breakfast meal on the device function of the DDS device is minimal.
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Meacock, Rachel, and Matt Sutton. "Elevated mortality among weekend hospital admissions is not associated with adoption of seven day clinical standards." Emergency Medicine Journal 35, no. 2 (November 8, 2017): 108–13. http://dx.doi.org/10.1136/emermed-2017-206740.
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IntroductionPatients admitted to hospital in an emergency at weekends have been found to experience higher mortality rates than those admitted during the week. The National Health Service (NHS) in England has introduced four priority clinical standards for emergency hospital care with the objective of reducing deaths associated with this ‘weekend effect’. This study aimed to determine whether adoption of these clinical standards is associated with the extent to which weekend mortality is elevated.MethodsWe used publicly available data on performance against the four priority clinical standards in 2015 and estimates of Trusts’ weekend effects between 2013/2014 and 2015/2016 for 123 NHS Trusts in England. We examined whether adoption of the priority clinical standards was associated with the extent to which weekend mortality was elevated, and changes over a 3 year period in the extent to which mortality was elevated.ResultsLevels of achievement of two of the four clinical standards (ongoing review and access to diagnostic services) had small positive associations with the magnitude of the weekend effect in 2015/2016. Levels of achievement of the remaining two standards (time to first consultant review and access to consultant directed interventions) had small negative associations with the magnitude of the weekend effect in 2015/2016. No association was statistically significant. The same pattern was observed in the associations between achievement of the standards and changes in the magnitudes of the weekend effect between 2013/2014 and 2015/2016.DiscussionWe found no association between Trusts’ performance against any of the four standards and the current magnitude of their weekend effects, or the change in their weekend effects over the past 3 years. These findings cast doubt on whether adoption of seven day clinical standards in the delivery of emergency hospital services will be successful in reducing the weekend effect.
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Llsley, S. E., and H. M. Miller. "Effect of dietary supplementation of sows with quillaja saponins during gestation on colostrum composition and performance of piglets suckled." Animal Science 80, no. 2 (April 2005): 179–84. http://dx.doi.org/10.1079/asc40360179.
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AbstractThe objective of this study was to assess the effect of dietary saponins, extracted from the plant Quillaja saponaria, on the concentrations of immunoglobulins in sow colostrum and milk, and additionally to observe any effect on piglet performance. Twenty-two sows were allocated to each of two dietary treatments on day 72 of gestation, balancing for parity, fatness and past reproductive performance. Treatments were : control (C) and supplemented (Q; 2.5 g saponin per day as a top-dressing). Sows received 2.5 kg food once per day throughout gestation. Between days 72 and 93 of gestation Q sows received a saponin top-dressing as described. After day 93, all sows were given the same diet and managed in an identical manner. Colostrum samples were taken from all sows at farrowing on delivery of the first piglet then 4, 8, 24 and 72 h later and again on day 21 of lactation. A group of eight sows from each treatment were also blood sampled at farrowing, day 3 and day 21 of lactation. Concentrations of immunoglobulins IgG and IgA in the colostrum, milk and blood were not affected by sow treatment during gestation at any sampling point. Fat, lactose and cell counts were also similar across treatments in colostrum and milk. Protein tended to be higher in milk on day 3 but lower on day 21 (P< 0.1) in Q sows. Piglet performance was not affected by sow treatment during week 1 of lactation. However pigs suckling Q sows grew more slowly between days 8 to 14 (P< 0.05) and days 15 to 21 (P< 0.1). Q sows also had fewer stillborn piglets in their litters at farrowing (7.67 v. 13.25%,P< 0.05, s.e. = 1.93). It is concluded that dietary quillaja saponin given during this time period has no influence on sow lacteal immunoglobulin secretions. However an adverse effect on performance of the sucking piglet was observed, the reasons for which are unclear, but may be related to reduced milk protein concentrations. Dietary quillaja saponin during gestation does however appear to reduce the incidence of stillborn piglets.
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Flanagan, Carolyn, and Gillian Janes. "Nurse-led sustainable plastic surgery trauma service transformation: a positive COVID-19 legacy." BMJ Open Quality 12, no. 4 (December 2023): e002280. http://dx.doi.org/10.1136/bmjoq-2023-002280.
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The aim of this quality improvement was to develop a sustainable nurse-led ‘See and Treat’ service in a regional plastic surgery unit in England for patients requiring plastic surgery under local anaesthetic following traumatic injury.Trauma-related injuries are a substantial part of the workload in the plastic surgery department in question; with people with the most minor injuries requiring surgery under local anaesthetic accounting for 17%. COVID-19 threatened the continuation of any minor surgery service, but the initial crisis-driven response to the pandemic provided the opportunity to develop a new, more effective, nurse-led service for this patient group.The Model for Improvement was used and four ‘Plan, Do, Study, Act’ cycles deployed over an 8-week period, involving 102 patients. Routine quantitative and qualitative data in the form of a semistructured patient feedback proforma were used to guide the improvement process, optimising the new service design and delivery.The results demonstrated that 98% (n=100) of patients received same-day surgery via the new ‘See and Treat’ service. Staff and patient satisfaction remained high throughout; all patients preferred same-day surgery. No negative unintended consequences, for example, postoperative infections, were identified. One positive unintended consequence was the reduction in carbon footprint achieved by decreasing clinical waste and patient travel.Improvement methodology was successfully used by a nurse-led team to enable the continuation and enhancement of surgical services for trauma patients during COVID-19-driven service disruption. This service transformation has resulted in the retention of the revised service delivery model as the ‘new normal’ approximately 2 years later. The COVID-19 pandemic challenged the resilience of the trauma surgery service but led to a positive long-term legacy that sustainably improved waiting times and patient experience while maintaining safety.
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Adams, Gregory P., Kai Ma, Feng Chen, Marion Scocca, Aranapakam Venkatesan, Cathy Reddick, Mary Hilgart, et al. "Abstract 1077: Stability and safety evaluation of ELU001, a targeted C’Dot drug conjugate for the potential treatment of folate receptor alpha-overexpressing cancers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1077. http://dx.doi.org/10.1158/1538-7445.am2022-1077.
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Abstract While several antibody-drug conjugates (ADCs) have shown efficacy in the treatment of solid tumors ADCs remain limited in their therapeutic efficacy due to long circulatory half-life and limited tumor penetration. Ultra-small (sub-10nm) C’Dot-drug-conjugates (CDCs) directly address this, exhibiting deep penetration and retention in solid tumor models, with limited systemic exposure following rapid renal clearance. CDCs can also achieve greater potency by delivering over 10x more payload and by binding to tumor cells with a higher avidity allowing effective killing of tumors with broader range of moderate to high expression of target antigens. ELU001 is a CDC that targets folate receptor alpha (FRα) overexpressing tumors via folic acid moieties on its surface and delivers an average of 21 exatecan topoisomerase-1 inhibitor molecules as its payload. FRα is overexpressed on a variety of tumors including ovarian, endometrial, triple negative breast and non-small cell lung, but is minimally expressed on normal tissues making it an attractive tumor-associated antigen for targeted drug delivery. ELU001 is highly stable in plasma and elicits antitumor efficacy in a variety of cell line and PDX-derived tumor models both in vitro and in vivo. In 15-day repeat dose toxicology and toxicokinetic studies performed in Wistar Han rats and Beagle dogs, ELU001 was well tolerated at up to 0.87 mg/kg/day in rats and 0.174 mg/kg/day in dogs based upon conjugated exatecan concentration when administered on a QWx3 schedule via a 1-hour infusion. Observed dose-related toxicities for both species were limited to the bone marrow and GI tract - the same organs as those observed when free payload (exatecan) was administered suggesting that the delivery of exatecan conjugated to the CDC did not broaden the tissue toxicity profile. Observed toxicities were recovered or substantially reduced by the end of a two-week recovery period. No drug-related hepatic, renal, pulmonary or ocular toxicities were observed and there were no drug-related deaths in the repeat dose toxicity study. TK parameters, estimated in the 15-day GLP studies revealed similar plasma exposure values in males and females for ELU001, Total Exatecan (conjugated and released) and Released Exatecan for rats and dogs, respectively. ELU001 exhibited an average circulatory half-life ranging from approximately 15 to 20 hrs in rats and 24 to 29 hrs in dogs with no accumulation of ELU001, Total Exatecan or Free Exatecan observed from day 1 to day 15. Based upon AUC0-last (hr*ng/ml) released payload levels in the circulation were less than approximately 0.3% and 0.1% of the total payload levels in the rat and the dog respectively. No ELU001 anti-drug antibodies were induced in either species. In summary, ELU001 has a favorable nonclinical safety/TK profile and is currently under evaluation in a clinical safety study - NCT05001282. Citation Format: Gregory P. Adams, Kai Ma, Feng Chen, Marion Scocca, Aranapakam Venkatesan, Cathy Reddick, Mary Hilgart, Thomas Gardinier, Fei Wu, Melik Turker, Peiming Chen, Tin Khor, Vaibhav Patel, Eliel Bayever. Stability and safety evaluation of ELU001, a targeted C’Dot drug conjugate for the potential treatment of folate receptor alpha-overexpressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1077.
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Mpekris, Fotios, Chrysovalantis Voutouri, Myrofora Panagi, James W. Baish, Rakesh K. Jain, and Triantafyllos Stylianopoulos. "Abstract A63: Normalizing the microenvironment with metronomic nanomedicine potentiates immune checkpoint inhibition in preclincial tumor models." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A63. http://dx.doi.org/10.1158/2326-6074.tumimm22-a63.
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Abstract IntroductionNanomedicines have been developed to preferentially delivery drugs to cancer cells or improve the drug pharmacokinetic properties for the treatment of solid tumors. Recent preclinical studies have shown that nanomedicines cannot only simply deliver drugs but also to normalize the tumor microenvironment, improving blood vessel functionality, tumor oxygenation and immunostimulation. Metronomic therapy is a different approach to substitute conventional chemotherapy, which is based on the low and more frequent administration of the therapeutic agent compared to the maximum tolerated dose (MTD) schedule of conventional treatment. When beneficial metronomic strategy can also induce normalization. We hypothesize that these two approaches can be viewed using the same unified framework as strategies that normalize the tumor microenvironment to potentiate immune checkpoint inhibition(ICI) in resistant to ICI murine models of breast cancer and sarcoma. MethodologyTo test our hypothesis, we performed in vivo experiments in murine breast and fibrosarcoma tumor models, and employed the clinically approved nanoparticle formulation Doxil(PEGylated liposomal doxorubicin). Doxil has an elimination half-life 20-30 hours and thus, we hypothesized that to produce similar to metronomic therapy effects, effective drug levels should be maintained. To this end, we employed three different dose schedules providing the same amount of Doxil on a weekly basis: every day(1mg/kg), every other day(2mg/kg) and every 6 days(6mg/kg). At the second week of Doxil treatment, we added to the treatment regimen an immune checkpoint inhibitor aPDL1(10 mg/kg) every 3 days (totally 3 doses) alone or in combination with Doxil. Given the increasing interest in nano-immunotherapy, our purpose was to investigate whether pretreatment with a normalizing dose of nanomedicine can optimize nano-immunotherapy. ResultsWe found that low and more frequent doses of Doxil (either 1mg/kg or 2mg/kg) -compared to high and less frequent doses- decrease tumor stiffness, improve perfusion and exhibit enhanced anti-tumor effects either alone or in combination with immunotherapy. Use of appropriately-sized nanoparticles to normalize the tumor microenvironment could be advantageous over MTD chemotherapy because preferential targeting of tumor tissue could ameliorate adverse effects of MTD chemotherapy, whereas improved vascular function could increase the effectiveness of the immune system and importantly the intratumoral delivery of nanoparticles, which is the main barrier for the effective use of nanomedicines today. Importantly, to account for heterogeneity among different tumors types, we employed two tumor models, the 4T1 breast cancer and the MCA205 fibrosarcoma and found similar normalization and anti-tumor effects.ConclusionPretreatment with a normalizing dose of Doxil can improve the efficacy of immune checkpoint inhibition in murine models of breast cancer and sarcoma. Citation Format: Fotios Mpekris, Chrysovalantis Voutouri, Myrofora Panagi, James W Baish, Rakesh K Jain, Triantafyllos Stylianopoulos. Normalizing the microenvironment with metronomic nanomedicine potentiates immune checkpoint inhibition in preclincial tumor models [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A63.
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Aliyu, B., U. Mohammed, and Y. J. Oyeniyi. "Effects of melatonin consumption on some oxidative stress biomarkers of stress-exposed pregnant rats." Sokoto Journal of Medical Laboratory Science 7, no. 3 (November 15, 2022): 32–46. http://dx.doi.org/10.4314/sokjmls.v7i3.5.
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Melatonin acts as a free radical scavenger and nuclear and mitochondrial DNA from free radicals-induced damage. This study was designed to test the hypothesis that melatonin may mitigate the effect of restraint stress in pregnant rats by mechanisms associated with stimulation of antioxidant enzymes and reduction in malondialdehyde (MDA) levels. Pregnant Wistar rats aged between 10-12 weeks and weighing 125±5.5g (mean ±SEM), were randomly divided into three groups (n= 8 each) that had the following treatments: non- stress with vehicle (NSV), stress with vehicle (SV) and stress with melatonin (SM). During the second week of pregnancy, the rats were individually restrained for 1 hour a day for one week. Melatonin (10mg/kg) was administered orally to the treatment group (SM) every day throughout the stress exposure period while the control groups (NSV and SV) received the vehicle (water). Three weeks after delivery, the rats were euthanized and the antioxidant enzymes [catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)] and MDA levels were measured. The CAT values SV rats were significantly (P<0.001) lower than in NSV and SM rats. The values for GPx and SOD followed the same pattern with CAT. The MDA value obtained from the SV rats were significantly (P<0.0001) higher than the values obtained from NSV and SM rats. The MDA values obtained from the SM rats were significantly (P<0.05) higher than in NSV rats. Results suggest that melatonin helps in countering the effects of restraint stress in pregnant Wistar rats by increasing the serum levels of CAT, GPx and SOD while reducing the serum level of MDA. It is concluded that stress- induced reduction in antioxidant enzymes and attendant increase in lipid peroxidation are mitigated by melatonin.
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Nafie, Ebtesam, Chiara Pastori, Mukta Wagh, Fatima Murad, Mohit Trikha, and Robert Neal. "Pulsed electrical fields in combination with anti-PD1 and survival of mice with TNBC (EMT6) murine breast tumor." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 540. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.540.
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540 Background: Delivery of pulsed electric field (PEF) energy is used to destabilize cells through multiple biochemical processes. We questioned whether a specific PEF treatment type could synergize with anti-PD1 in an orthotopic Triple Negative Breast Cancer (TNBC) EMT6 mouse model. Our previous studies have demonstrated that PEF treatment induces neo-antigen presentation and triggers an innate and adaptive immune response. Anti-PD1 therapy is ineffective at blocking growth of (TNBC) EMT6 tumors that are orthotopically implanted in mice. We evaluated whether a biphasic monopolar form of PEF could synergize with anti-PD1 when it was administered intraperitoneally or intra-tumorally, and whether there was a change in immune response post treatment. Methods: Forty-eight female Balb/c mice were implanted with 200,000 EMT6 cells into the mammary fat pads. Once tumor diameter reached 5 mm they were randomized into 6 groups of 8 animals: 1) Sham/IgG; 2) intra-tumoral (IT) anti-PD-1; 3) intra-peritoneal (IP) anti-PD-1; 4) PEF + anti-PD-1(IP); 5) PEF + anti-PD-1(IT) 6) 2X PEF on day 0 and day 7 + anti-PD-1(IT administered weekly). Sham-PEF mimicked the same procedure but without PEF. Anti-PD1 was administered weekly, IT or IP at 200 µg/mouse and PEF was delivered once on day of randomization. Tumors were measured three times per week, and animal survival was monitored until tumor volume necessitated euthanasia (≥2000mm3). Blood was collected on day 14 for flow cytometric analysis of systemic immune response which included quantifying CD3 positive T cells, B cells and NK cells. Results: Anti-PD1 treatment (IT or IP) did not reduce tumor growth, nor did it prolong survival compared to Sham/IgG treated animals. All anti-PD1 alone (IT or IP) as well as Sham treated animals had to be euthanized by day 35. In contrast, PEF combined with anti-PD1 given IT and IP significantly reduced tumor growth by 83% and 70%, respectively, on Day 14 compared to anti-PD-1 only treated animals (p = 0.03). Interestingly, EMT6 bearing mice treated with double PEF + IT administered anti-PD1 survived longer compared to mice treated with single PEF + IT administered anti-PD1. On day 65, 71% of double PEF + IT administered anti-PD1 were still alive compared to 12.5% of mice treated with PEF + IT administered anti-PD1 (p = 0.002). Flow cytometry analysis on day 14 indicated an increase in circulating adaptive (T- and B-cells) and innate (NK cells) immunocytes in the PEF + anti-PD1 treated animals compared to the control. Conclusions: Collectively, these results indicate that some types of PEF ablation synergize with weekly anti-PD1 in stimulating an increase of CD3+ T cells, B cells and NK cells, reducing tumor growth and prolonging survival of tumor bearing mice. These results suggest the synergistic potential of combining Immunotherapy with some forms of PEF, which warrants further study in patients.
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Paul, James, and Ted Otvos. "Comparison of Nasal Cannulas and the OxyArm in Patients Requiring Chronic Domiciliary Oxygen Therapy." Canadian Respiratory Journal 13, no. 8 (2006): 421–26. http://dx.doi.org/10.1155/2006/729878.
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OBJECTIVES: The present study was designed to compare the performance of a new oxygen delivery device, the OxyArm (OA) (Southmedic Inc, Canada), with a standard nasal cannula (NC) (Salter-Style 1600, Salter Labs, USA) for both oxygen delivery and patient preference in patients on long-term oxygen therapy (LTOT).DESIGN AND SETTING: Randomized crossover study conducted in an outpatient setting.PATIENTS AND METHODS: Twenty-five clinically stable LTOT patients were randomly assigned to an oxygen device (NC or OA) sequence. The baseline saturation level was determined, and patients were then treated at oxygen flow rates of 2 L/min, 3 L/min, 4 L/min, 5 L/min, 6 L/min and 7 L/min for 10 min each while at rest. Patients were then crossed over to the second device and the procedure was repeated. Oximetry values were then obtained following a 5 min walk test using the same device sequence. Lastly, the patients were sent home for a four-week home OA trial, after which, they filled out a questionnaire.RESULTS: This sample of patients was primarily elderly ex-smokers with severe chronic obstructive pulmonary disease on oxygen therapy for the majority of the day. The primary findings were that the OA and NC were equally effective in delivering oxygen to patients and maintaining their oxygen saturation at both rest (P=0.82) and during a 5 min walk test (P=0.83). A patient’s personal experience and comfort were identified as the most important factors in deciding on an oxygen device. Most patients felt that the OA was most suited for oxygen therapy while at rest.CONCLUSIONS: The OA proved to be similar to the NC in delivering oxygen and maintaining saturation in patients on LTOT. The OA is one of the few alternatives to using NCs for these patients and, with its current design, appears to be most suited for resting conditions.
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Sweeney, Nicola, Blair Merrick, Rui Pedro Galão, Suzanne Pickering, Alina Botgros, Harry D. Wilson, Adrian W. Signell, et al. "Clinical utility of targeted SARS-CoV-2 serology testing to aid the diagnosis and management of suspected missed, late or post-COVID-19 infection syndromes: Results from a pilot service implemented during the first pandemic wave." PLOS ONE 16, no. 4 (April 7, 2021): e0249791. http://dx.doi.org/10.1371/journal.pone.0249791.
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During the first wave of the global COVID-19 pandemic the clinical utility and indications for SARS-CoV-2 serological testing were not clearly defined. The urgency to deploy serological assays required rapid evaluation of their performance characteristics. We undertook an internal validation of a CE marked lateral flow immunoassay (LFIA) (SureScreen Diagnostics) using serum from SARS-CoV-2 RNA positive individuals and pre-pandemic samples. This was followed by the delivery of a same-day named patient SARS-CoV-2 serology service using LFIA on vetted referrals at central London teaching hospital with clinical interpretation of result provided to the direct care team. Assay performance, source and nature of referrals, feasibility and clinical utility of the service, particularly benefit in clinical decision-making, were recorded. Sensitivity and specificity of LFIA were 96.1% and 99.3% respectively. 113 tests were performed on 108 participants during three-week pilot. 44% participants (n = 48) had detectable antibodies. Three main indications were identified for serological testing; new acute presentations potentially triggered by recent COVID-19 e.g. pulmonary embolism (n = 5), potential missed diagnoses in context of a recent COVID-19 compatible illness (n = 40), and making infection control or immunosuppression management decisions in persistently SARS-CoV-2 RNA PCR positive individuals (n = 6). We demonstrate acceptable performance characteristics, feasibility and clinical utility of using a LFIA that detects anti-spike antibodies to deliver SARS-CoV-2 serology service in adults and children. Greatest benefit was seen where there is reasonable pre-test probability and results can be linked with clinical advice or intervention. Experience from this pilot can help inform practicalities and benefits of rapidly implementing new tests such as LFIAs into clinical service as the pandemic evolves.
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Chorro-Mari, Veronica, and Nanna Christiansen. "SETTING UP OF A HOMECARE SYSTEM FOR HIGH COST NEBULISERS IN A PAEDIATRIC CYSTIC FIBROSIS CENTRE." Archives of Disease in Childhood 101, no. 9 (August 17, 2016): e2.57-e2. http://dx.doi.org/10.1136/archdischild-2016-311535.60.
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AimDue to national changes to the commissioning process of high cost nebulisers (HCN) for Cystic Fibrosis (CF) patients, CF centres have to repatriate the prescribing of the HCN to the tertiary care centres.1 The following nebulisers will no longer be prescribed by primary care: Cayston® (Aztreonam); Colomycin®, Pomixin®, Clobreathe® (Colistimethate); Pulmozyme® (Dornase alfa); Tobi®, Tobi Podhaler ®, Bramitob® (Tobramycin).This abstract explains how the Royal London Hospital (RLH) Paediatric Pharmacy recruited over 100 paediatric (CF) patients smoothly within a period of 4 months and set up a homecare system to avoid patients and families having to travel large distances to obtain their medication.MethodsA number of homecare companies were evaluated initially. Parameters looked at were reports of customer satisfaction, delivery cost, turn-around time once the prescription was received and availability of same day delivery service.In order to capture existing patients we met with CF Specialist Nurses to establish the total number of patients on HCN, what nebulised treatment they were on and their respective doses. We prioritised patients that had known problems with GP prescribing and anybody newly starting on HCN.To communicate the change to parents, a letter was sent to all parents explaining the changeover to homecare delivery and tertiary prescribing. In addition a section in the parent bulletin was dedicated to the topic as well. Following this we contacted parents via phone and in clinic to request consent and explain the process.Up to 10 patients were contacted weekly (average of 7); the consent form and registration form were then faxed to the Homecare company for patient registration. In parallel to this prescriptions were requested for the patients that had been set up in the previous week, ensuring that prescribing was spread out over time to avoid having peak times for repeat prescriptions.In addition to the letter to parents GP surgeries were also informed in writing about the changes in commissioning and planned repatriation of HCN. This information was also included on discharge prescriptions for patients on any of the HCNs as part of the pharmacy screening process.A system for follow up prescriptions as repeat was set up between the team so we would not have unexpected urgent requests and we could avoid missed doses, urgent delivery charge or stress in the team. In order to manage the prescriptions and ease communication across the team a database was developed.ResultsFrom March to July 2014 (16 weeks) one hundred and four patients were successfully repatriated to tertiary care.ConclusionA planned method and agreed standard operation procedure was key to effectively capture and repatriate all patients while at the same time keeping the increase on workload for the pharmacy team to a minimum. The fact of having a strong pharmacy presence as part of the multidisciplinary team attending CF clinics and ward rounds was vital in making this work.
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El Hamssili, D., T. Bouattar, R. Bayahia, and L. Benamar. "Siamese twin pregnancy in peritoneal dialysis : first case in the world." Bulletin de la Dialyse à Domicile 1, no. 1 (March 13, 2018): 39–42. http://dx.doi.org/10.25796/bdd.v1i1.35.
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Introduction: The probability of conception is low in peritoneal dialysis (PD), and the probability of successful pregnancy is even lower. Nearly 60 years after the first reported case of successful pregnancy in a dialysis patient, many questions about pregnancy during dialysis remain unresolved, namely the required dialysis dose, the follow-up rhythm, the choice of the the most appropriate dialysis technique.
Case report: We report the first case worldwide of twin Siamese pregnancy in a patient on continuous ambulatory peritoneal dialysis (CAPD). The pregnancy was diagnosed at 7 weeks of amenorrhea (WA). The patient was initially under 2 exchanges per day, with 2-liter bags of Dianealof 1.36% glucose. As soon as the pregnancy was discovered, the prescription was modified, putting the patient under 3 exchanges a day with the same concentrates. The infusion volume was maintained at 2 liters up to 18 WA , and then reduced to 1.5 liters due to patient discomfort and abdominal hyperpressure. Daily ultrafiltration ranged from 180 to 800 ml with 1 liter diuresis. The blood pressure was well controlled, with an average of 125/80 mmHg, without need of antihypertensive drugs. On a biological level, the Kt / V was 2.2, nPCR was 0.8, and the weekly clearance was 80 L / 1.73 m². The average hemoglobin was 11.5 g / dl under erythropoietin 9000 units per week. At 20 WA, obstetrical ultrasound revealed a mono-chorionic, mono-amniotic twin pregnancy. Due to high maternal and fetal risks, closer obstetrical control was indicated. At 24 WA, morphological obstetrical ultrasound coupled with Doppler examination of the uterine and umbilical arteries favored the diagnosis of mono-amniotic mono-chorionic twin pregnancy with strong suspicion of Siamese contiguous to the pelvis, with a cerebral malformation in one of the fetuses. The patient experienced intense contractions and pelvic pain leading to an emergency cesarean section with two surviving Siamese twins, contiguous to the pelvis, weighing 900g, but who died one day after delivery.
Conclusion: Pregnancy during dialysis is at high maternal and fetal risks. It is necessary to prepare and follow this pregnancy to optimize the chances of success. This implies an adaptation of the medical treatment and dialysis prescription, including the volume and modality of exchanges. The same holds true for gynecological and obstetrical follow-up, which must be regular and strict, in order to prevent any maternal-fetal complications.
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Bökamp, Lena. "dm startet Same-Day-Delivery." Lebensmittel Zeitung 73, no. 19 (2021): 49. http://dx.doi.org/10.51202/0947-7527-2021-19-049-7.
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dm-Drogeriemarkt testet die taggleiche Auslieferung von Online-Bestellungen. Der Händler kommissioniert in einer Filiale in Karlsruhe, lokale Subunternehmer liefern per Fahrrad aus – zu teilweise hohen Liefergebühren.
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Tabesh, Hadi, Zahra Elahi, Zeinab Amoabediny, and Fojan Rafiei. "Elimination of Induced Hypoxic Regions in Depth of 3D Porous Silk Scaffolds by the Introduction of Channel Configuration." BioMed Research International 2022 (March 16, 2022): 1–12. http://dx.doi.org/10.1155/2022/9767687.
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Development of large, clinically sized tissue constructs with efficient mass transport is a tremendous need in tissue engineering. One major challenge in large tissue-engineered constructs is to support homogeneous delivery of oxygen and nutrients throughout the tissue scaffold while eliminating induced hypoxic regions in depth. To address this goal, we introduced an especial channeled architecture on porous silk-based tissue scaffolds to improve supplying of oxygen to the cells in central regions of the scaffolds. Oxygen gradients were measured and evaluated in three scaffold prototypes, namely, one unchanneled and two channeled scaffolds with different channel diameters (500 μm and 1000 μm). The channels were introduced into the constructs using stainless-steel rods arranged uniformly in stainless-steel mold, a fabrication method that enables precise control over channel diameter and the distance between channels. During 2-week culture of G292 cells, the 1000 μm channeled scaffolds demonstrated higher oxygen concentration at the center compared to 500 μm channeled prototype; however, the oxygen concentration approached the same level around the last days of culture. Nevertheless, homogenous oxygen distribution throughout the 1000 μm channeled constructs and the consequence of higher cell proliferation at day 14 postseeding corroborate the efficient elimination of induced hypoxic regions; and therefore, it holds promise for clinically relevant sized scaffold especially in bone tissue engineering.
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Campana, Luca G., Marco Scarpa, Antonio Sommariva, Elena Bonandini, Sara Valpione, Leonardo Sartore, and Carlo R. Rossi. "Minimally invasive treatment of peristomal metastases from gastric cancer at an ileostomy site by electrochemotherapy." Radiology and Oncology 47, no. 4 (December 1, 2013): 370–75. http://dx.doi.org/10.2478/raon-2013-0051.
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Abstract Background. Peristomal metastases are rare, but potentially associated with relevant morbidity. Surgical resection, followed by stoma relocation, represent the gold standard in most patients. We describe electrochemotherapy (ECT), a minimally invasive method for locally-enhancing drug delivery by means of electric pulses, as an alternative approach. Patient and methods. A 49-year-old man with advanced gastric cancer developed skin metastases around an ileostomy site. The ulcerated and oozing tumor growth impaired patient’s quality of life due to continuous trouble in fitting the ostomy appliance, its poor adherence and consequent stools spillage. ECT consisted of a 20-minute course under mild general sedation. A bleomycin bolus of 15 000 IU/m2 was followed by the percutaneous application of multiple, 1.5 ms -long electric pulses by means of a needle electrode. Results. Post ECT course was uneventful and the patient was discharged on the same day. After one week, tumor nodules were flattened and partial tumor regression was appreciable at one-month follow-up. More importantly, peristomal skin conditions significantly improved, thus allowing for an effective application of the ostomy appliance during the following moths, until patient’s death. Conclusions. This report suggests the feasibility of ECT as a minimally invasive approach for peristomal tumors. In selected cases, ECT, by achieving a rapid tumor control, may ensure effective ostomy management and preserve patients’ quality of life.
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Schmidt, M., P. M. Kragh, J. Li, L. Lin, Y. Liu, G. Vajta, and H. Callesen. "78 ESTABLISHMENT OF PREGNANCIES IN LARGE WHITE SOW RECIPIENTS AFTER TRANSFER OF CLONED EMBRYOS OF DIFFERENT PIG BREEDS." Reproduction, Fertility and Development 22, no. 1 (2010): 197. http://dx.doi.org/10.1071/rdv22n1ab78.
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Production of cloned piglets, using normal or transgenic donor cells, has been of limited efficiency. One reason could be breed differences between recipient and embryos. The aim of this study was to compare pregnancies after transfer to Large White (LW) sow recipients of cloned LW embryos or cloned, transgenic minipig embryos. Large White donor cells were from LYxD, and minipig cells were transgenic with 1 of 5 genes related to different human diseases and from either Göttingen or Yucatan. The cells were used on Day 0 for handmade cloning (Du et al. 2005 Cloning Stem Cells 7, 199-205). The reconstructed embryos were cultured in vitro until transfer on Day 5 to 6. As recipients, 70 LW sows were weaned and anesthetized 4 days after natural heat. Through an abdominal incision the ovaries were controlled (CL formation, absence of cysts) and the embryos slowly introduced into the uterus via a catheter inserted 5 to 6 cm into the tip of the upper horn. To each of 33 recipients, 40 to 60 LW embryos were transferred, and 37 recipients each received 50 to 100 transgenic minipig embryos. Pregnancies were examined by ultrasound scanning every second week. Abortions were defined as absence of earlier confirmed scanning or delivery of aborted fetuses. Caesarean sections were performed on Day 114 (minipig) or Day 116 (LW) 24 h after injection of a prostaglandin analogue. At delivery, placental gross morphology was recorded with samples taken for later histology. The piglets were fed every 3 h with colostrum for the first 24 h and then by the recipient LW sow. Data were analyzed by Fisher’s Exact test with a significance level of P < 0.05. The overall pregnancy rate was 49% (34/70) with an abortion rate of 29% (8 aborted + 2 resorbed/34) from Day 30 to 45 giving 24/70 deliveries (34% of the transfers). There was no significant difference between minipig (54%, 20/37) and LW pregnancy results (42%, 14/33), although there tended to be more abortions with minipig pregnancies (8/20 v. 2/14; P = 0.14) resulting in 12 minipig and 12 LW litters of which 4 and 9, respectively, have grown up to adulthood. In almost every recipient the placenta and fetal membranes showed abnormal thick and edematous morphology. The total litter sizes ranged from 1 to 10 piglets (mean 4.4 ± 0.6), and in 13 of 24 litters there were 1 to 5 stillborn piglets. Except for one litter of 9 transgenic Yucatan piglets that all died within their first 2 weeks, the postnatal mortality of both LW- and mini-piglets seemed similar to that of farm piglets of the same age, and the piglets appeared normal with respect to weight gain, gross morphology, and behavior. These results demonstrate that, in spite of a rather high abortion rate and some fetal mortality, an acceptable birth rate can be achieved after transfer to LW recipients of cloned LW embryos (36%) as well as cloned, transgenic minipig embryos (32%). Therefore, a breed difference between the embryos and their recipient seems not to influence the pregnancy results. The authors thank B. Synnestvedt, H. Kristiansen, S. Starsig, A. Pedersen, J. Adamsen, R. Kristiansen, and K. Villemoes for invaluable technical assistance.
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Lima, Rodrigo, Lais Navarro, Fernando Cesani, Hal K. Hawkins, Frederick Huang, Daneshvari R. Solanki, Thomas Philbeck, and Larry Miller. "Repeated Doses of Adriamycin May Be Safely Delivered through the Intraosseous Route In Different Bones In Swine." Blood 116, no. 21 (November 19, 2010): 4344. http://dx.doi.org/10.1182/blood.v116.21.4344.4344.
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Abstract Abstract 4344 Background: Vascular access is critical to the management of patients undergoing chemotherapeutic treatments. Chemotherapy regimens are delivered via long-term vascular access, which are associated with increased rate of infection and vessel damage. The safety of intraosseous (IO) drug delivery of common cardiovascular drugs has been well established and is accepted as the primary alternative to IV access. The safety of multiple rounds of tissue disruptive chemotherapeutic agents via the IO route, however, is unknown. A 2007 study conducted by this group examined single dose administration of Mitomycin, Adriamycin, and CHOP (cyclophosphamide, doxorubicine hydrochloride, Oncovin, and prednisolone) through the IO route. Results suggested that the IO route of infusing chemotherapy agents could be a safe alternative to IV infusion, based on the short-term evaluation of 7 days. But in a 2008 follow-up study of Adriamycin administered through the IO route in the same bone 3 times over a 72-day period, 10 of 14 animals suffered osteomyelitis and/or fractures in the bones used for the infusions. The current study was designed to explore different drug administration regimens designed to prevent these complications. Method: This study consisted of two groups of swine, each receiving three rounds of Adriamycin infusions, in three different limbs spaced 21 days apart. Group 1: (High Dose-High Concentration, n = 6): 60mg/m2 of Adriamycin was delivered into the bone over 15 minutes (concentration 2mg/ml). Group 2: (Low Dose-Low Concentration, n=6): 25mg/m2 of Adriamycin was delivered into the bone over 15 minutes (concentration 0.4 mg/ml). Sedation was induced with Ketamine, Xylazine, and Telazol and maintained with Propofol. An IO needle (EZ IO, Vidacare Corporation, Shavano Park, TX) was aseptically placed into the left humerus (first infusion), or left tibia (second infusion), or right tibia (third infusion). Saline was delivered before (manual syringe flush of 10 ml) and after the IO drug infusion (10ml/min over 5 minutes via syringe pump) in both groups. Radiographic images were obtained before and after every drug infusion and prior to euthanasia. Animals were monitored daily for signs of pain, swelling, or tissue necrosis and treated as needed for the duration of the study. Thirty days after the last drug infusion, animals were anesthetized and euthanized. Bone samples were harvested and sent for histological evaluation. A scoring system, in which changes in morphology were scored on a 0 to 4 scale with 4 representing the most severe changes, was used for the histological evaluation. Result: The clinical complications observed were related to the usual adverse events of the drug, such as diarrhea and vomiting observed during the first week post injection in both groups. There was no clinical, radiological, or histological evidence of osteomyelitis or fracture. Radiological evaluation showed a delay of the healing process and an increase of the osteoblastic activity in the bones previously injected with Adriamycin in both groups. Histological evaluation showed higher scores for blood (p<0.001), scar (p=0.002), and edema (p=0.04) in the left tibia of the animals of Group 1 versus Group 2. There was a higher incidence of normal marrow tissue present in the left tibia of the animals of Group 2 (p=0.04) and a higher incidence of normal bone spicules was found in the right tibia of the animals of Group 2 versus Group 1 (p=0.04). Conclusion: The IO delivery of lower dose and diluted concentrations of Adriamycin was safer and resulted in less tissue abnormality when compared with higher dose/higher concentration. The IO route with rotation of sites for placement of IO needles may be a feasible option for Adriamycin or other vesicant delivery. Disclosures: Lima: Vidacare Corporation: Research Funding. Navarro:Vidacare Corporation: Research Funding. Philbeck:Vidacare Corporation: Employment. Miller:Vidacare Corporation: Employment, Equity Ownership.
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Hardianti, Arini, Siswanto Agus Wilopo, Mohammad Hakimi, and Althaf Setiawan. "The Primary Health Center Factors Associated with Contraceptive Use Among Women in Indonesia." Jurnal Ners dan Kebidanan Indonesia 8, no. 4 (January 8, 2021): 261. http://dx.doi.org/10.21927/jnki.2020.8(4).261-269.
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<em><em>Access to health care, especially health care’s days open was one of the important poin to increasing contraceptive user. Many people who want to use contraception tend to want to get the method in the same day when visited the health care. The aim of this study is to find the relationship health care days open and contraceptive utilization. The cross-sectional study used Performance Monitoring and Accountability (PMA) 2020 data in 33 provinces of Indonesia in 2015. The research subjects were primary health care (Puskesmas). In this research, a number of districts were merged to reach a minimum number of respondents of 30 women. One hundred and four health center were studied and analyzed with t-test and correlation, and multivariable analysis by looking at the level of significance p <0.05, and multivariable analysis. Female, household, and service delivery point questionnaire were used in this study. Result: All health centers in 76% area in Indonesia open more than five days a week and no stock out more than five contraceptive methods. All health centers in 69% area provides more than 5 methods. Days open statistically significant with modern contraceptive utilization after considering the stock out and method provides. Conclusion: contraceptive days open in health care generally good and have relation with contraceptive utilization after considers the stock and how many methods they provide.</em></em>
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Couey, Marcus A., Matthew Taylor, Tarsem Moudgil, Yoshinobu Koguchi, Anne Stadum, Tanisha Christie, William L. Redmond, et al. "Abstract CT123: Trial in progress: First-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma." Cancer Research 83, no. 8_Supplement (April 14, 2023): CT123. http://dx.doi.org/10.1158/1538-7445.am2023-ct123.
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Abstract Background: Glucocorticoid-Induced Tumor Necrosis Factor Receptor-related protein (GITR) is a co-stimulatory pathway that when triggered has potent effects on T-cell memory, proliferation and anti-tumor activity. Preclinical models identified significant synergy between anti-GITR agonist therapy and cancer vaccines to generate stronger tumor specific CD8 T cell responses. DPV-001 is an “off-the-shelf” multivalent autophagosome vaccine generated by in vitro manipulation of the autophagy pathway in human cancer cell lines. The vaccine delivers short-lived proteins (SLiPs) and defective ribosomal products (DRiPs) which are likely the dominant epitopes directly presented by MHC class I of tumor cells; but because of proteosomal degradation, are normally unavailable for cross-presentation, hence the delivery via vaccine. We hypothesize that addition of aGITR to DPV-001 vaccine will augment expansion of reactive CD4 and CD8 T cells, attenuate contraction of this response, and improve the therapeutic effect of treatment, and will result in the development of a coordinated T and B cell response to some of the same proteins, detectable using a cutting-edge seromics approach, as a window to TCR target identification for immunodynamic tracking of induced anti-cancer responses at an advanced level. Methods: Patient recruitment began in August 2022, for this first-in-human immunotherapy-trio study of DPV-001, with sequenced checkpoint inhibition (aPD-1 mAb; retifanlimab), with or without aGITR agonist mAb (INCAGN-1949), in recurrent or metastatic HNSCC (NCT04470024). Patient population to include HPV-positive or HPV-negative, ECOG 0-2, with therapy continued until confirmed progression (RECIST 1.1), up to 2 years. Primary objective is safety, DLT ≤ 33%, with secondary efficacy objectives of ORR (PR+CR) and 2 year OS. Initial safety lead-in (n = 3+3 per arm), will be followed by phase Ib expansion of one/both arms if immunologically promising, 28 patients per arm, futility if <4/15 responses. Study Drugs Cyclophosphamide 300mg/m2 IV, priming Day (-2) onlyVaccine (DPV-001)- Day 1 intranodal US bilateral inguinal- Days 8,15 intradermal, then q2wks to week 22- Thereafter q4wks until progression, up to 2 yearsaPD-1 (retifanlimab) 500mg IV q4wks, start Day 15 (Arms 1 & 2)aGITR (INCAGN01876) 300mg IV q2wks, start Day 1 (Arm 2 only) Response (RECIST 1.1) CT weeks 8 and 12, then q3mos Immunologic Monitoring PBL and sera are collected regularly and PBL are evaluated by flow cytometry. Biopsies obtained at baseline, Day 15 and Day 57, analyzed by mIF and 10x scRNA-Seq. Sera analyzed by phage immunoprecipitation (PhIP) sequencing for reactivity against the human proteome. Immune monitoring modifications that allow for improved characterization of immune cell subsets will be presented. Citation Format: Marcus A. Couey, Matthew Taylor, Tarsem Moudgil, Yoshinobu Koguchi, Anne Stadum, Tanisha Christie, William L. Redmond, Christopher Paustian, Ryan Meng, Venkatesh Rajamanickam, Lessli Rushforth, Abigail Peterson, Brady Bernard, Richard B. Bell, Carlo B. Bifulco, Traci L. Hilton, Shawn M. Jensen, Hong-Ming Hu, Brian Piening, Walter J. Urba, Bernard A. Fox, Rom S. Leidner. Trial in progress: First-in-human immunotherapy-trio for advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT123.
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Klapp, Mathias A., Alan L. Erera, and Alejandro Toriello. "Request acceptance in same-day delivery." Transportation Research Part E: Logistics and Transportation Review 143 (November 2020): 102083. http://dx.doi.org/10.1016/j.tre.2020.102083.
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Alvarez, R. H., V. Valero, R. L. Bassett, C. Lu, N. Dallas, G. Kiriakova, J. A. Bankson, T. L. Madden, G. N. Hortobagyi, and J. E. Price. "Mechanistic evaluation of the combination effect of paclitaxel (Pac) and bevacizumab (Bev) in breast cancer xenografts." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 11007. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11007.
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11007 Background: Chemosensitization is the ability to augment the effects of standard chemotherapy. One of the possible mechanisms for chemosensitization is improving intratumoral chemotherapy concentrations by increasing total or regional delivery of chemotherapy to the tumor. This mechanism potentially leads to a decreased tumor interstitial fluid pressure (IFP). This study evaluates the interaction between tumor IFP, intra-tumor drug accumulation and blood vessel perfusion. Methods: GILM2 human breast cancer (triple negative phenotype) cells were injected into the mammary fat pad of female nude mice. Mice were randomized to 4 arms: Control, Pac 24 mg/Kg, Bev 10 mg/Kg, and the same dose for the combination Pac + Bev, twice a week for 3 weeks. Tumor IFP was assessed using an ultraminiature catheter-tip technique (Ozerdem 2005). Concentration of Pac in tumor tissue was measured using liquid chromatography mass spectrometry (LC/MS) and blood vessel perfusion was assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Ultrastructural morphology changes were assessed by electron microscopy (EM). Results: Treatment started 35 days after implantation; tumor tissue concentration of Pac was significantly increased when combined with Bev (P = 0.03). In mice treated with the combination of Pac + Bev, IFP values decreased more gradually, with sustained and significant reduction at the end of the treatment (P = 0.0068; mean SEM day 0: 28,44 ± 6,1; mean SEM day 21: 7,41 ± 2,0). The IFP changes in the other 3 experimental arms did not reach statistical significance. The combination of Pac and Bev produced substantial changes to the proportions of endothelial cell/pericytes and increased apoptosis in tumor cells by 75% (detected by immunostaining for cleaved-caspase 3). Conclusions: The combination of Pac and Bev produces significant tumor reduction and increases three-fold the concentration of Pac in the tumor. This intra-tumor augmentation of Pac was correlated with the decrease of tumor IFP, which was independent of the action of Bev alone. Results of DCE-MRI and EM analyses of the treated tumors will also be presented. No significant financial relationships to disclose.
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Bellová, Veronika, Alena Pechová, Rudolf Dvořák, and Leoš Pavlata. "Influence of Full-fat Soybean Seeds and Hydrolyzed Palm Oil on the Metabolism of Lactating Dairy Cows." Acta Veterinaria Brno 78, no. 3 (2009): 431–40. http://dx.doi.org/10.2754/avb200978030431.
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The aim of the study was to compare the influence of fat supplementation in the form of full-fat soybean seeds and hydrolyzed palm oil as energy sources for dairy cows in early lactation. During the first 8 lactation weeks, 17 dairy cows divided into group S (n = 8) and group C (n = 9) were observed. The basic diet was the same for both groups. The differences were in the composition of the concentrate mixture, which had a balanced content of nutrients. In group S the fat source was heat-treated soybean seeds, while in group C the fat source used was hydrolyzed palm oil. The two diets started to be fed on the day of calving. Blood samples were taken weekly (1st–5th week) and 8 weeks after delivery. At the end of the experiment ruminal fluid was taken. During the experiment BCS in both groups deteriorated similarly. In group S it decreased from 3.8 ± 0.2 to 3.3 ± 0.3 and in group C from 3.5 ± 0.4 to 3.1 ± 0.4. A better performance of hepatic metabolism was proved in group S. In group S lower concentrations of non-esterified fatty acids were identified in the 3rd (0.96 ± 0.38 vs. 1.76 ± 0.63 mmol l-1; p < 0.01) and 8th (0.32 ± 0.29 vs. 0.78 ± 0.48 mmol l-1; p < 0.05) week after calving. The gamma-glutamyl transferase (EC 2.3.2.2) activity in serum indicates a better liver parenchyma condition in group S where no increased activity was identified above the reference range. An increased activity was identified in group C from the 2nd week with a significant difference between groups detected in the 2nd (0.41 ± 0.07 vs. 0.66 ± 0.25 μkat l-1; p < 0.05) and 4th (0.42 ± 0.05 vs. 0.64 ± 0.25 μkat l-1; p < 0.05) weeks after delivery. There were no significant differences found between groups in bilirubin and aspartate transaminase (EC 2.6.1.1) but a general tendency toward lower values is apparent in group S. No significant differences were found between groups by the examination of ruminal fluid. Based on these results we can conclude that full-fat soy was better utilised than hydrolysed palm oil and represents a suitable alternative for increasing energy concentration in the diet for dairy cows. On the other hand, the development of liver steatosis in cows make controversial the usage of fat as an energy source for fresh cows even if their BCS is around 3.5–3.8 and it may not be recommended generally.
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Pisudde, PM, Shamshad Ahmad, Ramkesh Prasad, Ashish Yadav, and Dutt Rekha. "Breastfeeding Week Celebrations at ESI Hospitals." Journal of Comprehensive Health 3, no. 2 (October 24, 2020): 52–54. http://dx.doi.org/10.53553/jch.v03i02.007.
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In August 2014, the Department of Community Medicine celebrated breastfeeding week in our hospital(ESIC hospital, Joka) and field practice area (ESI hospital budge budge) which is our Urban health training centre in southern part of Kolkata. The theme for this year is “Breastfeeding: A Winning Goal for Life!†The theme for this year's World Breastfeeding Week asserts the importance of increasing and sustaining the Protection, Promotion and Support of Breastfeeding for achieving the Millenium Development Goals (MDGs) and improving child survival and nutrition in the Post 2015 development agenda of sustainable development goals.1To begin with, we referred to National Family Health Survey-3 data and tried to find out the status of breastfeeding practices in our areas. We found that percentage of children who received breastfeeding in one hour was just 23.7%.2 . District level health survey shows that percentage of children who received breastfeeding in one hour is 38.5% only while that the Mothers who received any antenatal check-up is 96.1% 3 This signifies poor implementation of breastfeeding policies in health care facilities and also signifies the missed opportunity to health educate the mother and her relatives about importance of exclusive breastfeeding. In the settings, where the ANC check up is high, the staff of healthcare facilities should ensure education of the mothers regarding exclusive breastfeeding, positioning, and attachment of infant to the breast while providing the ANC care and same should be continued after delivery. To achieve this, staff of the health care facility should be educated and trained in the importance of exclusive breastfeeding, positioning, and attachment of breast. Hence, as a part of breastfeeding week celebrations, we decided to conduct one-day workshop for the staff nurse working in maternity and paediatric wards and OPD of the ESIC hospital Joka and ESI hospital budge budge. We used this time to explain how important is exclusive breastfeeding and how does it influences neonatal mortality by decreasing it six times if exclusive breastfeeding is given.4 We showed how the mother can position the child and attach the child to the breast. We used an Integrated Management of Neonatal and Childhood Illness (IMNCI) guidelines, which is recommended under National Rural Health Mission (NRHM). We could offer these skills-based training to 44 staff nurse of two hospital and 4 ward ayaa from ESI budge budge hospital. We used photographs, Power Point presentations and videos. We also emphasized the importance of breastfeeding week and its theme. We also emphasize on stopping or discontinuation of use of infant milk substitute, feeding bottles and infant foods which is also stated by government of India, in 1992 (IMS act) as provided by Ministry of Health and Family Welfare (MoHFW), India. Faculty of Community Medicine department, of which one is trained in IMNCI strategy, conducted the sessions.
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Lim, Jasmine. "Improving outcomes in frail older adults with complex care needs in an ambulatory setting through timely, integrated person-centered care. A case for rapid access frailty clinics in Singapore." International Journal of Integrated Care 23, S1 (December 28, 2023): 462. http://dx.doi.org/10.5334/ijic.icic23515.
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Background: Frailty is a significant risk factor for recurrent hospital admissions and emergency department presentations. Frail older adults are especially vulnerable to hospital related adverse outcomes recognisably functional decline, delirium, institutionalisation and mortality. Fragmentation of care resulting in poorly defined care responsibilities, together with the limitation of community resources to manage acute issues in this group of patients, increase the likelihood of them presenting to an acute care setting.
Methods: A retrospective study evaluated frail older adults seen in an ambulatory Geriatric clinic in a government funded public hospital from 2021 to 2022. The aim of the study was to determine if timely evaluation of acute issues in an ambulatory setting could avoid a hospital admission or an emergency department presentation.
Results: Preliminary data in this study showed that (1) timely review of acute issues (<1 week from presentation) led to avoidance of hospital admission, emergency department presentation as well as admission in the next 30 days; (2) the common presentations successfully managed include worsening behavioral and psychological symptoms of dementia (BPSD), delirium, infections and falls; (3) majority of the patients seen were moderately to severely frail based on their clinical frailty score (CFS). Additionally, there was high level of patient and caregiver satisfaction reported.
Conclusion: This study shows that hospital admissions and emergency department presentations can potentially be avoided in frail older adults whose acute medical issues are recognised and managed early. Important contributing factors to the effective management of these patients include: easy accessibility to the primary geriatrician involved, same day investigations, timely follow ups, good social/family support as well as the engagement of community services. Rapid access frailty clinics, a service model built upon the similar recognition that acute issues in frail older adults needed to be addressed promptly, has been described and shown to have benefit elsewhere. In Singapore, innovations in care delivery both within the hospital and in the community has become ever more crucial with an increasingly frail population and in already overwhelmed healthcare institutions. Rapid access frailty clinics can be a useful hospital-based service delivery model to improve care of our frail older adults.
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Cukierski, Matthew J., Paul A. Johnson, and James C. Beck. "Chronic (60-Week) Toxicity Study of DUROS Leuprolide Implants in Dogs." International Journal of Toxicology 20, no. 6 (November 2001): 369–81. http://dx.doi.org/10.1080/109158101753333659.
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The toxicity and pharmacodynamics of leuprolide acetate delivered from subcutaneously implanted DUROS leuprolide implants were examined in sexually mature male beagle dogs. The DUROS leuprolide implant is a sterile, nonpyrogenic, nonerodible, single-use, implantable, osmotically driven, drug delivery system for the palliative treatment of advanced prostate cancer. It contains 65 mg of leuprolide and is designed to deliver leuprolide continuously at a nominal rate of 120 μg per day for at least 12 months. Serum drug and testosterone concentrations were compared to values from dogs receiving monthly intramuscular injections of Lupron Depot 3.75 mg or no treatment (sham-operated). The local tissue response induced by subcutaneously implanted DUROS leuprolide implants was also evaluated. Beagles were implanted with a DUROS leuprolide implant for 52 weeks followed by removal and implantation of a new DUROS leuprolide implant for an additional 8 weeks. No mortality or morbidity occurred in this study. No treatment-related changes occurred in mean body weights, blood chemistry, or hematology during the study. Treatment-related atrophy of the testes, epididymides, and prostate gland, consistent with the known pharmacological effects of the drug, was observed in all dogs receiving the DUROS leuprolide implant or the Lupron Depot. Histological examination of these organs showed no distinguishable difference between dogs treated with the DUROS leuprolide implant or Lupron Depot. Weekly serum samples from dogs with DUROS leuprolide implants indicated continuous leuprolide delivery over 60 weeks, while some samples from the Lupron Depot group fell below measurable concentrations. Analysis of serum samples collected every 28 days just before Lupron Depot injection showed that 80 % of these samples had leuprolide concentrations below the limit of quantitation (0.1 ng/ml). Serum testosterone concentrations were below castrate levels (< 50 ng/dl) by 4 weeks after implantation of DUROS leuprolide implant and remained so for the duration of the study. Lupron Depot 3.75 mg also effectively lowered serum testosterone concentrations, but required reinjection every 28 days. All local tissue reactions to the DUROS leuprolide implant at implant sites were classified as mild following macroscopic examination. Microscopic site scores were mild to moderate. The DUROS leuprolide implant was shown to be safe, to provide continuous leuprolide delivery, and to effectively lower serum testosterone concentrations below castrate levels.
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Donnellan, William B., Jesus Berdeja, Dianna Shipley, Edward Arrowsmith, David Wright, Scott Lunin, Richard H. Brown, James Essell, and Ian Flinn. "A Phase II Trial Evaluating the Safety of Rapid Infusion Ofatumumab (OFA) in Patients (pts) with Previously Treated Chronic Lymphocytic Leukemia (CLL)." Blood 124, no. 21 (December 6, 2014): 3336. http://dx.doi.org/10.1182/blood.v124.21.3336.3336.
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Abstract Background: OFA is a fully humanized, anti-CD20 antibody that is approved for use with chlorambucil in previously untreated CLL and as a single agent in refractory CLL. Using the currently recommended administration scheme there is a low rate of severe infusion reactions. However, this scheme requires long infusion times with averages of 6.8 hrs, 6.8 hrs and 4.2-4.4 hrs for 2000 mg OFA doses 1, 2, and 3+, respectively. We evaluated whether an accelerated infusion regimen would allow OFA to be delivered safely over a shorter period of time. Methods: This was a phase II, single-arm study, still enrolling patients. Eligibility criteria included pts with relapsed CD20+ CLL, ≥ 1 prior therapy, no antibody therapy in the prior 3 months, ECOG PS ≤1, negative hepatitis B serology, and adequate organ function. Previous treatment with OFA was allowed if the pt had maintained a PR or better for ≥ 6 months. Pts were pre-medicated with acetaminophen 1000mg PO, diphenhydramine 50 mg PO/IV or equivalent and dexamethasone 10 mg IV. The 1st dose of OFA (300 mg/500 mL [0.6 mg/mL]), was given on week 1 day 1 starting at 6 mL/hr and doubling every 30 min until a rate of 400 mL/hr was reached. The planned infusion durations of the 1st and 2nd infusions under this administration schema are 226 min and 167 min respectively. If tolerated, the 2nd dose (1000 mg/500 mL [2 mg/mL]) was given on week 1 day 3 starting at 25 mL/hr and doubling every 30 min until a rate of 400 mL/hr was reached. If no grade (G) 3 or 4 infusion reaction was encountered, a 3rd dose (2000 mg/500 mL [4 mg/mL]) was given on week 2 day 1 at 200 mL/hr over the first 30 min and if tolerated at 267 mL/hr over the next 90 min (goal infusion time 120 minutes). Subsequent infusions given in the same manner were planned weekly for 8 weeks and then monthly for 4 months. The primary endpoint was the number of subjects able to complete the 3rd dose (2000 mg) within 15 min of the goal infusion time. Results: Between July 2013 and May 2014 23 pts were treated. Pts were 48% male and had a median age of 69 yrs. Rai stage was 12%/20%/20%/12%/32%/4% for stages 0/1/2/3/4/ unknown, respectively. IgVH was mutated in 40% of patients, non-mutated in 44% of patients and unknown in 16% of patients. CD38 was positive in 44%, negative in 44% and unknown in 12%. FISH studies were unknown in 4%, normal in 32% and abnormal in 64% (11q del 24%, 13q del 53%, 17p del 28%, trisomy 12 28%). At the time of analysis 8 pts (35%) were on active treatment, 8 pts (35%) had completed treatment, and 7 patients (30%) had stopped treatment prior to completion due to patient request (3pts), intercurrent illness (2 pts), toxicity (1 pt) and disease progression (1 pt) There were 4 G3 infusion-related reactions (3 occurred in a single patient) and 14 G1/G2 reactions. All but 1 infusion-related reaction occurred during the 1st 2 infusions. Nineteen patients have received the week 2 day 1 rapid infusion dose. There was only 1 infusion-related reaction (sneezing) and 14 of 19 pts (74%) received the full dose within 15 min of the planned 2 hr treatment duration. An additional 2 pts (11%) received the full dose within 20 min of the planned infusion time, and the remaining 2 pts completed within 30 min of the planned 2 hr treatment duration. Median infusion times were 303 min, 182 min and 126 min for infusions 1, 2, and 3 respectively. G 3/4 hematologic AEs observed regardless of cause were: thrombocytopenia (G3 8% and G4 4%), neutropenia (G3 8%), and pancytopenia (G3 8%). There were no treatment-related G3/4 non-hematologic toxicities with the exception of 2 infusion-related reaction (G3 9%).Response data is preliminary, but shows an overall response rate of 29%. Conclusion: Using this stepped up dosing regimen, a rapid infusion of OFA is safe and well-tolerated. Almost all infusion related reactions occurred during the 1st 2 infusions (1 was associated with the 2000 mg rapid infusion). This accelerated infusion regimen decreased infusion times while preserving the delivery of OFA in a safe manner. Disclosures Flinn: GlaxoSmithKline: Research Funding.
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Park, So Hyun, Ciaran M. Lee, Daniel P. Dever, Timothy H. Davis, Joab Camarena, Yankai Zhang, Matthew Porteus, Vivian A. Sheehan, and Gang Bao. "Highly Efficient Editing of the Beta-Globin Gene in Patient Derived Hematopoietic Stem and Progenitor Cells to Treat Sickle Cell Disease." Blood 132, Supplement 1 (November 29, 2018): 2192. http://dx.doi.org/10.1182/blood-2018-99-117371.
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Abstract Sickle cell disease (SCD) is an inherited blood disorder associated with a debilitating chronic illness. SCD is caused by a point mutation in the β-globin gene (HBB). A single nucleotide substitution converts glutamic acid to a valine that leads to the production of sickle hemoglobin (HbS), which impairs the function of red blood cells. Here we show that delivery of Streptococcus pyogenes (Sp) Cas9 protein and CRISPR guide RNA as a ribonucleoprotein complex (RNP) together with a short single-stranded DNA donor (ssODN) template into CD34+ hematopoietic stem and progenitor cells (HSPCs) from SCD patients' bone marrow (BM) was able to correct the sickling HBB mutation, with up to 33% homology directed repair (HDR) without selection. Further, CRISPR/Cas9 cutting of HBB in SCD HSPCs induced gene conversion between the HBB sequences in the vicinity of the target locus and the homologous region in δ-globin gene (HBD), with up to 4.4% additional gene correction mediated by the HBD conversion in cells with Cas9 cutting only. The erythrocytes derived from gene-edited cells showed a marked reduction of the HbS level, increased expression of normal adult hemoglobin (HbA), and a complete loss of cell sickling, demonstrating the potential in curing SCD. We performed extensive off-target analysis of gene-edited SCD HSPCs using the in-silico prediction tool COSMID and unbiased, genome-wide assay Guide-Seq, revealing a gross intrachromosomal rearrangement event between the on- and off-target Cas9 cutting sites. We used a droplet digital PCR assay to quantify deletion and inversion events from Day 2 to Day 12 after RNP delivery, and found that large chromosomal deletion decreased from 1.8% to 0.2%, while chromosomal inversion maintained at 3.3%. We demonstrated that the use of high-fidelity SpCas9 (HiFi Cas9 by IDT) significantly reduced off-target effects and completely eliminated the intrachromosome rearrangement events, while maintaining the same level of on-target gene editing, leading to high-efficiency gene correction with increased specificity. In order to determine if gene-corrected SCD HSPCs retain the ability to engraft, CD34+ cells from the BM of SCD patients were treated with Cas9/gRNA RNP and ssODN donor for HBB gene correction, cryopreserved at Day 2 post genome editing, then intravenously transplanted into NSG mice shortly after thawing. These mice were euthanized at Week 16 after transplantation, and the BM was harvested to determine the engraftment potential. An average of 7.5 ±5.4% of cells were double positive for HLA and hCD45 in mice injected with gene-edited CD34+ cells, compared to 16.8 ±9.3% with control CD34+ cells, indicating a good level of engraftment of gene-corrected SCD HSPCs. A higher fraction of human cells were positive for CD19 (66 ±28%), demonstrating lymphoid lineage bias. DNA was extracted from unsorted cells, CD19 or CD33 sorted cells for gene-editing analysis; the HBB editing rates were respectively 29.8% HDR, 2.4% HBD conversion, and 42.8% non-homologous end joining (NHEJ) pretransplantation, and editing rates at Week 16 posttransplantation were respectively 8.8 ±12% HDR, 1.8 ±1.7% HBD conversion, and 24.5 ±12% NHEJ. The highly variable editing rate and indel diversity in gene-edited cells at Week 16 in all four transplanted mice suggest clonal dominance of a limited number of HSPCs after transplantation. Taken together, our results demonstrate highly efficient gene and phenotype correction of the sickling mutation in BM HSPCs from SCD patients mediated by HDR and HBD conversion, and the ability of gene-edited SCD HSPCs to engraft in vivo. We also demonstrate the importance of genome-wide analysis for off-target analysis and the use of HiFi Cas9. Our results provide further evidence for the potential of moving genome editing-based SCD treatment into clinical practice. Acknowledgments: This work was supported by the Cancer Prevention and Research Institute of Texas grants RR140081 and RP170721 (to G. B.), and the National Heart, Lung and Blood Institute of NIH (1K08DK110448 to V.S.) Disclosures Porteus: CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Somani, Shreya P., Bhavsh N. Astik, Hita H. Mehta, and Milan D. Jhavar. "Efficacy and safety of iontophoresis combined sodium salicylate in acquired plantar keratoderma-a randomized controlled study." International Journal of Research in Dermatology 8, no. 1 (December 24, 2021): 101. http://dx.doi.org/10.18203/issn.2455-4529.intjresdermatol20214919.
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<p><strong>Background</strong>: Palmoplantar keratoderma is a heterogenous group of disorders, hereditary or acquired, characterized by thickening of palms and soles. Though it is not a life-threatening condition, it affects individual’s quality of life. As treatment of keratoderma has always been troublesome, upgraded treatment modalities which improves keratoderma efficiently are always encouraged.</p><p><strong>Methods</strong>: In this randomized controlled study, patients of plantar keratoderma of age group of 18-65 years were randomly divided in group A and group B. In group A, iontophoresis combined sodium salicylate was offered to patients twice weekly for 8 weeks of duration, during which DC current was supplied at 5-15 mA for 10 min of duration. Whereas, in group B patients applied topical salicylic acid 12% ointment at home twice a day for 8 weeks.</p><p><strong>Results</strong>: Our study of 70 patients of keratoderma, revealed diffuse (94%) pattern of involvement with female preponderance (55.7%) and occupation wise, most common among laborers (54.2%) followed by housewives (27.1%). Statistically significant number of patients showed reduction in severity grading of parameters, in both groups at end of 8 weeks. Same way, mean values of parameter grading significantly reduced at 8 weeks in both the groups. But intergroup values showed no significant difference. Mean EASI (Eczema Area Severity Index) score showed statistically significant reduction in group B as compared to group A at 8<sup>th</sup> week. Percentage of reduction of EASI score was also significantly higher in group B at end of treatment.</p><p><strong>Conclusions:</strong> Here both treatment modalities are safe and effective, topical being slightly more efficacious than iontophoresis. So, we can conclude that no additional privilege of drug delivery through iontophoresis.</p>
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Koss, Catherine A., Diane V. Havlir, James Ayieko, Dalsone Kwarisiima, Jane Kabami, Gabriel Chamie, Mucunguzi Atukunda, et al. "HIV incidence after pre-exposure prophylaxis initiation among women and men at elevated HIV risk: A population-based study in rural Kenya and Uganda." PLOS Medicine 18, no. 2 (February 9, 2021): e1003492. http://dx.doi.org/10.1371/journal.pmed.1003492.
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Background Oral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, but data are limited on HIV incidence among PrEP users in generalized epidemic settings, particularly outside of selected risk groups. We performed a population-based PrEP study in rural Kenya and Uganda and sought to evaluate both changes in HIV incidence and clinical and virologic outcomes following seroconversion on PrEP. Methods and findings During population-level HIV testing of individuals ≥15 years in 16 communities in the Sustainable East Africa Research in Community Health (SEARCH) study (NCT01864603), we offered universal access to PrEP with enhanced counseling for persons at elevated HIV risk (based on serodifferent partnership, machine learning–based risk score, or self-identified HIV risk). We offered rapid or same-day PrEP initiation and flexible service delivery with follow-up visits at facilities or community-based sites at 4, 12, and every 12 weeks up to week 144. Among participants with incident HIV infection after PrEP initiation, we offered same-day antiretroviral therapy (ART) initiation and analyzed HIV RNA, tenofovir hair concentrations, drug resistance, and viral suppression (<1,000 c/ml based on available assays) after ART start. Using Poisson regression with cluster-robust standard errors, we compared HIV incidence among PrEP initiators to incidence among propensity score–matched recent historical controls (from the year before PrEP availability) in 8 of the 16 communities, adjusted for risk group. Among 74,541 individuals who tested negative for HIV, 15,632/74,541 (21%) were assessed to be at elevated HIV risk; 5,447/15,632 (35%) initiated PrEP (49% female; 29% 15–24 years; 19% in serodifferent partnerships), of whom 79% engaged in ≥1 follow-up visit and 61% self-reported PrEP adherence at ≥1 visit. Over 7,150 person-years of follow-up, HIV incidence was 0.35 per 100 person-years (95% confidence interval [CI] 0.22–0.49) among PrEP initiators. Among matched controls, HIV incidence was 0.92 per 100 person-years (95% CI 0.49–1.41), corresponding to 74% lower incidence among PrEP initiators compared to matched controls (adjusted incidence rate ratio [aIRR] 0.26, 95% CI 0.09–0.75; p = 0.013). Among women, HIV incidence was 76% lower among PrEP initiators versus matched controls (aIRR 0.24, 95% CI 0.07–0.79; p = 0.019); among men, HIV incidence was 40% lower, but not significantly so (aIRR 0.60, 95% CI 0.12–3.05; p = 0.54). Of 25 participants with incident HIV infection (68% women), 7/25 (28%) reported taking PrEP ≤30 days before HIV diagnosis, and 24/25 (96%) started ART. Of those with repeat HIV RNA after ART start, 18/19 (95%) had <1,000 c/ml. One participant with viral non-suppression was found to have transmitted viral resistance, as well as emtricitabine resistance possibly related to PrEP use. Limitations include the lack of contemporaneous controls to assess HIV incidence without PrEP and that plasma samples were not archived to assess for baseline acute infection. Conclusions Population-level offer of PrEP with rapid start and flexible service delivery was associated with 74% lower HIV incidence among PrEP initiators compared to matched recent controls prior to PrEP availability. HIV infections were significantly lower among women who started PrEP. Universal HIV testing with linkage to treatment and prevention, including PrEP, is a promising approach to accelerate reductions in new infections in generalized epidemic settings. Trial registration ClinicalTrials.gov NCT01864603.
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Elsherif, Laila, Raymond V. Ortines, Jack T. Saari, and Y. James Kang. "Congestive Heart Failure in Copper-Deficient Mice." Experimental Biology and Medicine 228, no. 7 (July 2003): 811–17. http://dx.doi.org/10.1177/15353702-0322807-06.
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Copper Deficiency (CuD) leads to hypertrophic cardiomyopathy in various experimental models. The morphological, electrophysiological, and molecular aspects of this hypertrophy have been under investigation for a long time. However the transition from compensated hypertrophy to decompensated heart failure has not been investigated in the study of CuD. We set out to investigate the contractile and hemodynamic parameters of the CuD mouse heart and to determine whether heart failure follows hypertrophy in the CuD heart. Dams of FVB mice were fed CuD or copper-adequate (CuA) diet starting from the third day post delivery and the weanling pups were fed the same diet for a total period of 5 weeks (pre- and postweanling). At week 4, the functional parameters of the heart were analyzed using a surgical technique for catheterizing the left ventricle. A significant decrease in left ventricle systolic pressure was observed with no significant change in heart rate, and more importantly contractility as measured by the maximal rate of left ventricular pressure rise (+dP/dt) and decline (−dP/dt) were significantly depressed in the CuD mice. However, left ventricle end diastolic pressure was elevated, and relaxation was impaired in the CuD animals; the duration of relaxation was prolonged. In addition to significant changes in the basal level of cardiac function, CuD hearts had a blunted response to the stimulation of the β-adrenergic agonist isoproterenol. Furthermore, morphological analysis revealed increased collagen accumulation in the CuD hearts along with lipid deposition. This study shows that CuD leads to systolic and diastolic dysfunction in association with histopathological changes, which are indices commonly used to diagnose congestive heart failure.
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Biggeri, Annibale, Lucia Bilanci, Lucia Caselli, Stefano Lucarelli, Carlo Niccolai, Sabrina Paterniti, Franco Sirianni, and Maurizio Ferrara. "Assistenza psichiatrica a Firenze. Indagine “ad hoc” sulla prevalenza dei casi in trattamento nei servizi psichiatrici pubblici (1991)." Epidemiologia e Psichiatria Sociale 4, no. 3 (1995): 187–97. http://dx.doi.org/10.1017/s1121189x00010393.
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SummaryObjective - The aim of our research is to evaluate the prevalence of psychiatric illnesses by means of data collected at the Florence municipality community mental health services encompassing all hospital and extramural activities, providing the same kind of information given by Psychiatric Case Register (PCR) covered areas. Design - It has been carried out a one week prevalence assessment through a cross-sectional analysis of clinical records gathered by psychiatric services of the submitted area. Population studied - The inquiry has considered the area of USL (Administative Local Authority of National Health Service) 10/A, 10/B, 10/C and 10/D, which constituite togheter with USL 10/E, the Florence municipality area. Results - Total and specific rates for diagnostic categories, sex and age reveal a large variability among the four considered USLs confirmed by standardized rates: the 10/A and 10/B USLs, that include the historic centre of Florence, present the highest standardized rates (10/A 207/100.000, 10/B 189/100.000), especially for the most severe disorders (Schizophrenia: 10/A 110/100.000, 10/B 87/100.000; Major Affective Disorders: 10/A 32/100.000, 10/B 38/100.000; Organic Psichosys: 10/A 6/100.000, 10/B 9/100.000). Conclusion - In the present study, the prevalence rate for all diagnoses for the whole area considered, is about 150.6/100.000, quite close to the estimate calculated in Verona-Sud (200/100.000). As to the different rates among USLs we have to bear in mind the development of the delivery care system, and the available clinical settings (on day hospital and residentials activities for long-term patients).