Статті в журналах з теми "IUS/14"

Abstract Background Intestinal ultrasound (IUS) is a non-invasive monitoring tool increasingly being used to assess response to therapy in Crohn’s disease (CD). Herein we describe the longitudinal evolution of IUS parameters, and its correlation with clinical, laboratorial and endoscopic parameters during the first year of infliximab (IFX) therapy. Methods Prospective multicentre cohort study of patients with active CD starting IFX. Harvey-Bradshaw index (HBI), C-reactive protein (CRP), fecal calprotectin (FC) and IUS were performed at week (W) 0, 14, 30 and 54. Ileocolonoscopy was performed at W0 and W54. IFX through levels (ITL) were measured at W14, 30 and 54. Clinical remission (CR) was defined as HBI<5 and laboratorial remission (LR) as CRP <0.5mg/dL and FC <150ug/g. IUS response was defined as a reduction >25% in bowel wall thickness (BWT) and IUS remission as normalization of BWT (≤3mm), color doppler sign (CDS≤1), wall stratification and inflammatory fat. The IBUS-SAS score was used to assess disease activity and includes BWT, doppler sign, stratification and inflammatory fat. Endoscopic response was defined as 50% reduction of SES-CD in most affected segment and endoscopic healing as total SES-CD <3. Results 62 patients with CD (50% male; mean age 36±15y) were included: all with IUS at W0 and W14, 58 (94%) patients with IUS at W30 and 53 (85%) at W54. Following therapy initiation there was a positive evolution of all assessed parameters; IUS response and remission increased gradually from baseline to week 54 (Table 1 and Figure 1). Figure 2 illustrates the reduction of BWT and IBUS-SAS score from baseline to week 54. The reduction of BWT and IBUS-SAS were significantly more pronounced in the first 14 weeks of therapy (BWT: DW0-14 vs DW14-30, p=0.015; IBUS-SAS: DW0-14 vs DW14-30, p=0.004; DW0-14 vs DW30-54, p=0.037). There was a good agreement between IUS and colonoscopy for evaluation of the most affected segment at baseline (kappa 0.788, p<0.001). In all time points, there was a significantly fair to moderate correlation between ultrasonographic parameters (BWT, CDS and IBUS-SAS score) and laboratorial biomarkers (specially fecal calprotectin) (Table 2). After induction (week 14), there were also a fair correlation between IBUS-SAS and ITL (r=-0.277, p=0.034). Conclusion We found a significantly fair to moderate correlation between IUS parameters and laboratorial and endoscopic parameters during the first year of infliximab therapy. BWT and IBUS-SAS score reduction was more pronounced during induction therapy. IUS can be reliably used to monitor disease activity longitudinally, in a tight monitoring strategy.

ObjectiveThe aim of the study was to evaluate the efficacy of the levonorgestrel intrauterine system (LNG-IUS) for treatment of endometrial hyperplasia (EH).MethodsA prospective multicenter study was conducted from November 2010 to March 2014. Patients with histologically confirmed EH were treated with LNG-IUS. At 3, 6, and 9 months after LNG-IUS insertion, follow-up endometrial aspiration biopsies with the LNG-IUS in the uterus were undertaken. At the 12th month of follow-up, endometrial tissues were obtained via 2 methods: endometrial aspiration biopsy with the LNG-IUS in the uterus, followed by dilatation and curettage (D&C) after LNG-IUS removal. The primary outcome was the regression rate at 12 months after LNG-IUS insertion, and the secondary outcome was the consistency of the results between the endometrial aspiration biopsy and the D&C.ResultsThe study population comprised 75 patients, including 37 with simple hyperplasia without atypia; 3 with atypical simple hyperplasia; 23 with complex hyperplasia without atypia, and 12 with atypical complex hyperplasia. Of these patients treated with the LNG-IUS, 38 (50.7%) were followed up at 12 months after LNG-IUS insertion. The complete regression rate at 12 months was 94.7% (36/38): 100% (6/6) of patients with atypical EH and 93.7% (30/32) with EH without atypia. In all of the cases (100%, 36/36), patients achieved complete regression within 3 months of LNG-IUS insertion. A comparison of the pathologic results from endometrial aspiration biopsy and D&C was carried out for 15 patients. In the histologic results by endometrial aspiration biopsy, 14 patients were diagnosed as “normal endometrium” and 1 as “insufficient tissue for pathologic evaluation.” Among the 14 cases of normal endometrium by endometrial aspiration biopsy, 1 was diagnosed as “residual EH” by D&C, and the 1 case with insufficient tissue was diagnosed as normal endometrium by D&C.ConclusionsLevonorgestrel intrauterine system is an effective and favorable method for treatment of EH.

Intrauterine smoke exposure (IUS) is a strong risk factor for development of airways responsiveness and asthma in childhood. Runt-related transcription factors (RUNX1–3) have critical roles in immune system development and function. We hypothesized that genetic variations in RUNX1 would be associated with airway responsiveness in asthmatic children and that this association would be modified by IUS. Family-based association testing analysis in the Childhood Asthma Management Program genome-wide genotype data showed that 17 of 100 RUNX1 single-nucleotide polymorphisms (SNPs) were significantly ( P < 0.03–0.04) associated with methacholine responsiveness. The association between methacholine responsiveness and one of the SNPs was significantly modified by a history of IUS exposure. Quantitative PCR analysis of immature human lung tissue with and without IUS suggested that IUS increased RUNX1 expression at the pseudoglandular stage of lung development. We examined these associations by subjecting murine neonatal lung tissue with and without IUS to quantitative PCR ( N = 4–14 per group). Our murine model showed that IUS decreased RUNX expression at postnatal days (P)3 and P5 ( P < 0.05). We conclude that 1) SNPs in RUNX1 are associated with airway responsiveness in asthmatic children and these associations are modified by IUS exposure, 2) IUS tended to increase the expression of RUNX1 in early human development, and 3) a murine IUS model showed that the effects of developmental cigarette smoke exposure persisted for at least 2 wk after birth. We speculate that IUS exposure-altered expression of RUNX transcription factors increases the risk of asthma in children with IUS exposure.

Background/Aims: Capsule enteroscopy (CE) and intestinal ultrasonography (IUS) are techniques that are currently used for investigating small-bowel (SB) diseases. The aim of this study was to compare the main imaging findings and the lesion detection rate (LDR) of CE and IUS in different clinical scenarios involving the SB.Methods: We retrospectively enrolled patients who underwent CE and IUS for obscure gastrointestinal bleeding (OGIB), complicated celiac disease (CeD), and suspected or known inflammatory bowel disease (IBD). We evaluated the LDR of both techniques. The accuracy of IUS was determined using CE as the reference standard.Results: A total of 159 patients (113 female; mean age, 49±19 years) were enrolled. The LDR was 55% and 33% for CE and IUS (p<0.05), respectively. Subgroup analysis showed that the LDR of CE was significantly higher than that of IUS in patients with OGIB (62% vs. 14%, p<0.05) and CeD (55% vs. 35%, p<0.05). IUS showed a similar LDR to CE in patients with suspected or known IBD (51% vs. 46%, p=0.83).Conclusions: CE should be preferred in cases of OGIB and CeD, whereas IUS should be considered an early step in the diagnosis and follow-up of IBD even in patients with a proximal SB localization of the disease.

Background: In utero smoke (IUS) exposure is associated with asthma susceptibility. Objective: We sought to test the hypothesis that changes in miRNA expression by IUS exposure during human lung development is associated with asthma susceptibility. Methods: Gene expression was profiled from 53 IUS unexposed and 51 IUS exposed human fetal lung tissues. We tested for the differential expression of miRNAs across post-conception age and by IUS using linear models with covariate adjustment. We tested the IUS-associated miRNAs for association with their gene expression targets using pair-wise inverse correlation. Using our mouse model, we investigated the persistence of the IUS-associated miRNA signature using RT-PCR from the lungs of mouse pups with and without IUS at postnatal day 14. MiRNAs were then tested for association with asthma and exacerbations using whole blood gene expression profiles from Asthma BRIDGE. Results: Five miRNAs were differentially expressed across post-conception age (adjusted p < 0.0002) including two that were differentially expressed by IUS exposure in human fetal lung (p < 0.05). MiR-15a was differentially expressed by post-conception age (p = 0.00002), IUS exposure in human fetal lung (p = 0.005), and in the post-natal mouse lung (p = 0.01). MiR-15a was also associated with the in utero expression of GSDMB (adjusted p = 0.0002), a known childhood asthma gene and with asthma exacerbations (p = 0.0009) in Asthma BRIDGE. Thus, miR-15a is expressed during human lung development, is impacted by IUS exposure, regulates the intrauterine expression of asthma genes, and is associated with asthma severity. Conclusions: These results provide evidence for the role of miR-15a in the fetal origin of asthma.

Abstract Background Bowel wall thickness (BWT) is an accurate sonographic parameter to assess disease activity in Crohn’s disease (CD). International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) was developed to allow a reproducible assessment of intestinal inflammation in CD using bowel ultrasound (IUS). Aim to assess BWT and IBUS-SAS variation after induction therapy with infliximab (IFX) and their correlation with clinical and laboratory parameters. Methods Prospective multicentre study including patients with active CD starting IFX. Harvey-Bradshaw index (HBI), C-reactive protein (CRP), faecal calprotectin (FC) and IUS were performed at week 0 (W0) and 14 (W14). IUS response and remission were defined as a reduction in BWT ≥25% and its normalization(≤3mm) in the most affected segment, respectively. IBUS-SAS was calculated using BWT, Doppler signal, bowel wall stratification (BWS) and inflammatory fat. Results We included 37 patients (62% males; median age 30 years, range 16–73). According to Montreal classification, most patients were A2 (70%), had ileocolonic disease (L3 57%) and an inflammatory phenotype (B1 60%); 41% had perianal disease. Most were anti-TNF therapy naive(84%), and combination therapy was used in 62%. Terminal ileum was the most affected segment identified by IUS (60%). Table 1 shows clinical, laboratory and sonographic parameters [median (IQR)]. At W14, 81% were in clinical remission, 43% in laboratorial remission (normal CRP and FC), 24% had IUS response and 11% had IUS remission. There was a significant reduction in HBI, CRP, FC and sonographic parameters (except for BWS) between W0 and W14. We found a fair to good correlation between BWT and HBI(r=0.363, p=0.03), CRP(r=0.391, p=0.02) and FC(r=0.373, p=0.03) at W14. IBUS-SAS had also a fair to good correlation with CRP(r=0.340, p=0.04) and FC(r=0.527, p=0.001) at W14. The area under the curve of IBUS-SAS for predicting clinical and laboratorial remission was 0.60; best-cut off 64.65 (sens. 57%; specif. 63%). Conclusion There was a significant reduction in sonographic parameters after 14 weeks of IFX and one quarter of our patients had an IUS response, suggesting that reduction in BWT could be an early marker of response to therapy. We found a good correlation between IUS and clinical and laboratory parameters at W14. IUS evaluation after induction therapy can be a helpful tool to monitor disease activity and guide CD patient management in our daily practice.

Abstract BACKGROUND Intraoperative ultrasound (iUS) is an excellent aid for neurosurgeons to perform better and safer operations thanks to real time, continuous, and high-quality intraoperative visualization. OBJECTIVE To develop an innovative training method to teach how to perform iUS in neurosurgery. METHODS Patients undergoing surgery for different brain or spine lesions were iUS scanned (before opening the dura) in order to arrange a collection of 3-dimensional, US images; this set of data was matched and paired to preoperatively acquired magnetic resonance images in order to create a library of neurosurgical cases to be studied offline for training and rehearsal purposes. This new iUS training approach was preliminarily tested on 14 European neurosurgery residents, who participated at the 2016 European Association of Neurosurgical Societies Training Course (Sofia, Bulgaria). RESULTS USim was developed by Camelot and the Besta NeuroSim Center as a dedicated app that transforms any smartphone into a “virtual US probe,” in order to simulate iUS applied to neurosurgery on a series of anonymized, patient-specific cases of different central nervous system tumors (eg, gliomas, metastases, meningiomas) for education, simulation, and rehearsal purposes. USim proved to be easy to use and allowed residents to quickly learn to handle a US probe and interpret iUS semiotics. CONCLUSION USim could help neurosurgeons learn neurosurgical iUS safely. Furthermore, neurosurgeons could simulate many cases, of different brain/spinal cord tumors, that resemble the specific cases they have to operate on. Finally, the library of cases would be continuously updated, upgraded, and made available to neurosurgeons.

Abstract Background Exclusive enteral nutrition (EEN) is a nutrition-based therapy for active Crohn’s Disease (CD). Transmural healing is a novel therapeutic paradigm in CD, holding benefit beyond endoscopic mucosal healing. There are limited data exploring EEN and transmural healing in CD. We aimed to examine the effect of EEN on inducing transmural response and healing as assessed by intestinal ultrasonography (IUS). Methods This was a prospective, multi-centre, open-label cohort study. Adults ≥18 years with active CD were enrolled between March to September 2022. Eligible, consenting participants were nutritionally assessed by a specialised IBD dietitian and prescribed 6 weeks of EEN therapy. A 1.5kcal/ml polymeric, low lactose, fibre-free formula was used and EEN prescriptions were personalised to 25-30kcal/kg IBW and 1.2-1.5g protein/kg IBW/day. Patients were allowed concurrent tapering corticosteroid therapy and biological therapy. Participants completed clinical, biochemical and nutritional assessments at weeks 0, 3 and 6 and IUS at weeks 0 and 6. This included Harvey Bradshaw Index (HBI), C-Reactive protein, faecal calprotectin (FCP), body mass index (BMI). IUS assessment was conducted at baseline and at week 6 and images were centrally read by a blinded, IUS-trained gastroenterologist. Transmural response was defined by ≥25% bowel wall thickness (BWT) reduction from baseline. Transmural healing was defined as BWT≤3mm, Doppler signal score≤1, normal bowel wall stratification, and absence of inflammatory fat. Results Fourteen patients, 9 were female (64.3%) and mean age of 44.4 years, were consecutively enrolled and completed 6-weeks of EEN therapy. Ten patients (71.4%) had ileal disease (L1), 4/10 had ileocolonic (L3) and predominant phenotype was inflammatory (B1, 7/14) and stricturing (B2, 6/14) disease. Mean disease activity was HBI 5.1±4.0.Two patients had perianal disease (14.3%). Nine patients (64.3%) reported 100% adherence and 4 patients (28.6%) reported 75-99% adherence to the exclusive diet by predefined adherence categories. At week 6, 11/14 (78.6%) of patients achieved clinical remission with 12/14 (85.7%) showing clinical response. Reductions in CRP and FCP were not statistically significant. Numerical reduction in BWT was observed 5.6±1.4mm vs 4.8±2.1mm (95% CI -1.94, 0.265, p = 0.124). Transmural response was achieved in 8/14 (57.1%) and transmural healing was reached in 2 (14.3%) patients. Most common side effect was constipation (42.9%). Conclusion EEN was identified to induce early transmural response and healing in patients with active CD. Further studies are required to evaluate the capacity for EEN to induce transmural healing and the role of IUS as an early assessment tool in monitoring therapeutic response in CD.

Abstract BACKGROUND Endometrial ablation/resection and the levonorgestrel intra-uterine system (LNG-IUS) are well-established treatment options for heavy menstrual bleeding to avoid more invasive alternatives, such as hysterectomy. OBJECTIVE The aim was to compare the efficacy and safety of endometrial ablation or resection with the LNG-IUS in the treatment of premenopausal women with heavy menstrual bleeding and to investigate sources of heterogeneity between studies. SEARCH METHODS We searched the databases MEDLINE, EMBASE, CENTRAL, Web of Science, Biosis and Google Scholar as well as citations and reference lists published up to August 2019. Two authors independently screened 3701 citations for eligibility. We included randomized controlled trials published in any language, comparing endometrial ablation or resection to the LNG-IUS in the treatment of premenopausal women with heavy menstrual bleeding and a normal uterine cavity. OUTCOMES Thirteen studies (N = 884) were eligible. Two independent authors extracted data and assessed the quality of included studies. Random effect models were used to compare the modalities and evaluate sources of heterogeneity. No significant differences were observed between endometrial ablation/resection and the LNG-IUS in terms of subsequent hysterectomy (primary outcome, risk ratio (RR) = 1.13, 95% CI 0.60 to 2.11, P = 0.71, I2 = 14%, 12 studies, 726 women), satisfaction, quality of life, amenorrhea and treatment failure. However, side effects were less common in women treated with endometrial ablation/resection compared to the LNG-IUS (RR = 0.52, 95% CI 0.37 to 0.71, P &lt; 0.001, I2 = 0%, 10 studies, 580 women). Three complications were reported in the endometrial ablation/resection group and none in the LNG-IUS group (P = 0.25). Mean age of the studied populations was identified as a significant source of heterogeneity between studies in subgroup analysis (P = 0.01). In fact, endometrial ablation/resection was associated with a higher risk of subsequent hysterectomy compared to the LNG-IUS in younger populations (mean age ≤ 42 years old, RR = 5.26, 95% CI 1.21 to 22.91, P = 0.03, I2 = 0%, 3 studies, 189 women). On the contrary, subsequent hysterectomy seemed to be less likely with endometrial ablation/resection compared to the LNG-IUS in older populations (mean age &gt; 42 years old), although the reduction did not reach statistical significance (RR = 0.51, 95% CI 0.21 to 1.24, P = 0.14, I2 = 0%, 5 studies, 297 women). Finally, sensitivity analysis taking into account the risk of bias of included studies and type of surgical devices (first and second generation) did not modify the results. Most of the included studies reported outcomes at up to 3 years, and the relative performance of endometrial ablation/resection and LNG-IUS remains unknown in the longer term. WIDER IMPLICATIONS Endometrial ablation/resection and the LNG-IUS are two excellent treatment options for heavy menstrual bleeding, although women treated with the LNG-IUS are at higher risk of experiencing side effects compared to endometrial ablation/resection. Otherwise, younger women seem to present a lower risk of eventually requiring hysterectomy when treated with the LNG-IUS compared to endometrial ablation/resection.

Abstract Background Higher infliximab trough levels (ITL) have been shown to be associated with better rates of clinical remission and mucosal healing. Transmural healing (TMH) assessed by cross-sectional imaging [such as intestinal ultrasound (IUS)] is emerging as a potential target in Crohn′s disease (CD) treatment, but whether there is any relation with ITL remains unclear. Our goal was to investigate the association between ITL and bowel wall thickness (BWT) in patients with CD after induction therapy with IFX. Methods Prospective multicentric cohort study of CD patients who started IFX in mono or combination therapy. Patients performed IUS and ITL at weeks 0 and 14. TMH was defined as BWT ≤3 mm in the most affected segment. A ROC curve was plotted to determine the best cut-off point of ITL to predict TMH. Chi-square test, Mann-Whitney test and Spearman correlation were performed to assess the ITL relation with BWT. Results We included 57 patients, 30 (53%) of whom were men with mean age of 36±15 years. Disease extension according to Montreal classification was L1 in 19 (33%), L2 in 8 (14%) and L3 in 30 (53%) patients; 6 (11%) patients also had L4 extension and 19 (33%) patients had perianal disease. Disease behavior was B1 in 36 (63%), B2 in 13 (23%) and B3 in 8 (14%) of patients. Most patients (61%) were under immunomodulators and 15 (26%) were under corticosteroids when infliximab was started; most (88%) were naïve for infliximab. At week 0, all patients had endoscopic activity and 97% had increased BWT at the most affected segment. The most affected segment on IUS at week 0 was the terminal ileum in 38 (67%) patients and the ascending, transverse, descending and sigmoid colon in 5 (9%), 2 (3%), 7 (12%) and 5 (9%) patients, respectively. There was a very good agreement between IUS and colonoscopy for evaluation of the most affected segment at baseline (kappa 0.81, p&lt;0.001). Median ITL at week 14 was 4.30 μg/ml (IQR 0.01–21). TMH at week 14 was achieved in 13 (23%) patients. ITL and BWT at week 14 were negatively correlated, with a fair correlation (r=-0.3, p=0.03). The AUC of ITL for BWT was 0.661 (best cut-off value 7.65, sensitivity 54%, specificity 89%). ITL ≥7.65 μg/ml was associated with higher rates of TMH (44% vs 15%, OR 4.47 [95%CI 1.2–16.4], p=0.04). Conclusion In our cohort of CD patients completing induction therapy with infliximab, higher ITL were associated with higher ultrasonographic transmural healing rates. The best cut-off for predicting TMH was ITL above 7.65μg/ml.

Abstract Commercial Law and Legal History This invited article summarizes the main points of my recent book 'Historia del Derecho Mercantil' from the commercial culture of the Ancien Régime to the legal culture of the legislative State (2016), adding one additional finding by Paolo Prodi. Inhalt: Präsentation. (1) ius mercatorum als Handelskultur. (2) Recht und Kultur. (3) Verdächtige, aber notwendige und legitime Aktivitäten. (4) Strukturen des ius mercatorum (5) Handelsregeln und ökonomische Macht der Monarchie. (6) „Non rubare" ein bedauerliches Versäumnis. (7) Beschreibung des Handelsrechts. (8) Die Kodifizierung des Handels. (9) Das Spanische Handelsgesetzbuch und sein Ruhm. (10) Territorialer Widerstand. (11) Der Código de comercio und allgemeines Privatrecht. (12) Die Aktiengesellschaft. (13) Die Handelsgerichtsbarkeit im Staat. (14) Recht (und Nicht-Recht) des Handels im liberalen Jahrhundert. (15) Abschließende Überlegungen

Abstract Background Transmural healing is a treatment goal in the management of Crohn’s disease, and intestinal ultrasound (IUS) is potentially a sensitive, non-invasive and reproducible means to assess the response to treatment. Methods The STRIDENT (Stricture Definition and Treatment) study was a randomised controlled trial of standard dose monotherapy adalimumab versus intensive high-dose adalimumab combined with a thiopurine. Crohn’s disease patients with symptomatic intestinal strictures were randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) with 40mg fortnightly maintenance plus thiopurine, with possible dose escalation at 4 and 8 months, versus standard dose adalimumab monotherapy. The primary endpoint was clinical response, defined as a reduction in the Obstructive Symptom Score (OSS) of ≥1, at 12 months. IUS was performed at baseline, 4, 8 and 12 months. IUS endpoints included stricture resolution (normalisation of pre-stenotic dilation (&lt;2.5cm); reduced stricture bowel wall thickness (BWT ≥25% reduction); reduced colour doppler blood flow (inflammation, Limberg score ≤1) and normalisation of BWT (≤3mm). Patients with good quality baseline IUS and IUS-visible strictures were included for analysis. Results 77 patients underwent therapy randomisation. Of 63 patients with IUS-visible strictures 43 (68%) were in the intensive arm. Primary outcome was achieved by 32 (74%) patients in the intensive and 14 (70%) in the standard arms. Stricture resolution was seen in 1/5 non-responders and 18/45 responders. Median BWT reduced from 6.4mm (IQR 5.2-7.3mm) at baseline to 4.9mm (IQR 3-6mm) at 12 months (P&lt;0.001). Clinical responders had significant reduction in median BWT from 6.0mm (IQR 4.5-7.1) at baseline to 4.3mm (IQR 3-5.7) at 12 months (P&lt;0.001). There was no significant reduction in BWT at 4, 8 or 12 months in non-responders (P=0.26, P=0.29, P=0.26 respectively). BWT &gt;3mm at 12 months occurred more often in non-responders than responders (P&lt;0.05). Stricture resolution was seen in 13/36 in the intensive arm and 6/14 standard arm (P=0.75). The intensive arm had significant reduction in median BWT from 6.6mm (IQR 5.5-7.4mm) at baseline to 5.1mm (IQR 3-6.4mm) at 12 months (P&lt;0.001). There was no significant reduction in BWT at 4, 8 or 12 months in the standard arm (P=0.75, P=0.42, P=0.09 respectively). There was no significant difference in BWT&gt;3mm between trial arms at 12 months (P=1). Conclusion Stricture resolution and bowel wall thickness normalisation were demonstrated on intestinal ultrasound in stricturing Crohn’s disease patients treated with adalimumab therapy. Adalimumab therapy is associated with clinical improvement, and transmural improvement and healing, in patients with Crohn’s disease strictures.

BackgroundThe objective was to analyse the contribution of the provision at no cost to users of the 20 µg/day levonorgestrel-releasing intrauterine system (LNG-IUS) towards disability-adjusted life years (DALY) averted over a 9-year period.MethodsWe analysed data from 15 030 new users of the LNG-IUS who had the device inserted at 26 Brazilian teaching hospitals between January 2007 and December 2015. The devices came from the International Contraceptive Access Foundation (ICA), a not-for-profit foundation that donates the devices to developing countries for use by low-income women who desire long-term contraception and who freely choose to use this device. Estimation of the DALY averted included live births averted, maternal morbidity and mortality, child mortality and unsafe abortions averted.ResultsA total of 15 030 women chose the LNG-IUS as a contraceptive method during the study period. Over the 9 years of evaluation, the estimated cumulative contribution of the Brazilian program in terms of DALY averted consisted of 486 live births, 14 cases of combined maternal mortality and morbidity, 143 cases of child mortality and 410 unsafe abortions.ConclusionsProvision of the LNG-IUS at no cost to low-income Brazilian women reduced unwanted pregnancies and probably averted maternal mortality and morbidity, child mortality and unsafe abortions. Family planning programs, policymakers and stakeholders based in low-resource settings could take advantage of the information that the provision of this contraceptive at no cost, or at affordable cost to a publicly-insured population, is an effective policy to help promote women’s health.

ObjectiveThe aim of this study was to evaluate the oncologic and pregnancy outcomes of combined oral medroxyprogesterone acetate (MPA)/levonorgestrel-intrauterine system (LNG-IUS) treatment in young women with grade 2–differentiated stage IA endometrial adenocarcinoma who wish to preserve fertility.MethodsWe retrospectively reviewed the medical records of patients with grade 2 stage IA endometrial adenocarcinoma who had received fertility-sparing treatment at CHA Gangnam Medical Center between 2011 and 2015. All of the patients were treated with combined oral MPA (500 mg/d)/LNG-IUS, and follow-up dilatation and curettage were performed every 3 months.ResultsA total of 5 patients were included in the study. The mean age was 30.4 ± 5.3 years (range, 25–39 years). After a mean treatment duration of 11.0 ± 6.2 months (range, 6–18 months), complete response (CR) was shown in 3 of the 5 patients, with partial response (PR) in the other 2 patients. One case of recurrence was reported 14 months after achieving CR. This patient was treated again with combined oral MPA/LNG-IUS and achieved CR by 6 months. The average follow-up period was 44.4 ± 26.2 months (range, 12–71 months). There were no cases of progressive disease. No treatment-related complications arose.ConclusionsCombined oral MPA/LNG-IUS treatment is considered to be a reasonably effective fertility-sparing treatment of grade 2 stage IA endometrial cancer. Although our results are encouraging, it is preliminary and should be considered with experienced oncologists in well-defined protocol and with close follow-up.

Abstract Background Mucosal and transmural healing are associated with better outcomes in Crohn’s disease. Magnetic resonance imaging (MRI) and intestinal ultrasound (IUS) provide non-invasive cross-sectional assessment of disease activity and transmural healing. This systematic review addresses the utility of MRI and IUS in the assessment of disease activity and transmural healing in response to drug therapy when compared to endoscopy in patients with luminal Crohn’s disease. Methods Database searches were undertaken (Medline, Embase, Emcare, APA PsycInfo, CINAHL, Cochrane Library) following the PRISMA statement. Studies with ≥10 luminal Crohn’s disease patients with paired endoscopy and imaging (MRI or IUS) following treatment initiation were included. Records were screened on title and abstract, then full text by two independent reviewers. Results 5760 records were identified, 1707 duplicates removed, 1468 excluded; 2585 screened on title and abstract, 65 underwent full text review, resulting in 24 studies meeting inclusion criteria. 10 studies examined IUS, 12 examined MRI and 2 compared both. There was good correlation between IUS and endoscopic remission with biologic and or thiopurine treatment (k = 0.63, P&lt;0.001; k = 0.73, P&lt;0.001), and good correlation for IUS score and Simple Endoscopic score-Crohn’s disease (SESCD) at baseline and reassessment (r=0.521; P&lt;0.001). Early reduction in bowel wall thickness (BWT) at 4-8 weeks of anti-TNF therapy predicted endoscopic response at 12-38 weeks (AUROC 0.77; OR 10.80 P=0.012). Significant reductions in BWT after 2 weeks of anti-TNF therapy was associated with clinical and endoscopic response at 14 weeks. A significant reduction in BWT as early as 4 weeks with ustekinumab therapy correlated with endoscopic response at 48 weeks (k = 0.21; 95%CI 0.04-0.38). IUS transmural remission rates were higher in colonic disease than terminal ileal disease (OR 2.59; 95%CI 1.43-4.70, P&lt;0.05). MRI MaRIA score had a high accuracy for predicting endoscopic remission (AUROC 0.967; sensitivity 93%, specificity 77%, P&lt;0.05). Intestinal healing detected by MRI and endoscopy after 1 year of anti-TNF was predictive of long-term clinical remission (sensitivity 75%, specificity 72%; P=0.02). The simplified MaRIA score correlates with endoscopic response and was responsive to change after drug therapy (r=0.72; 95%CI 0.53-0.85). Conclusion Intestinal ultrasound and magnetic resonance imaging are reliable non-invasive modalities for assessing transmural healing in Crohn’s disease and accurate in monitoring response to drug therapy. Early changes in ultrasound are predictive of response to treatment. Intestinal ultrasound can monitor response to biologic induction.

Si présenta la versione polacca della relazione tenu ta il 14 novembre 1996 al Convegno internaziale di studi organizzato delle Università degli studi „La Sapienza” e „Tor Vergata” e dal Pontificio Ateneo della Santa Croce a Roma 13-16.11.1996 sul tema: La Scienza Canonistica nella seconda metj del 1900: Fondamenti, metodi, prospettive in D’Avack - Lombardia - Gismondi - Corecco. Il testo originale é pubblicato in „Ius Ecclesiae” 1997.

Abstract Background A less invasive examination that can estimate endoscopic remission is needed. Intestinal ultrasound (IUS) is a promising option. The bowel wall thickness (BWT) is a widely-accepted objective parameter in IUS to assess colonic inflammation, but BWT is influenced by intestinal peristalsis and the volume of luminal content. A feasible, objective index that is not affected by these factors could improve the diagnostic potential of IUS. The submucosa, which is observed as the third layer of the intestinal wall on IUS, becomes swollen and standing out in the active UC. Given BWT and submucosa thickness (SMT) can be influenced by the peristalsis and luminal content simultaneously, we hypothesized that the ratio of SMT to BWT can be an index for submucosal swelling regardless of those factors and this index can be a new parameter to estimate endoscopic remission. Methods Inclusion criteria were (1) both IUS and endoscopy (sigmoidoscopy or colonoscopy) for UC were performed in Kyorin University Hospital between April 2019 and December 2020 and (2) time-interval between IUS and endoscopy was within 2 weeks. BWT and SMT were measured based on IUS images for ascending (A/C), transverse (T/C), descending (D/C), and sigmoid colon (S/C), respectively. We defined the submucosa index (SMI) as a percentage of SMT to BWT (Figure 1). When SMT was too thin to be measured, we scored 0 for SMI. The loss of stratification (LOS) was defined as the condition where the submucosa cannot be identified even with BWT &gt; 3 mm (Figure 2). The parts with LOS were considered as inflamed mucosa. Mayo endoscopic subscore (MES) was scored for each part of the colon based on the endoscopic images. MES of 0/1 was defined as the endoscopic remission. Informed consent was obtained in the opt-out method. This study was approved by the Institutional Review Board of Kyorin University School of Medicine (IRB No. 1668). Results In total 68 parts of the colon (A/C: 11, T/C: 12, D/C: 14, and S/C: 31) were analyzed. With ROC analysis with the Youden index, the cutoff value of BWT for endoscopic remission was 3.7 mm (AUC: 0.84). Among the parts without LOS, the cutoff value of SMI for endoscopic remission was 47.9 (AUC: 0.75). The positive predictive value for endoscopic remission of the diagnostic criteria (1) BWT ≤ 3.7 mm, (2) BWT ≤ 3.7 mm and no LOS, (3) SMI ≤ 48 (no LOS), and (4) BWT ≤ 3.7 mm, SMI ≤ 48 (no LOS) was 83.3%, 88.2%, 60.7%, and 93.3%, respectively. The negative predictive value was 88.0%, 88.2%, 90.0%, and 86.8%, respectively. Conclusion Given the feasibility and objectiveness of assessing bowel wall structure, our findings provide “proof of concept” that SMI can be an additional sonographic parameter for endoscopic remission.

Abstract Background In the assessment of treatment response in Crohn’s Disease (CD) objective measures are superior to clinical improvement. Intestinal ultrasound (IUS) is an emerging modality with high accuracy to detect CD disease activity. Less is known about early transmural changes at IUS in treatment follow-up. Therefore, we aimed to investigate conventional IUS and contrast-enhanced ultrasound (CEUS) parameters and how they are associated with endoscopic treatment response. Methods In this longitudinal prospective cohort study, consecutive patients with active CD according to the simplified endoscopic score (SES-CD≥3) starting anti-TNF-α treatment were included. We recorded clinical, biochemical, IUS and CEUS parameters at baseline (T0), after 4–8 weeks (T1) and at 12–34 weeks (T2). IUS parameters were scored as previously established1. The SES-CD was scored per segment by a gastroenterologist immediately after endoscopy. The bowel segment with highest SES-CD score and thickest wall on IUS was identified. At T2, endoscopic response (decrease SES-CD≥50%) and endoscopic remission (SES-CD=0) were scored per segment. IUS and CEUS were scored blindly by two readers using recorded videos. Results 40 patients were included (Table 1) with 23 completing follow-up. The other 17 patients had side-effects and stopped treatment (n=9), underwent bowel surgery (n=5) or were lost to follow-up (n=3). At T2, 14 reached endoscopic remission, 17 had endoscopic response. The absolute decrease in BWT at T1 and T2 paralleled endoscopic response (Figure 1). Decrease in BWT of 18% at T1 (Fig 2) predicted endoscopic response accurately (OR: 10.8, 95%CI: 1.7–69.0, p=0.012). For T2, 29% decrease in BWT (Fig 2) was most accurate to determine endoscopic response (OR: 37.5, 95%CI: 2.8–507.5, p=0.006). At T2, a BWT of 3.2 mm was most accurate (AUROC: 0.940, 95%CI: 0.862–1.000, p&lt;0.0001, sensitivity: 92%, specificity: 85%) to determine endoscopic remission (OR: 39.4, 95%CI: 7.7–202.6, p&lt;0.0001). Normalization of Colour Doppler Signal (CDS) (no signal or single vessel) (OR: 13.8, 95%CI: 1.3–147.8, p=0.03) or Wash-out Rate (WoR) at CEUS (1 dB increase: OR: 0.8, 95%CI: 0.60–0.96, p=0.019) added significantly to BWT to determine endoscopic remission at T2. Conclusion Decrease of BWT 4–8 weeks after treatment initiation predicted endoscopic response later during follow-up. In addition, we have provided accurate cut-off values for (Δ)BWT associated with endoscopic response and remission at different time-points. CDS or WoR were both of additional value to determine endoscopic remission after 12–34 weeks. As CEUS is time consuming, CDS might be sufficient in the close follow-up of CD patients. Reference 1. Novak et al, JCC 2021

Abstract Background Bowel wall thickness (BWT) is an accurate ultrasonographic parameter to assess disease activity in Crohn’s disease (CD). The IBUS-SAS score includes BWT, doppler sign, loss of stratification and inflammatory fat (i-fat) and allows a reproducible assessment of inflammation in CD using intestinal ultrasound (IUS). Our aim: to assess clinical, laboratorial and ultrasonographic predictors of mucosal healing (MH) at 1 year of infliximab (IFX) therapy. Methods Prospective multicentric cohort study including patients with active CD starting IFX. Harvey-Bradshaw index, C-reactive protein (CRP), fecal calprotectin (FC) and IUS were performed at week 0, 14, 30 and 54. IUS remission was defined as BWT normalization (≤3mm) in the most affected segment. Ileocolonoscopy was performed at W0 and W54. MH was defined as SES-CD &lt;3 with no ulcers. Results We included 28 patients with CD (61% male; mean age of 34±12y). Clinical, laboratory and sonographic parameters are shown in Table 1. At week 54, 89% were in clinical remission, 79% had normalization of CRP and FC, 50% had IUS remission and 39% had MH. MH at W54 was associated with lower BWT at W14 (3.7 vs 5.2mm, p=0.049), lower Limberg score at W14 (1 vs 2, p=0.006), lower levels of i-fat at W14 (18 vs 72%, p=0.006) and lower IBUS-SAS score at W0, W14 and W30 (47 vs 71, p=0.002; 26 vs 58, p=0.001; 25 vs 50 p=0.046). We found a fair to good correlation between SES-CD W54 and BWT at W14 (r=0.45, p=0.015), Limberg score at W14 (r=0.4, p=0.037), IBUS-SAS at W0 and W14 (r=0.49, p=0.008; r=0.58, p=0.001). The area under the curve of IBUS-SAS for MH was 0.86 at W0 and W14 and 0.69 at W30. Best IBUS-SAS cut-off value was 27.6 at W14. Conclusion Lower values of BWT, Limberg score and i-fat after induction (W14) were associated with MH at 1 year of therapy. IBUS-SAS score at W14 had the highest AUC to predict MH at 1 year. Early IUS monitoring can be a helpful tool to predict response to therapy in CD patients at 1 year.

La Facultad de Derecho y Ciencias Polí cas de la Universidad de Cartagena presenta a laacademia el número 14 de la Revista Jurídica Mario Alario D’ Filippo, el cual es resultadodel trabajo cien co de los ius inves gadores que conforman la presente edición. Las líneas de derecho cons tucional, penal y criminología y loso a del derecho fueron lasseleccionadas por los pares evaluadores, quienes privilegiaron con su rigor la escogenciade los ar culos publicados.

Abstract Background Endoscopic healing (EH) is currently the consensual long-term treatment target to achieve in Crohn’s disease (CD). However, optimization of therapy based on an endoscopic response implies a delay as endoscopy is an invasive procedure and cannot be used longitudinally, stressing the need for non-invasive predictors of EH. We aimed to assess the predictive role of biomarkers and intestinal ultrasound (IUS) parameters after induction therapy to predict EH one year after infliximab (IFX) therapy. Methods Prospective multicentre cohort study including patients with active CD starting IFX. Harvey-Bradshaw index (HBI), C-reactive protein (CRP), faecal calprotectin (FC), and IUS were performed at week (W) 0, 14, 30, and 54. Ileocolonoscopy was performed at W0 and W54. Clinical remission (CR) was defined as HBI&lt;5 and laboratory remission (LR) as CRP &lt;0.5mg/dL and FC &lt;150ug/g. Transmural healing (TH) was defined as the normalization of bowel wall thickness (BWT≤3mm), doppler sign (≤1), wall stratification, and inflammatory fat in the most affected segment. The IBUS-SAS (International Bowel Ultrasound Segmental Activity Score) was used to assess disease activity and includes BWT, doppler sign, loss of stratification, and inflammatory fat. EH was defined as total SES-CD &lt;3. Results We included 52 patients with CD (54% male; mean age 35±14y). Baseline characteristics are available in Table 1. At W14, 89% were in CR, 46% had LR and 19% had TH. After 1 year of IFX therapy, 90% were in CR, 62% had LR, 43% had TH and 37% had EH. At W14, patients with EH had lower BWT (3.3 vs 4.6mm, p=0.01), lower IBUS-SAS (15 vs 61, p&lt;0.01), and lower FC (44 vs 239ug/g, p&lt;0.01). At W14, both TH (OR 11.3, 95%CI 2.1-61.4, p&lt;0.01) and FC remission (OR 7.4, 95%CI 1.8-30.7, p&lt;0.01) were significant predictors for EH. In a multivariate analysis including significant baseline characteristics and early non-invasive monitoring targets at W14 (table 2), TH was an independent predictor of EH (OR 8.6, 95%CI 1.2-61.7, p=0.03). Even after adjusting for the baseline ultrasonographic severity according to the IBUS-SAS, TH at W14 remained a significant predictor of EH (OR 6.5, 95%CI 1.02-40.9, p=0.047). Using a ROC curves analysis, the IBUS-SAS at W14 was the best predictor for EH, with an AUC of 0.81 and the best cut-off value of 32.2 (Table 3). Conclusion Early assessment of ultrasonographic remission at week 14 can help predict EH after one year of therapy and offers an opportunity for early therapy optimization. TH at week 14 assessed by IUS was an independent predictor for EH after one year of therapy. Our results support the use of early IUS monitoring to predict response to therapy in CD patients.

Abstract Background Therapeutic drug monitoring (TDM) in patients receiving infliximab (IFX) has a role in assessing treatment and managing outcomes. Infliximab trough levels (ITL) have been suggested as useful markers for treatment optimization in Crohn’s disease (CD).Our goals were: to assess the relationship between ITL and transmural inflammation as assessed by intestinal ultrasound(IUS), following induction therapy with IFX; to assess which clinical, laboratorial or IUS parameters better predicted adequate levels by the end of induction therapy. Methods Prospective multicentric cohort study including patients with active CD starting IFX therapy. Clinical disease activity assessed using the Harvey-Bradshaw index (HBI), C-reactive protein (CRP), fecal calprotectin (FC) were measured at week 0 and after induction therapy (week 14). IUS was performed at week 0 and 14, bowel wall thickness (BWT) from the worst segment was selected for analysis. Ileocolonoscopy was performed at W0 and SES-CD was registered. ITL were measured at W14. Results We included 36 patients with CD (61% male; median age 30 years (range 16–73)). According to Montreal classification, most patients were A2 (69%), had ileocolonic disease (L3 56%) and an inflammatory phenotype (B1 58%).Perianal disease was present in 42%. Combination therapy was used in 61%. After induction therapy, 81% were in clinical remission (HBI &lt;5) and 43% had laboratorial remission (normal CRP and FC). IUS response (decrease &gt;25% in BWT) was observed in 24% of patients and remission (BWT normalization) in 11%. Median ITL were 4.3 (IQR 2.3–8.1) and 64% had ITL &gt;3 ug/ml. There was a good negative correlation between ITL and SES-CD (r=-0.492, p=0.003). Adequate ITL were associated with lower HBI (1.5 vs 4.5, p=0.052), laboratory remission (61% vs 15%, p=0.014), lower BWT (4 vs 5.5 mm, p=0.009) and sonographic response (39% vs 0%, p=0.014) at W14. At the end of induction, we found a fair to good correlation between ITL and HBI (r=-0.430, p=0.009),CRP (r=-0,510, p=0.001), FC (r=-0.590, p=0.001) and BWT (R=-0.506, p=0.002). Receiver operating characteristic (ROC) curve analysis showed that FC at W14 had the largest area under the curve (AUC) in predicting adequate ITL (0.813 vs 0.716 vs 0.739 vs 0.772, p&lt;0.05). Conclusion Patients with higher disease burden measured by ileocolonoscopy at baseline had lower ITL after induction. Adequate ITL were associated with laboratorial remission and sonographic response at the end of induction, with a good correlation with clinical, laboratorial and sonographic parameters. These findings suggest that adequate IFX levels after induction are associated with a better control of inflammation in IBD, so early proactive TDM during induction may be helpful in treatment management.

Conditions in the body during aerobic exercise increase the level of lipid peroxidation (LP). LP is associated with elevated concentration of modified low-density lipoproteins that are implicated in development of cardiovascular disease. Supplementation with antioxidant vitamin E to athletes at 267 mg (400 IUs) or greater has been reported to reduce levels of LP associated with exercise. Little is currently known about the effects of modest supplementation of vitamin E on previously sedentary adults who initiate an aerobic fitness program. In the present study, sedentary subjects (n = 14) kept 24-hour diet records to establish antioxidant intake of vitamins E and C and collected 24-hour urine samples that were used to determine baseline urinary malondialdehyde (MDA) concentrations, one measure of in vivo LP. No significant differences were noted in the parameters between groups. Seven subjects were randomly selected and supplemented daily with 133 mg (200 IUs) of vitamin E. All subjects participated in moderate-intensity aerobic training for 8 weeks. Post-training, non-supplemented subjects excreted significantly more MDA (p&<0.05) and consumed significantly fewer antioxidants than the supplemented group. Vitamin E supplementation appears to suppress elevated LP associated with beginning an aerobic exercise regimen in previously sedentary subjects.

Abstract Background Current therapeutic goals in Crohn’s disease (CD) include not only the mere absence of symptoms but also the objective resolution of macroscopic lesions, so-called deep remission (DR), which has been related to better outcomes. DR is usually acknowledged by endoscopy, although magnetic resonance (MR) or intestinal ultrasound (IUS) are also reliable, provide extramucosal information and may be more appropriate in certain clinical scenarios. Data regarding the achievement of DR with ustekinumab in real-life clinical practice is still scarce. Methods Retrospective cohort study carried out in a tertiary hospital between April 2017 and April 2019 including patients who had clinically active CD (Harvey–Bradshaw index [HBI] ≥ 4) objectively assessed by either endoscopy, MR or IUS; received intravenous induction with ustekinumab, had achieved clinical remission and had treatment response assessed by either endoscopy, MR or IUS. DR was defined by SES-CD 0–3 or Rutgeerts index i0 if endoscopically assessed, or by complete normalisation of inflammatory parameters on cross-sectional imaging. Endoscopic response was defined by the decrease of SES-CD of 50% compared with baseline. Radiographic response was defined by improvement in bowel wall thickness, inflammatory fat, mural blood flow and hyperenhancement compared with baseline imaging by physician global assessment. Demographics, clinical data and information regarding ustekinumab treatment were collected. Results 90 patients treated with ustekinumab at our centre were analyzed, but only 28 met inclusion criteria (14(50%) female; median age 45 (43–50)) with a median follow-up of 19 (IQR: 15–23) months. All of them had previously failed to antiTNFα and 20 (71%) failed to ≥2 biologics. Treatment response assessment was made by endoscopy (22 cases; 79%) or cross-sectional imaging technique (6 cases; 21%) in a median time of 10 months (IQR: 7–13) from the start of treatment. Deep remission was achieved in 18 (64%) patients. Endoscopic response was achieved in 5 (18%) additional patients. Five (18%) remaining patients obtained no objective response to ustekinumab despite being in clinical remission. Patients who had received prior treatment with ≥2 biologics or those classified as B2 or B3 according to Montreal Classification were less likely to achieve deep remission, although those associations did not reach statistical significance. Conclusion In our experience, a majority of refractory CD patients who achieved clinical remission with ustekinumab also reached deep remission assessed by either endoscopy, MR or IUS.

En voulant encourager les Romains à posséder plusieurs descendants Auguste prevoya les nom breux privilèges pour ceux qui avaient des enfants; Les hommes possédant des descendants avaient une position privilégiée dans le droit public (Gell. 2.15.4—6; Tac. Ann.2 .51; D. 4.2.2);. les époux qui avaient au moins un enfant regagnaient la capacitas totale dans le droit des successions. Mais c’est seulement lorsqu’on avait trois enfants qu’on recevait des privilèges spéciaux dans le domaine du froit civil. Ius trium liberorum concernait aussi bien les femmes que les hommes (Ep. Ulp. 16.1 a). L’homme ne pouvait se référer qu’aux enfants nés en iustum matrimonium (Paul. Sent. 4.8.4), tandis que la femme, depuis les temps de Claudius, pouvait se référer aussi aux enfants vulgo quaesiti (D. 38.17.2.1 conf. avec I. 3.3.1). La femme qui possédait trois enfants était exempte de protection (G. 1.145); elle était exempte du devoir de se remarie; en dépit de lex Voconia elle était égalisée le droit des successions avec les hommes (G. 2.274; Paul. Sent. 4.8.20) et a obtenu, probablement depuis Claudius, selon I. 3.3.1 la possibilité d’hériter de ses enfants. La latine recevait en plus la nationalité romaine (Paul. Sent. 4.9.8; Ep. Ulp. 3.1). Les deux époux qui possédaient trois enfants, même décédés, récupéraient envers eux mêm es la pleine capacitas dans le droit des successions; en outre la situation d’affranchi s’améliora (G. 3.42). L’homme pouvait s’abstenir de muneribus civilibus (D. 50.5.2.1; I. 1.25 pr.). La législation d’Auguste accorda ce privilège aux personnes qui pouvait se féféreir à ses descendants naturals, mais on prenait également en considération les enfants adoptés (Gell. 2.15.4; Tac. Ann. 15.19). Dans le cours du temps on commença à accorder ce privilège aux personnes particulières, mais Claudius l’accorda pour la première fois aux groupes entiers — aux soldat, en 44 de n. è. (Dio Cass. 60.24.3), en 51 aux femmes construisant des vaisseaux (Svet. Claud. 18.2— 19 conf. avec G. 1.32 c et Tac. Ann. 12.43.1); Prévu par lex Iulia et Papia vacatio (Ep. Ulp. 14) Claudius étendit sur les hommes qui s’occupaient de la construction des vaisseaux (Svet. Claud. 19). Ius trium liberorum fut formellement supprim é seulement en 410 (C. Th. 8.17.2 = C. I. 8.57.2).

Objective: Cystic echinococcosis (CE) is a parasitic zoonosis caused by Echinococcus granulosus sensu lato. Immunodiagnostic techniques such as Western blot (WB) or enzyme-linked immunosorbent assay (ELISA), with different antigens, can be applied to the diagnosis of sheep for epidemiological surveillance purposes in control programs. However, its use is limited by the existence of antigenic cross-reactivity between different species of taeniidae present in sheep. Therefore, the usefulness of establishing surveillance systems based on the identification of infection present in a livestock establishment, known as the (Epidemiological) Implementation Unit (IU), needs to be evaluated. Materials and Methods: A new ELISA diagnostic technique has been recently developed and validated using the recombinant EgAgB8/2 antigen for the detection of antibodies against E. granulosus. To determine detection of infection at the IU level using information from this diagnostic technique, simulations were carried out to evaluate the sample size required to classify IUs as likely infected, using outputs from a recently developed Bayesian latent class analysis model. Results: Relatively small samples sizes (between 14-29) are sufficient to achieve a high probability of detection (above 80%), across a range of prevalence, with the recently recommended Optical Density cut-off value for this novel ELISA (0.496), which optimizes diagnostic sensitivity and specificity. Conclusions: This diagnostic technique could be potentially used to identify the prevalence of infection in an area under control, measured as the percentage of IUs with the presence of infected sheep (infection present), or to individually identify the IU with ongoing transmission, given the presence of infected lambs, on which control measures should be intensified.

Abstract BACKGROUND Although surgery for endometriosis can improve pain and fertility, the risk of disease recurrence is high. There is little consensus regarding the benefit of medical therapy in preventing recurrence of endometriosis following surgery. OBJECTIVE AND RATIONALE We performed a review of prospective observational studies and randomised controlled trials (RCTs) to evaluate the risk of endometriosis recurrence in patients undergoing post-operative hormonal suppression, compared to placebo/expectant management. SEARCH METHODS The following databases were searched from inception to March 2020 for RCTs and prospective observational cohort studies: MEDLINE, Embase, Cochrane CENTRAL and Web of Science. We included English language full-text articles of pre-menopausal women undergoing conservative surgery (conserving at least one ovary) and initiating hormonal suppression within 6 weeks post-operatively with either combined hormonal contraceptives (CHC), progestins, androgens, levonorgesterel-releasing intra-uterine system (LNG-IUS) or GnRH agonist or antagonist. We excluded from the final analysis studies with &lt;12 months of follow-up, interventions of diagnostic laparoscopy, experimental/non-hormonal treatments or combined hormonal therapy. Risk of bias was assessed using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale (NOS) for observational studies. OUTCOMES We included 17 studies (13 RCTs and 4 cohort studies), with 2137 patients (1189 receiving post-operative suppression and 948 controls), which evaluated various agents: CHC (6 studies, n = 869), progestin (3 studies, n = 183), LNG-IUS (2 studies, n = 94) and GnRH agonist (9 studies, n = 1237). The primary outcome was post-operative endometriosis recurrence, determined by imaging or recurrence of symptoms, at least 12 months post-operatively. The secondary outcome was change in endometriosis-related pain. Mean follow up of included studies ranged from 12 to 36 months, and outcomes were assessed at a median of 18 months. There was a significantly decreased risk of endometriosis recurrence in patients receiving post-operative hormonal suppression compared to expectant management/placebo (relative risk (RR) 0.41, 95% CI: 0.26 to 0.65), 14 studies, 1766 patients, I2 = 68%, random effects model). Subgroup analysis on patients treated with CHC and LNG-IUS as well as sensitivity analyses limited to RCTs and high-quality studies showed a consistent decreased risk of endometriosis recurrence. Additionally, the patients receiving post-operative hormonal suppression had significantly lower pain scores compared to controls (SMD −0.49, 95% CI: −0.91 to −0.07, 7 studies, 652 patients, I2 = 68%). WIDER IMPLICATIONS Hormonal suppression should be considered for patients not seeking pregnancy immediately after endometriosis surgery in order to reduce disease recurrence and pain. Various hormonal agents have been shown to be effective, and the exact treatment choice should be individualised according to each woman’s needs.

Penelitian ini bertujuan untuk mengetahui dan memahami batasan perlindungan hukum bagi anak yang dapat dipertanggungjawabkan sebagai pelaku kejahatan dan mengetahui dan memahami faktor-faktor yang mempengaruhi pertimbangan perlindungan hukum bagi anak yang dapat dipertanggungjawabkan sebagai pelaku kejahatan. Penelitian ini menggunakan pendekatan yuridis normatif. Adapun metode analisis dilakukan dengan cara mengidentifikasi secara sistematis, dipolarisasi, dikategorisasi dan dikelompokkan sesuai dengan alur pembahasan dalam penelitian ini. Berdasarkan uraian hasil dan pembahasan, maka dapat disimpulkan bahwa batasan perlindungan hukum bagi anak yang dapat dipertanggungjawabkan sebagai pelaku kejahatan yakni umur 12 tahun ke bawah, anak yang berumur 12 tahun ke atas atau berusia belum berusia 14 tahun dikenakan sanksi pidana berupa tindakan (tindakan dalam artian yuridis). Sanksi pidana penjara adalah alternatif terakhir bagi anak pelaku kejahatan, berbeda dengan orang dewasa. Adapun faktor-faktor yang mempengaruhi perlindungan hukum bagi anak yang dapat dipertanggungjawabkan sebagai pelaku kejahatan, yaitu aspek sosiologis serta kriminilogis. Aspek kriminologis terdiri dari tiga sub yang penting, yaitu ekonomi, lingkungan, dan keluarga. Selain itu, adapun terkait konsep diversi yang dipertajam dengan konsep restoratif justice belum saatnya menjadi ius constitutum di Indonesia, oleh karena kejahatan yang ada di Indonesia merupakan kejahatan yang masif dan sistematis.

The current wave and future trend of the novel coronavirus disease 2019 (COVID-19) has triggered public uncertainty, causing unbearable psychological pressure on people. A cross-sectional online questionnaire was conducted among back-to-school students in Wuhan from 31 August 2020, to 14 September 2020, by using convenience sampling. A total of 1017 participants voluntarily provided sociodemographic characteristics and accomplished the following scales: the Intolerance of Uncertainty Scale (IUS-12), the Social Support Scale (SSQ), the Generalized Anxiety Disorder Scale (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), and the Insomnia Severity Index-7 (ISI-7). Results revealed that the levels of anxiety, depression, and insomnia were moderate, moderate and subthreshold, respectively. A one-way multivariate analysis of variance indicated that those with different attitudes toward the trajectory of the COVID-19 epidemic in China showed significantly different results in anxiety and depression (p < 0.001). Moderation modeling implicated that social support significantly moderated the predictive relationship between intolerance of uncertainty and mental health variables including anxiety and depression, but failed on insomnia. Findings indicate that back-to-school students in Wuhan experience mental health problems and improving social support measures could buffer the effect of intolerance of uncertainty with respect to COVID-19 on mental health.

As the gateway to the criminal justice system, law enforcement that carried out by polri always influenced by social change factors. In accordance with the development of law today, polri required to be able to resolve criminal acts by prioritizing restorative justice approach. However it hasn’t been regulated in statutory. The research purposes to describe and analyze the settlement of criminal acts with restorative justice approach in investigation level at the present and the future. The research used normative legal research, using a statute approach, historical approach and comparative approach, using primary and secondary legal materials that collected by a systematic method and then analyzed by descriptive and interpretation techniques. The research show that polri has carried out several policies to answer the community expectations and demands in accordance with the development of law today by issuing several letters and regulations, namely Surat Kapolri No. Pol. B/3022/XII/2009/Sde Ops, ST Kabareskrim No. ST/110/V/2011, STR Kabareskrim No. STR/583/VIII/2012, Perkap 15/2013, Perkap 3/2015, SE Kapolri No. SE/7/VII/2018 and SE Kapolri No. SE/8/VII/2018. In perspective of “ius constituendum,” it is needed criminal law policy to regulate the settlement of criminal acts with restorative justice approach in investigation level, by carrying out a renewal of material criminal law, including the understanding of criminal acts, objectives and guidelins for criminal actions and also renewal of formal criminal law including updating KUHAP, Perkap 14/2012 and Perkap 3/2015. Sebagai pintu gerbang sistem peradilan pidana, penegakan hukum yang dilakukan polri selalu dipengaruhi oleh faktor perubahan sosial. Dalam perkembangan hukum dewasa ini, polri dituntut mampu menyelesaikan tindak pidana dengan mengedepankan pendekatan restorative justice. Akan tetapi hal itu belum diatur dalam peraturan perundang-undangan. Penelitian ini bertujuan untuk mendeskripsikan dan menganalisis pendekatan restorative justice dalam penyelesaian tindak pidana di tingkat penyidikan pada saat ini dan pada masa yang akan datang. Metode penelitian yang digunakan adalah jenis penelitian hukum normatif, menggunakan pendekatan perundang-undangan, pendekatan kasus, pendekatan historis, pendekatan perbandingan dan pendekatan konsep, dengan menggunakan bahan-bahan hukum primer dan bahan-bahan hukum sekunder yang dikumpulkan dengan metode sistematis yang selanjutnya dianalisis dengan teknik deskriptif dan interpretasi. Hasil penelitian menunjukkan bahwa polri telah melakukan beberapa kebijakan untuk menjawab harapan dan tuntutan masyarakat sesuai dengan perkembangan hukum dewasa ini dengan menerbitkan beberapa surat dan peraturan, yaitu Surat Kapolri No. Pol. B/3022/XII/2009/Sde Ops, ST Kabareskrim No. ST/110/V/2011, STR Kabareskrim No. STR/583/VIII/2012, Perkap 15/2013, Perkap 3/2015, SE Kapolri No. SE/7/VII/2018 dan SE Kapolri No. SE/8/VII/2018. Dalam perspektif ius constituendum diperlukan kebijakan hukum pidana untuk mengatur penerapan konsep restorative justice dalam penyelesaian tindak pidana di tingkat penyidikan, dengan melakukan pembaharuan hukum pidana materiil, mencakup pengertian tindak pidana, tujuan dan pedoman pemidanaan, serta melakukan pembaharuan hukum pidana formil, mencakup pembaharuan KUHAP, Perkap 14/2012 dan Perkap 3/2015.

Abstract Background Faecal calprotectin (FCal) is considered an intermediate target for monitoring disease activity in IBD. However, it is unknown whether early FCal variations during induction therapy may be a significant predictor of treatment response. We aimed to investigate FCal variation after infliximab induction therapy and its association with clinical, endoscopic, and ultrasonographic remission by the end of one year of treatment. Methods Prospective multicentric cohort study including patients with active CD without previous intestinal surgeries, who were starting IFX therapy and were followed for, 54 weeks. FCal was measured at week, 0 and after induction therapy (week, 14) and relative FCal changes from baseline (%FCal0-14) were calculated. At week, 54, clinical remission (defined as Harvey-Bradshaw index (HBI) &lt;5), endoscopic healing (defined as SES-CD score &lt;3) and transmural healing (defined as bowel wall thickness (BWT) assessed by intestinal ultrasound (IUS) ≤3mm) were evaluated. Results We included, 33 patients (60.6% male; median age, 30 years old (IQR, 24–42)). Most patients were diagnosed between, 17–40 years old (75.8%) had ileocolonic disease (57.6%) and an inflammatory phenotype (57.6%). At week, 54, 90.9% of the patients were in clinical remission, 30.3% had endoscopic healing and, 39.4% had transmural healing. The median FCal value at week, 0 was, 765µg/g (IQR, 312–1313) and at week, 14 was, 124.5µg/g (IQR, 46–432.5). At week, 14, 20 patients (60.6%) had FCal&lt;250µg/g. There was no correlation between FCal at week, 0 and the baseline total SES-CD (r=0.28, p=0.13) and BWT of the most affected segment (r=0.02, p=0.90). Patients who achieved clinical remission had a low variation in %FCal0-14 (87.4% vs, 80.1%, p=0.42), as opposed to patients who achieved endoscopic healing (58.5 vs, 91.3%, p&lt;0.001) and transmural healing (68.6% vs, 84.4%, p=0.16) who had more significant changes in %FCal0-14, although only statistically significant for endoscopic healing. When stratifying %FCal0-14 changes in, 25% quartiles, FCal variation at the end of induction was only able to predict endoscopic healing (OR, 8.13 (95%CI, 1.01–65.46), p=0.049), being non-significant for clinical remission (OR, 0.51 (95%CI, 0.09–2.92), p=0.45) and transmural healing (OR, 1.61 (95%CI, 0.73–3.57), p=0.24). A normalization of FCal below, 250 µg/g was also a predictor of endoscopic healing (OR, 9.82 (95%CI, 1.06–90.59), p=0.04). The AUC for the prediction of endoscopic healing with %FCal0-14 changes was, 0.85 (Figure, 1) and a cut-off of variation of, 80.3% was calculated. Conclusion FCal variation at the end of induction seems to be a good predictor of endoscopic healing at week, 54 but does not seem to be able to predict clinical and ultrasonographic remission.

Abstract Abstract 1121 Factor IX (FIX) replacement therapy is the standard of care for patients with haemophilia B. FIX products currently available have a relatively short half-life, requiring 2–3 times a week intravenous prophylactic treatment to achieve a significant bleeding reduction. A recombinant FIX albumin fusion protein (rIX-FP) was generated by genetic fusion of human recombinant albumin to rFIX to extend the half life of FIX. A Phase I/II open-label, multicenter, clinical study of rIX-FP has been completed in previously treated patients with severe hemophilia B (FIX ≤ 2%) as part of the PROLONG - 9FP clinical developmental program. The objectives of the study were to evaluate the prevention of bleeding episodes during once weekly prophylaxis and to assess the hemostatic efficacy of rIX-FP for the treatment of bleeding, in addition to safety and pharmacokinetic (PK) assessments. The study consisted of a 10 to 14 day PK evaluation period, and a 3 to 12 month safety and efficacy evaluation period, during which subjects received either on-demand or prophylaxis treatment. Subjects receiving weekly prophylactic treatment were initially treated with a dose based upon the subject's PK profile, bleeding phenotype, and physical activity level. The dose could be adjusted based on clinical outcome, while maintaining a 7 day treatment interval. Subjects receiving on-demand treatment were treated with a dose based upon the subject's PK profile and WFH recommendations for treatment of bleeding episodes. Seventeen study subjects from hemophilia treatment centers in Israel and Bulgaria participated in the study, 13 of whom received weekly prophylaxis treatment and 4 of whom received on-demand treatment. Following a single infusion of 25 IU/kg rIX-FP (n=13), the PK parameters (t1/2 = 94 hrs, AUC0-inf= 3414 hr*IU/dL) were comparable to those previously reported from the Phase I study (Blood prepublished Aug 2, 2012). In addition, rIX-FP maintained a baseline-corrected mean trough level of 3.8% and 2.7% at Day 7 and Day 14, respectively, after 25 IU/kg rIX-FP administration. There were no AEs considered as possibly related to rIX-FP. There were no allergic reactions, inhibitors to FIX or antibodies to rIX-FP reported. All 10 prophylaxis subjects who were previously receiving routine prophylaxis with FIX were maintained successfully on weekly treatment with rIX-FP for the entire study. Furthermore, three prophylaxis subjects who were previously treated on-demand were maintained successfully on weekly prophylaxis treatment with rIX-FP with at least 85% reduction in the annualized spontaneous and total bleeding rate compared to the annualized bleeding rate prior to study entry. All of the bleeding events were treated successfully, including approximately 90% of the events with a single infusion of rIX-FP. The mean weekly product consumption of rIX-FP (IUs) was reduced compared to the consumption of the previous FIX product (IUs). No subject was withdrawn from the study due to safety concerns or lack of hemostatic efficacy. This Phase I/II study has demonstrated the clinical efficacy of rIX-FP for once weekly routine prophylaxis to prevent spontaneous bleeding episodes and treatment of bleeding episodes, in addition to the excellent safety characteristics and improved PK profile. A detailed analysis of the efficacy of weekly routine prophylaxis and treatment of bleeding episodes, improved PK and safety properties of rIX-FP will be presented. Disclosures: Martinowitz: CSL Behring: Honoraria, Investigator for CSL clinical study of rIX-FP Other. Lubetsky:CSL Behring: Investigator for CSL clinical trial of rIX-FP Other. Santagostino:CSL Behring: Honoraria, Investigator for CSL Behring clinical trial of rIX-FP Other, Research Funding, Speakers Bureau. Jotov:CSL Behring: sub-investigator for CSL clinical trial of rIX-FP Other. Barazani-Brutman:CSL Behring: study coordinator for CSL Behring clinical trial of rIX-FP Other. Voigt:CSL Behring: Employment. Moises:CSL Behring: Employment. Jacobs:CSL Behring: Employment. Lissitchkov:CSL Behring: Investigator for CSL Behgring clinical trial of rIX-FP Other.

14542 Background: A multi-center phase II trial has been designed to evaluate toxicity, anti-tumour and immune-biological activity of the bio-chemotherapy GOLFIG regimen in advanced colorectal cancer (A-CRC). Methods: The trial involved 46 patients (34/46 2nd line or more). The biweekly GOLFIG regimen consisted of gemcitabine (1,000 mg/m2, day 1), oxaliplatin (85 mg/m2, day 2), levofolinic acid (100 mg /m2, day 1,2) and 5-FU (400 mg/m2 as a bolus, and 800 mg/m2 as 24 hour infusion, days 1,2) followed by sc GM-CSF (100 μg, days 3 to 8) and sc IL-2 (0.5 X 106 IUs twice a day, days 9 to 14). Results: GOLFIG regimen was well tolerated and resulted very active (ORR = 56.5%; disease control = 91.3%), fulfilling the pre-selected (40–60%) target of activity, with a promising TTP [12.26 months, 95% CI; 9.2–15.2 mo.] and OS [18.76 months, 95% CI; 15.2–22.3 mo.]. We detected a significant rise in lymphocyte number and colon cancer-specific cytotoxic T cells (CTLs) paralleled by a reduction in suppressive T-regulatory CD4+CD25+ FoxP3+ lymphocytes -Treg. Self-limiting autoimmunity (AI) occurred in 6 (14%) patients. 1 patient developed cutaneous lesions, with pathological diagnosis of Discoid Lupus Erythematosus (DLE), while 5 other presented a mono / oligoarticular arthritis mainly localized at the knees, elbows, shoulders and fingers with signs of synovitis (pain and swelling) paralleled by a significant increase of inflammatory markers (ESR, C-RP and rheumatoid factor). Subgroup analysis disclosed a mean time to progression of 23.8 months (95% CI; 12.1–35.56 mo.) and an overall survival of 31.83 months (95% CI; 19.9–43.7 mo.) in the 6 AI patients, significantly longer than in patients who did not develop AI [TTP and OS respectively 10.52 (95% CI; 7.7–13.3) and 16.8 months (95% CI; 13.3–20.2)], P ≤ 0.0039 and 0.0080. 5/6 AI patients are still alive and 3 have so far achieved a survival of 37, 41 and 50 months. Conclusions: The GOLFIG regimen exerts immunological and anti-tumour activity and has manageable toxicity in A-CRC. The occurrence of AI is predictive of a favourable outcome. These results provided the rationale for a presently ongoing phase III trial aimed to compare the efficacy of GOLFIG vs. FOLFOX-4 regimen as first line treatment in A- CRC patients. No significant financial relationships to disclose.

3587 We have recently described a poly-chemotherapy (GOLF) regimen that: A) is active in colon carcinoma patients as second line of therapy; B) induces high levels of necrosis and apoptosis in colon cancer cells; C) up-regulates the expression and release of heat shock proteins (HSP)-70 and -90 and tumour-associated antigens (2,3); and D) down-regulates tumour cell resistance to the death signals of cytotoxic-T-lymphocytes.These effects represented the rationale for projecting GOLFIG regimen. Here we describe the results of a multi-center translational phase II trial designed to evaluate the toxicity, anti-tumour activity of a novel regimen designated as GOLFIG-1, composed by the GOLF poly-chemotherapy followed by the subcutaneous (sc.) administration of GM-CSF and low-dose IL-2 in colorectal carcinoma patients. The study involved 37 patients (21M and 16F, mean age 62.5 years), 24 of whom had received a previous line of treatment, and 24 had liver involvement. All the patients received biweekly chemotherapy with gemcitabine (1g/m2, day 1 and 15), oxaliplatin (85 mg/m2, day 2 and 16), levo-folinic acid (100 mg /m2, day 1, 2, 15, 16) and 5-Fluorouracil (400 mg/m2 as a bolus, and 800 mg/m2 as 24 hour infusion, days 1, 2, 15, 16). These patients also received sc GM-CSF (100 μg, day 3 to 8) followed by sc IL-2 (0.5 X 106 IUs twice a day from day 9 to 14 and from 17 to 29). The treatment was well tolerated and very active in colon carcinoma patients, with high objective response (64.9%) and disease control rates (97.3%), with an average time to progression of 12.94 months (CI 95%: 9.98–15.91). An immunological study confirmed the immunological response to colon carcinoma antigen, a significant reduction in suppressive regulatory T lymphocytes (CD4+CD25+T-reg) and a significant reduction of VEGF levels reported in a previous study. In conclusion, these results suggest that the GOLFIG regimen exerts strong immunological and anti-tumour activity in colorectal cancer patients. A randomized phase III trials aimed to compare the efficacy of GOLFIG-1 with FOLFOX-4 regimen in patients with advanced colorectal carcinoma is presently ongoing. No significant financial relationships to disclose.

Abstract Background Traditionally Crohn’s disease strictures have been treated by a single endoscopic balloon dilation (EBD), repeated only for obstructive symptom recurrence. We postulated that scheduled repeated EBD may result in greater dilation effect than a single EBD; and that needle-knife stricturotomy (NKSt) may be a valuable salvage intervention in patients with strictures. Methods In this prospective observational study, patients with endoscopically accessible and short (&lt;5cm), symptomatic Crohn’s disease stricture were assessed clinically (using an Obstructive Symptom Score [OSS]) and by imaging (colonoscopy, MRI and IUS). All patients had drug treatment optimized to decrease inflammation. Patients were treated with 3 serial balloon dilatations each 3 weeks apart, single EBD, or needle-knife stricture incision. The primary endpoint was improved OSS at 6m. Secondary outcomes; ability to endoscopically pass the stricture, treatment failure / surgery, stricture morphology on imaging, and safety. Results Twenty-one consecutive patients were included in the analysis. Of these 17 (81%) were receiving treatment with a biologic therapy. Median stricture length at baseline was 20mm (IQR 20mm) and median estimated stricture diameter was 8mm (IQR 3mm). 18 (86%) had visible ulceration. Of the 21 patients 11 (52%) underwent more than one EBD, 5 (24%) had ≥1 NKSt and 5 (21%) underwent a single EBD. Four of the 21 patients (19%) strictures were passable before endoscopic treatment. All procedures were technically successful. 14/21 (67%) had improvement in OSS at 6m, including 8/11 (73%) with 3 serial EBD, 4/5 (80%) with NKSt and 2/5 (40%) patients undergoing a single EBD. Two patients required surgery. At 6m, 3/8 (38%) who had repeat dilations, 4/5 (80%) who had NKSt, and 2/5 (40%) having a single EBD had a passable stricture. All 4 patients with highly elevated stricture inflammation (stricture magnetic resonance index of activity [MaRIA] score ≥20) at the 6m MRI had a non-passable stricture at study endpoint, whilst 9/12 (75%) were passable when stricture MARIA was &lt;20 (P=0.019). No major complications occurred. Conclusion Endoscopic stricture treatment was safe and technically successful in all patients with accessible Crohn’s disease strictures and was associated with symptom improvement in most. Progression to surgery in this symptomatic and advanced disease was low at 6m. The highest rates of symptom improvement were seen in patients who had NKSt. Lesser stricture inflammation on MRI was associated with a better outcome, suggesting that controlling inflammation is important in preventing stricture recurrence after dilation. NKSt should be considered when balloon dilation is not possible or has failed, as a salvage treatment alternative to surgery.

Abstract Background Acute leukemia patients are at risk for cytomegalovirus (CMV) retinitis following hematopoietic stem cell transplantation, though the disease can also occur in non-transplant adult leukemia patients. Emerging data suggest a shift to pediatric-inspired chemotherapy regimens in adults with acute lymphoblastic leukemia (ALL) can lead to increasing cytopenias and impaired functional immunity, placing these patients at risk for this opportunistic infection. Here we describe a case of CMV retinitis in an ALL patient following a lower-intensity regimen during maintenance chemotherapy. Methods Chart review. Results A 55-year-old male with ALL presented to his optometrist with complaints of visual changes including “fogginess” and “floaters”. The patient had completed 8 cycles of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) and achieved complete remission. He had been on maintenance chemotherapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP) for 2 months at the time of symptom onset. He was referred to his local ophthalmologist who had concerns for bilateral, zone 1 CMV retinitis based on fundoscopic exam (Figure 1). Vitreous aspiration was performed and CMV DNA PCR returned positive at 1.6 million IUs/ml. Peripheral blood CMV DNA PCR was also positive at 1133 IU/ml. He was started on combination therapy with intravitreal ganciclovir injections and oral valganciclovir 900 mg twice daily (Figure 2). The patient received 14 intravitreal injections with resultant stability of his eye exam, though he remained on induction valganciclovir for 5 months due to persistent blood CMV DNAemia. Letermovir was added to help suppress his peripheral CMV DNAemia and he attained partial vision recovery. Figure 1. Fundoscopic images Conclusion CMV retinitis is an uncommon and highly morbid infection that can occur during maintenance chemotherapy in adult non-transplant ALL patients. Early identification of the disease is imperative as delay can result in blindness or further systemic CMV disease. Treatment is challenging, involving systemic and intravitreal antiviral therapy, serial ophthalmologic exams, serum CMV monitoring, and close coordination with the treating hematologist. Disclosures Michael Boeckh, MD PhD, AlloVir (Consultant)Ansun Biopharma (Grant/Research Support)Astellas (Grant/Research Support)EvrysBio (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Gilead Sciences (Consultant, Grant/Research Support)GlaxoSmithKline (Consultant)Helocyte (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Janssen (Grant/Research Support)Kyorin (Consultant)Merck (Consultant, Grant/Research Support)Moderna (Consultant)Symbio (Consultant)Takeda (formerly known as Shire) (Consultant, Grant/Research Support)VirBio (Consultant, Grant/Research Support) Ryan Cassaday, MD, Amgen (Grant/Research Support, Advisor or Review Panel member)Kite/Gilead (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)Pfizer (Grant/Research Support, Advisor or Review Panel member)Seagen (Other Financial or Material Support, Spouse is employee and hold stock)Vanda Pharmaceuticals (Grant/Research Support)

8029 Background: LYG is a rare angiocentric-destructive process with EBV+ B-cells and reactive T-cells. LYG is graded with grades I-II showing rare-moderate large EBV+ B-cells (usually polyclonal or oligoclonal) and grade III showing numerous large EBV+ B-cells (usually monoclonal), likely reflecting progressive transformation. Historically, steroids and/or chemotherapy have a 14 mos median survival. Methods: We are investigating Interferon-a (I-a) for grade I/II and dose-adjusted EPOCH ±Rituximab (R) for grade III LYG. Results: Characteristics of 53 pts are: male sex 68%; median age (range) 46 (17–67) and median ECOG P.S. 1 (0–3). Disease sites include lung 98%, CNS 38%, kidney 15%, skin 17%, liver 19% and nodes 4%. On study LYG grades are I-30%, II-26% and III-44%. Prior treatment was none-28%, chemotherapy± R-34%, and steroids alone-40% of pts. For grades I/II, I-a is begun at 7.5 million IUs TIW and escalated as tolerated until disease regression and continued 1 yr after CR. Of 31 patients treated with I-a, PFS is 62% at the median f/u of 5.3 yrs. Of 25 evaluable pts (3 NE; 3 TE), 60% had sustained CR for a median of 60 mos (4–175). In 9 pts who progressed on I-a, grade III was found in 5. Thus, in 20 pts with only grade I/II, 75% had sustained CR with I-a. In 11 evaluable pts with CNS disease, 81% achieved remission with I-a alone. The median time to remission is 9 mos (3–40) and median I-a dose is 20 MIU (7–40). Among 24 pts receiving DA-EPOCH±R, PFS is 40% at the median f/u of 28 mos. Of 21 evaluable pts (2 NE, 1 TE), 66% achieved CR. OS of all 53 pts is 68% at the median f/u of 4 yrs. Median EBV viral loads in 29 pts at study entry were 18 copies/10e6 genome equivalents (0–22727) (normal<200). Lymphocyte subsets in 30 pts showed a median CD4–428 (24–2322) and CD8–165 cells/mm3 (42–1316). In 12 pts in CR and with serial values, the mean CD8 cells (131 ± 44) (p2= 0.013) but not CD4 cells (65 ± 75) increased with treatment. Conclusions: High dose I-a produces sustained remissions in grade I/II LYG and is effective in CNS LYG. DA-EPOCH±R can produce durable CRs in grade III LYG. We hypothesize LYG emerges in a compromised immune milieu and undergoes progressive transformation if not effectively treated. Historical results suggest steroids may allow transformation by compromising immune function. No significant financial relationships to disclose.

AbstractEs geht hier nicht um eine Bibliographie, sondern um eine grobe Angabe der Hauptgebiete der Forschung, mit einigen Anregungen für die Arbeit in der nächsten Zukunft. In Belgien hat man sich wesentlich weniger mit dem mittelalterlichen römischen Recht beschäftigt als in den Niederlanden: das ist zu erklären durch die Bedeutung von Meijers und Feenstra, durch die Bevorzugung des kanonischen Rechts in Belgien und durch den Umstand, daß die südlichen Niederlande im Mittelalter höher entwickelt waren als die nördlichen, weshalb das einheimische Recht in Belgien den Forschern verhältnismäßig mehr zu bieten hat. In den meisten Hand- und Einführungsbüchern wird das mittelalterliche römische Recht übrigens gebührend berücksichtigt. Vor einigen Jahren hat Schrage zwei gerade für den beginnenden Forscher wichtige Bücher herausgegeben. Die Bedeutung von Meijers und Feenstra wird kurz skizziert, wobei auch auf die Rolle des Handschriftensammlers D'Ablaing verwiesen wird. In der Rezeptionsgeschichte sind die Rechtshistoriker richtig zu Hause. Da sind die Beiträge von Van Caenegem und Hermesdorf im Ius romanum medii aevi; da sind Studien über Bücherverzeichnisse, über den Einfluß ausländischer Gelehrte, über bestimmte einheimische Juristen, über das römische Recht in friesischen Rechtsquellen. Die Geschichte der Rechtsprechung und die Vergleichung des urkundlich überlieferten Materials mit der Literatur des gelehrten Rechts könnten einen großen Ertrag geben. Die Universitätsgeschichte hat vor allem Löwen und Orleans beobachtet. In der Buch-geschichte hat insbesondere F. Soetermeer beachtenswerte Leistungen erbracht. Feenstra hat verschiedene Überblicke über die Forschung in bezug auf Orleans veröffentlicht. Hier wird vor allem gewiesen auf das Terzett der Dissertationen von Waelkens, Bezemer und Van Soest-Zuurdeeg, die drei Einstiege veranschaulichen: den dogmenhistorischen, den literarhistorischen und den editorischen. Was getan wird: M. Duynstee beschäftigt sich mit dem bisher etwas vernachlässigten 14. Jhdt.; was gemacht werden könnte: eine Edition der ersten vier Bücher der Lectura Digesti veteris von Jacques de Revigny, aber wohl mit den entsprechenden additiones von ihm in Vetus-handschriften. Zu den Untersuchungen über die Quellen wird die Hoffnung ausgesprochen, daß es einmal möglich sein wird, eine zweite, erweiterte und korrigierte Ausgabe des Verzeichnisses von Dolezalek zu machen. Was in näher Zukunft gemacht werden könnte: auch kodikologisch genaue Beschreibungen der sich in Belgien und den Niederlanden befindenden Corpus-iuris-Handschriften. Gewarnt wird vor dem alleinigen Gebrauch von Mikrofilmen, Texte sollten nicht nur zweidimensional studiert werden. Was die Dogmengeschichte betrifft, besteht die Gefahr einer zu isolierten Betrachtung des gelehrten Rechts. Man sollte vielleicht eher versuchen Themen zu wählen, für die man auch über andere Quellen verfügen kann als die Rechtsliteratur. Der Gefahr des unrepräsentativen Quellenauswahls kann man entgegentreten mit Bescheidenheit. Zum Schluß wird noch mal die Bedeutung des mittelalterlichen römischen Rechts für die europäische Kulturgeschichte betont, und wird darauf hingewiesen, daß daraus auch für den akademischen Unterricht Konsequenzen zu ziehen sind.

Tujuan dari adanya penelitian ini yaitu : pertama untuk mengetahui ruang lingkup pengaturan Peraturan terkait dengan wilayah pesisir di Provinsi Bali. Kedua untuk mengetahui bagaimanakah pengaturan yang ideal dimasa yang akan datang terkait dengan Rencana Zonasi Wilayah Pesisir dan Pulau-Pulau Kecil di Provinsi Bali agar dapat menjamin suatu kepastian hukum bagi masyarakat. Metode yang digunakan adalah penelitian hukum yang bersifat yuridis normatif yaitu metode yang mengacu kepada peraturan perundang-undangan dengan studi kepustakaan yang mempergunakan data sekunder, berupa bahan hukum primer dan bahan hukum sekunder. Hasil studi dalam penelitian ini menunjukkan bahwa Ranperda Rencana Zonasi Wilayah Pesisir dan Pulau-Pulau Kecil tahun 2020-2040 memiliki 14 (empat belas) ruang lingkup yang diatur didalamnya. Dan diperlukannya pengesahan terhadap Rancangan Peraturan Daerah terkait dengan Zonasi Wilayah Pesisir dan Pulau-Pulau kecil ini agar dapat memberikan kepastian hukum bagi masyarakat yang melakukan pemanfaatan pada wilayah pesisir yang memberikan dampak negatif bagi ekosistem di wilayah pesisir dan pulau-pulau kecil. The purpose of this research are: first to find out the scope of regulation related to coastal areas in Bali Province. Second, to find out how the ideal arrangement in the future is related to the Zoning Plan for Coastal Zone and Small Islands in Bali Province in order to guarantee legal certainty for the community. The method used is a legal research that is juridical normative, namely a method that refers to legislation with a literature study that uses secondary data, in the form of primary legal materials and secondary legal materials. The results of the study in this study indicate that the Ranperda for the Zoning Plan for Coastal Areas and Small Islands for 2020-2040 has 14 (fourteen) scopes set out in it. And it is necessary to ratify the Draft Regional Regulation related to the Zoning of Coastal Areas and Small Islands in order to provide legal certainty for people who make use of coastal areas that have a negative impact on ecosystems in coastal areas and small islands.

Introduction. Festival forms of socio-cultural behavior, as an algorithm for displaying agitation, educational, and entertainment functions during mass events, have recently become the object of study. The need for scientific generalization creates an environment of mutual understanding to strengthen intercultural dialogue, have highlighted the attention to historical experience of such cross-cultural events, for analysis of strategies and mechanisms of translation of information and forms of behavior to create understanding in society and among the participants, promoting a positive image of the country. The subject of the study was the methods of youth mobilization used by the Komsomol in the Mordovian ASSR, during the VI (Moscow, July 28 – August 11, 1957; 3,400 participants; 131 countries; the motto “For peace and friendship”) and VII (Austria, Vienna; 18,000 participants; 112 countries; motto “For peace, friendship and peaceful coexistence”) of the World youth and student festivals (WFMS). Materials and Methods. Materials from the archives of the Republic of Mordovia, statistical data, as well as scientific literature were used to solve the research tasks. The research was conducted on the principle of historicism, objectivity and consistency. The statistical method was used for data processing. Results. Based on the study of archival sources and available scientific literature were the main problems of the festival movement, as well as the participation of Mordovia Komsomol festivals of youth and students in the second half of 1950-ies. Against the background of increasing participation of the Komsomol in the festival movement, the processes of self-organization and innovative activity of Komsomol organizations in conducting youth policy are shown. Discussion and Conclusion. As you know, such festivals have been held since 1947. They are organized by the world Federation of democratic youth (WFDY) and the International Union of students (IUS). The decision to create the WFDY and hold festivals was made at the world conference of youth and students in London in 1945. The tradition of holding irregular festivals of left-wing youth organizations is still attractive in modern youth politics. The XIX festival was held in Russia (Moscow/Sochi; October 14–22, 2017, 185 countries, the motto “For peace, solidarity and social justice, we fight against imperialism-respecting the past, we build the future”. VI world festival of youth and students 1957 (Moscow), still perceived as a unique event for the Soviet Union in the framework of international cultural policy during the cold war. In the article, through the activities of the Komsomol of Mordovia, an attempt is made to consider the goals and objectives of the VI and VII world festival of youth and students, in the context of the youth festival policy in the Soviet Union. As it is known, in the 1950s, the festival movement was organized in the format of traditional political, social and cultural events for the Soviet society. However, it should be taken into account that during their implementation, new forms of communication, methods of mobilization, and broadcasting of information were also born to create mutual understanding among young people.

ABSTRAK Penelitian ini bertujuan untuk memetakan penelitian-penelitian sebelumnya tentang audit syariah dan perannya dalam meningkatkan kepatuhan syariah di lembaga keuangan syariah (LKS). Penelitian ini juga menguraikan tantangan yang dihadapi oleh LKS dan solusi dalam mengimplementasikan audit syariah. Sebanyak 308 publikasi diperoleh dari database Google scholar, Emerald Insight, Research Gate, Crossref, Microsoft Academic and Pubmed yang diakses dengan perangkat lunak Publish or Perish (PoP) dalam kurun waktu 2008-2021. Studi ini menerapkan analisis bibliometrik menggunakan VOSviewer, yang mengubah metadata publikasi menjadi visualisasi sesuai dengan co-occurrence. Hasil penelitian ini menemukan bahwa audit syariah telah diterapkan di beberapa negara yang didominasi oleh Malaysia. Sebagian besar praktik audit syariah merupakan bagian dari fungsi audit internal. Audit syariah diidentifikasi sebagai mekanisme untuk memastikan kepatuhan syariah. Tantangan utama dalam pelaksanaan audit syariah antara lain: kurangnya kerangka dan standar audit syariah yang menyebabkan perselisihan di antara praktisi LKS, kurangnya auditor syariah yang berkualitas yang memiliki pengetahuan syariah yang memadai dan terlatih dengan baik, audit syariah dianggap menciptakan masalah inefisiensi. Peran komite tata kelola syariah dan dewan pengawas syariah direkomendasikan agar lebih optimal untuk memastikan efektivitas audit syariah. Penelitian ini memberikan pembahasan komprehensif tentang audit syariah, perannya dalam meningkatkan kepatuhan syariah, tantangan dan solusi yang ditawarkan belajar dari berbagai negara. Kata Kunci: Audit syariah, kepatuhan syariah, lembaga keuangan syariah, bibliometrik. ABSTRACT This study aimed to map out previous studies on sharia auditing and its role in improving sharia compliance in Islamic financial institutions (IFIs). It also outlined the challenges faced by IFIs and solutions in implementing shariah audit. A total of 308 publications were obtained from the Google scholar database, Emerald Insight, Research Gate, Crossref, Microsoft Academic and Pubmed which were accessed using the Publish or Perish (PoP) software in the 2008-2021 period. This study finds that sharia audits have been implemented in several countries, dominated by Malaysia. Most shariah audit practices are part from internal audit function of IFIs. Sharia audit is identified as a mechanism to assure shariah compliance. The main challenges in implementing sharia audit include: a lack of framework and standard of shariah audit that led to dispute among IFIs practitioners, a lack of qualified shariah auditors who have an adequate shariah knowledge and well trained , shariah audit identifed creating an efficiency issue. The role of the shariah governance committee and the shariah supervisory board may be optimized to ensure the effectiveness of shariah audit. This study provides a comprehensive discussion of shariah audit, its role in improving shariah compliance, challenges, and solutions offered learned from various countries. Keywords: Sharia audit, sharia compliance, Islamic financial institution, bibliometric. REFERENCES Abd Rahman, N., & Mastuki, N. (2019). Internal Shariah audit change: A conceptual paper. Journal of Muwafaqat, 2(April), 45–59. Abdul Rahman, A. R. (2010). Shari’ah audit for Islamic financial services: The needs and challenges. The Journal of Muamalat and Islamic Finance Research, 7(1), 133–145. Akbar, T., Mardian, S., & Anwar, S. (2015). Mengurai permasalahan audit syariah dengan analytical network process (ANP). Jurnal Akuntansi Dan Keuangan Islam, 2(2), 101–123. https://doi.org/10.35836/jakis.v3i2.32 Alahmadi, H. A., Hassan, A. F. S., Karbhari, Y., & Nahar, H. S. (2017). Unravelling shariah audit practice in Saudi Islamic Banks. International Journal of Economic Research, 14(15), 255–269. Alam, T., Aziz, H. A. A., & Iqbal, M. (2020). The current practice of IFI Shariah audit and what it ought to be evidence from Pakistan. Sci.Int, 32(4), 497–500. Alam, T., & Hassan, T. (2017). Competency of Shariah Auditors: Issues and Challenges in Pakistan. Journal of Internet Banking and Commerce, 22(2), 1-11. Algabry, L., Alhabshi, S. M., Soualhi, Y., & Othman, A. H. A. (2020). Assessing the effectiveness of internal Sharīʿah audit structure and its practices in Islamic financial institutions: A case study of Islamic banks in Yemen. Asian Journal of Accounting Research, 6(1), 2–22. https://doi.org/10.1108/AJAR-04-2019-0025 Ali, A., Ahmi, A., & Wan Ahmad, W. N. (2018). The current state of the internal audit research: A bibliometric analysis. Proceedings of the 5th International Conference on Accounting Studies (ICAS 2018), October, 108–113. Ali, N. A. M., Mohamed, Z. M., & Shahimi, S. (2015). Competency of shariah auditors in Malaysia: Issues and challenges. Journal of Islamic Finance, 4(1), 22–30. https://doi.org/10.12816/0024798 Alzeban, A. (2020). Internal audit as an antecedent of economic growth. Journal of Economic Studies, 48(7), 1267-1283. https://doi.org/10.1108/JES-08-2019-0350 Amir Husin, M. N., Zakaria, M. Z., Salleh, A. Z., Mochammad Sahid, M., Abdullah Saidi, H. ’Azeemi, Ab Rahman, M. F., Ab. Aziz, M. R., & Ab. Jalil, M. A. (2019). Ratification of shariah non-compliance issues: Solutions and its implementation in Islamic financial institutions-With Specific reference to tawarruq-based products and services. Graduate International Conference, Pascasarjana IAIN Bukittinggi, Sumatra Barat, November, 1–13. Antonio, M. S. (2001). Bank syariah dari teori ke praktek. Jakarta: Gema Insani. Antonio, M. S., Laela, S. F., & Jazil, T. (2020). Abu Zahrah’S maqasid sharia model as a performance measurement system. Jurnal Akuntansi Multiparadigma, 11(3), 519–541. https://doi.org/10.21776/ub.jamal.2020.11.3.30 Aprillianto, B., Roziq, A., Agustini, A. T., Sayekti, Y., & Jember, U. (2017). Praktik audit syariah dalam perspektif internasional. Prosiding Seminar Nasional Ekonomi dan Bisnis (SNAPER_EBIS 2017), 169-178. Arwani, A. (2018). Issues and challenges of shariah auditing in Islamic financial institutions and corporate governance compliance. Media Riset Akuntansi, Auditing & Informasi, 18(2), 169–186. https://doi.org/10.25105/mraai.v18i2.3008 Auda, J. (2008). Maqasid al syariah as philosophy of Islamic law. The international institute of Islamic thought. Baehaqi, A., & Suyanto, S. (2019). Audit internal lembaga keuangan syariah dalam perpektif al-hisbah. Jurnal Riset Keuangan Dan Akuntansi, 4(2), 15–24. https://doi.org/10.25134/jrka.v4i2.1694 Behrend, J., & Eulerich, M. (2018). Exploring the scientific landscape of internal audit research: A bibliometric analysis. SSRN Electronic Journal, July, 1–65. https://doi.org/10.2139/ssrn.3178362 Behrend, J., & Eulerich, M. (2020). Four decades of audit committee research: A bibliometric analysis (1977 – 2018). SSRN Electronic Journal, 1–46. https://doi.org/10.2139/ssrn.3496040 BNM-SGDP. (2019). Bank Negara Malaysia (Shariah Governance 2019). Bank Negara Malaysia. Retrieved from BNM/RH/PD 028-100, 1–22. Ciger, A. (2020). Audit quality: A bibliometric analysis (1981-2020). Scientific Annals of Economics and Business, 67(4), 473–494. https://doi.org/10.47743/saeb-2020-0031 Eck, N. J. Van, Waltman, L., Dekker, R., & Berg, J. Van Den. (2010). A comparison of two techniques for bibliometric mapping: Multidimensional scaling and VOS. Journal of the American Society for Information Science and Technology, 61(12), 2405–2416. https://doi.org/10.1002/asi.21421 Farida, F., & Dewi, V. S. (2018). Kompetensi auditor dan shariah compliance terhadap praktik audit syariah. Jurnal Analisis Bisnis Ekonomi, 16(1), 45–52. https://doi.org/10.31603/bisnisekonomi.v16i1.2130 Fauzi, A., & Supandi, A. F. (2019). Perkembangan audit syariah di Indonesia. Jurnal Istiqro, 5(1), 24. https://doi.org/10.30739/istiqro.v5i1.339 Fitriyani, N. I., & Kusnugroho, Y. A. (2021). Audit syariah dan audit konvensional: Bukti empiris di Indonesia. AFRE (Accounting and Financial Review), 4(1), 137–145. https://doi.org/10.26905/afr.v4i1.5642 Ghani, N. L. A., & Rahman, A. R. A. (2015). An analysis of Shari’ah audit practices in Islamic banks in Malaysia. Jurnal Pengurusan, 43, 107–118. Ghozali, M., Zeid, A. H., Prastyaningsih, I., & Syauqoti, R. (2020). The implementation of sharia compliance in the murabaha contract. 409(SoRes 2019), 479–481. https://doi.org/10.2991/assehr.k.200225.103 Haleem, A., Khan, M. I., Khan, S., & Jami, A. R. (2020). Research status in Halal: A review and bibliometric analysis. Modern Supply Chain Research and Applications, 2(1), 23–41. https://doi.org/10.1108/mscra-06-2019-0014 Hameed, S., & Ibrahim, M. (2005). The emerging issues on the objectives and characteristics of Islamic accounting for Islamic business organizations. Malaysian Accounting Review, 4(1), 75–92. Hanefah, M. M., Kamaruddin, M. I. H., Salleh, S., Shafii, Z., & Zakaria, N. (2020). Internal control, risk and Sharīʿah non-compliant income in Islamic financial institutions. ISRA International Journal of Islamic Finance, 12(3), 401–417. https://doi.org/10.1108/IJIF-02-2019-0025 Harande, Y. (2001). An investigation of the relationship using the literature of technology. Libri, 51, 124–127. Hassan, A. F. S., & Haridan, N. M. (2019). Shariah auditing and shariah compliance assurance in Malaysian Islamic Banks. Global Journal Al-Thaqafah, December, 61–72. Hassan, R. (2016). Shariah non-compliance risk and its effects on Islamic financial institutions. Al-Shajarah, 21(Special issue), 21–39. ICD - Thomson Reuters Islamic Finance Development Report 2021. (2021). Islamic finance development report (Issue 93 Islamic Banking 96 Takaful 98 Regulatory and Supervisory Framework 99 Talent). Isa, F., Ariffin, N., & Abidin, N. (2020). Shariah Audit practices in Malaysia: Moving forward. Journal of Islamic Finance (ISSN: 2289-2109 e-ISSN: 2289-2117), 9(2), 42–58. ISLAM, K. M. A., & BHUIYAN, A. B. (2021). Determinants of the effectiveness of internal shariah audit: Evidence from Islamic banks in Bangladesh. Journal of Asian Finance, Economics and Business, 8(2), 223–230. https://doi.org/10.13106/jafeb.2021.vol8.no2.0223 Islam, K. M. A., Sadekin, M. S., Rahman, M. T., & Chowdhury, M. A. H. (2021). The impact of shariah supervisory board and shariah audit committee on corporate social responsibility adoption at Islamic banks in Bangladesh. Journal of Asian Finance, Economics and Business, 8(3), 479–485. https://doi.org/10.13106/jafeb.2021.vol8.no3.0479 Islamic Financial Services Board. (2005). Guiding principles of risk management for institutions (Other than insurance institutions) offering only Islamic financial services. Islamic Financial Service Board, December, 1–36. https://www.ifsb.org/published.php Kamaruddin, M. I. H., & Hanefah, M. M. (2017). Enhancing shariah audit practices in Islamic financial institutions in Malaysia. Journal of Modern Accounting and Auditing, 13(11). https://doi.org/10.17265/1548-6583/2017.11.001 Karim, M. R., & Shetu, S. A. (2020). Shariah audit in Islamic financial institutions (IFIs): A literature review. BUFT Journal of Business & Economics (BJBE), 1, 45–66. Kasim, N., Sanusi, Z. M., Mutamimah, T., & Handoyo, S. (2013). Assessing the current practice of Auditing in Islamic Financial Institutions in Malaysia and Indonesia. International Journal of Trade, Economics and Finance, 4,6(January), 414–418. https://doi.org/10.7763/IJTEF.2013.V4.328 Khalid, A. A. (2020). Role of audit and governance committee for internal shariah audit effectiveness in Islamic banks. Asian Journal of Accounting Research, 5(1), 81–89. https://doi.org/10.1108/AJAR-10-2019-0075 Khalid, A. A., Haron, H., & Masron, T. A. (2018). Competency and effectiveness of internal Shariah audit in Islamic financial institutions. Journal of Islamic Accounting and Business Research, 9(2), 201–221. https://doi.org/10.1108/JIABR-01-2016-0009 Khalid, A. A., & Sarea, A. M. (2021). Independence and effectiveness in internal Shariah audit with insights drawn from Islamic agency theory. International Journal of Law and Management, 63(3), 332–346. https://doi.org/10.1108/IJLMA-02-2020-0056 Laela, S. F., Rossieta, H., Wijanto, S. H., & Ismal, R. (2018). Management accounting-strategy coalignment in Islamic banking. International Journal of Islamic and Middle Eastern Finance and Management, 11(4), 667–694. https://doi.org/10.1108/IMEFM-04-2017-0088 Laili, N., Ghani, A., Ariffin, N. M., Rahim, A., Rahman, A. (2019). The measurement of effective internal shariah audit function in Islamic financial institutions. International Journal of Economics, Management and Accounting, 27(1), 141–165. Lamboglia, R., Lavorato, D., Scornavacca, E., & Za, S. (2020). Exploring the relationship between audit and technology. A bibliometric analysis. Meditari Accountancy Research. https://doi.org/10.1108/MEDAR-03-2020-0836 Mardiyah, Q., & Mardian, S. (2015). Praktik audit syariah. Akuntabilitas, 8(1), 1–17. Martasari, L., & Mardian, S. (2015). Persepsi masyarakat terhadap penerapan sharia compliance pada bank syariah di kecamatan Barabai. Jurnal Dinamika Akuntansi Dan Bisnis, 2(1), 45–58. https://doi.org/10.24815/jdab.v2i1.3607 Md Helal Uddin, M. H. U. & M. M. H. (2013). An overview on the basics of Islamic audit. European Journal of Business and Management, 5(28), 9–18. Minarni, M. (2013). Audit syariah, dan tata kelola lembaga keuangan syariah. La_Riba, 7(1), 29–40. https://doi.org/10.20885/lariba.vol7.iss1.art3 Mohamad Puad, N. A., Abdullah, N. I., & Shafii, Z. (2020). Follow up in Shariah auditing: Multiple approaches by Takaful operators. International Journal of Islamic Economics and Finance Research, 3(1), 14–29. Mohd Ali, N. A., Shafii, Z., & Shahimi, S. (2020). Competency model for Shari’ah auditors in Islamic banks. Journal of Islamic Accounting and Business Research, 11(2), 377–399. https://doi.org/10.1108/JIABR-09-2016-0106 Muhammad, R. (2018). Shariah governance for Islamic banking: What can be learnt from Malaysia? Conference on Islamic Management Accounting and Economics, 1(1999), 111–123. Mulazid, A. S. (2016). Pelaksanaan sharia complience pada bank syariah (Studi kasus pada bank syariah mandiri, Jakarta). Madania, 20(1), 37–54. Nurcahyo, A., & Hudrasyah, H. (2017). The influence of halal awareness, halal certification, and personal societal purchase intention. Journal of Business and Management, 6(1), 21–31. Nurhasanah, N. (2013). Pengawasan Islam dalam operasional lembaga keuangan syariah. MIMBAR, Jurnal Sosial Dan Pembangunan, 29(1), 11. https://doi.org/10.29313/mimbar.v29i1.362 Nurhisam, L. (2016). Kepatuhan syariah (Sharia compliance) dalam Industri Keuangan Syariah. Jurnal Hukum IUS QUIA IUSTUM, 23(1), 77–96. https://doi.org/10.20885/iustum.vol23.iss1.art5 Omar, M. (2019). Issues and Challenges of Shariah Compliance Auditing in Islamic Financial Institution. Advanced International Journal of Banking, Accounting and Finance, 1(1), 13–24. https://doi.org/10.35631/aijbaf.11002 Oussii, A. A., & Boulila, N. (2020). Evidence on the relation between audit committee financial expertise and internal audit function effectiveness. Journal of Economic and Administrative Sciences, ahead-of-p(ahead-of-print). https://doi.org/10.1108/jeas-04-2020-0041 PricewaterhouseCoopers. (2011). Shariah Audit: Industry Insights. 1–28. Puneri, A., Chora, M., Ilhamiddin, N., & Benraheem, H. (2020). The Disclosure of Sharia Non-Compliance Income: Comparative Study between Full-fledged and Subsidiaries Malaysian Islamic Banks. JESI (Jurnal Ekonomi Syariah Indonesia), 9(2), 104. https://doi.org/10.21927/jesi.2019.9(2).104-117 Rahman, M. J. (2013). The current perception and practice of “Shariah Auditing” in Bangladeshi Islamic Banks. In Thesis MBA (Issue September). Rahman, N. A., Mastuki, N., Osman, M. R., & Kasim, N. (2020). Islamic legal maxim for Shari’ah audit in Islamic bank. Journal of Islamic Accounting and Business Research, 11(2), 457–471. https://doi.org/10.1108/JIABR-11-2017-0170 Ratu, M. K., & Meiriasari, V. (2021). Analisis perbandingan audit syariah pada lembaga keuangan Islam di Asia Tenggara (Studi literatur di Indonesia, Malaysia, Dan Brunei). Jurnal Proaksi, 8(1), 50–57. https://doi.org/10.32534/jpk.v8i1.1526 Rohmah, F., & Kusumo, R. W. (2020). Faktor-faktor yang mempengaruhi kualitas audit syariah pada perusahaan yang terdaftar di JII (Jakarta Islamic Index) tahun 2014-2018. The 11th University Research Colloquium 2020 Universitas ‘Aisyiyah Yogyakarta, 64–77. Salleh, S., Hanefah, M. M., & Shafii, Z. (2019). Shariah audit practices in Malaysian Islamic Banks: An Audit Expectation. Shariah Governance and Assurance in Islamic Financial Sectors, 113-145. Shafii, Z., Salleh, S., Zakaria, N., Hanefah, M. M., Mohd Ali, N. A., & Yunanda, R. A. (2014). Shariah audit certification contents: Views of regulators, shariah committee, shariah reviewers and undergraduate students. International Journal of Economics and Finance, 6(5). https://doi.org/10.5539/ijef.v6n5p210 Shafii, Z., Supiah, S., & Syahidawati, S. (2010). Management of shariah non-compliance audit risk in the Islamic financial institutions via the development of shariah compliance audit framework and shariah audit programme. Kyoto Bulletin of Islamic Area Studies, March, 14. Shah, S. A., Azhar, S. M., & Bhutto, N. A. (2019). Halal marketing: a marketing strategy perspective. Journal of Islamic Marketing, 11(6), 1641–1655. https://doi.org/10.1108/JIMA-11-2018-0211 Shahzad, M. A., Saeed, S. K., & Ehsan, A. (2017). Governance framework: Exploratory study of Islamic banks in Pakistan. Business & Economic Review, 9(1), 103–118. Sidiq, M. (2019). Panduan analisis bibliometrik sederhana. Journal Article, June. https://doi.org/10.13140/RG.2.2.15688.37125 Siswadi, I. (2013). Mengenal konsep penetapan kata kunci. Jurnal Pustakawan Indonesia, 12(2), 53–55. Syed Alwi Mohammed Sultan. (2007). A mini guide to shari’ah audit for Islamic financial institutions: A primer. Kuala Lumpur: CERT Publications Sdn. Bhd. Tanudjaja, I., & Kow, G. Y. (2018). Exploring bibliometric mapping in NUS using BibExcel and VOSviewer. IFLA WLIC Kuala Lumpur, 1–9. Widialoka, W., Hidayat, A. R., & Azib. (2016). Analisis pengaruh kepatuhan syariah (shariah compliance) terhadap dana pihak ketiga pada bank umum syariah di Indonesia periode tahun 2010-2015. Prosiding Keuangan Dan Perbankan Syariah, 2(2), 672–678. Wuttichindanon, S., & Issarawornrawanich, P. (2020). Determining factors of key audit matter disclosure in Thailand. Pacific Accounting Review, 32(4), 563–584. https://doi.org/10.1108/PAR-01-2020-0004 Yaacob, H., & Donglah, N. K. (2012). Shari’ah audit in Islamic financial institutions: The postgraduates’ perspective. International Journal of Economics and Finance, 4(12), 224–239. https://doi.org/10.5539/ijef.v4n12p224 Yahya, Y., & Mahzan, N. (2012). The role of internal auditing in ensuring governance in Islamic financial institution (IFI). 3rd International Conference on Business and Economic Research, March, 1634–1661. Yasoa’, M. R., Abdullah, W. A. W., & Endut, W. A. (2020). A comparative analysis between shariah audit and shariah review in Islamic banks in Malaysia: Practitioners’ perspective. Environment-Behaviour Proceedings Journal, 5(14), 195–200. https://doi.org/10.21834/ebpj.v5i14.2208 Yasoa, M. R., Amalina, W., Abdullah, W., Sultan, U., Abidin, Z., Endut, W. A., Sultan, U., & Abidin, Z. (2018). Shariah audit effectiveness in Islamic banks: A conceptual framework. Journal of Humanities, Language, Culture and Business (HLCB), 2(10), 12–19. Yazkhiruni, Y., Nurmazilah, M., & Haslida, A. H. (2018). A review of shariah auditing practices in ensuring governance in Islamic financial institutions (IFIs): A preliminary study. Advances in Social Sciences Research Journal, 5(7), 196–210. Yunas Ali, M., & Hassan, F. (2019). The study of potential shariah non-compliance risks in murabahah along with their risk management. Journal of Finance & Economics Research, 4(1), 44–58. https://doi.org/10.20547/jfer1904104 Yussof, S. A. (2013). Prospects of a shari’ah audit framework for Islamic financial institution in Malaysia. ICR Journal, 4(1), 80–102. https://doi.org/10.52282/icr.v4i1.493 Zahrah, M. A. (1997). Ushul fiqh. Darul Fikr. Zuhaili, W. (1997). Al-Fiqh al-islamy wa adilatuhu. Daar el-Fikr.

OBJECTIVES/SPECIFIC AIMS: If intranasal ketamine can be utilized for pain control in cancer patients, this could provide them with superior analgesia and better quality of life, without the risk of significant respiratory depression associated with opioid medications. We seek to obtain preliminary data via a clinical trial addressing safety, feasibility, and utility of this novel technique for the treatment of persistent uncontrolled cancer pain. These findings would be an important initial step towards testing the effectiveness of intranasal ketamine as a non-opioid medication for cancer pain used as potential maintenance outpatient therapy. These initial findings would be applied to a subsequent trial to determine the effectiveness and associated toxicities of ketamine in a larger sample of cancer patients, and address the compelling need to identify new, successful management therapies for cancer pain. Specific Aims: 1. To evaluate (pharmacodynamic) effects of NAS ketamine on Patient Reported Outcomes (PROs), such as pain scores, side effects, depression, quality of life, and functional status. A clinical trial will be conducted where NAS ketamine will be given to a sample of patients with cancer related pain. Patient Reported Outcomes (PROs), such as pain scores, depression, quality of life, and functional status will be noted on Numerical Pain Rating Scale (NPRS), Montgomery Asberg Depression Rating Scale (MADRS), and Edmonton Symptom Assessment (ESAS), Eastern Cooperative Oncology Group (ECOG) and Patient Reported Outcome Measurement Information System (PROMIS) scales respectively. 1. To measure pharmacokinetics of NAS ketamine through analysis of ketamine and its metabolite norketamine to determine pharmacokinetic properties. During this clinical trial blood samples will be drawn at specified intervals and sent for analysis. 3. To determine opioid sparing effect of NAS ketamine. Opioid use will be measured by documenting use of rescue medications prior to and during the study and by evaluating total opioid consumption prior to and during the study. METHODS/STUDY POPULATION: Study sample: In the search for improved therapies for chronic cancer pain, medications with novel mechanisms of action have been sought. One such promising pharmacologic approach is ketamine. We specifically intend to measure utility of ketamine in patients with pain related to cancer or cancer treatment. Ketamine has shown to reverse central sensitization and opioid tolerance in rat models. Since ketamine is Scheduled III in United States and has abuse potential, we do not intend for ketamine to replace opioids, but use in patients who have failed opioid therapy. Since the investigators of the study practice at Emory, subjects will be from oncology and pain clinics (the supportive oncology clinic, oncology clinics, the pain clinic and Acute Pain Service) at Emory. The trial will be conducted at the Phase 1 Unit of the Winship Cancer Institute (WCI) at Emory. Subjects may be identified and contacted via telephone with information about the study prior to their next clinic appointment in order to allow time for them to consider the study. Eligibility criteria: Patients will be eligible to participate if they are: 1. Adults with uncontrolled cancer related pain a. Male and female subjects at least 18 years of age. b. Patients with uncontrolled pain related to cancer or cancer treatment. c. Uncontrolled pain will be defined as i. pain which persists for more than 7 days and is rated >/=4 on NPRS, and/or ii. use of breakthrough medication more than 4 times in 24 hours d. Failed other pain medications such non-steroidal anti-inflammatories such as ibuprofen, acetaminophen, opioids such as tramadol, hydrocodone, oxycodone etc. and antineuropathics such as gabapentin. 2. Able to provide informed consent a. Patients who are able to understand written and verbal English. Patients will be excluded from the study if they have any of the following: 1. Conditions increasing the risk of side effects from ketamine a. Conditions not safe due to cardiovascular effects of ketamine i. Presence of severe cardiac disease-EF <15% in patients with known history of cardiac disease ii. Uncontrolled Stage 2 hypertension or greater (systolic blood pressure > 160 and/or diastolic blood pressure >100) iii. Baseline tachycardia, HR >100 b. Conditions not safe due to potential effect of ketamine on intracranial and intraocular pressure i. Presence of elevated ICP ii. Uncontrolled glaucoma c. Presence of uncontrolled depression or other psychiatric comorbidity with psychosis 2. Conditions not safe due to potential side effects reported in ketamine abusers a. History of liver disease b. History of interstitial cystitis 3. Conditions where delivery of intranasal medications may be unreliable a. Active allergic or infectious rhinitis b. Patients with lesions of nasal mucosa 4. Conditions where fetus may be exposed to ketamine in utero (ketamine is category C medication) a. Pregnant women, nursing mothers and women of childbearing potential not using contraception known to be highly effective. b. Highly effective contraception methods include combination of any two of the following: Use of oral, injected or implanted hormonal methods of contraception or; Placement of an intrauterine device (IUD) or intrauterine system (IUS); Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; Total abstinence; Male/female sterilization. 5. Conditions with medication abuse potential a. Illicit substance abuse within the past 6 months b. Documented history of medication abuse/misuse (e.g. Unsanctioned dose escalation, broken opioid agreement etc.) 6. Conditions where ketamine metabolism may be altered, resulting in erroneous dose response relationship a. Clinical requirement for medications that are concurrent inducers or strong inhibitors of CYP3A4. CYP3A4 substrates are allowed. (Ketamine is metabolized by CYP3A4) Study sample limitations: Subject factors that may affect the final resultant study sample of subjects with full data for analysis. 1. Subjects who may not get pain relief with ketamine may not follow up and resulting incomplete data not eligible for analysis that may erroneously enhance positive effect of ketamine on pain relief. To account for this effort will be made to document the reason for lack of follow-up by contacting patient via telephone or at next scheduled clinic visit within Emory Healthcare. 2. Since patients coming to Emory are typically insured, the study will not adequately capture indigent population. It is not the intention of the current study to investigate differences in pain characteristics or responses of patients with insurance vs indigent population and will need to be addressed via future trials. Since this is a single center trial, the results of this trial might lack external validity required to support widespread changes in practice. This will be a pilot trial to figure out likely most efficacious dose. If this trial is successful, a multi-site randomized clinical trial will be conducted next. Primary Study Measures Primary exposure Intranasal Ketamine for cancer related pain Ketamine is an FDA approved anesthetic with amnesic, analgesic, dissociative, and sedative properties. It is unique among anesthetic agents in that it does not depress cardiovascular and respiratory systems. Ketamine is a noncompetitive, antagonist of N-methyl-D-aspartate (NMDA) receptors that blocks the NMDA channel in the open state by binding to the phencyclidine (PCP) site located within the lumen of the channel. Antagonism of NMDA receptors produces antinociception of persistent or neuropathic pain in animal models and analgesia in pain states in humans. The NMDA receptor is believed to play a role in the development of opioid tolerance and ketamine has been shown in a rat model to prevent fentanyl-induced hyperalgesia and subsequent acute morphine tolerance 5. Ketamine also interacts at a number of other receptor sites to block pain. Some of these sites include voltage-sensitive calcium channels, depression of sodium channels, modulation of cholinergic neurotransmission, and inhibition of uptake of serotonin and norepinephrine. Ketamine also interacts with kappa and mu opioid receptors; however, in humans, naloxone, an opioid antagonist, does not antagonize the analgesic effects of ketamine. Safety and efficacy of ketamine as an anesthetic and analgesic agent is well-documented 2-4. Ketamine is not labeled by the FDA as an analgesic agent. Low (subanesthestic) doses of ketamine have minimal adverse impact upon cardiovascular or respiratory function but produce analgesia and modulate central sensitization, hyperalgesia, and opioid tolerance. Cancer pain, especially in end stages, can be very complicated and is mediated by a variety of pathways: visceral, nociceptive, neuropathic and central. If ketamine can be utilized for pain in end stage cancer patients, this could provide them with superior analgesia and better quality of life, without the risk of significant respiratory depression associated with opioid medications. One of the challenges that we face with ketamine is the route of administration. The most common route is intravascular or intramuscular. Although it has been given orally and rectally, the bioavailability of ketamine when given via these routes is limited to 20-30%. Intranasal (NAS) administration has advantages of being needle free method of administration with potential for outpatient therapy. It lacks hepatic first pass effect resulting in higher bioavailability compared to oral route. Large surface area, uniform temperature, high permeability and extensive vascularity of the nasal mucosa facilitate rapid systemic absorption of intranasal administered drugs 6. In the pilot trial conducted by the study investigators, single dosage of intranasal ketamine has been shown to be feasibility and effective option for temporary pain reduction in patients with cancer related pain. The investigators now seek to obtain feasibility and efficacy data on long-term use of intranasal ketamine for cancer related pain. Ketamine is a scheduled III medication. A physician with a DEA license can order intranasal ketamine from a compounding pharmacy. Primary outcome of interest: Pain scores will be recorded on Numerical Pain Rating Scale (NPRS) at regular intervals throughout the study. NPRS is the most responsive tool to document pain intensity when compared to Visual Analogue Scale (VAS) and Visual Rating Scale (VRS) for measuring pain, 7 showing higher compliance rates, better responsiveness, ease of use, and good applicability relative to VAS/VRS8. Minimal clinically important differences (MCIDs) for pain ratings varies substantially based on patient population and statistical technique used, range of 0.4 to 3.7 points has been reported as a MCID. In general, improvements of pain severity</=1.5 points on NPRS could be seen as clinically irrelevant 9-13. Above that value, the cutoff point for “clinical relevance” depends on patients’ baseline pain severity, and ranges from 2.4 to 5.3 11-13. Higher baseline scores require larger raw changes to represent clinically important differences 14. Primary aim: To determine efficacy of intranasal ketamine in reducing cancer related pain. A clinical trial will be conducted to determine effect of intranasal ketamine on cancer related pain. Pain scores will be recorded on Numerical Pain Rating Scale (NPRS) at regular intervals throughout the study. Minimal clinically important differences (MCIDs) for pain ratings varies substantially based on patient population and statistical technique used, range of 0.4 to 3.7 points has been reported as a MCID. In general, improvements of pain severity</=1.5 points on NPRS could be seen as clinically irrelevant 9-13. Above that value, the cutoff point for “clinical relevance” depends on patients’ baseline pain severity, and ranges from 2.4 to 5.3 11-13. Higher baseline scores require larger raw changes to represent clinically important differences 14. Several clinical trials for pain have reported a reduction of 2 points on NPRS to be clinically important.15-17 Therefore for the purposes of this study, MCID of 2 was used for sample size calculations. A prior research study done by Carr et al. studied effects of intranasal ketamine for breakthrough pain in patients with chronic pain of various etiologies. 18 Total number of subjects in this study was 20 (4 of these had cancer related pain).This study demonstrated a mean reduction of 2.7 units on NPRS (P<0.0001), with standard deviation of 1.87. Since MCID is 2, effect size using this (MCID/SD) = 1.05. Power and sample size table: Assumptions: 1. T-test is the appropriate test (may not be the appropriate test since we have a small sample size and may not be able to assume normality of means based on the central limit theorem) 2. Distribution of reductions in pain score is normal 3. Effect size of 1.05 is clinically meaningful; Sample Size: A sample size of 7 from a population of 20 (in the study done by Carr etal.) achieves 80% power to detect a NPRS difference of −2 between the null hypothesis mean of 0.0 and the alternative hypothesis mean of 2 with an estimated standard deviation (SD) of 1.87 and with a significance level (alpha) of 0.05 using paired t-test assuming that the actual distribution is normal. We will include 10 patients to account for the possibility that the observed pain reduction in the current study may be different than the study done by Carr, as in this study patients were given ketamine for breakthrough pain, as opposed to for baseline pain. We will enroll 25 patients in the study to account for potential dropouts. RESULTS/ANTICIPATED RESULTS: Majority of subjects experienced the largest decrease in their pain with the 10mg IV dose. Side effects included nausea/vomiting and a feeling of unreality. All side effects resolved by the end of each study visit. No severe adverse events occurred. DISCUSSION/SIGNIFICANCE OF IMPACT: Further study is required to elucidate safety of NAS ketamine with long term use for cancer related pain.

Abstract Background and Aims Intestinal ultrasound (IUS) has been increasingly reported to distinguish inflammatory or fibrotic intestinal stenosis in Crohn's disease (CD) patients. However, the diagnostic value is unclear. This systematic review and meta-analysis aimed to assess the diagnostic role of different modes of IUS parameters. Methods We searched PubMed, Embase, Web of Science, and Cochrane Library from inception to August 2021. Regarding effect sizes, weighted mean differences (WMDs) or standardized mean differences (SMDs) were used. We pooled data using a random-effects or fixed-effects model according to heterogeneity. The diagnostic accuracy of IUS for distinguishing fibrosis was pooled. Results 19 studies were retained for qualitative analysis, and 14 were included in the meta-analysis (with 511 total subjects and 635 bowel segments). In patients with fibrotic stenosis, the pooled WMDs for bowel wall thickness were 1.30 mm (95% CI 0.69-1.91) thicker than patients with inflammatory stenosis, and the pooled SMDs for strain value and strain ratio were 0.80 (95 % CI 0.41-1.20) and 1.08 (95 % CI 0.55-1.60) harder than patients with inflammatory stenosis, respectively. The percentage of maximal enhancement of fibrotic stenosis was lower than that of inflammatory stenosis (WMD -10.03, 95% CI -17.91- -2.16). The diagnostic accuracy of IUS was not performed because only a few studies provided relevant diagnostic indicators, and these studies used different modes and parameters. Conclusions IUS currently is inaccurate to differentiate fibrotic or inflammatory stenosis in CD patients, and more studies assessing the significance of each parameter and its cut-off value in different modes of IUS are needed to be conducted in the future.

IntroductionTo compare efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) with medical treatments for women with heavy menstrual bleeding.Materials and methodsWe searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI), and Wanfang databases for relevant randomized controlled trials (RCTs) in November 2021. All meta-analyses were performed using the random-effects model. PROSPERO registration number: CRD42021295379.ResultsA total of trials (with 14 references) reporting on 1,677 women were included in this systematic review. The majority of the included RCTs were rated with low-to-unclear risk of bias in selection, detection, attrition, reporting, and other bias. All RCTs were rated as high risk in performance bias because blinding was difficult to ensure in the compared groups. Results of meta-analyses revealed that the number of clinical responders was greater in the LNG-IUS group than that in the medical treatments group at both 6-month (steroidal: five RCTs; n = 490; risk ratio [RR]: 1.72 [1.13, 2.62]; I2 = 92%; nonsteroidal: one RCT; n = 42; RR: 2.34 [1.31, 4.19]) and 12-month (steroidal: three RCTs; n = 261; RR: 1.31 [1.01, 1.71]; I2 = 74%) endpoints, with no clear differences on number of dropouts, and the incidence of adverse events.ConclusionEvidence indicates that LNG-IUS is superior to the medical treatments in short-term and medium-term clinical responses, blood loss control, compliance, and satisfaction. Meanwhile, frequency of adverse events related to LNG-IUS is acceptable.Systematic review registrationPROSPERO, identifier CRD42021259335, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021295379.

Abstract Background To assess treatment response, objective measures are superior to clinical improvement in Crohn’s Disease (CD). Intestinal ultrasound (IUS) is an attractive, non-invasive alternative to endoscopy demonstrating early transmural changes after treatment initiation. Therefore, we investigated IUS and contrast-enhanced ultrasound (CEUS) to predict (early) endoscopic treatment response. Methods Consecutive patients with endoscopically active CD starting anti-TNFα therapy were included. Clinical, biochemical, IUS and CEUS parameters at baseline (T0), after 4-8 weeks (T1) and 12-34 weeks (T2) were collected. The most severely inflamed segment at endoscopy (highest segmental SES-CD) and IUS (highest segmental bowel wall thickness (BWT)) was identified. At T2, endoscopic response (decrease SES-CD≥50%) and remission (SES-CD=0) were scored. Results 40 patients were included, 14 reached endoscopic remission and 17 endoscopic response. At T1 (3.1 mm [1.9-4.2] vs 5.3 mm [3.8-6.9], p=0.005) and T2 (2.0 mm [1.8-3.1] vs 5.1 [3.0-6.3] mm, p=0.002) BWT was lower in patients with endoscopic remission. At T1 and T2, 18% (AUROC: 0.77; OR: 10.80, p=0.012) and 29% (AUROC: 0.833; OR: 37.50, p=0.006) BWT decrease predicted endoscopic response, respectively. 3.2 mm was most accurate to determine endoscopic remission (AUROC: 0.94; OR: 39.42, p&lt;0.0001) at T2. In addition, absence of Colour Doppler Signal (OR: 13.76, p=0.03) and the CEUS parameter Wash-out Rate (OR: 0.76, p=0.019) improved the prediction model. Conclusion Reduction in BWT, already after 4-8 weeks of follow-up, predicted endoscopic response and remission. CEUS parameters were of limited value. Furthermore, we have provided accurate cut-offs for BWT reflecting endoscopic response and remission at different time points.