Journal articles on the topic 'NEU-Med'

SummaryOb in der Drogerie oder in der Apotheke: Die Fülle von Nahrungsergänzungsmitteln ist enorm. Hinzu kommen neu erscheinende Studien sowie zahlreiche Werbebotschaften. Dadurch ist es oft schwierig, den Überblick über relevante Mittel und ihre validen Anwendungsmöglichkeiten zu behalten. Im Gespräch mit Dr. med. Volker Schmiedel erfahren wir mehr über verschiedene Zusammenhänge und sinnvolle sowie womöglich weniger sinnvolle Anwendungen von Nahrungsergänzungsmitteln.

Abstract. In this study we analyze drought features at the European level over the period 1901–2019 using three drought indices: the standardized precipitation index (SPI), the standardized precipitation evapotranspiration index (SPEI), and the self-calibrated Palmer drought severity index (scPDSI). The results based on the SPEI and scPDSI point to the fact that Central Europe (CEU) and the Mediterranean region (MED) are becoming dryer due to an increase in the potential evapotranspiration and mean air temperature, while North Europe (NEU) is becoming wetter. By contrast, the SPI drought does not reveal these changes in the drought variability, mainly due to the fact that the precipitation does not exhibit a significant change, especially over CEU. The SPEI12 indicates a significant increase both in the drought frequency and area over the last three decades for MED and CEU, while SPI12 does not capture these features. Thus, the performance of the SPI may be insufficient for drought analysis studies over regions where there is a strong warming signal. By analyzing the frequency of compound events (e.g., high temperatures and droughts), we show that the potential evapotranspiration and the mean air temperature are becoming essential components for drought occurrence over CEU and MED. This, together with the projected increase in the potential evapotranspiration under a warming climate, has significant implications concerning the future occurrence of drought events, especially for the MED and CEU regions.

Background : Colorectal carcinoma (CRC) is the most frequently observed malignancy worldwide. The incidence of CRC is 3.5% in Bangladesh. Conflicting data exist about the prevalence of HER-2/neu over expression in colorectal cancer ranging from 0 to 83%. The aim of this study was to evaluate the expression of Her-2/neu protein in colorectal cancers. Materials and methods: This descriptive cross-sectional study was conducted in the Department of Pathology of Chittagong Medical College, Chittagong, Bangladesh from 1st January 2017 to 31st December 2017. A total of 52 cases with a histopathological diagnosis of colorectal cancers included in the study as sample size, HER2 status was evaluated by immunohistochemistry (IHC) in formalin fixed, paraffin embedded tissue.Positive expression was assigned a score from 0–3+.IHCs were analysed with grades of colon cancers. Results: The mean age in this study was 47.62years range from 12 to 85 years ,53.8% were female. Among 52 specimens 30 (57.7%) cases were from colon and all the cases were adenocarcinoma and rest of all (42.3%) were from rectum.33 (63.5%) cases were Grade-I, 8 (15.4%) were Grade-II, and 11 (21.2%) were Grade-III. Only 8 (15.4%) of 52 cases showed HER2 positive, 4 (50.0%) cases were from grade- Iand another 4 (50.0%) were grade- II tumours. HER2 overexpression were significantly associated with well differentiated CRC than poorly differentiated (p=0.044). Conclusion: HER2/neu protein expression was observed in colorectal cancer but HER-2/neu protein is less likely to be expressed in colon cancer cell lines among our patients. Chatt Maa Shi Hosp Med Coll J; Vol.21 (1); January 2022; Page 52-56

582 Background: DD q 2 weekly (w) AC → T is superior to conventionally scheduled (cs) AC → T and safe w/long follow-up (Hudis et al, SABCS 2005). With q 3 wk AC, adjuvant (adj) H is safe and effective (Romond et al and Perez et al, NEJM 2005). We therefore tested DD q 2 w AC → T + H × 1 year (y) as adj treatment (Rx) of patients (pts) with HER2/neu (+) BCA to determine cardiac safety. Based on the reported cardiac event (CE) rate of ≤ 4% in the randomized trials using cs chemotherapy (CRx) + H, we evaluated DD q 2 w AC → T + H with a 1° endpoint of cardiac safety defined as discontinuation (DC) of H due to 1) cardiac death or 2) congestive heart failure (CHF). The 2° endpoint is time to recurrence and overall survival. Methods: Pts with HER2/Neu IHC 3+ or FISH-amplified BCA were enrolled, regardless of tumor size or nodal status. Rx consisted of AC at 60/600 mg/m2 × 4 → T at 175 mg/m2 × 4 q 2 w w/pegfilgrastim 6 mg on d 2 + H × 1 y. Multi-gated radionuclide angiography scan (MUGA) is obtained at baseline and at months (mo) 2 (after AC × 4), 6 (after T × 4), 9, and 18. Pts w/baseline LVEF of ≥ 55% and w/o cardiac illnesses are eligible. Pts w/significant (sig) asymptomatic (asx) LVEF ↓ after DD AC based on mo 2 MUGA did not receive H, and pts w/sig asx LVEF ↓ during H had it DC’d. If the CE rate is > 4%, Rx is deemed not feasible. Results: From January 4, 2005 to November 1, 2005, 70 pts were enrolled. Median (med) age is 49 years (range, 27–72). Forty one of 70 pts (60%) had node (+) BC and 27/70 pts (40%) had (-) nodes. Med baseline LVEF is 68% (range, 55%-81%). As of January 9, 2005, all pts had mo 2 MUGA after DD AC and there is no sig LVEF ↓ and the med LVEF is 67% (range, 58%-79%). To date 39 pts had mo 6 MUGA w/med LVEF of 66% (range, 56%-75%) and one pt had a sig asx LVEF ↓ from baseline of 74% to 56%; H was DC’d. Twenty-three pts had mo 9 MUGA w/a med LVEF of 64% (range, 57%-69%). One patient had clinical CHF at mo 4 w/EF of 45% and improved sig w/cardiac medications. One had pneumonitis during radiation (RT). One had atrial fibrillation w/pericarditis after completion of RT. Discussion: DD AC → T + H appears to have an acceptable cardiac toxicity profile w/1/70 pts having a CE. Updated cardiac safety data will be presented. [Table: see text]

Introduction: Now a days immunohistochemistry and genomic testing for patient with Non- Small Cell Lung Cancer (NSCLC) is becoming new standard of care in clinical decision making. A renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Aim of this present study was clinicopathological correlation of HER-2/neu expression by IHC in NSCLC. Method: This was a Cross sectional and observational study done at Sir Salimullah Medical College and National Institute of Disease of the Chest and Hospital (NIDCH) and other private hospitals in Dhaka city during July / 2014 to June / 2016. Adult of both gender with histologically diagnosed as a case of NSCLC was include in the study. Immunohistochemistry was done to see the positivity for HER/neu and clinical characteristics were observed. Result: A total 45 patients with NSCLC were enrolled in the study. Male was 77.8% (n=35) and female was 22.2% (n=10). The mean age was 55.67 (SD± 12) years and mean age of male was higher compared to female (57.54±11.64 years verses 49.1±11.38 years). Most of the male were smokers (71.1%) and female were nonsmokers (90%). 57.78% (n=26) of patients and 42.22% (n=19) of patients had adenocarcinoma and squamous cell carcinoma respectively. Most squamous cell carcinoma patients were elderly, had wasting and having higher TNM staging. Serum LDH level was higher with advance staging and grading. Only 8.89% (n=4) had HER-2/neu positive expression affected by male. Patients with HER 2/neu positive expression were relatively older (mean age 62.5±17.08). However, there were equal in histopathological categorization (50% SCC and 50% Adenocarcinoma). Mean LDH was slightly higher in HER-2 positive patients was compared to HER-2 negative patients (569.5±232.6 versus 469.7±181.8). Conclusion: About nine percent of patients having HER-2/neu positive was relatively older and had more high level of LDH. A large-scale study should be conducted in Bangladeshi population to characterize epidemiological, clinicopathological feature in patients with NSCLC with HER-2 expression. J Dhaka Med Coll. 2021; 29(1): 99-110

Genetic parameters for liveweight (LWT), greasy fleece weight (GFW), mean fibre diameter (MFD), standard deviation of MFD (MFD-s.d.), mean fibre curvature (CURVE) percentage of medullated (%MED) and kemp (%KEMP) fibres, faecal worm egg count (WEC), packed cell volume (PCV), mean corpuscular volume (MCV) mean corpuscular haemoglobin content (MCHC), circulating anti-nematode IgG (IgG) and counts of circulating eosinophils (EOS), lymphocytes (LYM), neutrophils (NEU), basophils (BASO) and monocytes (MONO) up to 18 months of age were estimated in Australian Angora goats (608 animals, 14 sires 3 years of birth). Measurements were made during a period of natural parasite challenge up to 5 months of age, or following artificial challenge with 10 000 infective larvae of Trichostrongylus colubriformis at 5.25 months of age. Year of birth had a significant impact on production and parasite-associated traits at all ages studied. Sex had a marked effect on production and erythrocyte traits. Birth type had no effect on any traits in animals older than 6 months. Maternal effects were not significant except for LWT at 3, 5 and 6 months and for IgG at 3 months. Most production traits were highly (LWT, GFW, MFD, %MED) or moderately (CURVE, MFD-s.d.) heritable (range 0.17–0.59) with only %KEMP having a low heritability (0.02–0.14). The heritability estimates (±s.e.) for CURVE are novel for goats and ranged from 0.18 ± 0.09 at first shearing to 0.44 ± 0.14 at third shearing. Heritability estimates were low for WEC (0.02–0.16) and for specific IgG during natural infection (0.14–0.15) but higher for IgG following artificial challenge with T. colubriformis (0.42 ± 0.13). Of the haematological variables NEU and all red cell traits were highly heritable (0.45–0.71), LYM and MONO were moderately to highly heritable (0.31–0.55), and EOS was weakly to moderately heritable (0.06–0.28). Strong phenotypic correlations existed between production traits. MFD was positively correlated with GFW and negatively correlated with CURVE, indicating that finer fibres have a higher crimp or wave count. WEC had consistent negative phenotypic correlations with PCV, LYM and EOS, and positive correlations with NEU. Correlations with IgG were positive up to 5 months and negative thereafter. Phenotypic correlations between WEC and LWT as well as with GFW and MFD were negative. Heritability estimates for production traits were generally consistent with other studies. Haematological and fibre curvature findings are completely novel for Angora goats. Estimates of heritability for WEC fell in mid range of published findings for other goat breeds, and these results suggest that there is some scope for breeding for worm resistance in Angoras but the response is likely to be slow.

Background & objective: The importance of establishing hormone receptor status of tumors for the treatment of women with hormone receptor-positive breast cancer is often emphasized. It is critical to evaluate hormone receptor status when considering response to endocrine therapy. The present study was intended to evaluate the usefulness of hormone receptor status in breast carcinoma. Materials & Methods: The present study was conducted in the Department of Pathology, Dhaka Medical College, Dhaka over a period 12 months from July 2009 to June 2010. A total of 30 histopathologically diagnosed cases of breast tumors who were also subjected to immunohistochemical (IHC) test for ER, PR status and HER-2/neu were consecutively included in the study. Patients who have already been treated for malignancy or who had a history of receiving radiotherapy were excluded. Result: Age distributions shows that 40% of the patients were early middle-aged (30-40 years), 30% middle-aged and the rest were either < 30 years or >50 years old. Left breast was involved more often (56.7%) than the right breast (43.3%). The predominant location was upper outer quadrant (43.3%), followed by upper inner quadrant (20%), lower outer quadrant (20%), lower inner quadrant (10%) and central (6.7%). Over half (53.3%) of the tumors were < 5 cm and the rest 5 cm or more. Nearly half (46.7%) of the tumors were moderately differentiated, 36.6% well-differentiated and 16.7% poorly differentiated. In majority (83.3%) of the cases lymph-nodes (axillary lymph nodes) were involved. Based on estrogen and progesterone receptor status, over half (53.3%) of the tumors were ER and PR positive and 40% were Her2/neu overexpressed. Conclusion: The study concluded that half of the Bangladeshi breast cancer patients are ER and PR positive and two in every five cases are Her2/neu overexpressed. J Shaheed Suhrawardy Med Coll, December 2018, Vol.10(2); 70-73

Background : Receptor status and molecular subtyping of breast cancers are crucial for patient management.We present here our initial experience on the status of different molecular subtypes and clinicopathological characteristics of invasive breast carcinomas in Bangladeshi population especially in Chittagong zone.Methods : A total of 59 histopathologically confirmed cases of invasive ductal carcinoma were selected for this study. Fifteen out of 59 cases were reported as HER2 equivalent and could not be categorized into any subtype because of the lack of availability of fluorescence in situ hybridization. The remaining 44 cases were distributed into different molecular subtypes and then the clinicopathological characteristics were compared for each molecular subtype.Results : Age ranges from 24-70 years with a mean age of 43.95 years. Most of the patients were in 41-50 years age group. Among the 44 cases, most common subtype was HER2/neu amplification 13 cases (29.55%). Luminal A, luminal B and basal like subtypes were 11 (25%) 10 (22.73%) and 10 (22.73%) respectively. The mean tumor size was 3.46 cm and the highest mean tumor size was in basal like subtype (4.01cm). Twenty five out of 59 cases (42.37%) showed axillary lymph node metastasis. Lowest axillary lymph node metastasis was found in luminal A subtype (3/11=27.27%).Conclusion : HER2/neu amplification subtype was found to be more common in this region. Luminal A subtype was found to be more favorable in comparison to the other subtypes in terms of axillary lymph node metastasis.Chatt Maa Shi Hosp Med Coll J; Vol.16 (2); July 2017; Page 1-4

Introduction: Breast cancer is a common malignancy among female in Bangladesh.But its molecular subtypes are not evaluated due to lack of expert investigationsupport. So objectives of the present study are to evaluate the molecular subtypesof breast cancer patients according to St Gallen classification in our contest. Materials and methods: It is retrospective study done among histopathologicallyproved 40 breast cancer patients visiting Medical Oncology and Radiotherapydepartment of Chattogram Maa-O-Shishu Hospital. Molecular subtypes wasevaluated by immunohistochemistry according to St Gallen Classification. Results: In this study a total of 40 cases of invasive female breast cancers wereincluded. Age of the patients ranged from 31-62 years, with a mean age of 41 ±13.5 years. ER expression was seen in 60% and PR in 55% of cases and Her-2/neupositivity in 16%. Majority (52.5%) of the tumors were located in the left breast. Thepercentage of ER but not PR positivity increased with age, though this differencewas not statistically significant. Majority of the cases were diagnosed at stage IIwith a percentage of 42.5%. Stage II tumors showed more ER and PR positivity.Among all 57.9% of ER positive and 49.5% of PR positive tumors were present while72.2% of tumors were negative for Her-2/neu. The triple-negative breast tumorswere more commonly found at grade 2. Regarding luminal status 14(35%) wasLuminal A, 5(12.5%) was Luminal B, 9(22.5%) was TNBC and 12(30%) was HER 2positive. Conclusion: In this study luminal A was the commonest molecular subtypes. LuminalA subtypes tumors had a long term risk of distant matastatic disease which can bereduced by hormonal treatment. Chatt Maa Shi Hosp Med Coll J; Vol.19 (1); January 2020; Page 55-58

Abstract OBJECTIVE: An understanding of the learning curve of a new surgical procedure is essential for its safe clinical integration, teaching, and assessment. This knowledge is currently deficient for lumbar microendoscopic discectomy (MED). The present article aims to profile the learning curve for MED of an individual surgeon in a hospital not previously exposed to this procedure. METHODS: The first 35 cases of MED for posterolateral lumbar disc prolapse causing radiculopathy performed at the Princess Alexandra Hospital, Brisbane, Australia, were studied prospectively. The learning curve was assessed using surgery time, conversion rate, complication rate, surgeon “comfort,” and key learning steps. RESULTS: The duration of surgical operating time decreased over the course of the study, initially rapidly and then more gradually. There were three conversions to open discectomy in the first 7 cases and none in the next 28 cases. The complexity of cases increased over the series, and the complication rate decreased. The asymptote of the learning curve seems to be approximately 30 cases. The specific learning tasks of MED include lateral lamina radiology, scope vision, visuospatial orientation, smaller field of view, angle of approach and tube position, and care and handling of endoscope equipment. CONCLUSION: A learning curve for MED has been demonstrated. Further assessment of this curve for a population of surgeons is necessary before a clinical assessment of open discectomy versus MED can be embarked upon.

Abstract BACKGROUND: Several authors have reported results obtained with the microendoscopic diskectomy (MED) technique, but the long-term outcome has not been described. This report summarizes our clinical experience with the lumbar MED technique with a long-term follow-up period. OBJECTIVE: To evaluate the efficacy of the MED for lumbar disk herniation and to report long-term outcome and complications (5-year follow-up). METHODS: One hundred twenty consecutive patients with lumbar disk herniation were treated with the METRx system.We included all types of lumbar herniated disks: contained, not contained, foraminal, and migrated disk herniations. The results were evaluated with the Visual Analog Scale (VAS) pain score, Oswestry Disability Index score, patient satisfaction questionnaire, and modified Macnab criteria. RESULTS: The average age of patients was 41 years; 65 were men and 55 were women. The most commonly affected level was L5-S1 (54.2%). The follow-up time after surgery was 5 years in all cases. We obtained good or excellent results in 75% of patients and regular results in 18%. Good subjective satisfaction was observed with surgery in 92% of patients. The mean decrease in the Oswestry Disability Index score was 52.8 ± 21.6; the mean decrease in leg VAS score was 6.1 ± 2.3; and the mean decrease in lumbar VAS score was 1.9 ± 3.3. Adjusted mean differences were statistically significant in all cases (P &lt; .05). CONCLUSION: MED not only reduces the incision, tissue damage, and postoperative period of incapacity but also offers long-term results comparable to those of conventional techniques.

Abstract OBJECTIVE: Minimally invasive spinal techniques have been developed for years in an attempt to minimize trauma. However, most endoscopic techniques have been unable to address uncontained or large contained disc herniations. The aim of this prospective study was to compare the results of microendoscopic discectomy (MED) and microsurgical discectomy in the treatment of patients with uncontained or large contained disc herniations. METHODS: An independent observer reviewed the treatment of 28 patients. The study group included 14 consecutive patients who underwent MED and 14 consecutive patients who underwent microsurgical discectomy for radicular pain secondary to uncontained or large contained disc herniations during the same period. Patients were followed up for an average of 12 months. They were assessed by use of Oswestry disability questionnaire and low back pain outcome score. RESULTS: The average outcome score improvement was of clinical significance in both patient groups. No difference in the scores was found between the two groups. Patients in the MED group required less postoperative analgesia during their stay. One patient in the MED group had a dural tear. CONCLUSION: MED is at least as effective as microsurgical discectomy for treatment of uncontained or large contained disc herniations, although the advantages over the open technique are short lived and did not reach significance. Nonetheless, for the surgeon accustomed to endoscopic techniques, MED seems to be a safe procedure.

Abstract OBJECTIVE We compared the intra- and postoperative differences, as well as the final outcome of patients with herniated lumbar discs who underwent either open discectomy (OD) or microendoscopic discectomy (MED). METHODS We performed a prospective controlled randomized study of 40 patients with sciatica caused by lumbar disc herniations nonresponsive to conservative treatment who underwent OD or MED with a 24-month follow-up period. Pre- and postoperative neurological status, pain, and functional outcome were evaluated. Other studied variables were the duration of the procedure, blood loss, time of hospital stay, and time to return to work. Statistical analysis with a P value less than 0.005 was carried out. RESULTS The only statistically significant differences found were for size of the incision, length of hospital stay, and operative time. The former two were greater in the OD group (P &lt; 0.01 and P = 0.05, respectively), and the latter was greater in the MED group (P &lt; 0.01). CONCLUSION The few parameters that were found to be statistically significant between the groups did not affect the overall outcome. In the current series, the final clinical and neurological results were similarly satisfactory in both the OD and the MED groups.

BackgroundAST-021p, which is derived from HLA class II binding epitopes of human HSP90 protein, is an investigational therapeutic cancer vaccine for the malignant neoplasms. AST-021p is designed to demonstrate the immunologic efficacy by activating antigen-specific CD4+ Th1 cell in humans. Due to their ability to link the innate with the adaptive immune response, Toll-like receptor (TLR) agonists are highly promising as adjuvants in vaccines against life-threatening and complex diseases such as cancer, AIDS and malaria. In this study, AST-021p was investigated to evaluate the immunogenicity and tumor growth inhibitory effect under the condition of combining with various immune adjuvants derived from TLR agonists, using in-vivo model.MethodsThree different agonists of TLR (TLR-4, TLR-2/3, TLR-7/8) were assigned to investigate the immunogenicity in each group (4 FVB mice/group, total 4 groups). AST-021p was intradermally injected 3 times with different TLR-agonists and the immunogenicity was assessed from mouse splenocyte by HSP90-specific IFN-γ ELISpot method. We also examined the efficacy of AST-021p and selected TLR-agonist in MMTVneu Tg mice (4 mice/group, conducted twice and A total 8 mice was assigned to each group). The combination of AST-021p and TLR-2/3 agonist (AST-021p plus TLR-2/3 agonist) was injected 3 times every 10 days to mice followed by inoculated mouse mammary cancer cell line. The tumor volume change and immunogenicity were evaluated.ResultsThe most effective TLR-agonist as a potent immune adjuvant was a TLR-2/3 agonist (L-pampoTM, supplied by CHA Vaccine Institute). In MMTV-Neu transgenic mice, AST-021p (100 μg) plus TLR-2/3 agonist significantly enhanced immunogenicity by increasing up to 130±10 HSP-90 epitope specific T cells per 1x105 splenocytes (P<0.001). AST-021p plus TLR-2/3 agonist also showed higher tumor growth inhibitory effect (170±108 mm3) on post-implantation 35th day by suppressing mouse mammary cancer cell line (5x105)-derived tumor growth, compared with a TLR-2/3 agonist alone (1031±450 mm3).ConclusionsCombination regimen of AST-021p and TLR-2/3 agonist (as immune adjuvant) demonstrated significant immunogenicity and tumor prevention effect in in-vivo study. These data supported the clinical study of AST-021p combined with TLR-2/3 agonist as active immune adjuvant in certain tumor types, and phase 1/2 clinical program would be expected to be initiated.AcknowledgementsNot applicableTrial RegistrationNot applicableReferencesCsermely P, Schnaider T, Soti C, Prohaszka Z, Nardai G. The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol Ther 1998;79,129–168.Wang H, Lu M, Yao M, Zhu W. Effects of treatment with an Hsp90 inhibitor in tumors based on 15 phase II clinical trials. Mol Clin Oncol 2016;5,326–334.Ramalingam S, Goss G, Rosell R. Schmid-Bindert G, Zaric B, Andric Z, Bondarenko I, Komov D, Ceric T, Khuri F. A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). Ann Oncol Off J Eur Soc Med Oncol 2015,26,1741–1748.Ethics ApprovalAll experimental procedures involving mice were performed with the guidance protocols approved by the Institutional Animal Care and Use Committee of Korea University (IACUC, Approval number: KOREA-2019-129)ConsentIt is not an abstract containing sensitive or identifiable information.

Die Bedeutung von Boethius allgemein und von seinem Traktat De consolatioe philosophiae (ca. 524) ist so allgemein bekannt, dass wir darüber hier keine weiteren Worte fallen lassen müssen. Die jüngere Forschung hat in immer wieder neuen Ansätzen nachzuweisen vermocht, welche kontinuierliche, globale Rezeption dieser spätrömische Philosophie quer durchs gesamte Mittelalter, dann während der Renaissance, der Reformation, und auch noch während des Barocks genoss, und eigentlich hat seine Beliebtheit auch danach an nichts eingebüßt. Im 19. und 20. Jahrhundert wurde der Text immer wieder neu herausgegeben und übersetzt, ob ins Deutsche oder in viele andere Volkssprachen.

Abstract: Zum 500ten Jahrestag des Bauhüttentags von 1518 in Annaberg veranstalteten das Institut für Kunst- und Musikwissenschaften der TU Dresden und das Institut für Kunstgeschichte der Universität Würzburg im September 2018 ein Kolloquium. Thema: ,,Baumeister im Konflikt – Der Annaberger Hüttenstreit und andere Streitfälle im Bauwesen des 15. und frühen 16. Jahrhunderts“. Die hierfür zusammengetragenen und z.T. neu erschlossenen Quellen zu den organisatorischen und rechtlichen Rahmenbedingungen des Baugewerkes, insbesondere zu den Handwerksordnungen der Steinmetze, ließen es in der Folge angezeigt erscheinen, die Sicht geografisch zu weiten und weitere Quellen zusammenzutragen und auszuwerten. Dies geschieht nun knapp 2 Jahre später in diesem Band.

Background: Early stage breast cancer can often be cured with surgery alone though there are chances of recurrent disease and decrease in survival. Adjuvant poly-chemotherapy with docetaxel-based regimens can improve both disease-free and overall survival in patients with operable breast cancer. Objective: This study was designed to evaluate the patient profile and current pattern of care with docetaxel based adjuvant regimen in operable breast cancer patients including the treatment outcome from clinical practice. Materials and method: This prospective, observational, non-comparative study planned to enroll newly diagnosed operable breast cancer patients with high risk of recurrence after surgery. Selection of docetaxel-based treatment strategy and dosage of therapy was at the discretion of individual oncologists as per routine clinical practice. Patient data were recorded during inclusion, each cycle of therapy, and follow-up at 1 year (+/- 1 month) after inclusion. Results: Between August 2008 and July 2011 a total of 85 patients with median age of 53 years (23-73 years) were enrolled and 53 (62.4%) patients were postmenopausal. Ductal carcinoma, the most common cancer type,was found in 73 (85.9%) patients. Receptor status was positive for estrogen, progesterone or Her2/neu/erbB2 in 65.9%, 47.1% and 5.8% patients, respectively. Mastectomy either partial or total was performed in 76 (89.4%) patients for the current disease. An average of 8 (range: 2-15) lymph nodes (LN) mostly in axilla were excised in 56 patients and average of 4 (range: 1-11) LN nodes were positive. Sentinel LNs were negative, excised in 4 patients. The mean tumor size was 5.5 cm and most (82.4%) patients were diagnosed at Stage II disease including some at Stage I and III (7.1%, 10.6%). Docetaxel (Taxotere®) was combined with cyclophosphamide alone or in addition with doxorubicin, epirubicin, 5 FU and trastuzumab either in combination or sequential regimen. Taxotere in combination with adriamycin and cyclophosphamide was planned for 63.5% patients. Trastuzumab as sequential therapy could be afforded by 1 patient only. Data regarding radiotherapy or hormone therapy was not recorded. At the end of four cycles, 83.5% of patients were found disease free and 5.9% had loco regional relapse. At 1 year 71 (93.4%) patients were alive, 63 (88.7%) were relapse-free and 8 (11.2%) had loco regional relapse. Nausea, vomiting, diarrhea, alopecia, anemia and neutropenia were most commonly reported adverse events classified as Grade 1 or Grade 2. Grade 3 neutropenia was reported in 5 patients and 2 patients reported grade 4 neutropenia. Grade 3 diarrhea was reported in 1 patient. Conclusion: Docetaxel as adjuvant chemotherapy offered one year survival in 93.4% (71/76) of the patients and 88.7% (63/71 patients) were disease-free. The safety profile of docetaxel based regimens was expected and manageable. Delta Med Col J. Jan 2019 7(1): 4-10

IntroductionINTRODUCTION-OBJECTIVES. Similar to philosophy (regina-scientiarum) is psychiatry fundamental-discipline for all-medical&social sciences. Immanuel KANT: Primus inter pares of ARISTOTELES&PLATON considered over 200years ago physiological and pragmatic anthropology-[1]. Social physiology is given-[3-4]. Consideration of social-psychopathology in German-justice-[2].Objectives REFERENCES. [1]-Kant,I: BdXI,371-393, BdXII,399,625-638:Suhrkamp-TB-Wiss. [2]-Neu,E/Michailov, M.Ch/Welscher,U/et-al.: 2a.-FISP-2018-Beijing/Philos (1348-50,1373-4,1420); 2013-Athens Abstr.Book(AB):464-5/503-4/766; 2008-Seoul-ProcVol.4: 101-108/195-214/229-237; 2003-Istanbul:273-281; IVR-2019-Luzern (Law), Progr-Book p.116. 2b.-EPA-2020-Madrid, Eur.Psychiatry 63S, EPP0834/5+EPV0581/1470; EPA-2019-Warsaw, 56S,S689; EPA-2018-Nice, 48/S1, S623&567&662. 2c.-WPA-2021-Bangkok (in-press). 2019-Lisbon, E-Poster WCP19-2137/-1822/-1839. 2018-Mexico-City, Abs.-Book WCP18-0584/-0625/-0643/-0654. 2011-Buenos-Aires, AB:PO1.200. [3]-Glasachev,O: Sechenov Physiol.J 80/no5, 1994,p.139-143 (Russian), ref. in English. [4]-Seeley,T.D: Social-Physiology Honey-Bee, Book-1996.Methods[5]-Daily-journal-“tz”-München, esp. every Tuesday 2016-2019: reports on Res.-Houses,e.g. 14.02.2019, 15.02.17, 06.12.16/p.10, 18.10.16/p.10, 17.11.2020/p.6. Süddt.Zeitung-München no172/p.30,2017. Mü.-Merkur:16.11.2020/p.32; 19.11.2020/p.29. FAZ:20.10.2019/p.53; 16.11.2020/p.21. BUROW,P: Justiz am Abgrund&Ein Richter klagt an. GNISA,J, Präs.-Dt.Richterverein: „Ende der Gerechtigkeit“, Herder-2017. SCHLEIF,T/Amtsrichter: Buch „Urteil: ungerecht“, zeit-online 24.10.2019. Hans-Jochen&Liselotte VOGEL:„Mehr Gerechtigkeit“, 2019 „Wohn-Irrsinn“(Enteignungen). ZANTKE,S (Richter-Amtsgericht-Zwickau): TV-Programm„Auf einen Blick“ Nr.47,2018,S.24. [6]-Luetge,Ch et-al.(ed): Experimental-Ethics, Palgrave-Macmillan 2014. [7]-Pegoraro,R/Vatican: «Arzt&Christ» 38:3-55,1992.ResultsRESULTS Prominent German experts for justice: Patrick BUROW, Jens GNISA/President Law-Association/Germany, Torsten SCHLEIF/Amtsrichter, Hans-Jochen VOGEL/Ex-Minister, Stephan ZANTKE/Richter reflect in their books fundamental-criticism of German justice [5]. Inst.-Ecol.-Med./IUM investigated psychopathology of juridical-offices&law-court in Munich (Amtsgericht). Analysis suggests presence of symptoms for pseudologia-phantastica, psychopathy, cyclophrenia (esp.mania),etc. conc. observations on many persons (n>30).ConclusionsCONCLUSION. Juridical situation in Germany demonstrates contradiction to human-rights (EU-CHARTA, art.1-8/25-26/33-35), ignoring moral-philosophy, related to human obligations/I.Kant-[1], experimental ethics/Ch.Luetge et-al.-[6], medical personnel/R.Pegoraro-[7]. Only paradigm change in law-policy incl. enlarged implication of moral philosophy-theology, psychiatry-psychology, social philosophy in juridical eduction & practices could counteract disastrous juridical situation in Germany and on global level, supporting UNO-AGENDA21 for better education-health-ecology-economy (see 2.).DisclosureNo significant relationships.

Mit etwas Verwunderung, oder schlicht tief beeindruckt nimmt man diese neue Edition zusammen mit ihrer ausführlichen Kommentierung in die Hand, ein zweibändiges Werk, in dem Wolframs von Eschenbach Parzival in einem Mammutverfahren nach der Handschrift D, heute in der Stiftsbibliothek von St. Gallen (Cod. 857) aufbewahrt, neu herausgegeben wird. Ihre Beschreibung findet sich im 2. Band, S. 18–22, worauf dann die Beschreibungen aller anderen Handschriften folgen, die den Parzival enthalten, was für sich genommen schon eine erstaunliche Leistung darstellt. Reichert geht hier weit über den Wissensstand hinaus, der online im Marburger Repetorium geboten wird (<ext-link ext-link-type="uri" xlink:href="http://www.handschriftencensus.de/werke/440">http://www.handschriftencensus.de/werke/440</ext-link>), insoweit als er detailliert die Angaben über den entsprechenden Textbestand vom Parzival liefert, wogegen er die historischen Informationen zu den Handschriften weitgehend weglässt, die man aber, wie gesagt, online finden kann.

Seit einiger Zeit haben die Prosaromane der Gräfin Elisabeth von Nassau-Saarbrücken steigendes Interesse erfahren, was schließlich auch dazu geführt hat, dass sich Bernd Bastert (Bochum) und Ute von Bloh (Potsdam) jeweils mit einem Forschungsteam von Studenten darum bemüht haben, alle ihre vier Werke in kritisch bearbeiteten Ausgaben neu herauszugeben. Nun liegt der letzte Band vor, der Huge Scheppel und die Königin Sibille enthält. Wie in ihren bisherigen Editionen haben sie ganz bewusst den Namen der Autorin weggelassen, weil sie ernsthaft bezweifeln, dass Elisabeth entscheidend, wenn überhaupt, an der Schaffung dieser Romane beteiligt gewesen war. Dies wird freilich hier noch nicht einmal diskutiert, und der Leser sieht sich schlicht anonymen Texten gegenüber, was an und für sich genommen schlicht nicht stimmt. Diese Anonymität bleibt nach meiner Meinung sehr zweifelhaft, denn die Beweislast, ihr die Autorschaft abzusprechen, liegt bei Bastert und von Bloh, die aber bisher nicht genügend Evidenz für ihre negative These produzieren konnten, und was auch im vorliegenden Band nicht belegt wird.

Man wird Harald Müller, dem Herausgeber des vorliegenden, auf ein Kolloquium im Historischen Kolleg München (März 2015) zurückgehenden Sammelbandes wohl zustimmen müssen: Gegenpäpste galten (und gelten) als ,,finstere Bedrohungen der wahren Kirche mit hohem dramatischen Wert und Aktualisierungspotenzial“ (2). Dies mag mit dafür verantwortlich sein, dass in den letzten Jahren das Interesse an Gegenpäpsten neu erwacht ist. Müller selbst hat daran maßgeblichen Anteil. Seine profunden Kenntnisse auf dem Gebiet <?page nr="515"?>entfaltet er in einem einleitenden Kapitel (Autorität und Krise. Der Verlust der Eindeutigkeit und seine Folgen am Beispiel der mittelalterlichen Gegenpäpste – einleitende Gedanken, 1–18). Strukturelle und konflikttheoretische Ansätze greifen hier ineinander: Spaltung sei, so Müller, stets als Vervielfältigung, als Multiplikation von Ämtern und Strukturen zu begreifen. Im Konflikt um das Papstamt gehe es um Eindeutigkeit, sowohl auf der Wahrnehmungs- als auch auf der Handlungsebene, setzten doch Papstprätendenten alles daran, eindeutige Zustände durch eine Überwindung der Konkurrenz herzustellen. Dazu gehört retrospektiv auch die Vereindeutigung in der memoria und Geschichtsschreibung. Das macht den Umgang mit ,,Gegenpäpsten“ nicht unbedingt einfacher, sind sie doch in erheblichem Maße Produkt, ja sogar Konstrukt krisenbegleitender Fremdzuschreibungen.

Nordengland ist anders: darauf machte bereits William of Malmesbury im 12. Jahrhundert aufmerksam, als er auf die ,,nichtverständliche“ Sprache verwies, in der man in diesen Landesteilen zu kommunizieren pflegte. Wer heute durch Städte wie Durham und York wandert oder gar der Ruinenromantik zisterziensischer Großabteien wie Fountains oder Rievaulx erliegt, spürt, über welchen kulturellen Reichtum der Norden Englands verfügte und noch immer verfügt. Teil dieses kulturellen Erbes sind die Heiligen. Ab dem 7. und 8. Jahrhundert entstanden einflussreiche Heiligenkulte in Northumbria. Oswald, Aidan, Hilda, Aebbe, Cuthbert, John of Beverly, Wilfrid, und wie sie alle heißen mögen, hielten ihre schützende Hand über den Norden und prägten die lokalen Identitäten entscheidend mit, kein Kult aber war einflussreicher als derjenige des Hl. Cuthbert. Um 634 wurde er geboren und nach einem heiligmäßigen Leben als Asket und Einsiedler zum Bischof von Lindisfarne erhoben. Er starb 687 als Eremit im Ruch der Heiligkeit. Heilungswunder an seinem Grab ereigneten sich unmittelbar nach seiner Beisetzung. 995 fand er seine endgültige Ruhestätte in Durham, die Translation in die neu erbaute Kathedrale erfolgte 1104. Doch auch wenn Cuthbert die Heiligenszene dominierte, pflegte man in sanctis keinen ausschließlichen Blick auf die Vergangenheit. Neue Kulte kamen im 12. Jahrhundert hinzu, darunter diejenigen des Godric von Finchale, Bartholomäus von Farne oder Waldef von Melrose, wobei sich die jeweilige Kultpraxis stark dem Vorbild des Hl. Cuthbert verbunden zeigte.

AbstractObjectiveThe acute-on-chronic liver failure associated with hepatitis B virus (HBV-ACLF) was a type of clinical syndrome with rapid deterioration of liver function. It was characterized by short-term elevated bilirubin, ascites, prolonged clotting time, hepatic encephalopathy, organ failures, and high short-term mortality. It was important to predict and evaluate the disease early. This study intended to comprehensively analyze the prognostic factors of patients with ACLF associated with HBV DNA infection through clinical manifestations and laboratory tests, and to establish a corresponding prediction and evaluation model for further clinical guidance.MethodsA total of 220 patients were first diagnosed with HBV-ACLF and admitted to and treated at the Department of Infectious Diseases of the First Affiliated Changhai Hospital of the Second Military Medical University from 2009 to 2018. These patients’ records were collected and divided into two groups: (1) 120 patients who were improved and discharged were classified as good prognosis group and (2) 100 patients who died or underwent liver transplantation were classified as poor prognosis group. By analyzing baseline characteristics and clinical indicators of the two groups, the main potential factors affecting prognosis were identified and the corresponding prognostic evaluation model was established. This model’s advantages and disadvantages were compared with classic prognostic scoring systems.ResultsThe proportion of ascites and the proportion of hepatic encephalopathy of poor prognosis group were significantly higher than those of good prognosis group. The total bilirubin, creatinine, white blood cell count, and NEU (%) levels of poor prognosis group were significantly higher than those of good prognosis group, and the international normalized ratio, albumin (ALB), alanine aminotransferase, Na, Cl, RBC, and PLT levels of poor prognosis group were significantly lower than those of good prognosis group. A new prediction model LR(p) = 1/(1 + e−Z) was established, where z = 10.0127 + 0.3687 × NEUT (%) − 0.0082 × PLT + 1.8157 × hepatic encephalopathy. The area under receiver operating characteristic (ROC) curve was 0.89, specificity was 80.83%, and sensitivity was 81%. The newly established prognostic model was compared with other three scoring systems including model for end-stage liver disease (MELD), MELD-Na, and ALBI scores. The results showed that the specificity, sensitivity, and area under the ROC curve of the newly established model were significantly higher than the other three scoring systems.ConclusionHepatic encephalopathy, NEU (%), and PLT levels were independent risk factors for predicting the prognosis of HBV-ACLF. The new prediction model LR(p) had better prediction accuracy than the other three scoring models of MELD, MELD-Na, and ALBI and could more accurately assess the prognosis of HBV-ACLF, but in the later stage, it was still necessary to expand the sample size for verification.

Background:The drugs that inhibit tumor necrosis factor (anti-TNF) alpha can reactivate a latent tuberculosis infection (ILTB) so requiring a rigorous screening before its onset. The tuberculin test (PT) has a high false negative rate in patients with immunomediated rheumatic diseases (IMID) and false positive in patients vaccinated with Bacillus Calmette Guérin (BCG). The neu methods of interferon gamma release (IGRA) seem to solve this problem, but its use is not standardized.Objectives:Establish the degree of concordance in the diagnosis of ILTB between PT and IGRA in patients who are going to star an anti-TNF drug, in general, and in different situation like taking corticosteroids, being treated with disease modifying drugs, have been vaccinated with BCG or have risk factor for ILTB.Methods:From May 2016 to November 2019, 195 patients with IMID who underwent ITLB screening prior to the initiation of an anti-TNF drug were included in this study. The concordance between PT and IGRA was calculated using the cohen’s kappa index, for the general sample first and then for subgroups. An analysis of the factor that influence the result of PT and IGRA has also been carried out.Results:The prevalence of ILTB was 26.7%. Of the total positive PT and Booster (n=50), QTF-G-IT was positive only in 15 patients (30%). The agreement between PT and QTF-G-IT was 0.33 (p<0.05). In the subproups, a moderate agreement was found in patients who did not take corticosteroids (k=0.45, p<0,05) and greater than the global one in those who had risk factor for ITLB (k=0.37, p<0.05).Conclusion:In our study the agreement between PT and QT-G-IT is low in general, being somewhat higher in unvaccinated patients and with a high probability for ILTB. Taking this result into account due to the low concordance, the ideal ILTB screening strategy in patients who are going to start a anti-TNF would consist of performing both tests.References:[1]Goletti D, Petrone L, Ippolito G, Niccoli L, Cantini F, Goletti D, et al. Expert Review of Anti-infective Therapy Preventive therapy for tuberculosis in rheumatological patients undergoing therapy with biological drugs with biological drugs. Expert Rev Anti Infect Ther. 2018;16(6):501-12.[2]Ortiz AM, González-álvaro I, Laffón A. Mecanism os de acción de fármacos modificadores de la evolución de la artritis reumatoide. 2001;420-7.[3]Algood HMS, Lin PL, Flynn JL. Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis. agosto de 2005;41 Suppl 3:S189-93.[4]Bopst M, Garcia I, Guler R, Olleros ML, Rulicke T, Muller M, et al. Differential effects of TNF and LTalpha in the host defense against M. bovis BCG. Eur J Immunol. junio de 2001;31(6):1935-43.[5]Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen P, et al. Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. diciembre de 2015;74(12):2107-16.[6]Randhawa PS. Lymphocyte subsets in granulomas of human tuberculosis: an in situ immunofluorescence study using monoclonal antibodies. Pathology. julio de 1990;22(3):153-5.[7]Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. marzo de 2003;3(3):148-55.[8]Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. octubre de 2001;345(15):1098-104.[9]Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. agosto de 2003;48(8):2122-7.Disclosure of Interests:None declared

Breast cancer stands first in the incidence of malignancy in women. Enormous studies have been conducted worldwide regarding hormone receptor status in breast cancer. The study was done in the department of pathology in Khulna Medical College, Khulna to compare the clinicopathologic features with four breast cancer subtypes defined by immunohistochemistry (IHC) expression of estrogen receptor (ER) or progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2): ER/PR+, Her2+; ER/PR+, Her2_; ER/PR_, Her2+; and ER/PR_, Her2_ and to evaluate hormone receptor status in breast cancer to estimate a patient's response to endocrine therapy and their prognosis for better clinical outcomes. It is a retrospective observational study from 1st January, 2015 to 31st December, 2017. A total 378 invasive breast cancer subjects who underwent diagnostic tests for hormone receptors status were included in this study. Clinical and pathologic features and survival of the four subtypes were compared. Data of oestrogen, progesterone and human epidermal growth factor receptor 2 expression statuses was analyzed. Overall record of 378 patients was studied of whom 43% were identified to have positive hormone receptor status. The age of the patients ranged from 24 to 86 years with 65% in 25-50 years, 30.8% in 51-75 years and 4.08% in 76- 100 years. Fiftyeight percent were diagnosed as Stage III, 37% Stage II and 5.3% Stage IV. Those diagnosed with oestrogen receptor (positive status) were 10.7%, human epidermal growth factor receptor 2 over-expression 8.7%, oestrogen/progesterone hormone receptor positivity 51% and 23.4% patients were positive for all the three receptors. The triple negative subtype has the worst overall and disease free survival. Faridpur Med. Coll. J. Jan 2019;14(1): 8-12

Background and Objective: Breast cancer incidence is increasing and it is highest in low income countries. The main challenge is regarding awareness, screening, late presentation and its management in a third-world country. Our objective was to share the experience faced in various presentations, diagnosis and management of locally advanced breast cancer (LABC) in a third world country and discuss if they are different with respect to developed countries. Methods: It is a retrospective case series study performed at Jinnah Postgraduate Medical Centre Karachi, from January 2015 to December 2017, over period of three years. Data was collected from the record maintained by authors about patients presenting in breast clinic. Patients of breast cancer were managed in breast clinic over 3 years. Our study included patients who presented with LABC based on their clinical presentation confirmed by histopathological diagnosis and followed by surgical management. Statistical analysis for students t-test was performed using SPSS (version 20.0). A p-value less than 0.05 was considered statistically significant. Results: One hundred twelve patients presented with LABC over period of 3 years. All but two were female. Mean age was 52 years (range 26-78 years), SD 18.96. On presentation size of tumor was 5cm & more in 103 (91.9%) patients. Involvement of axilla was in 86 (76.7%). Chest wall was involved in 22 (19.6%). Total T3 and T4 were 71 (63.3%) and 41 (36.6%) respectively Diagnosis of all patients was confirmed by histopathology. Neoadjuvant was given to all patients to downstage the tumor. ER/PR was positive in 46(41.1%), HER-2/neu positive in 31 (27.6%). On staging breast carcinoma was metastatic in 13(11.6%) with liver, lung and bone in 4 (3.5%), 3 (2.7%) and 6 (5.3%) respectively. Breast conservation was done in 6 (6.1%) patients, Modified Radical Mastectomy was done in 86 (86.9%), Radical Mastectomy in 3 (3.03%), Toilet Mastectomy in 4 (4.045) and 13 (11.6%) patients were not operated. Conclusion: In our series 65% of all breast cancers are LABC at presentation. In low/middle income countries high percentage of LABC at presentation result in high metastatic disease, poor prognosis and limits conservation of breast. Awareness and education can improve outcomes. doi: https://doi.org/10.12669/pjms.35.6.165 How to cite this:Manzoor S, Anwer M, Soomro S, Kumar D. Presentation, diagnosis and management of locally advanced breast cancer: Is it different in low/middle income countries (LMICs)?. Pak J Med Sci. 2019;35(6):1554-1557. doi: https://doi.org/10.12669/pjms.35.6.165 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This paper assesses the rate of lymph node metastasis and the correlation between lymph node metastasis and some pathological characteristics in special types of invasive breast cancer. In the paper, a descriptive cross‐sectional study was conducted on 200 patients with special types of invasive breast cancer at the Institute of Molecular Biology and Pathology - National Cancer Hospital from August 2020 to April 2021. The study results show that 32% of the 200 cases had nodal metastases. The factors associated with the increased risk of lymph node metastasis were of histological types (invasive lobular, invasive micropapillary carcinomas) (p = 0.000), high tumour grade (p = 0.000), the presence of lymphovascular invasion (p = 0.000), tumor-infiltrating lymphocytes (TILs) < 10% (p = 0.000), the presence of tumor necrosis (p = 0.001), Her-2/neu overexpression (p = 0.01), Ki-67 ≥ 20% (p = 0.036), HER2-positive breast cancer (p = 0.015). Overall, the rate of lymph node metastasis was 32%. Histological type, tumour grade, the presence of lymphovascular invasion, TILs, tumor necrosis, Her-2/neu and Ki-67 expression, and molecular subtype were factors related to lymph node metastasis in special types of invasive breast cancer. Keywords: Lymph node metastasis, invasive breast cancer, special types. References [1] World Health Organization, Breast Tumors (5th ed), International Agency for Research on Cancer, Lyon, France, 2019.[2] K. M. Masters, S. L.Wong, R. C. Martin et al., Dermal Injection of Radioactive Colloid Is Superior to Peritumoral Injection for Breast Cancer Sentinel Lymph Node Biopsy: Results of A Multiinstitutional Study, Annals of Surgery, Vol. 233, No. 5, 2001, pp. 676, https://doi.org/10.1097/00000658-200105000-00012. [3] A. V. Ashturkar, G. S. Pathak, S. D. Deshmukh, H. T. Pandave, Factors Predicting the Axillary Lymph Node Metastasis in Breast Cancer: Is Axillary Node Clearance Indicated in Every Breast Cancer Patient? 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Chan, Predictors of Axillary Lymph Node Metastases in Women with Early Breast Cancer in Singapore, Singapore Med J, Vol. 46, No. 12, 2005, pp. 693, https://doi.org/10.1016/s0959-8049(98)80134-2. [8] A. Barth, P. H. Craig, M. J. Silverstein, Predictors of Axillary Lymph Node Metastases in Patients with T1 Breast Carcinoma, Cancer, Vol. 79, No. 10, 1997, pp. 1918-1922, https://doi.org/10.1002/(SICI)10970142(19970515) 79:10<1918::AID-CNCR12>3.0.CO;2-Y. [9] Y. Iwasaki, Axillary Node Metastasis from T1N0M0 Breast Cancer: Possible Avoidance of Dissection in A Subgroup, Japanese Journal of Clinical Oncology, Vol. 28, No. 10, 1998, pp. 601-603, https://doi.org/10.1093/jjco/28.10.601. [10] G. Viale, S. Zurrida et al., Predicting the Status of Axillary Sentinel Lymph Nodes in 4351 Patients with Invasive Breast Carcinoma Treated in A Single Institution, Cancer, Vol. 103, No. 3, 2005, pp. 492-500, https://doi.org/10.1002/cncr.20809. [11] S. K. Çetintaş, M. Kurt et al., Factors Influencing Axillary Node Metastasis in Breast Cancer, Tumori Journal, Vol. 92, No. 5, 2006, pp. 416-422, https://doi.org/10.1177/030089160609200509. [12] T. V. To, A Study of Morphology, Immunohistochemistry and Their Prognostic Value in Breast Carcinoma, Ph.D Dissertation, Hanoi Medical University, Hanoi, 2004 (in Vietnamese).[13] R. Lauria, F. Perrone et al., The Prognostic Value of Lymphatic and Blood Vessel Invasion in Operable Breast Cancer, Cancer, Vol 76, No. 10, 1995, pp. 1772-1778, https://doi.org/10.1002/1097-0142(19951115)76 :10<1772::AID-CNCR2820761014>3.0.CO;2-O.[14] R. Yerushalmi, M. M. Hayes, K. A. Gelmon, Breast Carcinoma - Rare Types: Review of the Literature, Annals of Oncology, Vol. 20, No. 11, 2009, pp. 1763-1770, https://doi.org/10.1093/annonc/mdp245. [15] A. Caziuc, D. Schlanger, G. 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Vitamin E (VitE) is a potent antioxidant and contributes as an apoptosis inhibitor by preventing apoptotic death by suppressing cell membrane scrambling with phosphatidylserine translocation and caspase activites. Fas ligand (FasL) is well known to induce cell apoptosis. Activation of phosphoinositide 3 kinase (PI3K) signalling is stimulated by VitE. The present study addressed the effects of VitE on survival of mouse dendritic cells (DCs) and signalling molecules underlying. To this end, mouse bone marrow cells were isolated and cultured to attain bone marrow-derived DCs (BMDCs). The cells were treated with FasL in the presence or absence of VitE. Western blotting and FACS analysis were performed to determine expression of signalling molecules and their involvement in DC apoptosis. As a result, FasL treatment resulted in activation of caspase 8 and an increased number of Annexin V+ cells, the effects were significantly suppressed when VitE was present in the cell culture. Importantly, the anti-apoptotic effects of VitE were abolished by using pharmacological inhibition of PI3K signaling with LY294002. Our results showed that VitE inhibited FasL-mediated DC apoptosis through PI3K signalling, the effect is expected to facilitate the survival of DCs and promote the immune response against pathogens. Keywords Caspase, Dendritic cell; Fas ligand; PI3K and vitamin E. References [1] J. Banchereau, R.M. Steinman, Dendritic cells and the control of immunity, Nature 392 (1998) 245-52.[2] E. Ingulli, A. Mondino, A. Khoruts, M.K. Jenkins, In vivo detection of dendritic cell antigen presentation to CD4(+) T cells, J Exp Med 185 (1997) 2133-41.[3] C. Yang, H.Z. Liu, Z.X. Fu, PEG-liposomal oxaliplatin induces apoptosis in human colorectal cancer cells via Fas/FasL and caspase-8, Cell Biol Int 36 (2012) 289-96.[4] Q.G. Yan, J.G. Shi, F. Zhang, Q.T. Zhao, X.W. Pang, R. Chen, P.Z. Hu, Q.L. Li, Z. Wang, G.S. Huang, Overexpression of CYP2E1 enhances sensitivity of hepG2 cells to fas-mediated cytotoxicity, Cancer Biol Ther 7 (2008) 1280-7.[5] A. Hamai, C. Richon, F. Meslin, F. Faure, A. Kauffmann, Y. Lecluse, A. Jalil, L. Larue, M.F. Avril, S. Chouaib, M. Mehrpour, Imatinib enhances human melanoma cell susceptibility to TRAIL-induced cell death: Relationship to Bcl-2 family and caspase activation, Oncogene 25 (2006) 7618-34.[6] S. Lucken-Ardjomande, J.C. Martinou, Regulation of Bcl-2 proteins and of the permeability of the outer mitochondrial membrane, C R Biol 328 (2005) 616-31.[7] M. Rescigno, V. Piguet, B. Valzasina, S. Lens, R. Zubler, L. French, V. Kindler, J. Tschopp, P. Ricciardi-Castagnoli, Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1beta, and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses, J Exp Med 192 (2000) 1661-8.[8] C. Qian, L. Qian, Y. Yu, H. An, Z. Guo, Y. Han, Y. Chen, Y. Bai, Q. Wang, X. Cao, Fas signal promotes the immunosuppressive function of regulatory dendritic cells via the ERK/beta-catenin pathway, J Biol Chem 288 (2013) 27825-35.[9] L. Bo, S. Jiang, Y. Xie, H. Kan, W. Song, J. Zhao, Effect of Vitamin E and Omega-3 Fatty Acids on Protecting Ambient PM2.5-Induced Inflammatory Response and Oxidative Stress in Vascular Endothelial Cells, PLoS One 11 (2016) e0152216.[10] K.S. Ahn, G. Sethi, K. Krishnan, B.B. Aggarwal, Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis, J Biol Chem 282 (2007) 809-20.[11] E. Pierpaoli, V. Viola, F. Pilolli, M. Piroddi, F. Galli, M. Provinciali, Gamma- and delta-tocotrienols exert a more potent anticancer effect than alpha-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression, Life Sci 86 (2010) 668-75.[12] A.A. Albahrani, R.F. Greaves, Fat-Soluble Vitamins: Clinical Indications and Current Challenges for Chromatographic Measurement, Clin Biochem Rev 37 (2016) 27-47.[13] E. Shumilina, N. Zahir, N.T. Xuan, F. Lang, Phosphoinositide 3-kinase dependent regulation of Kv channels in dendritic cells, Cell Physiol Biochem 20 (2007) 801-8.[14] X. Jin, L. Song, X. Liu, M. Chen, Z. Li, L. Cheng, H. Ren, Protective efficacy of vitamins C and E on p,p'-DDT-induced cytotoxicity via the ROS-mediated mitochondrial pathway and NF-kappaB/FasL pathway, PLoS One 9 (2014) e113257.[15] B.C. Richardson, N.D. Lalwani, K.J. Johnson, R.M. Marks, Fas ligation triggers apoptosis in macrophages but not endothelial cells, Eur J Immunol 24 (1994) 2640-5.[16] J. Tschopp, M. Irmler, M. Thome, Inhibition of fas death signals by FLIPs, Curr Opin Immunol 10 (1998) 552-8.[17] J. Chung, Y.O. Yoon, J.S. Lee, T.K. Ha, S.M. Ryu, K.H. Kim, M.H. Jeong, T.R. Yoon, H.K. Kim, Inulin induces dendritic cells apoptosis through the caspase-dependent pathway and mitochondrial dysfunction, Biol Pharm Bull 34 (2011) 495-500.[18] S. Kreuz, D. Siegmund, J.J. Rumpf, D. Samel, M. Leverkus, O. Janssen, G. Hacker, O. Dittrich-Breiholz, M. Kracht, P. Scheurich, H. Wajant, NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP, J Cell Biol 166 (2004) 369-80.[19] S. Buonocore, S. Van Meirvenne, F.X. Demoor, F. Paulart, K. Thielemans, M. Goldman, V. Flamand, Dendritic cells transduced with viral interleukin 10 or Fas ligand: no evidence for induction of allotolerance in vivo, Transplantation 73 (2002) S27-30.[20] D. Ashany, A. Savir, N. Bhardwaj, K.B. Elkon, Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway, J Immunol 163 (1999) 5303-11.[21] D. Ashany, X. Song, E. Lacy, J. Nikolic-Zugic, S.M. Friedman, K.B. Elkon, Th1 CD4+ lymphocytes delete activated macrophages through the Fas/APO-1 antigen pathway, Proc Natl Acad Sci U S A 92 (1995) 11225-9.[22] S. Qi, W. Fu, C. Wang, C. Liu, C. Quan, A. Kourouma, M. Yan, T. Yu, P. Duan, K. Yang, BPA-induced apoptosis of rat Sertoli cells through Fas/FasL and JNKs/p38 MAPK pathways, Reprod Toxicol 50 (2014) 108-16.[23] L.P. Eberl, G. Egidy, F. Pinet, L. Juillerat-Jeanneret, Endothelin receptor blockade potentiates FasL-induced apoptosis in colon carcinoma cells via the protein kinase C-pathway, J Cardiovasc Pharmacol 36 (2000) S354-6.[24] N.T. Xuan, P.T. Trang, N. Van Phong, N.L. Toan, D.M. Trung, N.D. Bac, V.L. Nguyen, N.H. Hoang, N. Van Hai, Klotho sensitive regulation of dendritic cell functions by vitamin E, Biol Res 49 (2016) 45-54.[25] M. Baskiewicz-Masiuk, B. 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Photo by National Cancer Institute on Unsplash ABSTRACT Medical futility judgments for patients in prolonged disorders of consciousness (PDOC) frequently lead to withdrawal of life-sustaining treatment (LST), which is the leading cause of death for patients with traumatic brain injuries. The field of disorders of consciousness is pervaded by much uncertainty due to limitations on our current diagnostic tools, treatments, and outcome measures. In contrast, futility judgments are made in empirically tenuous confidence in the patient’s inability to survive or recover meaningfully. Despite emerging empirical evidence of PDOC patients’ potential for long-term recovery, an increasing sense of clinical nihilism leads to earlier and more frequent withdrawal of LST. In this paper, I argue against two kinds of futility judgments that may be used to justify the withdrawal of LST for PDOC patients: overly pessimistic predictions about the patient’s likelihood for meaningful recovery and rationing decisions that redirect hospital resources to patients who are more likely to recover. INTRODUCTION Brain injury is one of the leading causes of death and disability among children, young adults, and adults over the age of 75 years in the United States.[1] Yet we remain far from successfully diagnosing and treating brain injury patients who stay in states of prolonged disorders of consciousness. For this paper, the term “prolonged disorders of consciousness” means a vegetative state or a minimally conscious state, characterized by minimal to no signs of awareness up to and potentially exceeding five years.[2] Inadequate outcome measures and lack of empirical data for accurately predicting prolonged disorders of consciousness often force clinicians to assess patients based on their medical experience, knowledge of the medical literature, and clinical intuitions.[3] Futility judgments are clinical judgments made by healthcare providers about their patient’s health that can lead them to discontinue life-sustaining treatment. Dan Brock describes two different types of futility judgments. The first is a “true” futility judgment due to the perceived lack of expected benefit in treating the patient. The second is a hidden rationing decision in which the minor or unlikely benefit of treatment for the patient is not worth the cost in scarce hospital resources.[4] In this paper, I will critique the use of either kind of futility judgments to support the withdrawal of life-sustaining treatment for patients with prolonged disorders of consciousness. l. Futility Judgments about Likelihood Futility judgments reflect pessimism about the likelihood of a patient’s survival or recovery of consciousness. One of the most common reasons for withdrawing life-sustaining treatment from traumatic brain injury patients is the medical team’s perception of the patient’s poor chance of survival.[5] However, in a field characterized by much uncertainty, it seems imprudent to make futility judgments that project certainty or make the patient’s prospects of recovery or survival seem impossible. The unreliability of current bedside methods to determine consciousness and the inconsistent clinical trajectory of prolonged disorders of consciousness create considerable room for error in making predictions about the patient’s course of recovery. Despite such uncertainty, clinicians often end patients’ lives based on empirically tenuous beliefs regarding the patient’s inability to recover.[6] The grounds for futility judgments are further undermined by emerging data about the likelihood of long-term functional recovery in many patients with prolonged disorders of consciousness. For example, a recent study demonstrated that patients who failed to emerge from traumatic disorders of consciousness within 28 days, the minimum standard timeframe for prolonged disorders of consciousness, could still recover various target behaviors underpinning functional independence after four weeks.[7] The potential for patients to recover beyond this limited timeframe should motivate clinicians to sustain their patients’ lives to better understand the entire course of prolonged disorders of consciousness as it evolves. Even if clinicians remain unconvinced by the empirical evidence, prevailing judgments about futility can lead to increasingly premature withdrawal of life-sustaining treatment for patients with prolonged disorders of consciousness. For example, one multicenter study on level one trauma centers in Canada found that 70 percent of traumatic brain injury deaths were attributable to the withdrawal of life-sustaining treatment, and more than half of them occurred within the first 72 hours of injury.[8] When clinicians use futility to justify decisions to withdraw life-sustaining treatment, they risk ending the lives of individuals who may have survived and recovered. This, in turn, inflates mortality rates for prolonged disorders of consciousness and creates a self-fulfilling prophecy that reinforces the notion of very low odds of recovery.[9] Clinicians do not remove life-sustaining treatment without any evidence. But futility is not absolute. For example, suppose it is defined too broadly and includes cases where survival rates are low, but survival is possible. In that case, futility should not justify the removal of life-sustaining treatment. In those cases, other ethical justifications would be necessary. ll. Futility Judgments about Benefit Futility judgments also arise from pessimism about the actual benefit of the potential treatments. Another common reason for withdrawing life-sustaining treatment for traumatic brain injury patients is the clinical team’s belief in a poor long-term prognosis.[10] Based on their experience and data, clinicians who harbor pessimistic thoughts about the prognosis for patients with prolonged disorders of consciousness may inform the family members that the patients would not achieve meaningful recovery. They argue that continuing life-sustaining treatment would bring about no benefit to their wellbeing. However, these beliefs can be predicated on prejudiced perceptions about the quality of life of individuals with disabilities or chronic illnesses, a phenomenon commonly referred to as the disability paradox.[11] The paradox describes the discrepancy between patients with disabilities who report a quality of life much higher than non-disabled individuals would predict their ratings. Therefore, withdrawing life-sustaining treatment from populations with prolonged disorders of consciousness based on unjustified perceptions about what their quality of life might look like perpetuates ableist assumptions about what outcomes are acceptable to them. Some clinicians might respond that if they simply defer to the patient’s perspectives on being kept in a state of prolonged disorders of consciousness, perhaps through prior consultations with the patient or a family member’s knowledge, they can satisfy the patient’s subjective notion of wellbeing. In cases where the patient’s wishes are documented, the clinician’s judgment about the benefits (or lack thereof) of life-sustaining treatment would not matter as much. The decision can be based on the patient’s expressed preferences. However, studies demonstrate that a significant proportion of people who initially rated prolonged disorders of consciousness as a fate “worse than death” also wanted to receive life-sustaining treatment. After a discussion with a researcher about this contradiction, they increased their health rating of prolonged disorders of consciousness.[12] This change demonstrates a psychological discordance between people’s pessimistic perception of prolonged disorders of consciousness versus their preferences for being kept alive despite this perception. Clinicians should conscientiously navigate this discrepancy rather than act upon their initial prejudices against prolonged disorders of consciousness. By being mindful of their ableist biases and their patients, physicians can prevent pessimism from influencing their judgments about the benefits of continuing life-sustaining treatments. Discussions would ensure that patients are well informed when they create health directives or assign proxies for their care. In addition, the patient’s values and advance care decisions should be reassessed over time in conversation with the family, if possible, to ensure that treatment decisions reflect a more accurate and up-to-date understanding of the prognostic outcomes. lll. Hidden Rationing Decisions Some judgments about futility are hidden rationing decisions. “True” futility judgments evaluate the prospective benefit of treating a patient regardless of the resource costs, while rationing decisions evaluate treatments in the context of limited resources for other patients. A physician who determines the futility of continuing life-sustaining treatment might decide that the treatment would not be worth the cost to other patients who are more likely to benefit from the same resources. If healthcare resources ought to be distributed to maximize health utility for the highest number of patients, futility judgments for prolonged disorders of consciousness patients are justified. Life-sustaining treatments would be “wasted” on those patients compared to healthier patients.[13] However, prioritizing treatment for patients with a greater likelihood of survival based on the principle of utility maximization creates a healthcare system that is unwilling to take necessary risks to advance future therapies and build medical knowledge. Medical progress cannot be made if we pursue only treatments for those with the highest chances of survival or recovery. By providing life-sustaining treatment to facilitate the entire clinical course for prolonged disorders of consciousness, we can devote resources to improving the care, rehabilitation, and outcomes for those patients. Therefore, resource allocation is morally justified by its potential to benefit future populations of patients with prolonged disorders of consciousness, even if many individual cases will not result in a successful recovery.[14] Some physicians may respond that their role requires them to make clinical decisions that account for other patients since they must work within the practical reality of limited resources. They might argue that the physician’s duties are not bound to a single patient but to a network of societal constraints that require them to consider elements of distributive justice in their clinical care. Almost every medical decision is performed within the context of contractual obligations to a democratic society that expects a just distribution of healthcare resources.[15] Withdrawing life-sustaining treatment from patients with prolonged disorders of consciousness to direct those resources to other patients may be morally justified and obligatory for physicians to fulfill their societal duties properly. Although the physician’s obligations might extend to such societal duties, simply allocating resources to those most likely to benefit from treatment seems contrary to the principles of justice that undergird democratic society. We protect the most vulnerable members of our community, such as older adults and children, based on a principle of social solidarity that demands respect for all persons regardless of their weaknesses or dependence.[16] Withdrawing life-sustaining treatment from patients with prolonged disorders of consciousness based on beliefs about their lack of deservedness of medical treatment violates the respect we ought to accord them as vulnerable persons in need of social assistance. The principle of non-abandonment should apply. Rationing decisions do not justify “futility” judgments for prolonged disorders of consciousness patients since they contravene principles of social justice and impede medical progress for patient populations with lower rates of recovery. CONCLUSION Futility judgments presume a lack of likely benefit of treatment. They lead to frequent and premature withdrawals of life-sustaining treatment. The prevalence of prognostic uncertainty in the case of prolonged disorders of consciousness should incentivize clinicians to sustain rather than end their patients’ lives. By doing so, they can prevent a self-fulfilling prophecy from inflating mortality rates. Clinicians’ pessimism about the patients’ quality of life can also distort how they communicate the “benefits” of treatment to the patient, and they ought to conscientiously mitigate ableist biases. In addition, hidden rationing decisions disguised as futility judgments can fail to recognize the protections we grant to the most vulnerable members of society. Although physicians should be mindful of their societal obligations for resource allocation, those obligations should not displace their primary duty to their patients. Timothy Quill’s defense of the patient’s right to medical non-abandonment demonstrates “a world of difference between facing an uncertain future alone and facing it with a committed, caring, knowledgeable partner who will not shy away from difficult decisions when the path is unclear.”[17] As such, by advocating for their patients’ rights to life-sustaining treatment and refraining from making hasty futility judgments, clinicians can honor their enduring commitment to each patient’s wellbeing as they navigate the uncertain terrain of prolonged disorders of consciousness together. - [1] “Report to Congress: Traumatic Brain Injury in the United States | Concussion | Traumatic Brain Injury | CDC Injury Center.” 2019. January 31, 2019. https://www.cdc.gov/traumaticbraininjury/pubs/tbi_report_to_congress.html. [2] Foster, Charles. 2019. “It Is Never Lawful or Ethical to Withdraw Life-Sustaining Treatment from Patients with Prolonged Disorders of Consciousness.” Journal of Medical Ethics 45 (4): 265–70. https://doi.org/10.1136/medethics-2018-105250. [3] Hemphill, J. Claude, and Douglas B. White. 2009. “Clinical Nihilism in Neuro-Emergencies.” Emergency Medicine Clinics of North America 27 (1): 27–viii. https://doi.org/10.1016/j.emc.2008.08.009. [4] Brock, Dan. 2021. “Health Care Resource Prioritization and Rationing: Why Is It So Difficult?,” 25. [5] Turgeon, Alexis F., François Lauzier, Jean-François Simard, Damon C. Scales, Karen E.A. Burns, Lynne Moore, David A. Zygun, et al. 2011. “Mortality Associated with Withdrawal of Life-Sustaining Therapy for Patients with Severe Traumatic Brain Injury: A Canadian Multicentre Cohort Study.” CMAJ : Canadian Medical Association Journal 183 (14): 1581–88. https://doi.org/10.1503/cmaj.101786. [6] Schneiderman, Lawrence J. 1990. “Medical Futility: Its Meaning and Ethical Implications.” Annals of Internal Medicine 112 (12): 949. https://doi.org/10.7326/0003-4819-112-12-949. [7] Giacino, Joseph T., Mark Sherer, Andrea Christoforou, Petra Maurer-Karattup, Flora M. Hammond, David Long, and Emilia Bagiella. 2020. “Behavioral Recovery and Early Decision Making in Patients with Prolonged Disturbance in Consciousness after Traumatic Brain Injury.” Journal of Neurotrauma 37 (2): 357–65. https://doi.org/10.1089/neu.2019.6429. [8] Turgeon, Alexis F., François Lauzier, Jean-François Simard, Damon C. Scales, Karen E.A. Burns, Lynne Moore, David A. Zygun, et al. 2011. “Mortality Associated with Withdrawal of Life-Sustaining Therapy for Patients with Severe Traumatic Brain Injury: A Canadian Multicentre Cohort Study.” CMAJ : Canadian Medical Association Journal 183 (14): 1581–88. https://doi.org/10.1503/cmaj.101786. [9] Hemphill, J. Claude, and Douglas B. White. 2009. “Clinical Nihilism in Neuro-Emergencies.” Emergency Medicine Clinics of North America 27 (1): 27–viii. https://doi.org/10.1016/j.emc.2008.08.009. [10] Turgeon, Alexis F., François Lauzier, Jean-François Simard, Damon C. Scales, Karen E.A. Burns, Lynne Moore, David A. Zygun, et al. 2011. “Mortality Associated with Withdrawal of Life-Sustaining Therapy for Patients with Severe Traumatic Brain Injury: A Canadian Multicentre Cohort Study.” CMAJ : Canadian Medical Association Journal 183 (14): 1581–88. https://doi.org/10.1503/cmaj.101786. [11] Albrecht, G. L., and P. J. Devlieger. 1999. “The Disability Paradox: High Quality of Life against All Odds.” Social Science & Medicine (1982) 48 (8): 977–88. https://doi.org/10.1016/s0277-9536(98)00411-0. [12] Golan, Ofra G., and Esther-Lee Marcus. 2012. “Should We Provide Life-Sustaining Treatments to Patients with Permanent Loss of Cognitive Capacities?” Rambam Maimonides Medical Journal 3 (3): e0018. https://doi.org/10.5041/RMMJ.10081. [13] Brock, Dan. 2021. “Health Care Resource Prioritization and Rationing: Why Is It So Difficult?25. [14] Giacino, Joseph T., Yelena G. Bodien, David Zuckerman, Jaimie Henderson, Nicholas D. Schiff, and Joseph J. Fins. 2021. “Empiricism and Rights Justify the Allocation of Health Care Resources to Persons with Disorders of Consciousness.” AJOB Neuroscience 12 (2–3): 169–71. https://doi.org/10.1080/21507740.2021.1904055. [15] Misak, Cheryl J., Douglas B. White, and Robert D. Truog. 2014. “Medical Futility.” Chest 146 (6): 1667–72. https://doi.org/10.1378/chest.14-0513. [16] Golan, Ofra G., and Esther-Lee Marcus. 2012. “Should We Provide Life-Sustaining Treatments to Patients with Permanent Loss of Cognitive Capacities?” Rambam Maimonides Medical Journal 3 (3): e0018. https://doi.org/10.5041/RMMJ.10081. [17] Quill, Timothy E., Christine K. Cassel, and Ann Intern Med. 1995. “Nonabandonment: A Central Obligation for Physicians.” Annals of Internal Medicine, 368–74.