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We describe the design, using shape comparison and fast docking computer algorithms, and rapid parallel synthesis of a 1300 member array based on GSK7721, a 4-aminobenzonitrile androgen receptor (AR) antagonist identified by focused screening of the GSK compound collection. The array yielded 352 submicromolar and 17 subnanomolar AR agonists as measured by a cell-based reporter gene functional assay. The rapid synthesis of a large number of active compounds provided valuable information in the optimization of AR modulators, which may be useful in treating androgen deficiency in aging males. [ABSTRACT FROM AUTHOR]

Background: Findings from studies investigating the impacts of alcohol use and smoking on colorectal cancer (CRC) outcomes are inconclusive. This study aimed to investigate associations between alcohol use and smoking status at the time of diagnosis on recurrence and overall mortality among patients with CRC., Methods: The present study included 2,216 stage I-IV patients with CRC from the longitudinal multi-center ColoCare study, with available data on recurrence and CRC-specific mortality. Cox proportional hazards models adjusted for age, sex, race, ethnicity, stage, tumor site, treatment, comorbidities, body mass index, and study site were fit, with imputations for missing data., Results: We observed 235 recurrences and 308 CRC-specific deaths over an average of 3 years of follow-up. After adjusting for confounders, current alcohol consumption and ever smoking, relative to not current consumption and never smoking, respectively, were not statistically significantly associated with CRC recurrence (Alcohol - HR: 0.95. 95% CI: 0.71-1.29; Ever smoking - HR: 0.98, 95% CI: 0.75-1.29) or CRC-specific mortality (Alcohol - HR: 0.95. 95% CI: 0.74-1.22; Ever smoking - HR: 0.98, 95% CI: 0.77-1.24)., Conclusions: No associations were observed between alcohol and smoking at diagnosis and clinical outcomes in this well-annotated longitudinal cohort., Impact: Our cohort study reports no significant associations; however, limiting alcohol use and avoiding smoking are health behaviors recommended for CRC survivors for prevention of other cancers and chronic conditions.

Purpose: Colorectal cancer (CRC) incidence and mortality are increasing among young adults (YAs) aged 18-39. This study compared quality of life (QOL) between YA and older adult CRC survivors in the ColoCare Study., Methods: Participants were grouped by age (years) as follows: 18-39 (YA), 40-49, 50-64, and 65 + . Functional QOL (physical, social, role, emotional, cognitive) and global QOL were assessed with the EORTC-QLQ-C30 at enrollment, 3, 6, and 12 months. Average scores were compared between groups over time using longitudinal mixed-effect modeling. Proportions with clinically meaningful QOL impairment were calculated using age-relevant thresholds and compared between groups over time using logistic regression with mixed effects., Results: Participants (N = 1590) were n = 81 YAs, n = 196 aged 40-49, n = 627 aged 50-64, and n = 686 aged 65 + . Average physical function was better among YAs than participants aged 50-64 (p = 0.010) and 65 + (p < 0.001), and average social function was worse among YAs than aged 65 + (p = 0.046). Relative to YAs, all age groups were less likely to report clinically meaningful social dysfunction (aged 40-49 OR = 0.13, 95%CI = 0.06-0.29; aged 50-64 OR = 0.10, 95%CI = 0.05-0.21; aged 65 + OR = 0.07, 95%CI = 0.04-0.15) and role dysfunction (aged 40-49 OR = 0.36, 95%CI = 0.18-0.75; aged 50-64 OR = 0.41, 95%CI = 0.22-0.78; aged 65 + OR = 0.32, 95%CI = 0.17-0.61). Participants aged 40-49 were also less likely to report physical dysfunction (OR = 0.42, 95%CI = 0.19-0.93)., Conclusion: YA CRC survivors reported better physical and worse social function compared to older CRC survivors, and YA CRC survivors were more likely to report clinically meaningful social, role, and physical disfunction. Future work should further investigate QOL using age-relevant benchmarks to inform best practices for CRC survivorship care., Trial Registration: NCT02328677, registered December 2014., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Preoperative anticoagulant therapy is known to have a positive impact on the prognosis of patients with acute limb ischemia (ALI). However, little is known about its efficacy in elderly patients. We aimed to investigate the potential effect of anticoagulation in nonagenarian patients managed for ALI., Methods: Between January 2015 and December 2021, we identified all nonagenarian patients managed for ALI at a single center. Long-term anticoagulation and hemostasis parameters (prothrombin rate, activated partial thromboplastin time [APTT], platelet count) measured on admission were reviewed. The primary end point was mortality at 30-day mortality (D30) in patients with or without long-term anticoagulation therapy. We also studied the effect of these factors on the occurrence of revascularization failure in operated patients (initial failure, ischemic recurrence during hospitalization, necrosis requiring major amputation)., Results: A total of 68 nonagenarian patients were managed for ALI, with a mean age of 93.8 years (from 90-107 years), 76.5% of whom were women. Of these patients, 47 (69%) were managed surgically. Long-term anticoagulation therapy was associated with better survival at D30, both in nonoperated (P < 0.01) and operated (P < 0.05) patients. In operated patients, the absence of long-term anticoagulation therapy was associated with the occurrence of revascularization failure (P < 0.05). In operated patients, survival to D30 and successful revascularization were associated with a longer APTT (P < 0,05). We were able to observe the survival of 4 patients contraindicated for surgery and treated with a single medical therapy (intravenous unfractionated heparin)., Conclusions: Anticoagulation appears to have an impact on the survival and postoperative prognosis of nonagenarian patients with ALI. In addition, curative anticoagulation therapy may be an alternative treatment when surgery is contraindicated in this frail population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Contrast-enhanced computed tomography angiography (CTA) is commonly used to investigate acute abdominal conditions, but the risk of contrast-induced acute kidney injury (CI-AKI) has been poorly investigated in patients with acute mesenteric ischemia. The aim of the present study was to evaluate the incidence of CI-AKI in these patients and identify potential predictive factors., Methods: Patients admitted for acute mesenteric ischemia who had a diagnostic CTA with contrast medium and a follow-up of creatinine concentration were retrospectively included., Results: Among 53 patients included, 9 (16.9%) developed CI-AKI. The prevalence of chronic kidney disease did not differ significantly between those who developed CI-AKI and those who did not (33.3 vs 18.2%, p =.372). Plasma total bilirubin and conjugated bilirubin levels were significantly higher in patients who developed CI-AKI (17.5 vs 8.0 μmol/L, p =.013 and 8.0 vs 3.0 μmol/L, p =.031, respectively). The proportion of patients who had revascularization was similar between patients who developed CI-AKI and those who did not (11.1 vs 20.5%, p >.999). No significant difference was observed for 30-day mortality and all-cause mortality for a median follow-up of 168 days (22.2 vs 13.6%, p =.611; and 33.3 vs 61.4%, p =.153, respectively)., Conclusion: This study reports the incidence of CI-AKI in patients with acute mesenteric ischemia after diagnostic CTA with contrast medium. Plasma bilirubin levels were a predictive factor of CI-AKI in these patients. The administration of contrast media during revascularization was not associated with an increased risk of CI-AKI.

Introduction: Complementary and integrative health (CIH) modalities promote overall health and well-being and can be beneficial for individuals with a range of conditions. Traditionally, CIH has been delivered in person. COVID-19 created a need to identify sustainable remote delivery options to assure access to CIH while practicing public health recommendations. This scoping review maps the opportunities and challenges to remotely delivered CIH. Materials and methods: A scoping review was conducted between June 2020 and October 2020 using the following search engines: PubMed, Academic Search Premier, PsycINFO, CINAHL, Cochrane Reviews, and the Cochrane Clinical Trial Collections. Search results investigating remote CIH delivery were restricted to articles written in English, published after 1990. Results: Of the 10,884 articles identified, after review for content and methods, 330 articles were included. Most articles were randomized controlled trials ( n  = 170), applied mindfulness ( n  = 203), and targeted mental and behavioral health conditions ( n  = 182). Interventions were primarily delivered through mobile applications ( n  = 151) and web-based platforms ( n  = 86). Most commonly reported barriers were adherence ( n  = 24), resource requirements (e.g., time and space) ( n  = 23), and technology-related issues ( n  = 21). Although most studies did not report facilitators ( n  = 217), most commonly reported facilitators were social and technologic supports, accessibility, usability, perceptions, and rewards. Participant outcomes measured were broad and included movement ( n  = 88), stress ( n  = 68), and pain ( n  = 54). Intervention characteristic outcomes most often measured were satisfaction and usability ( n  = 5). Conclusions: This scoping literature review identified many articles addressing remote delivery of CIH, but few reporting on the implementation of remotely delivered CIH. Findings suggest remotely delivered CIH, specifically mindfulness and meditation-based modalities, is a viable treatment option for a diverse range of health conditions. Feasibility studies and larger sample sizes are recommended to strengthen the scientific evidence.

Objectives: Aberrant subclavian artery (ASCA) occurs rarely but is one of the most frequent anatomical variations of the supra-aortic trunks. No consensus has been established on its best treatment. The goal of this study was to report the outcomes of ASCA treated by the hybrid approach., Methods: This non-interventional retrospective multicentre analysis included patients treated for ASCA by the hybrid approach in 12 French university hospitals between 2007 and 2019. The hybrid approach was defined as an endovascular procedure combined with open surgery or a hybrid stent graft. Patients were divided in 4 groups (from less to more complex treatment). The primary end point was 30-day mortality. The secondary end points were 30-day complications and late mortality., Results: This study included 43 patients. The mean age was 65 (SD, standard deviation: 16) years. Symptoms were found in 33 patients. Subclavian revascularization combined with aberrant subclavian artery occlusion was undertaken in 13 patients. Unilateral and bilateral subclavian revascularization combined with a thoracic aortic stent graft was undertaken in 11 and 6 patients, respectively. Total aortic arch repair combined with a thoracic aortic stent graft was undertaken in 13 patients. Thirty-day mortality was 2.3% with a technical success rate of 95.3%. The 30-day major postoperative complication rate was 16.3%: 4 strokes, 2 tamponades, 1 acute respiratory distress syndrome. Mean follow-up was 56.3 (SD: 44.7) months. The late mortality was 18.6%., Conclusions: The ASCA hybrid approach is feasible, safe and effective with low early mortality. Morbidity is rather high. However, it increases with the complexity of the hybrid approach, which should be kept as simple as possible if the anatomical morphology allows., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: There is currently a lack of consensus and tools to easily measure vascular calcification using computed tomography angiography (CTA). The aim of this study was to develop a fully automatic software to measure calcifications and to evaluate the interest as predictive factor in patients with aorto-iliac occlusive disease., Methods: This study retrospectively included 171 patients who had endovascular repair of an aorto-iliac occlusive lesion at the University Hospital of Nice between January 2011 and December 2019. Calcifications volumes were measured from CTA using an automatic method consisting in three sequential steps: image pre-processing, lumen segmentation using expert system, and deep learning algorithms and segmentation of calcifications. Calcification volumes were measured in the infrarenal abdominal aorta and the iliac arterial segments, corresponding to the common and the external iliac arteries., Results: Among 171 patients included with a mean age of 65 years, the revascularization was performed on the native external and internal iliac arteries in, respectively: 83 patients (48.5%), 107 (62.3%), and 7 (4.1%). The mean volumes of calcifications were 2,759 mm 3 in the infrarenal abdominal aorta, 1,821 mm 3 and 1,795 mm 3 in the right and left iliac arteries, respectively. For a mean follow-up of 39 months, target lesion re-intervention was performed in 55 patients (32.2%). These patients had higher volume of calcifications in the right and left iliac arteries, compared with patients who did not have a re-intervention (2,274 mm 3 vs. 1,606 mm 3 , P = 0.0319 and 2,278 vs. 1,567 mm 3 , P = 0.0213)., Conclusions: The development of a fully automatic software would be useful to facilitate the measurement of vascular calcifications and possibly better inform the prognosis of patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Apraxia and action disorganization syndrome (AADS) after stroke can disrupt activities of daily living (ADL). Occupational therapy has been effective in improving ADL performance, however, inclusion of multiple tasks means it is unclear which therapy elements contribute to improvement. We evaluated the efficacy of a task model approach to ADL rehabilitation, comparing training in making a cup of tea with a stepping training control condition., Methods: Of the 29 stroke survivors with AADS who participated in this cross-over randomized controlled feasibility trial, 25 were included in analysis [44% females; mean(SD) age = 71.1(7.8) years; years post-stroke = 4.6(3.3)]. Participants attended five 1-hour weekly tea making training sessions in which progress was monitored and feedback given using a computer-based system which implemented a Markov Decision Process (MDP) task model. In a control condition, participants received five 1-hour weekly stepping sessions., Results: Compared to stepping training, tea making training reduced errors across 4 different tea types. The time taken to make a cup of tea was reduced so the improvement in accuracy was not due to a speed-accuracy trade-off. No improvement linked to tea making training was evident in a complex tea preparation task (making two different cups of tea simultaneously), indicating a lack of generalisation in the training., Conclusions: The clearly specified but flexible training protocol, together with information on the distribution of errors, provide pointers for further refinement of task model approaches to ADL rehabilitation. It is recommended that the approach be tested under errorless learning conditions with more impaired patients in future research., Trial Registration: Retrospectively registered at ClinicalTrials.gov on 5th August 2019 [NCT04044911] https://clinicaltrials.gov/ct2/show/NCT04044911?term=Cogwatch&rank=1., Competing Interests: The authors have declared that no competing interests exist.

Mycotic aneurysm is a life-threatening disease often caused by Salmonella, Staphylococci and Streptococci species. Interestingly, Escherichia Coli ( E. Coli ) is described as a rare causative agent. We report the case of a patient who developed a mycotic aortic and ruptured left iliac aneurysm due to E. Coli. The patient developed a secondary aortic graft infection due to a mesenteric ischemia with fecal peritonitis. A literature overview of the current knowledge on mycotic aortic aneurysms specifically due to E. Coli is discussed including the clinical characteristics of patients, the management of the disease and the post-operative outcomes.

Objective: Failed endovascular infrarenal aortic aneurysm repair (EVAR) due to development of late type Ia endoleak exposes patients to the risk of rupture and should be treated. The purpose of this study was to evaluate the results of fenestrated/branched EVAR (F/BEVAR) for treatment of failed EVAR with type Ia endoleak., Methods: From January 2010 to December 2019, a prospective multicentre study was conducted (ClinicalTrials.gov identifier: NCT04532450) that included 85 consecutive patients who had undergone F/BEVAR to treat a type Ia endoleak following EVAR. The primary outcome was overall freedom from any re-intervention or death related to the F/BEVAR procedure., Results: In 30 cases (35%) EVAR was associated with a short < 10 mm or angulated (> 60°) infrarenal aortic neck, poor placement of the initial stent graft (n = 3, 4%), sizing error (n = 2, 2%), and/or stent graft migration (n = 7, 8%). Type Ia endoleak was observed after a period of 59 ± 25 months following EVAR. The authors performed 82 FEVAR (96%) and three BEVAR (4%) procedures with revascularisation of 305 target arteries. Overall technical success was 94%, with three failures including one persistent Type Ia endoleak and two unsuccessful stent graft implantations. Intra-operative target artery revascularisation was successful in 303 of 305 attempts. The in hospital mortality rate was 5%. Cardiac, renal and pulmonary complications occurred in 6%, 14%, and 7% of patients, respectively. Post-operative spinal cord ischaemia occurred in four patients (4.7%). At three years, the survival rate was 64% with overall freedom from any re-intervention or aneurysm related death of 40%, and freedom from specific F/BEVAR re-intervention of 73%. At three years, the secondary patency rate of the target visceral arteries was 96%. During follow up, 27 patients (33%) required a revision procedure of the fenestrated (n = 11) or index EVAR stent graft (n = 16), including six open conversions., Conclusion: While manufactured F/BEVAR was effective in treating type Ia endoleak in patients with failed EVAR, it was at the cost of a number of secondary endovascular and open surgical procedures., (Copyright © 2021 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Introduction: Controlling insulin-treated diabetes is challenging in low-resource settings where only Neutral Protamine Hagedorn (NPH), regular (R) and premixed insulin formulations are available, self-monitoring of blood glucose (SMBG) supplies are scarce and food insecurity is common. We examined the impact of a treatment protocol that includes sliding scale-based 70/30 insulin adjustments in Haiti., Methods: Thirty young patients aged 11-28 years with diabetes treated with premixed 70/30 insulin twice daily were included in the study. The participants performed one or two daily self-monitoring of blood glucose (SMBG) tests and attended our diabetes clinic monthly. They were randomized to two treatment groups, with one group remaining on the 70/30 insulin formulation (group 70 [G70]) and the other group switching to self-mixed NPH + R (group NR [GNR]). Sliding scales for insulin correction doses and meal insulin doses were designed based on the total daily insulin dose (TDD), carbohydrate ratio and insulin sensitivity factor. SMBG tests and insulin were administered before the morning and evening meals. The frequency of visits to the diabetes clinic was increased to biweekly during a 14-week follow-up., Results: Fifteen patients of each group were included in the analysis. Baseline characteristics, increase in total daily dose and number of missed SMBG tests and skipped meals at 14 weeks did not differ between the two groups. Hemoglobin A1c (HbA1c) decreased from 9.5% (interquartile range [IQR] 8.8, 10.5) (80.3 mmol/mol) to 8.0% (IQR 7.1%, 9.0%) (63.9 mmol/mol) in G70 (p = 0.01), and from 10.6% (IQR 8.1,% 13.1)% (92.4 mmol/mol) to 9.0% (IQR 7.6%, 9.6%) (74.9 mmol/mol) in GNR (p = 0.10), with no significant between-group difference in reductions (p = 0.12). No serious acute complications were reported. Stopping the use of sliding scales and resuming monthly visits increased HbA1c to values not significantly different from baseline in both groups after 15 weeks., Conclusion: The use of sliding scales adjusted for missed SMBG tests and skipped meals, and frequent clinic visits that focus on patient self-management education significantly improved glycemic control in the patients with youth-onset diabetes in our study treated with premixed 70/30 human insulin in a low-resource setting., (© 2021. The Author(s).)

Rupture of splenic artery aneurysms (SAAs) is associated with a high mortality rate. The aim of this study was to identify the features of SAAs. Tissue sections from SAAs were compared to nonaneurysmal splenic arteries using various stains. The presence of intraluminal thrombus (ILT), vascular smooth muscle cells (VSMCs), cluster of differentiation (CD)-68+ phagocytes, myeloperoxidase+ neutrophils, CD3+, and CD20+ adaptive immune cells were studied using immunofluorescence microscopy. Analysis of SAAs revealed the presence of atherosclerotic lesions, calcifications, and ILT. Splenic artery aneurysms were characterized by a profound vascular remodeling with a dramatic loss of VSMCs, elastin degradation, adventitial fibrosis associated with enhanced apoptosis, and increased matrix metalloproteinase 9 expression. We observed an infiltration of immune cells comprising macrophages, neutrophils, T, and B cells. The T and B cells were found in the adventitial layer of SAAs, but their organization into tertiary lymphoid organs was halted. We failed to detect germinal centers even in the most organized T/B cell follicles and these lymphoid clusters lacked lymphoid stromal cells. This detailed histopathological characterization of the vascular remodeling during SAA showed that lymphoid neogenesis was incomplete, suggesting that critical mediators of their development must be missing.

Background: The prevalence of non-communicable diseases (NCDs) is rising in low and middle-income countries (LMIC). We aimed to report on the prevalence of NCDs in pregnancy and their associated perinatal outcomes in a regional hospital in Haiti., Methods: We conducted the "Diabète et hYpertension Artéerielle et leurs issues MAternelles et Néonatales" (DYAMAN) prospective cohort study in a regional hospital in Haiti. Pregnant women presenting to care at 24-28 weeks were screened and treated for diabetes (DM) and hypertensive disorders of pregnancy (HDP) using setting-adapted protocols. Prevalence of NCDs and associated maternal-neonatal outcomes were described., Results: 715 women were included, of which 51 (7.1%) had DM, 90 (12.6%) had HDP, and 30 (4.2%) had both DM and HDP (DM/HDP). Of 422 (59%) women delivered in hospital, 58 (13.7%) had preeclampsia, including 5 (8.6%) with eclampsia. Preterm birth <32 weeks was more common in the HDP than the control, DM, and DM/HDP groups. More low birth weight babies (n = 20, 25.6%) were born to the HDP group than to the control (n = 20, 7.1%), DM (n = 1, 2.7%), and DM/HDP (n = 3, 12%) groups ( P  < 0.001). Macrosomia and hypoglycemia affected 5 (8%) neonates of women with DM. Perinatal mortality, affecting 36/1000 births, was mainly driven by maternal NCDs., Conclusions: NCDs in pregnancy led to adverse maternal and perinatal outcomes. This study will help to prepare future refinements aimed at optimizing the management of NCDs in pregnancy in LMIC. Research is required to understand barriers to patient attendance at antenatal follow-up, treatment escalation for hyperglycemia, and in-hospital delivery., Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2021 by the Journal of Global Health. All rights reserved.)

Background: Vascular calcifications have been identified as predictors of mortality in several cardiovascular diseases but have not been investigated in context of acute mesenteric ischemia. The aim of this study was to investigate the impact of vascular calcifications in patients with acute mesenteric ischemia., Methods: Patients admitted for an acute mesenteric ischemia were retrospectively included. The presence of calcifications in the visceral aorta, the celiac trunk, the superior mesenteric artery, and the renal arteries was assessed on computed tomography scan images at the arterial phase. The calcification volumes were measured using the software Aquarius iNtuition Edition®., Results: The all-cause mortality was 55 out of 86 patients (63.9%) for a median follow-up of 3.5 days (1-243). The survival rate of patients with calcification in the superior mesenteric artery was significantly lower than that of those without calcification (22% vs. 55.6%, P = 0.019). Patients who died had significantly a higher frequency of calcifications in the superior mesenteric artery, the visceral aorta, the celiac trunk, and the renal arteries., Conclusions: The presence of vascular calcifications in the superior mesenteric artery is associated with increased mortality in patients diagnosed with acute mesenteric ischemia. Further studies are required to identify the mechanisms underlying this association., (Copyright © 2020 Elsevier Inc. All rights reserved.)