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INTRODUCTION: Takayasu’s arteritis (TA) is an inflammatory condition that affects large vessels and frequently involves the aortic valve causing valve regurgitation. Surgical management is recommended for symptomatic severe aortic regurgitation (AR); however, the optimal surgical approach is yet unclear. This study aims to review surgical treatment options for AR in TA and determine which procedure has a lower chance of late postoperative events and/or mortality. METHODS: An electronic database search was performed within PubMed, EMBASE, Web of Science, and SCOPUS to identify articles from 1975 to 2016 focusing on surgical management of the AR in TA. RESULTS: Twenty seven studies encompassing a total of 194 cases (77% females) were included. Isolated aortic valve replacement (AVR) was performed in 105/194 cases (54%) (Group A), while combined aortic valve and root replacement (CAVRR) was performed in 87/194 (45%) (Group B). Prosthetic valve detachment was reported in 10/105 cases (9.5%) in group A and 1/87 cases (1.2%) in group B (p = 0.02). Dilation of the residual aorta was reported in 10/105 cases (9.5%) in group A and 1/87 cases (1.2%) in group B (p = 0.02). Any late (≥ 30 d) postoperative cardiac event was reported in 26/105 cases (24.8%) in group A, and in 7/87 cases (8.1%) in group B (p = 0.003). CONCLUSIONS: Although CAVRR is a more complex procedure, it might offer a better outcome in terms of late postoperative cardiac events compared to isolated AVR procedure. Future prospective studies are required to help determine the best surgical approach in such a population.

To compare the obstetric and perinatal outcomes of deliveries conceived with embryos from single-step vs. sequential culture media systems.Historical cohort of Massachusetts vital records linked to assisted reproductive technology clinic data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System and laboratory embryology data from two large academic hospital fertility centers.Not applicable.Patients with singleton live birth deliveries between 2004 and 2017 conceived with autologous assisted reproductive technology cycles with fresh blastocyst transfer using either single-step (n = 1,058) or sequential (n = 474) culture media systems.None.Associations of single-step vs. sequential culture with obstetric outcomes (mode of delivery, placental abnormalities, pregnancy-induced hypertension, and gestational diabetes) and perinatal outcomes (preterm birth, low birthweight, small-for-gestational-age, and large-for-gestational-age [LGA]) were assessed with multivariate logistic modeling, adjusted for maternal age, race/ethnicity, education, parity, insurance type, protein supplementation, oxygen concentration, fertilization method, and number of transferred embryos.Compared with sequential culture, single-step culture was associated with increased odds of LGA (adjusted odds ratio 2.1, 95% confidence interval 1.04-4.22). There were no statistically significant differences between single-step and sequential culture media systems in the odds of placental abnormalities, pregnancy-induced hypertension, gestational diabetes, prematurity, small-for-gestational-age, or low birthweight.Single-step culture is associated with increased odds of LGA, indicating that embryo culture media systems may affect perinatal outcomes.

Although great effort has been expended to understand cancer’s origins, less attention has been given to the primary cause of cancer deaths—cancer recurrences and their sequelae. This interdisciplinary review addresses mechanistic features of aggressive cancer by studying metabolic enzyme patterns within ductal carcinoma in situ (DCIS) of the breast lesions. DCIS lesions from patients who did or did not experience a breast cancer recurrence were compared. Several proteins, including phospho-Ser226-glucose transporter type 1, phosphofructokinase type L and phosphofructokinase/fructose 2,6-bisphosphatase type 4 are found in nucleoli of ductal epithelial cells in samples from patients who will not subsequently recur, but traffic to the cell periphery in samples from patients who will experience a cancer recurrence. Large coclusters of enzymes near plasmalemmata will enhance product formation because enzyme concentrations in clusters are very high while solvent molecules and solutes diffuse through small channels. These structural changes will accelerate aerobic glycolysis. Agglomerations of pentose phosphate pathway and glutathione synthesis enzymes enhance GSH formation. As aggressive cancer lesions are incomplete at early stages, they may be unrecognizable. We have found that machine learning provides superior analyses of tissue images and may be used to identify biomarker patterns associated with recurrent and nonrecurrent patients with high accuracy. This suggests a new prognostic test to predict patients with DCIS who are likely to recur and those who are at low risk for recurrence. Mechanistic interpretations provide a deeper understanding of anticancer drug action and suggest that aggressive metastatic cancer cells are sensitive to reductive chemotherapy.

Prostate-Specific Membrane Antigen (PSMA) is a credentialed imaging and therapy (theranostic) target for the detection and treatment of prostate cancer. PSMA-targeted positron emission tomography (PET) imaging and molecular radiotherapy (MRT) are promising evolving technologies that will improve the outcomes of prostate cancer patients. In anticipation of this new era in prostate cancer theranostics, this article will review the history of PSMA from discovery, through early and late stage clinical trials. Since 1993, the Prostate Cancer Foundation (PCF) has funded critical and foundational PSMA research that established this theranostic revolution. The history and role of PCF funding in this field will be discussed.

Site-specific protein modifications are vital for biopharmaceutical drug development. Gluconoylation is a non-enzymatic, post-translational modification of N-terminal HisTags. We report high-yield, site-selective in vitro α-aminoacylation of peptides, glycoproteins, antibodies, and virus-like particles (VLPs) with azidogluconolactone at pH 7.5 in 1 h. Conjugates slowly hydrolyse, but diol-masking with borate esters inhibits reversibility. In an example, we multimerise azidogluconoylated SARS-CoV-2 receptor-binding domain (RBD) onto VLPs via click-chemistry, to give a COVID-19 vaccine. Compared to yeast antigen, HEK-derived RBD was immunologically superior, likely due to observed differences in glycosylation. We show the benefits of ordered over randomly oriented multimeric antigen display, by demonstrating single-shot seroconversion and best virus-neutralizing antibodies. Azidogluconoylation is simple, fast and robust chemistry, and should accelerate research and development.

Purpose To evaluate the impact of using consistent complication-avoidance protocols in patients undergoing endoscopic pituitary adenoma surgery including techniques for avoiding anosmia, epistaxis, carotid artery injury, hypopituitarism, cerebrospinal fluid leaks and meningitis. Methods All patients undergoing endoscopic adenoma resection from 2010 to 2020 were included. Primary outcomes included 90-day complication rates, gland function outcomes, reoperations, readmissions and length of stay. Secondary outcomes were extent of resection, short-term endocrine remission, vision recovery. Results Of 514 patients, (mean age 51 ± 16 years; 78% macroadenomas, 19% prior surgery) major complications occurred in 18(3.5%) patients, most commonly CSF leak (9, 1.7%) and meningitis (4, 0.8%). In 14 of 18 patients, complications were deemed preventable. Four (0.8%) had complications with permanent sequelae (3 before 2016): one unexplained mortality, one stroke, one oculomotor nerve palsy, one oculoparesis. There were no internal carotid artery injuries, permanent visual worsening or permanent anosmia. New hypopituitarism occurred in 23/485(4.7%). Partial or complete hypopituitarism resolution occurred in 102/193(52.8%) patients. Median LOS was 2 days; 98.3% of patients were discharged home. Comparing 18 patients with major complications versus 496 without, median LOS was 7 versus 2 days, respectively p Conclusion This study suggests that conformance to established protocols for endoscopic pituitary surgery may minimize complications, re-admissions and LOS while enhancing the likelihood of preserving gland function, although there remains opportunity for further improvements.

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society.

BACKGROUND With growing worldwide endoscopy experience, endonasal and supraorbital removal of tuberculum sellae meningiomas (TSM) has increased. OBJECTIVE To describe anatomic factors for guiding approach selection and outcomes. METHODS Retrospective analysis of patients undergoing endonasal or supraorbital TSM resection: approach criteria, clinical outcomes, acute magnetic resonance imaging (MRI) fluid-attenuated inversion-recovery (FLAIR)/T2 changes. RESULTS From 2008 to 2020, 33 patients (mean age 55 ± 11 yr) were identified: 20 (61%) had endonasal and 13 (39%) supraorbital removal. Comparing endonasal and supraorbital approaches, mean tumor volume (3.7 ± 3.5 cm3 vs 7.7 ± 8.5 cm3, P = .07); percent tumor above planum (42% vs 65%, P = .02), and lateral tumor beyond supraclinoid internal carotid arteries (1.4 ± 2.0 mm vs 4.0 ± 3.2 mm, P = .006) were greater for supraorbital route. Sellar depth was greater for endonasal route tumors (12.2 ± 2.6 mm vs 9.3 ± 2.4 mm, P = .003). Endoscopy, used in 10/13(77%) supraorbital cases, was helpful in additional tumor removal in 4/10(40%). Gross total removal and mean volumetric tumor resection were 16/20(80%) and 97.5% by endonasal, and 5/13(39%) and 96% by supraorbital route. Vision improved in 12/17 (71%) endonasal, 6/8 (75%) supraorbital operations, and worsened in 1 (3%) supraorbital case. Endonasal approach with optic canal decompression increased over study period: 15/20 (75%) endonasal patients vs 1/13(8%) supraorbital (P

Objective To facilitate the development of standards-based clinical decision support (CDS) systems, we review the current set of CDS standards that are based on Health Level Seven International Fast Healthcare Interoperability Resources (FHIR). Widespread adoption of these standards may help reduce healthcare variability, improve healthcare quality, and improve patient safety. Target Audience This tutorial is designed for the broad informatics community, some of whom may be unfamiliar with the current, FHIR-based CDS standards. Scope This tutorial covers the following standards: Arden Syntax (using FHIR as the data model), Clinical Quality Language, FHIR Clinical Reasoning, SMART on FHIR, and CDS Hooks. Detailed descriptions and selected examples are provided.

There is a growing trend toward verification of trauma centres, but its impact remains unclear. This systematic review aimed to synthesize available evidence on the effectiveness of trauma centre verification.We conducted a systematic search of the CINAHL, Embase, HealthStar, MEDLINE and ProQuest databases, as well as the websites of key injury organizations for grey literature, from inception to June 2019, without language restrictions. Our population consisted of injured patients treated at trauma centres. The intervention was trauma centre verification. Comparison groups comprised nonverified trauma centres, or the same centre before it was first verified or re-verified. The primary outcome was in-hospital mortality; secondary outcomes included adverse events, resource use and processes of care. We computed pooled summary estimates using random-effects meta-analysis.Of 5125 citations identified, 29, all conducted in the United States, satisfied our inclusion criteria. Mortality was the most frequently investigated outcome (n = 20), followed by processes of care (n = 12), resource use (n = 12) and adverse events (n = 7). The risk of bias was serious to critical in 22 studies. We observed an imprecise association between verification and decreased mortality (relative risk 0.74, 95% confidence interval 0.52 to 1.06) in severely injured patients.Our review showed mixed and inconsistent associations between verification and processes of care or patient outcomes. The validity of the published literature is limited by the lack of robust controls, as well as any evidence from outside the US, which precludes extrapolation to other health care jurisdictions. Quasiexperimental studies are needed to assess the impact of trauma centre verification.PROSPERO no. CRD42018107083.Le processus d’audit des centres de traumatologie gagne en popularité, mais ses effets concrets ne sont pas bien connus. La présente revue systématique a cherché à résumer les données probantes disponibles sur l’efficacité de l’audit des centres de traumatologie.Nous avons effectué des recherches systématiques dans les bases de données CINAHL, Embase, HealthSTAR, MEDLINE et ProQuest, de même qu’une recherche dans la littérature grise sur les sites Web d’organisations majeures du domaine des traumas, de leur création à juin 2019, sans restriction de langue. La population à l’étude était l’ensemble des patients blessés traités en centre de traumatologie. L’intervention était l’audit du centre de traumatologie. Les groupes de comparaison correspondaient aux centres de traumatologie n’ayant pas subi d’audit, ou le même centre, avant son premier audit ou un audit subséquent. Le principal résultat à l’étude était la mortalité en milieu hospitalier; les résultats secondaires étaient les événements indésirables, l’utilisation des ressources et les processus de soins. Nous avons calculé des estimations sommaires par méta-analyse à effets aléatoires sur données groupées.Sur les 5125 citations retenues, 29 publications sur des études menées aux États-Unis répondaient à nos critères d’inclusion. La mortalité était le résultat le plus souvent à l’étude (n = 20), puis suivaient les processus de soins (n = 12), l’utilisation des ressources (n = 12) et les événements indésirables (n = 7). Le risque de biais était important ou critique dans 22 études. Nous avons observé une association imprécise entre l’audit et une baisse de la mortalité (risque relatif 0,74; intervalle de confiance à 95 % 0,52 à 1,06) chez les patients ayant subi un trauma grave.Notre revue a conclu qu’il y avait des associations mitigées et manquant d’uniformité entre l’audit et les processus de soins ou les issues pour les patients. La validité des données à l’étude était limitée par un manque de contrôles fiables, ainsi que par l’absence de données provenant d’autres pays que les États-Unis, ce qui empêche l’extrapolation à d’autres systèmes de santé. Des études quasi expérimentales devront être menées pour évaluer les effets de l’audit des centres de traumatologie.Registre PROSPERO, numéro CRD42018107083.

The 28th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held virtually over 4 days, on October 28-29 and November 4-5, 2021.The Annual PCF Scientific Retreat is a leading global scientific conference that focuses on first-in-field, unpublished, and high-impact basic, translational, and clinical prostate cancer research, as well as research from other fields with high probability for impacting prostate cancer research and patient care.Primary areas of research discussed at the 2021 PCF Retreat included: (i) prostate cancer disparities; (ii) prostate cancer survivorship; (iii) next-generation precision medicine; (iv) PSMA theranostics; (v) prostate cancer lineage plasticity; (vi) tumor metabolism as a cancer driver and treatment target; (vii) prostate cancer genetics and polygenic risk scores; (viii) glucocorticoid receptor biology in castration-resistant prostate cancer (CRPC); (ix) therapeutic degraders; (x) new approaches for immunotherapy in prostate cancer; (xi) novel technologies to overcome the suppressive tumor microenvironment; and (xii) real-world evidence and synthetic/virtual control arms.This article provides a summary of the presentations from the 2021 PCF Scientific Retreat. We hope that sharing this knowledge will help to improve the understanding of the current state of research and direct new advances in prostate cancer research and care.

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

Despite advances in the screening and treatment of prostate cancer, the therapy options available, particularly for later stages of the disease, remain limited, and the treatment-resistant setting represents a serious unmet medical need. Moreover, disease heterogeneity and disparities in patient access to medical advances result in considerable variability in outcomes across patients. Disease classification based on genomic sequencing is a promising approach for identifying patients whose tumors exhibit actionable targets and for making more informed treatment decisions. Here we discuss how precision oncology can be accelerated to inform broader genomically driven clinical decisions for men with advanced prostate cancer, to inform drug development and, ultimately, to contribute to new treatment paradigms. Beltran and colleagues discuss the challenges in treating metastatic prostate cancer and strategies to accelerate precision oncology and improve therapy and clinical decisions in this setting.

Some patients treated for ductal carcinoma in situ (DCIS) of the breast will experience cancer recurrences, whereas other patients will not. Unfortunately, current techniques cannot identify which preinvasive lesions will lead to recurrent cancer. Because the mechanism of cancer recurrence is unknown, it is difficult to design a test that detects its activity. We propose that certain pentose phosphate pathway enzymes, glutathione synthesis enzymes, and RhoA cluster at the epithelial cell periphery before cancer recurrences. Enzyme clustering enhances metabolic flux. Using fluorescence microscopy, we show that phosphophorylated glucose transporter type-1, transketolase-like protein-1, glutathione synthetase, GTP-loaded RhoA, and RhoA accumulate as a peripheral layer near the epithelial cell surface in surgical biopsies of women who will suffer recurrences, but not in samples from women who will not experience recurrences as judged using 2×2 contingency tables. Machine-learning studies of phospho-glucose transporter type 1-labeled tissue sections of patients with DCIS demonstrated strong cross-validation and holdout performance. A machine study of individual cribriform, papillary, micropapillary, and comedo forms of DCIS demonstrated 97% precision and 95% recall in the detection of samples from women who will not experience a recurrence and 90% precision and 94% recall in the detection of lesions that will become recurrent. A holdout study of these patients showed 73% true negatives, 18% true positives, 4% false positives, and 4% false negatives at a 50% threshold. This work suggests mechanistic features of cancer recurrences that may contribute to a new clinical test distinguishing high from low-recurrence risk in patients with DCIS.

BackgroundPeriodic external accreditation visits aiming to determine whether trauma centres are fulfilling the criteria for optimal care are part of most trauma systems. However, despite the growing trend towards accreditation of trauma centres, its impact on patient outcomes remains unclear. In addition, a recent systematic review found inconsistent results on the association between accreditation and patient outcomes, mostly due to the lack of robust controls. We aim to address these gaps by assessing the impact of trauma centre accreditation on patient outcomes, specifically in-hospital mortality and complications, using an interrupted time series (ITS) design.MethodsWe included all major trauma admissions to five level I and four level II trauma centres in Quebec, Canada between 2008 and 2017. In order to perform ITS, we first obtained monthly and quarterly estimates of the proportions of in-hospital mortality and complications, respectively, for level I and level II centres. Prognostic scores were used to standardise these proportions to account for changes in patient case mix and segmented regressions with autocorrelated errors were used to estimate changes in levels and trends in both outcomes following accreditation.ResultsThere were 51 035 admissions, including 20 165 for major trauma during the study period. After accounting for changes in patient case mix and secular trend in studied outcomes, we globally did not observe an association between accreditation and patient outcomes. However, associations were heterogeneous across centres. For example, in a level II centre with worsening preaccreditation outcomes, accreditation led to −9.08 (95% CI −13.29 to −4.87) and −9.60 (95% CI −15.77 to −3.43) percentage point reductions in mortality and complications, respectively.ConclusionAccreditation seemed to be beneficial for centres that were experiencing a decrease in performance preceding accreditation.

Content: CART QUOL is a study that has recently opened in the University Hospital of Wales Cardiff and was designed and set up by the Chief Investigator Emma Williams. Emma is a nurse and has been working within haematology since 2009. The study will be used to inform a dissertation project though will be done within her capacity of a research manager of the Clinical Research Group. Cellular therapies and regenerative medicine are a research theme of specialist interest within the South Wales Bone Marrow Transplant programme and a joint initiative between them and Wales Blood Service to establish a translational research platform in which to bring novel therapies to clinics. As we have become more focused on establishing outcomes in a patient centred way, this project aligns to values based healthcare with its aim to collect real world data and experiences. The aim of this study is to build on previous published data looking at the quality of life of patients who undergo CART therapy and follows on from a study published by Mariarz et al in BJH 2019. Two quality of life tools will be used, one FACTLYM as used within the Mariarz study, specifically for Lymphoma patients and the EQ5DL tool which is widely established in clinical trials and recommended by health assessment bodies (EQ5DL 2019).The CART team looked at the tools used in the previous study and decided that the EQ5D was easier to navigate and the terminology was easier for our patients to understand. This study will align with Standard of care visits and patients will be consented after their initial CART counselling visit and prior to the infusion of cells. The rest of the quality of life forms will be collected at day 30, 3, 6, 9, 12 and 18 months. Our CART service aims to treat 12-15 patients per year with CART therapy and it has been estimated that accrual into the trial would be 8-10 patients per year. There is an invisibility of nursing research due to a number of factors Seidlecki (2016) and this abstract aims to highlight the need for projects such as this despite Covid being an added obstacle. The REC authority and all involved with this study could see its relevance, moreso at this difficult time due to heightened anxieties of patients. Emma has progressed from research nurse to research manager to PI and most recently CI and hopes this work will encourage others to take a lead on nursing projects which will in turn add breadth to the research portfolio. This project was initially designed as a pilot study and for a single centre however it has potential to become a multi centred study and grow and benefit the haematology community and our patients further. The author is also keen to share her experiences of the R&D process and REC submission and how projects can be turned around quite quickly as this one if thought through and collaboration has been made between all parties.

The novel coronavirus SARS-CoV-2, the infective agent causing COVID-19, is having a global impact both in terms of human disease as well as socially and economically. Its heavily glycosylated spike glycoprotein is fundamental for the infection process, via its receptor-binding domains interaction with the glycoprotein angiotensin-converting enzyme 2 on human cell surfaces. We therefore utilized an integrated glycomic and glycoproteomic analytical strategy to characterize both N- and O- glycan site-specific glycosylation within the receptor-binding domain. We demonstrate the presence of complex-type N-glycans with unusual fucosylated LacdiNAc at both sites N331 and N343 and a single site of O-glycosylation on T323.

Background Studies have reported racial disparities in access to and use of multiple myeloma (MM) treatments between African American (AA) and White patients. Although AA patients demonstrate longer disease‐specific survival, this has not uniformly translated into improved survival over time. The association between race and treatment patterns and survival outcomes was analyzed using data from the Connect MM Registry. Methods The Connect MM Registry is a large US, multicenter, prospective observational cohort study of patients with newly diagnosed MM. Patients who received first‐line (1L) stem cell transplantation (SCT) or who did not receive SCT (non‐SCT or non–stem cell transplantation [NSCT]) were grouped by raceEffects of race and transplantation status on the use of triplet treatment were estimated using logistic regression. Results Treatment patterns in 1L (types and duration of induction, posttransplantation maintenance) were similar between AA and White patients. SCT rates in 1L (32% vs 36%) and triplet treatment use (AA: 44% for NSCT patients and 72% for SCT patients; and White: 48% for NSCT patients and 72% for SCT patients) during first induction were similar. No significant effect of race or transplantation status on 1L triplet treatment use was observed. Race was not found to be associated with survival outcomes among patients who underwent NSCT; however, AA patients who received SCT had significantly longer overall survival compared with White patients who underwent SCT (not reached vs 88.2 months; hazard ratio, 0.56; 95% CI, 0.35‐0.89 [P = .0141]). Conclusions AA and White patients were found to have similar treatment patterns in the Connect MM Registry, suggesting that both groups had equal access to health care. In this real‐world setting, AA patients received standard‐of‐care treatment, which might have contributed to better MM‐specific survival compared with White patients., Real‐world data from the mostly community‐based Connect MM Registry demonstrated that African American patients have multiple myeloma treatment patterns that are similar to those of White patients. Similar (progression‐free survival) and better (overall survival) survival outcomes are reported in African American individuals.

INTRODUCTION Pediatric venous thromboembolism (VTE) is a concern for orthopaedic surgeons. We sought to query the Pediatric Orthopaedic Society of North America (POSNA) members on current VTE prophylaxis practice and compare those results with those of a previous survey (2011). METHODS A 35-question survey was emailed to all active and candidate POSNA members. The survey consisted of questions on personal and practice demographics; knowledge and implementation of various VTE prophylaxis protocols, mechanical and chemical VTE prophylaxis agents, and risk factors; and utilization of scenarios VTE prophylaxis agents for various clinical scenarios. One- and two-way frequency tables were constructed comparing results from the current survey and those of the 2011 survey. RESULTS Two hundred thirty-nine surveys were completed (18% respondent rate), with most respondents from an academic/university practice reporting one or two partners (>60%). Half were in practice ≥15 years, and >90% reported an almost exclusive pediatric practice. One-third of the respondents reported familiarity with their institution-defined VTE prophylaxis protocol, and 20% were aware of an institutionally driven age at which all patients receive VTE prophylaxis. The most frequently recognized risk factors to guide VTE prophylaxis were oral contraceptive use, positive family history, and obesity. Respondents indicated a similar frequency of use of a VTE prophylaxis agent (either mechanical or chemical) for spinal fusion, hip reconstruction, and trauma (60% to 65%), with lower frequency for neuromuscular surgery (34%) (P < 0.001). One hundred thirty-seven respondents had a patient sustain a deep vein thrombosis, and 66 had a patient sustain a pulmonary embolism. Compared with responses from 2011, only 20 more respondents reported familiarity with their institution VTE prophylaxis protocol (75 versus 55). In 2018, aspirin was used more frequently than in 2011 (52% versus 19%; P < 0.0001) and enoxaparin was used less frequently (20% versus 41%; P < 0.0001). DISCUSSION Over the past 7 years since the first POSNA survey on VTE prophylaxis, most POSNA members are still unaware of their institution specific VTE prophylaxis protocol. Most respondents agree that either mechanical or chemical VTE prophylaxis should be used for spinal fusion, hip reconstruction, and trauma. The use of aspirin as an agent of chemical VTE prophylaxis has increased since 2011. LEVEL OF EVIDENCE Level IV. Type of evidence: therapeutic.

Approximately 75% of xenobiotics are primarily eliminated through metabolism; thus the accurate scaling of metabolic clearance is vital to successful drug development. Yet, when data is scaled from in vitro to in vivo, hepatic metabolic clearance, the primary source of metabolism, is still commonly underpredicted. Over the past decades, with biophysics used as a key component to restore aspects of the in vivo environment, several new cell culture settings have been investigated to improve hepatocyte functionalities. Most of these studies have focused on shear stress, i.e., flow mediated by a pressure gradient. One potential conclusion of these studies is that hepatocytes are naturally “mechanosensitive,” i.e., they respond to a change in their biophysical environment. We demonstrate that hepatocytes also respond to an increase in hydrostatic pressure that, we suggest, is directly linked to the lobule geometry and vessel density. Furthermore, we demonstrate that hydrostatic pressure improves albumin production and increases cytochrome P-450 (CYP) 1A2 expression levels in an aryl hydrocarbon-dependent manner in human hepatocytes. Increased albumin production and CYP function are commonly attributed to the impacts of shear stress in microfluidic experiments. Therefore, our results highlight evidence of a novel link between hydrostatic pressure and CYP metabolism and demonstrate that the spectrum of hepatocyte mechanosensitivity might be larger than previously thought.

Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease in which the insulin-producing β cells within the pancreas are destroyed. Identification of target Ags and epitopes of the β cell–reactive T cells is important both for understanding T1D pathogenesis and for the rational development of Ag-specific immunotherapies for the disease. Several studies suggest that proinsulin is an early and integral target autoantigen in T1D. However, proinsulin epitopes recognized by human CD4+ T cells have not been comprehensively characterized. Using a dye dilution–based T cell cloning method, we generated and characterized 24 unique proinsulin-specific CD4+ T cell clones from the peripheral blood of 17 individuals who carry the high-risk DR3-DQ2 and/or DR4-DQ8 HLA class II haplotypes. Some of the clones recognized previously reported DR4-restricted epitopes within the C-peptide (C25-35) or A-chain (A1-15) of proinsulin. However, we also characterized DR3-restricted epitopes within both the B-chain (B16-27 and B22-C3) and C-peptide (C25-35). Moreover, we identified DQ2-restricted epitopes within the B-chain and several DQ2- or DQ8-restricted epitopes within the C-terminal region of C-peptide that partially overlap with previously reported DQ-restricted epitopes. Two of the DQ2-restricted epitopes, B18-26 and C22-33, were shown to be naturally processed from whole human proinsulin. Finally, we observed a higher frequency of CDR3 sequences matching the TCR sequences of the proinsulin-specific T cell clones in pancreatic lymph node samples compared with spleen samples. In conclusion, we confirmed several previously reported epitopes but also identified novel (to our knowledge) epitopes within proinsulin, which are presented by HLA class II molecules associated with T1D risk.

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence. Objective: To present the results from the APCCC 2019. Design, setting, and participants: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naive prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions. Outcome measurements and statistical analysis: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process. Results and limitations: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material. Conclusions: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials. Patient summary: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.

Survivorship care for patients with prostate cancer requires careful consideration of unique disease-specific factors, including the prolonged natural disease history, the potential for competing health risks, and the consequences of long-term androgen deprivation therapy. However, current prostate cancer survivorship research is unfortunately limited by the lack of a robust supportive evidence base, variability in the definitions and measurement of survivorship outcomes, and a heavy reliance on expert opinion. As a result, the conduct of quality prostate cancer survivorship research is of increasing importance for patients, medical providers, and other key stakeholders. This manuscript harmonizes a path forward for improving prostate cancer survivorship by defining prostate cancer survivorship and survivorship research, as well as by highlighting key research priorities and cooperative mechanisms for survivorship studies within prostate cancer, with a particular focus on men with advanced disease.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Background The Surveillance, Epidemiology, and End Results (SEER) database and National Cancer Database (NCDB) show improved overall survival (OS) in patients with multiple myeloma (MM) over the last 15 years. This analysis evaluated the validity of the largely community‐based Connect MM Registry as a national reference for MM. Methods Baseline disease characteristics and survival in US newly diagnosed MM patients were examined using the Connect MM Registry as well as SEER and NCDB databases. Baseline characteristics predictive of longer survival in Connect MM were also identified. Results As of February 2017, 3011 patients were enrolled in the Connect MM Registry; 2912 were treated. Median age at time of MM diagnosis and age range were numerically similar from 2010 to 2015 across all 3 registries; SEER had a higher representation of nonwhite racial groups than that in the other 2 registries. OS rates suggest proportionate improvement with year of diagnosis among the 3 registries. A Cox proportional hazards model suggests that younger age (, Survival data from the Connect MM Registry, which is representative of the national MM population, reflect national trends of improvement. This establishes the Connect MM Registry as a reference for MM survival in the US.

Regulatory T cell (Treg) adoptive cell therapy (ACT) represents an emerging strategy for restoring immune tolerance in autoimmune diseases. Tregs are commonly purified using a CD4

Background:Innovations in treatments, imaging and molecular characterisationhave improved outcomes for people with advanced prostate cancer; however, many aspectsof clinical management are devoid of high-level evidence. At the Advanced Prostate CancerConsensus Conference (APCCC) 2019, many of these topics were addressed, and consensuswas not always reached. The results from clinical trials will most reliably plus the gaps.Methods:An invited panel of 57 experts voted on 123 multiple-choice questions on clinicalmanagement at APCCC 2019. No consensus was reached on 88 (71.5%) questions definedas

Background Physical distancing contains the corona virus, but compliance with physical distancing across religious minorities in Israel has been shown to be relatively poorer than in the majority population. This study tests the power of messages as drivers of willingness to comply with physical distancing across religious minorities in Israel during the first wave of the COVID-19 from March till June 2020. Methods 896 Israeli Muslims, Druze, Bedouins, Jewish Orthodox, Christians, and Jewish Seculars participated in this conjoint-based experimental design. The size of the total sample and of the subgroups is consistent with the suggested size in conjoint analysis studies, particularly when aiming at stability of coefficients rather than stability of means. The dependent variable was ‘willingness to comply’. Independent variables were known contributors to compliance: perceived risk, practices of physical distancing, ways to assure compliance, and the agent communicating the policy. Results A regression analysis indicated minor differences in the power of messages across groups despite dramatic cultural differences amongst them. We identified three distinct mindsets that transcend religious cultures from the responses of the study subjects to various messages and named them “pandemic observers,” “obedient followers,” and “sensitive interpreters.” Compliance of "Pandemic Observers" (n = 306) may be improved by messages such as, “Dangerous virus spreading wildly” and “Health experts suggest what to do but the government is reactive rather than proactive” (β = 14, p Conclusions Mindset-assignment reflects how people think rather than their religious affiliation. A personal viewpoint identifier was developed to predict mindset-assignment and enable health authorities to enhance compliance through mindset-tailored messages for members of each mindset segment. We recommend that health authorities and policy makers consider these different personality types, which range across religious minorities and emphasize the messages that each type responds to in developing and implementing a communication plan to improve physical distancing as an important public health measure.

INTRODUCTION. The 2021 Coffey - Holden Prostate Cancer Academy (CHPCA) Meeting, “Prostate Cancer Research in the 21st Century,” was held virtually, from June 24 – 25, 2021. METHODS. The CHPCA Meeting is organized by the Prostate Cancer Foundation (PCF) as a unique discussion-oriented meeting focusing on critical topics in prostate cancer research envisioned to bridge the next major advances in prostate cancer biology and treatment. The 2021 CHPCA Meeting was virtually attended by 89 investigators and included 31 talks over nine sessions. RESULTS. Major topic areas discussed at the meeting included: cancer genomics and sequencing, functional genomic approaches to studying mediators of plasticity, emerging signaling pathways in metastatic castration resistant prostate cancer (mCRPC), Wnt signaling biology and the challenges of targeted therapy, clonal hematopoiesis, neuroendocrine cell plasticity and anti-tumor immunity, cancer immunotherapy and its synergizers, and imaging the tumor microenvironment and metabolism. DISCUSSION. This meeting report summarizes the research presented at the 2021 CHPCA Meeting. We hope that publication of this knowledge will accelerate new understandings and the development of new biomarkers and treatments for prostate cancer.

Human islet antigen reactive CD4+ memory T cells (IAR T cells) play a key role in the pathogenesis of autoimmune type 1 diabetes (T1D). Using single-cell RNA sequencing (scRNA-Seq) to identify T cell receptors (TCRs) in IAR T cells, we have identified a class of TCRs that share TCRα chains between individuals ("public" chains). We isolated IAR T cells from blood of healthy, new-onset T1D and established T1D donors using multiplexed CD154 enrichment and identified paired TCRαβ sequences from 2767 individual cells. More than a quarter of cells shared TCR junctions between 2 or more cells ("expanded"), and 29/47 (~62%) of expanded TCRs tested showed specificity for islet antigen epitopes. Public TCRs sharing TCRα junctions were most prominent in new-onset T1D. Public TCR sequences were more germline like than expanded unique, or "private," TCRs, and had shorter junction sequences, suggestive of fewer random nucleotide insertions. Public TCRα junctions were often paired with mismatched TCRβ junctions in TCRs; remarkably, a subset of these TCRs exhibited cross-reactivity toward distinct islet antigen peptides. Our findings demonstrate a prevalent population of IAR T cells with diverse specificities determined by TCRs with restricted TCRα junctions and germline-constrained antigen recognition properties. Since these "innate-like" TCRs differ from previously described immunodominant TCRβ chains in autoimmunity, they have implications for fundamental studies of disease mechanisms. Self-reactive restricted TCRα chains and their associated epitopes should be considered in fundamental and translational investigations of TCRs in T1D.

Background The 25th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held in Carlsbad, CA, from 26 to 28 October 2018. Methods The PCF Scientific Retreat is the foremost scientific research conference in the world that focuses on the most significant and promising recent advancements in basic, translational, and clinical prostate cancer research, as well as research from other fields that has substantial potential to advance prostate cancer research. Results The major topic areas discussed at this year's meeting included (a) new insights into prostate cancer biology and treatment; (b) approaches for accelerating precision medicine for prostate cancer; (c) prostate-specific membrane antigen-targeted therapy and imaging for prostate cancer; (d) updates on Poly (ADP-ribose) polymerase (PARP)-inhibitor clinical trial results; (e) the biology and role of prostate cancer stem cells; (f) new approaches for targeting the androgen receptor and other steroid hormone receptor pathways; (g) racial disparities in prostate cancer treatment and outcomes; (h) the role of the nervous system in prostate cancer development and progression; (i) the role of the WNT signaling pathway in normal prostate and prostate cancer biology; (j) novel immunotherapy approaches; and (k) the ecology of prostate cancer. Conclusions This article reviews the research presented by the speakers at the 2018 PCF Scientific Retreat for the purpose of disseminating this knowledge to the global research community and ultimately accelerating new understandings and treatment strategies for prostate cancer.

Although recurrent cancers can become life threatening, little is known about the intracellular events required for cancer recurrences. Due to this lack of mechanistic information, there is no test to predict cancer recurrences or nonrecurrences during early stages of disease. In this retrospective study, we use ductal carcinoma in situ of the breast as a framework to better understand the mechanism of cancer recurrences using patient outcomes as the physiological observable. Conventional pathology slides were labeled with anti-phosphofructokinase type L (PFKL) and anti-phosphofructokinase/fructose-2,6-bisphosphatase type 4 (PFKFB4) reagents. PFKL and PFKFB4 were found in ductal epithelial cell nucleoli from DCIS samples of women who did not experience a cancer recurrence. In contrast, PFKL and PFKFB4 may be found near the plasma membrane in samples from patients who will develop recurrent cancer. With the use of machine learning to predict patient outcomes, holdout studies of individual patient micrographs for the three biomarkers PFKL, PFKFB4, and phosphorylated glucose transporter 1 (GLUT1) demonstrated 38.6% true negatives, 49.5% true positives, 11.9% false positives, and 0% false negatives ( n = 101). A subpopulation of recurrent samples demonstrated PFKL, PFKFB4, and phosphorylated GLUT1 accumulation at the apical surface of epithelial cells, suggesting that carbohydrates can be harvested from the ducts’ luminal spaces as an energy source. We suggest that PFK isotype patterns are metabolic switches representing key mechanistic steps of recurrences. Furthermore, PFK enzyme patterns within epithelial cells contribute to an accurate diagnostic test to classify DCIS patients as high or low recurrence risk.

Parasellar meningiomas involving the cavernous sinus and Meckel's cave pose a management challenge because of invasion around neurovascular structures and the pituitary gland. The management options range from aggressive resection to focused radiotherapy alone. We present a strategy for these tumors that includes endonasal bony decompression, partial tumor removal, and stereotactic radiotherapy (SRT) in select cases.The tumor location, previous treatments, cranial neuropathies, pituitary dysfunction, tumor control rates, use of stereotactic radiosurgery, SRT, and complications were retrospectively evaluated.Twenty patients (age range, 43-81 years; 65% women; 90% with World Health Organization grade I; median follow-up, 57 months; 14 without previous debulking and RT; 6 with previous debulking and RT) underwent endonasal bony decompression and partial tumor removal. The most common tumor locations were cavernous sinus (95%), Meckel's cave (95%), sella (75%), petroclival (60%), and optic canal/orbit (30%). Three patients with large meningiomas underwent staged transcranial and endonasal debulking. Of the 14 patients without previous debulking and RT, 11 had undergone postoperative SRT, with tumor shrinkage in 3 (27%). At the last follow-up examination, for these 14 patients and the 6 patients who had undergone previous surgery and RT, tumor control was 100% and 33% (P0.001) and the cranial neuropathies had improved in 57% and 33%, respectively. Major complications occurred in 2 patients: a permanent sixth cranial nerve palsy and cerebrospinal fluid leakage requiring reoperation.Endonasal bony decompression and selective tumor removal, followed by SRT, appears to be a reasonable treatment option for most previously untreated parasellar meningiomas. For patients who have undergone previous debulking and RT, new targeted treatment strategies are needed.

BACKGROUND: Tests and treatments that are not supported by evidence and could expose patients to unnecessary harm, referred to here as low-value clinical practices, consume up to 30% of healthcare resources. Choosing Wisely and other organisations have published lists of clinical practices to be avoided. However, few apply to injury and most are based uniquely on expert consensus. We aimed to identify low-value clinical practices in acute injury care. METHODS: We conducted a scoping review targeting articles, reviews and guidelines that identified low-value clinical practices specific to injury populations. Thirty-six experts rated clinical practices on a 5-point Likert scale from clearly low-value to clearly beneficial. Clinical practices reported as low-value by at least one level I, II or III study and considered clearly or potentially low-value by at least 75% of experts were retained as candidates for low-value injury care. RESULTS: Of 50,695 citations, 815 studies were included and led to the identification of 150 clinical practices. Of these 63 were considered candidates for low-value injury care; 33 in the emergency room, 9 in trauma surgery, 15 in the intensive care unit and 5 in orthopaedics. We also identified 87 'grey zone' practices, which did not meet our criteria for low-value care. CONCLUSIONS: We identified 63 low-value clinical practices in acute injury care that are supported by empirical evidence and expert opinion. Conditional on future research, they represent potential targets for guidelines, overuse metrics and de-implementation interventions. We also identified 87 'grey zone' practices, which may be interesting targets for value-based decision-making. Our study represents an important step towards the de-implementation of low-value clinical practices in injury care. LEVEL OF EVIDENCE: III.