Heterogeneity in Systematic Reviews of Medical Imaging Diagnostic Test Accuracy Studies: A Systematic Review.

Importance: Systematic reviews of medical imaging diagnostic test accuracy (DTA) studies are affected by between-study heterogeneity due to a range of factors. Failure to appropriately assess the extent and causes of heterogeneity compromises the interpretability of systematic review findings. Objective: To assess how heterogeneity has been examined in medical imaging DTA studies. Evidence Review: The PubMed database was searched for systematic reviews of medical imaging DTA studies that performed a meta-analysis. The search was limited to the 40 journals with highest impact factor in the radiology, nuclear medicine, and medical imaging category in the InCites Journal Citation Reports of 2021 to reach a sample size of 200 to 300 included studies. Descriptive analysis was performed to characterize the imaging modality, target condition, type of meta-analysis model used, strategies for evaluating heterogeneity, and sources of heterogeneity identified. Multivariable logistic regression was performed to assess whether any factors were associated with at least 1 source of heterogeneity being identified in the included meta-analyses. Methodological quality evaluation was not performed. Data analysis occurred from October to December 2022. Findings: A total of 242 meta-analyses involving a median (range) of 987 (119-441 510) patients across a diverse range of disease categories and imaging modalities were included. The extent of heterogeneity was adequately described (ie, whether it was absent, low, moderate, or high) in 220 studies (91%) and was most commonly assessed using the I2 statistic (185 studies [76%]) and forest plots (181 studies [75%]). Heterogeneity was rated as moderate to high in 191 studies (79%). Of all included meta-analyses, 122 (50%) performed subgroup analysis and 87 (36%) performed meta-regression. Of the 242 studies assessed, 189 (78%) included 10 or more primary studies. Of these 189 studies, 60 (32%) did not perform meta-regression or subgroup analysis. Reasons for being unable to investigate sources of heterogeneity included inadequate reporting of primary study characteristics and a low number of included primary studies. Use of meta-regression was associated with identification of at least 1 source of variability (odds ratio, 1.90; 95% CI, 1.11-3.23; P = .02). Conclusions and Relevance: In this systematic review of assessment of heterogeneity in medical imaging DTA meta-analyses, most meta-analyses were impacted by a moderate to high level of heterogeneity, presenting interpretive challenges. These findings suggest that, despite the development and availability of more rigorous statistical models, heterogeneity appeared to be incomplete, inconsistently evaluated, or methodologically questionable in many cases, which lessened the interpretability of the analyses performed; comprehensive heterogeneity assessment should be addressed at the author level by improving personal familiarity with appropriate statistical methodology for assessing heterogeneity and involving biostatisticians and epidemiologists in study design, as well as at the editorial level, by mandating adherence to methodologic standards in primary DTA studies and DTA meta-analyses.

Epiretinal membrane in uveitis: Rate, visual prognosis, complications and surgical outcomes.

BACKGROUND: Epiretinal membrane (ERM) is a common finding in patients with uveitis that contributes to visual impairment. We describe the long-term visual acuity (VA) and morphometric progression in patients with uveitis and epiretinal membrane (ERM). METHODS: Retrospective cohort study of patients with uveitic ERM from a tertiary centre database. Multivariate analysis of risk factors for ERM progression was calculated using a marginal Cox regression model to estimate hazard ratios (HR). RESULTS: Two hundred and sixteen eyes (4%) of a total 5450 eyes with uveitis were identified to have an ERM. The most common diagnosis was idiopathic uveitis in 45 patients (28.7%), followed by sarcoidosis in 21 (13.4%), HLAB27-related uveitis in 15 (9.6%) and toxoplasmosis in 15 (9.6%). Risk factors for ERM development include age (HR 1.03), intermediate uveitis (HR 2.33), posterior uveitis (HR 1.53) and ERM fellow eye (HR 18.28). Anterior uveitis (HR 0.53) and alternating disease (HR 0.53) were protective. Median VA was 20/40 at diagnosis of ERM and 20/40 at final follow up. Progression of ERM grade occurred in 17 eyes (7.9%) during the study period. ERM peel was performed in 44 eyes (20.4%). Median VA was 20/60 and 20/40 at baseline and 12 months after surgery, respectively. Improvement in visual acuity occurred in 23 eyes (60.5%) following surgery. CONCLUSIONS: In addition to intermediate and posterior uveitis, fellow eye involvement is a strong risk factor for ERM development. In treated uveitis, the majority maintain their long-term vision and rates of ERM progression are low.

Systematic review of adherence to the standards for reporting of diagnostic accuracy studies (STARD) 2015 reporting guideline in cerebral aneurysm imaging diagnostic accuracy studies.

BACKGROUND: Diagnostic neuroimaging plays an essential role in guiding clinical decision-making in the management of patients with cerebral aneurysms. Imaging technologies for investigating cerebral aneurysms constantly evolve, and clinicians rely on the published literature to remain up to date. Reporting guidelines have been developed to standardise and strengthen the reporting of clinical evidence. Therefore, it is essential that radiological diagnostic accuracy studies adhere to such guidelines to ensure completeness of reporting. Incomplete reporting hampers the reader's ability to detect bias, determine generalisability of study results or replicate investigation parameters, detracting from the credibility and reliability of studies. OBJECTIVE: The purpose of this systematic review was to evaluate adherence to the Standards for Reporting of Diagnostic Accuracy Studies (STARD) 2015 reporting guideline amongst imaging diagnostic accuracy studies for cerebral aneurysms. METHODS: A systematic search for cerebral aneurysm imaging diagnostic accuracy studies was conducted. Journals were cross examined against the STARD 2015 checklist and their compliance with item numbers was recorded. RESULTS: The search yielded 66 articles. The mean number of STARD items reported was 24.2 ± 2.7 (71.2% ± 7.9%), with a range of 19 to 30 out of a maximum number of 34 items. CONCLUSION: Taken together, these results indicate that adherence to the STARD 2015 guideline in cerebral aneurysm imaging diagnostic accuracy studies was moderate. Measures to improve compliance include mandating STARD 2015 adherence in instructions to authors issued by journals.

Tixagevimab and Cilgavimab Administration for Hemodialysis Patients at Community-Based Dialysis Centers in Singapore as Pre-Exposure Prophylaxis for SARS-CoV-2 Infection.

INTRODUCTION:  Hemodialysis patients are deemed to be immunosuppressed and may not be able to mount an adequate response to vaccination against the SARS-CoV-2 virus. Due to the higher morbidity and mortality in this vulnerable group, pre-exposure prophylaxis with monoclonal antibodies was introduced as an additional measure for protection in selected community-based hemodialysis patients in Singapore. Tixagevimab and cilgavimab, available as Evusheld, were used for this purpose. METHODS:  A government-sponsored clinical administration program with the provision of 200 doses of Evusheld at no cost to the patients was implemented. Patient selection criteria to further risk-stratify this vulnerable hemodialysis patient cohort was developed and 200 patients were finally selected. Evusheld administration was done over a period of two months, as two consecutive injections were given at two separate intramuscular sites, which constituted one administration. Data were collected as part of a retrospective clinical audit, as part of a routine quality monitoring process for this patient care program. Real-world evidence was generated to assess the impact on mortality, hospitalization rate, reason for hospitalization, and any associated morbidity. RESULTS:  No adverse events from the Evusheld administration were noted. All recipients had received COVID-19 vaccinations prior to Tixa-Cilga, with a range of one to five doses. A total of 198 (99%) completed two doses and 189 (95%) completed three doses, out of which, 14 (7%) patients contracted COVID-19 infection over three months. The overall hospitalization rate was 2% (four out of 200 patients). Severe illness that required intensive care unit stay was therefore seen in only 2 (1%) out of 200 patients. None of the infected patients died. DISCUSSION:  A significant reduction in severity of illness, hospitalization rate, and mortality was found with pre-exposure prophylaxis with tixagevimab and cilgavimab, in this real-world experience from Singapore. Evusheld administration reduced the hospitalization rate from 42.5% to 2%, which is a reduction of 95.3% (p<0.0001). Symptoms in infected patients were mild, with only 1% being admitted to the intensive care unit. The mortality rate from COVID-19 infection was reduced from 2.5% to 0% with Evusheld.  Conclusion: Mass administration of prophylactic treatments for vulnerable populations can be challenging in community-based settings and the successful implementation of such a program has been described. The findings can have health policy implications for the protection of such immunocompromised patients in the future. The combination of tixagevimab and cilgavimab, available as Evusheld in Singapore, was safe to use in hemodialysis patients, with no adverse events noted. There was a significant reduction in hospitalization rates and intensive care unit admissions with a zero-mortality rate due to COVID-19 infection, after pre-exposure prophylaxis.

A therapist-guided internet-based cognitive behavioral therapy program for Hong Kong university students with psychological distress: A study protocol for a randomized controlled trial.

Background: University students are at high risk of various mental health problems due to high levels of psychological distress. However, university counseling services are often inadequate to meet their mental health needs due to shortage of mental health professionals, especially in Hong Kong. Internet-based cognitive behavioral therapy (iCBT) has shown similar effects as those of face-to-face CBT in addressing these mental health concerns, but few iCBT programs have been developed for Hong Kong university students. Objective: This study protocol aims to develop and evaluate a culturally and linguistically appropriate iCBT program called "REST Online" to reduce the psychological distress and improve the mental health of Chinese university students in Hong Kong in a randomized controlled trial (RCT). Method: The contents and functionality of the "REST Online" program which includes both web- and app-based versions, are described. A blended mode of service delivery is adopted, with 8 online modules and 2 counseling sessions. Therapist support will be provided by a CBT therapist. A total of 338 Chinese university students with mild to moderate levels of psychological distress will be openly recruited and randomized to three groups: the (1) web-based and (2) app-based "REST Online" groups, and (3) waitlist control group. The program effectiveness is evaluated in psychological distress, depression and anxiety symptoms, and positive and negative emotions and positive and negative thoughts at pre-, post- and 3-month follow-up tests. Linear mixed effect models will be conducted for data analysis. Discussion: The "REST Online" program is among the first of its kind to address the mental health needs of Hong Kong university students by an internet intervention. Theoretically, this study will provide some empirical evidence for the effectiveness of this iCBT program in the Hong Kong context for Chinese clients. Practically, if proven effective, this program can be provided to local university counselors as an option for service delivery. Strengths and limitations are also discussed.

DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation.

The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.

Loss of Brca1 and Trp53 in adult mouse mammary ductal epithelium results in development of hormone receptor-positive or hormone receptor-negative tumors, depending on inactivation of Rb family proteins.

BACKGROUND: Breast cancer is a heterogenous disease with several histological and molecular subtypes. Models that represent these subtypes are essential for translational research aimed at improving clinical strategy for targeted therapeutics. METHODS: Different combinations of genetic aberrations (Brca1 and Trp53 loss, and inhibition of proteins of the Rb family) were induced in the mammary gland by injection of adenovirus expressing Cre recombinase into the mammary ducts of adult genetically engineered mice. Mammary tumors with different genetic aberrations were classified into molecular subtypes based on expression of molecular markers and RNAseq analysis. In vitro potency assays and Western blots were used to examine their drug sensitivities. RESULTS: Induction of Brca1 and Trp53 loss in mammary ductal epithelium resulted in development of basal-like hormone receptor (HR)-negative mammary tumors. Inhibition of Rb and Trp53 loss or the combination of Rb, Trp53 and Brca1 aberrations resulted in development of luminal ductal carcinoma positive for ER, PR, and Her2 expression. HR positivity in tumors with Rb, Trp53 and Brca1 aberrations indicated that functionality of the Rb pathway rather than Brca1 status affected HR status in these models. Mammary tumor gene expression profiles recapitulated human basal-like or luminal B breast cancer signatures, but HR-positive luminal cancer models were endocrine resistant and exhibited upregulation of PI3K signaling and sensitivity to this pathway inhibition. Furthermore, both tumor subtypes were resistant to CDK4/6 inhibition. CONCLUSIONS: Examination of molecular expression profiles and drug sensitivities of tumors indicate that these breast cancer models can be utilized as a translational platform for evaluation of targeted combinations to improve chemotherapeutic response in patients that no longer respond to hormone therapy or that are resistant to CDK4/6 inhibition.

Unbiased approach to identify and assess efficacy of human SARS-CoV-2 neutralizing antibodies.

Coronavirus disease 2019 (COVID-19) continues to significantly impact the global population, thus countermeasure platforms that enable rapid development of therapeutics against variants of SARS-CoV-2 are essential. We report use of a phage display human antibody library approach to rapidly identify neutralizing antibodies (nAbs) against SARS-CoV-2. We demonstrate the binding and neutralization capability of two nAbs, STI-2020 and STI-5041, against the SARS-CoV-2 WA-1 strain as well as the Alpha and Beta variants. STI-2020 and STI-5041 were protective when administered intravenously or intranasally in the golden (Syrian) hamster model of COVID-19 challenged with the WA-1 strain or Beta variant. The ability to administer nAbs intravenously and intranasally may have important therapeutic implications and Phase 1 healthy subjects clinical trials are ongoing.

Small Study Effects in Diagnostic Imaging Accuracy: A Meta-Analysis.

Importance: Small study effects are the phenomena that studies with smaller sample sizes tend to report larger and more favorable effect estimates than studies with larger sample sizes. Objective: To evaluate the presence and extent of small study effects in diagnostic imaging accuracy meta-analyses. Data Sources: A search was conducted in the PubMed database for diagnostic imaging accuracy meta-analyses published between 2010 and 2019. Study Selection: Meta-analyses with 10 or more studies of medical imaging diagnostic accuracy, assessing a single imaging modality, and providing 2 × 2 contingency data were included. Studies that did not assess diagnostic accuracy of medical imaging techniques, compared 2 or more imaging modalities or different methods of 1 imaging modality, were cost analyses, used predictive or prognostic tests, did not provide individual patient data, or were network meta-analyses were excluded. Data Extraction and Synthesis: Data extraction was performed in accordance with the PRISMA guidelines. Main Outcomes and Measures: The diagnostic odds ratio (DOR) was calculated for each primary study using 2 × 2 contingency data. Regression analysis was used to examine the association between effect size estimate and precision across meta-analyses. Results: A total of 31 meta-analyses involving 668 primary studies and 80 206 patients were included. Fixed effects analysis produced a regression coefficient for the natural log of DOR against the SE of the natural log of DOR of 2.19 (95% CI, 1.49-2.90; P < .001), with computed tomography as the reference modality. Interaction test for modality and SE of the natural log of DOR did not depend on modality (Wald statistic P = .50). Taken together, this analysis found an inverse association between effect size estimate and precision that was independent of imaging modality. Of 26 meta-analyses that formally assessed for publication bias using funnel plots and statistical tests for funnel plot asymmetry, 21 found no evidence for such bias. Conclusions and Relevance: This meta-analysis found evidence of widespread prevalence of small study effects in the diagnostic imaging accuracy literature. One likely contributor to the observed effects is publication bias, which can undermine the results of many meta-analyses. Conventional methods for detecting funnel plot asymmetry conducted by included studies appeared to underestimate the presence of small study effects. Further studies are required to elucidate the various factors that contribute to small study effects.

Abrogation of Rb Tumor Suppression Initiates GBM in Differentiated Astrocytes by Driving a Progenitor Cell Program.

Glioblastoma (GBM) remains lethal with no effective treatments. Despite the comprehensive identification of commonly perturbed molecular pathways, little is known about the disease's etiology, particularly in early stages. Several studies indicate that GBM is initiated in neural progenitor and/or stem cells. Here, we report that differentiated astrocytes are susceptible to GBM development when initiated by perturbation of the RB pathway, which induces a progenitor phenotype. In vitro and in vivo inactivation of Rb tumor suppression (TS) induces cortical astrocytes to proliferate rapidly, express progenitor markers, repress differentiation markers, and form self-renewing neurospheres that are susceptible to multi-lineage differentiation. This phenotype is sufficient to cause grade II astrocytomas which stochastically progress to GBM. Together with previous findings, these results demonstrate that cell susceptibility to GBM depends on the initiating driver.

Systematic Analysis of Publication Bias in Neurosurgery Meta-Analyses.

BACKGROUND: Statistically significant positive results are more likely to be published than negative or insignificant outcomes. This phenomenon, also termed publication bias, can skew the interpretation of meta-analyses. The widespread presence of publication bias in the biomedical literature has led to the development of various statistical approaches, such as the visual inspection of funnel plots, Begg test, and Egger test, to assess and account for it. OBJECTIVE: To determine how well publication bias is assessed for in meta-analyses of the neurosurgical literature. METHODS: A systematic search for meta-analyses from the top neurosurgery journals was conducted. Data relevant to the presence, assessment, and adjustments for publication bias were extracted. RESULTS: The search yielded 190 articles. Most of the articles (n = 108, 56.8%) were assessed for publication bias, of which 40 (37.0%) found evidence for publication bias whereas 61 (56.5%) did not. In the former case, only 11 (27.5%) made corrections for the bias using the trim-and-fill method, whereas 29 (72.5%) made no correction. Thus, 111 meta-analyses (58.4%) either did not assess for publication bias or, if assessed to be present, did not adjust for it. CONCLUSION: Taken together, these results indicate that publication bias remains largely unaccounted for in neurosurgical meta-analyses.

Outcomes of perineal reconstruction with inferior gluteal artery myocutaneous flaps and primary closure following abdominoperineal resection.

BACKGROUND: Perineal wound morbidity following abdominoperineal resection (APR) is a significant challenge. Myocutaneous flap-based techniques have been developed to overcome morbidity associated with perineal reconstruction. We reviewed outcomes for patients undergoing APR in a hospital that performs inferior gluteal artery myocutaneous (IGAM) island transposition flaps and primary closure (PC) for perineal reconstruction. METHODS: A retrospective study of patients who underwent APR for malignancy between January 2012 and March 2020 was performed and outcomes between IGAM reconstruction and PC compared. Primary outcomes were wound infection and dehiscence. Secondary outcomes included return to theatre, operative time, length of stay, flap loss and perineal hernia incidence. RESULTS: One-hundred and two patients underwent APR, with 50 (49%) who had PC and 52 (51%) had IGAM flap reconstructions. There were no differences between each group with regards to wound infection (23 vs. 22%, P = 0.55) or wound dehiscence (25 vs. 24%, P = 0.92). Thirteen (25%) IGAM patients required a return to theatre compared to three PC patients (6%) (P = 0.008). IGAM procedures required twice the overall operative time (506 vs. 240 min, P = 0.001) with no differences between groups when comparing the APR component (250 vs. 240 min, P = 0.225). The IGAM group had a longer length of stay (median 13 days vs. 9 days, P = 0.001). Only one IGAM flap was lost and no symptomatic hernias were identified. CONCLUSION: Perineal closure technique did not affect the incidence of wound infection or dehiscence. Closure technique should be tailored to underlying patient characteristics and surgical pathology.

Clinical Significance of Hepsin and Underlying Signaling Pathways in Prostate Cancer.

The hepsin gene encodes a type II transmembrane serine protease. Previous studies have shown the overexpression of hepsin in prostate cancer, and the dysregulation of hepsin promotes cancer cell proliferation, migration, and metastasis in vitro and in vivo. The review incorporated with our work showed that hepsin expression levels were specifically increased in prostate cancer, and higher expression in metastatic tumors than in primary tumors was also observed. Moreover, increased expression was associated with poor outcomes for patients with prostate cancer. Using in silico protein-protein interaction prediction, mechanistic analysis showed that hepsin interacted with eight other oncogenic proteins, whose expression was significantly correlated with hepsin expression in prostate cancer. The oncogenic functions of hepsin are mainly linked to proteolytic activities that disrupt epithelial integrity and regulatorily interact with other genes to influence cell-proliferation, EMT/metastasis, inflammatory, and tyrosine-kinase-signaling pathways. Moreover, genomic amplifications of hepsin, not deletions or other alterations, were significantly associated with prostate cancer metastasis. Targeting hepsin using a specific inhibitor or antibodies significantly attenuates its oncogenic behaviors. Therefore, hepsin could be a novel biomarker and therapeutic target for prostate cancer.

Cataract surgery in herpes simplex virus ocular disease.

PURPOSE: To investigate the outcomes and complications associated with cataract surgery in eyes with herpes simplex virus (HSV)-related anterior segment ocular disease. SETTING: Public tertiary center in Auckland, New Zealand. DESIGN: Retrospective observational cohort study. METHODS: Clinical records of patients diagnosed with HSV-related keratitis and/or anterior uveitis who underwent subsequent cataract surgery in the affected eye were reviewed. Main outcomes measured were visual outcome, complications, and recurrence. RESULTS: 37 eyes of 37 patients were included. Intraoperative complications occurred in 1 patient (2.7%) with iris prolapse. Keratitis or uveitis recurred postoperatively in 17 patients (45.9%) 8 patients (22.5%); 22.5% experienced recurrences in the first year postoperatively. 1 case (2.7%) of postoperative cystoid macular edema and 1 (2.7%) postoperative endophthalmitis occurred. Corrected distance visual acuity at 3 months was >20/50 in 21 patients (70.0%), 20/50 to 20/200 in 4 patients (12.9%), and ≤20/200 in 6 patients (19.4%). Vision improved in 26 eyes (83.9%) and worsened in only 1 eye (3.2%). Risk for recurrent inflammation was associated with a greater number of recurrences prior to surgery (hazard rate [HR] 1.31), time quiescent prior to surgery (HR 0.48), and iris transillumination defect at preoperative assessment (HR 57.66). CONCLUSIONS: Cataract surgery in eyes with previous HSV disease may improve visual acuity for most of the eyes but, overall, carries a guarded prognosis, particularly in eyes with corneal scarring. There is a significant risk for recurrent inflammation in the first year postoperatively. If possible, surgeons should ensure a period of disease quiescence prior to surgery.

Association of germline rare pathogenic mutations in guideline-recommended genes with prostate cancer progression: A meta-analysis.

BACKGROUND: Germline mutations in several genes, mainly DNA repair genes, have been associated with prostate cancer (PCa) progression. However, primarily due to the rarity of mutations, statistical evidence for these associations is not consistently established. The objective of this study is to synthesize evidence from multiple studies using a meta-analysis. METHODS: Genes analyzed were chosen based on National Comprehensive Cancer Network guidelines recommendations (10 genes) and a commonly reported gene (NBN). PCa progression in this analysis was defined as either having metastases or PCa-specific mortality. We searched PubMed for papers published before April 26, 2021, using selected keywords. Pooled odds ratio (OR) was estimated in all races and Caucasians-only using both fixed- and random-effect models. RESULTS: The search identified 1028 papers and an additional five from a manual review of references. After a manual process that excluded noneligible studies, 11 papers remained, including a total of 3944 progressors and 20,054 nonprogressors. Combining results from these eligible studies, mutation carrier rates were significantly higher in progressors than nonprogressors for NBN, BRCA2, ATM (under both fixed- and random-effect models), for CHEK2 (under fixed-effect model only), and for PALB2 (under random-effect model only), p < 0.05. Pooled OR (95% confidence interval) was 6.38 (2.25-18.05), 3.41 (2.31; 5.03), 1.93 (1.17-3.20), and 1.53 (1.00-2.33) for NBN, BRCA2, ATM, and CHEK2, respectively, under fixed-effect model and 2.63 (1.12-6.13) for PALB2 under random-effect model. No significant association was found for the six remaining genes. Certainty of evidence was low for many genes due primarily to the limited number of eligible studies and mutation carriers. CONCLUSIONS: Statistical evidence for five genes was obtained in this first meta-analysis of germline mutations and PCa progression. While these results may help urologists and genetic counselors interpret germline testing results for PCa progression, more original studies are needed.

SARS-CoV-2 monoclonal antibodies with therapeutic potential: Broad neutralizing activity and No evidence of antibody-dependent enhancement.

Monoclonal antibodies (mAbs) are emerging as safe and effective therapeutics against SARS-CoV-2. However, variant strains of SARS-CoV-2 have evolved, with early studies showing that some mAbs may not sustain their efficacy in the face of escape mutants. Also, from the onset of the COVID-19 pandemic, concern has been raised about the potential for Fcγ receptor-mediated antibody-dependent enhancement (ADE) of infection. In this study, plaque reduction neutralization assays demonstrated that mAb 1741-LALA neutralizes SARS-CoV-2 strains B.1.351, D614 and D614G. MAbs S1D2-hIgG1 and S1D2-LALA mutant (STI-1499-LALA) did not neutralize B.1.351, but did neutralize SARS-CoV-2 strains D614 and D614G. LALA mutations did not result in substantial differences in neutralizing abilities between clones S1D2-hIgG1 vs STI-1499-LALA. S1D2-hIgG1, STI-1499-LALA, and convalescent plasma showed minimal ability to induce ADE in human blood monocyte-derived macrophages. Further, no differences in pharmacokinetic clearance of S1D2-hIgG1 vs STI-1499-LALA were observed in mice expressing human FcRn. These findings confirm that SARS-CoV-2 has already escaped some mAbs, and identify a mAb candidate that may neutralize multiple SARS-CoV-2 variants. They also suggest that risk of ADE in macrophages may be low with SARS-CoV-2 D614, and LALA Fc change impacts neither viral neutralization nor Ab clearance.

Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort.

BACKGROUND: Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established. METHODS: We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort. Mutations were annotated based on prostate-specific transcripts using the American College of Medical Genetics and Genomics standards. Associations were tested in 4399 PCa cases and 85,403 unaffected male controls using logistic regression adjusting for age and genetic background. p < .005 was considered significant based on Bonferroni correction. RESULTS: Among the 10 tested genes, significantly higher mutation carrier rates in PCa cases versus controls were found for four genes at p < .005; HOXB13, BRCA2, ATM, and CHEK2, with odds ratios (95% confidence interval) estimated at 4.96 (3.62-6.69), 3.23 (2.23-4.56), 2.95 (2.01-4.22), 1.94 (1.43-2.58), respectively. No significant association was found between mutation carrier status and age at PCa diagnosis or family history of PCa. Despite the large sample size of this study, statistical power remains limited, especially for genes where pathogenic mutation carrier rates are extremely rare (<0.03%). CONCLUSION: Observed evidence for PCa risk was found for four of the 10 guideline-recommended genes in this large population-based study. Mutations in these four genes can be interpreted with confidence in genetic counseling for PCa risk assessment. Evidence for the remaining six genes needs to be further evaluated in larger studies.

Sociality and migration predict hybridization across birds.

Hybridization represents a natural experiment that can provide insight into processes of speciation and diversification. Though considerable research has focused on hybrid zone dynamics, macroevolutionary investigations of the factors that influence hybridization are few. Here, we compile a database of avian hybrids and perform comparative analyses to determine whether several social and life-history variables influence broad patterns of hybridization. We perform three main analyses: phylogenetic logistic regression to examine variables that are associated with the presence of hybridization, phylogenetic Poisson regression of only those species exhibiting hybridization to determine which variables are associated with the extent of hybridization, and a phylogenetic logistic regression on a subset of data to assess potential pseudoreplication. After testing several social and life-history variables, we found that social bond duration is associated with the presence and extent of hybridization. Specifically, lengthy social bonds are negatively associated with the presence and extent of hybridization. In addition to social bond length, migration is positively linked with a greater likelihood of hybridization. The broad-scale correlations between species-specific traits and hybridization across diverse avian lineages suggest commonalities in the fine-scale processes involved in mating with heterospecifics, which in turn has implications for how we think about, study and understand hybridization processes and their influence on evolutionary trajectories.

Reversal of direct oral anticoagulants: Highlights from the Anticoagulation Forum guideline.

The 2019 guideline from the Anticoagulation Forum provides clear instructions on how to use 2 agents for reversing the effects of direct oral anticoagulants (DOACs): idarucizumab for dabigatran-associated bleeding and andexanet alfa for bleeding associated with rivaroxaban and apixaban. The guideline also discusses off-label use of andexanet alfa for bleeding associated with edoxaban and betrixaban and the use of hemostatic agents such as activated prothrombin complex concentrate and 4-factor prothrombin complex concentrate. Lastly, it offers approaches for building and managing stewardship programs at the health system level.