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The article presents a case study of a 52-year-old postmenopausal woman with red and swollen right arm. Ultrasonographic examination showed internal jugularis vein thrombosis (IJVT) on the right of the neck. The article discusses a unique case of primary Non-Hodgkin's lymphoma (NHL) of both ovaries which is preceded by an internal IVJT as paraneoplastic syndrome.

Objective: Viruses have a role in the pathogenesis of various forms of arthritis. This study aimed at determining whether viral DNA can be detected in joint samples in the early stages of idiopathic arthritides.Methods: Synovial fluid (SF) and synovial tissue (ST) samples were obtained from 73 patients, with undifferentiated arthritis (n=22), rheumatoid arthritis (n=13), spondyloarthropathy (n=17), crystal arthropathy (n=8), osteoarthritis (n=7), septic arthritis (n=5), and trauma (n=1). The presence of viral DNA was investigated by polymerase chain reaction analysis.Results: Cytomegalovirus was present in 25 patients, parvovirus B19 in 15 patients, Epstein-Barr virus in 12 patients, and herpes simplex virus in 16 patients (in ST, SF, or both), respectively. The joint samples were negative for viral DNA from adenovirus and varicella-zoster virus. In ST, eight patients were double positive for parvovirus B19 and another viral DNA, with herpes simplex virus being the most prevalent. Seven patients were double positive for other viruses (cytomegalovirus, herpes simplex virus, Epstein-Barr virus). In SF, four patients were double or triple positive for viral DNA. Paired samples were available in 56 patients. In these, viral DNA was detected in 37 patients in ST, as compared with 19 in SF.Conclusion: These data show that one or more viruses can be detected in the synovial specimens of patients with early arthritis, irrespective of the clinical diagnosis. This observation might be explained by migration of inflammatory cells harbouring viral DNA into the inflamed joints. [ABSTRACT FROM AUTHOR]

Abstract Background Treatment of chronically infected wounds is a challenge, and bacterial environmental contamination is a growing issue in infection control. Ozone may have a role in these situations. The objective of this study was to determine whether a low dose of gaseous ozone/oxygen mixture eliminates pathogenic bacteria cultivated in Petri dishes. Methods A pilot study with 6 bacterial strains was made using different concentrations of ozone in an ozone-oxygen mixture to determine a minimally effective dose that completely eliminated bacterial growth. The small and apparently bactericidal gaseous dose of 20 μg/mL ozone/oxygen (1:99) mixture, applied for 5min under atmospheric pressure was selected. In the 2nd phase, eight bacterial strains with well characterized resistance patterns were evaluated in vitro using agar-blood in adapted Petri dishes (105 bacteria/dish). The cultures were divided into 3 groups: 1- ozone-oxygen gaseous mixture containing 20 μg of O3/mL for 5 min; 2- 100% oxygen for 5 min; 3- baseline: no gas was used. Results The selected ozone dose was applied to the following eight strains: Escherichia coli, oxacillin-resistant Staphylococcus aureus, oxacillin-susceptible Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, carbapenem-resistant Acinetobacter baumannii, Acinetobacter baumannii susceptible only to carbapenems, and Pseudomonas aeruginosa susceptible to imipenem and meropenem. All isolates were completely inhibited by the ozone-oxygen mixture while growth occurred in the other 2 groups. Conclusion A single topical application by nebulization of a low ozone dose completely inhibited the growth of all potentially pathogenic bacterial strains with known resistance to antimicrobial agents.

Abstract Background Considering the increasing use of polymyxins to treat infections due to multidrug resistant Gram-negative in many countries, it is important to evaluate different susceptibility testing methods to this class of antibiotic. Methods Susceptibility of 109 carbapenem-resistant P. aeruginosa to polymyxins was tested comparing broth microdilution (reference method), disc diffusion, and Etest using the new interpretative breakpoints of Clinical and Laboratory Standards Institute. Results Twenty-nine percent of isolates belonged to endemic clone and thus, these strains were excluded of analysis. Among 78 strains evaluated, only one isolate was resistant to polymyxin B by the reference method (MIC: 8.0 μg/mL). Very major and major error rates of 1.2% and 11.5% were detected comparing polymyxin B disc diffusion with the broth microdilution (reference method). Agreement within 1 twofold dilution between Etest and the broth microdilution were 33% for polymyxin B and 79.5% for colistin. One major error and 48.7% minor errors were found comparing polymyxin B Etest with broth microdilution and only 6.4% minor errors with colistin. The concordance between Etest and the broth microdilution (reference method) was respectively 100% for colistin and 90% for polymyxin B. Conclusion Resistance to polymyxins seems to be rare among hospital carbapenem-resistant P. aeruginosa isolates over a six-year period. Our results showed, using the new CLSI criteria, that the disc diffusion susceptibility does not report major errors (false-resistant results) for colistin. On the other hand, showed a high frequency of minor errors and 1 very major error for polymyxin B. Etest presented better results for colistin than polymyxin B. Until these results are reproduced with a large number of polymyxins-resistant P. aeruginosa isolates, susceptibility to polymyxins should be confirmed by a reference method.

Purpose: Whey protein ingestion is typically considered an optimal dietary strategy to maximize myofibrillar protein synthesis (MyoPS) after resistance exercise. Although single-source plant protein ingestion is typically less effective, at least partly, due to less favorable amino acid profiles, this could theoretically be overcome by blending plant-based proteins with complementary amino acid profiles. We compared the postexercise MyoPS response after the ingestion of a novel plant-derived protein blend with an isonitrogenous bolus of whey protein., Methods: Ten healthy, resistance-trained, young adults (male/female: 8/2; age: 26 ± 6 yr; BMI: 24 ± 3 kg·m -2 ) received a primed continuous infusion of L-[ ring - 2 H 5 ]-phenylalanine and completed a bout of bilateral leg resistance exercise before ingesting 32 g protein from whey (WHEY) or a plant protein blend (BLEND; 39.5% pea, 39.5% brown rice, 21.0% canola) in a randomized, double-blind crossover fashion. Blood and muscle samples were collected at rest, and 2 and 4 h after exercise and protein ingestion, to assess plasma amino acid concentrations, and postabsorptive and postexercise MyoPS rates., Results: Plasma essential amino acid availability over the 4 h postprandial postexercise period was ~44% higher in WHEY compared with BLEND ( P = 0.04). From equivalent postabsorptive values (WHEY, 0.042 ± 0.020%·h -1 ; BLEND, 0.043 ± 0.015%·h -1 ) MyoPS rates increased after exercise and protein ingestion (time effect; P < 0.001) over a 0- to 2-h period (WHEY, 0.085 ± 0.037%·h -1 ; BLEND, 0.080 ± 0.037%·h -1 ) and 2- to 4-h period (WHEY, 0.085 ± 0.036%·h -1 ; BLEND, 0.086 ± 0.034%·h -1 ), with no differences between conditions during either period or throughout the entire (0-4 h) postprandial period (time-condition interactions; all P > 0.05)., Conclusions: Ingestion of a novel plant-based protein blend stimulates postexercise MyoPS to an equivalent extent as whey protein, demonstrating the utility of plant protein blends to optimize postexercise skeletal muscle reconditioning., (Copyright © 2024 by the American College of Sports Medicine.)

Whole-body tissue protein turnover is regulated, in part, by the postprandial rise in plasma amino acid concentrations, although minimal data exist on the amino acid response following non-animal-derived protein consumption. We hypothesised that the ingestion of novel plant- and algae-derived dietary protein sources would elicit divergent plasma amino acid responses when compared with vegan- and animal-derived control proteins. Twelve healthy young (male (m)/female (f): 6/6; age: 22 ± 1 years) and 10 healthy older (m/f: 5/5; age: 69 ± 2 years) adults participated in a randomised, double-blind, cross-over trial. During each visit, volunteers consumed 30 g of protein from milk, mycoprotein, pea, lupin, spirulina or chlorella. Repeated arterialised venous blood samples were collected at baseline and over a 5-h postprandial period to assess circulating amino acid, glucose and insulin concentrations. Protein ingestion increased plasma total and essential amino acid concentrations ( P < 0·001), to differing degrees between sources ( P < 0·001), and the increase was further modulated by age ( P < 0·001). Postprandial maximal plasma total and essential amino acid concentrations were highest for pea (2828 ± 106 and 1480 ± 51 µmol·l -1 ) and spirulina (2809 ± 99 and 1455 ± 49 µmol·l -1 ) and lowest for chlorella (2053 ± 83 and 983 ± 35 µmol·l -1 ) ( P < 0·001), but were not affected by age ( P > 0·05). Postprandial total and essential amino acid availabilities were highest for pea, spirulina and mycoprotein and lowest for chlorella (all P < 0·05), but no effect of age was observed ( P > 0·05). The ingestion of a variety of novel non-animal-derived dietary protein sources elicits divergent plasma amino acid responses, which are further modulated by age.

Background: Spirulina [SPIR] (cyanobacterium) and chlorella [CHLO] (microalgae) are foods rich in protein and essential amino acids; however, their capacity to stimulate myofibrillar protein synthesis (MyoPS) in humans remains unknown., Objectives: We assessed the impact of ingesting SPIR and CHLO compared with an established high-quality nonanimal-derived dietary protein source (fungal-derived mycoprotein [MYCO]) on plasma amino acid concentrations, as well as resting and postexercise MyoPS rates in young adults., Methods: Thirty-six healthy young adults (age: 22 ± 3 y; BMI: 23 ± 3 kg·m -2 ; male [m]/female [f], 18/18) participated in a randomized, double-blind, parallel-group trial. Participants received a primed, continuous infusion of L-[ring- 2 H 5 ]-phenylalanine and completed a bout of unilateral-resistance leg exercise before ingesting a drink containing 25 g protein from MYCO (n = 12; m/f, 6/6), SPIR (n = 12; m/f, 6/6), or CHLO (n = 12; m/f, 6/6). Blood and bilateral muscle samples were collected at baseline and during a 4-h postprandial and postexercise period to assess the plasma amino acid concentrations and MyoPS rates in rested and exercised tissue., Results: Protein ingestion increased the plasma total and essential amino acid concentrations (time effects; all P < 0.001), but most rapidly and with higher peak responses following the ingestion of SPIR compared with MYCO and CHLO (P < 0.05), and MYCO compared with CHLO (P < 0.05). Protein ingestion increased MyoPS rates (time effect; P < 0.001) in both rested (MYCO, from 0.041 ± 0.032 to 0.060 ± 0.015%·h -1 ; SPIR, from 0.042 ± 0.030 to 0.066 ± 0.022%·h -1 ; and CHLO, from 0.037 ± 0.007 to 0.055 ± 0.019%·h -1 , respectively) and exercised tissue (MYCO, from 0.046 ± 0.014 to 0.092 ± 0.024%·h -1 ; SPIR, from 0.038 ± 0.011 to 0.086 ± 0.028%·h -1 ; and CHLO, from 0.048 ± 0.019 to 0.090 ± 0.024%·h -1 , respectively), with no differences between groups (interaction effect; P > 0.05), but with higher rates in exercised compared with rested muscle (time × exercise effect; P < 0.001)., Conclusions: The ingestion of a single bolus of algae-derived SPIR and CHLO increases resting and postexercise MyoPS rates to a comparable extent as MYCO, despite divergent postprandial plasma amino acid responses., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Pea protein is an attractive nonanimal-derived protein source to support dietary protein requirements. However, although high in leucine, a low methionine content has been suggested to limit its anabolic potential. Mycoprotein has a complete amino acid profile which, at least in part, may explain its ability to robustly stimulate myofibrillar protein synthesis (MyoPS) rates. We hypothesized that an inferior postexercise MyoPS response would be seen following ingestion of pea protein compared with mycoprotein, which would be (partially) rescued by blending the two sources. Thirty-three healthy, young [age: 21 ± 1 yr, body mass index (BMI): 24 ± 1 kg·m -2 ] and resistance-trained participants received primed, continuous infusions of l-[ ring - 2 H 5 ]phenylalanine and completed a bout of whole body resistance exercise before ingesting 25 g of protein from mycoprotein (MYC, n = 11), pea protein (PEA, n = 11), or a blend (39% MYC, 61% PEA) of the two (BLEND, n = 11). Blood and muscle samples were taken pre-, 2 h, and 4 h postexercise/protein ingestion to assess postabsorptive and postprandial postexercise myofibrillar protein fractional synthetic rates (FSRs). Protein ingestion increased plasma essential amino acid and leucine concentrations (time effect; P < 0.0001), but more rapidly in BLEND and PEA compared with MYC (time × condition interaction; P < 0.0001). From similar postabsorptive values (MYC, 0.026 ± 0.008%·h -1 ; PEA, 0.028 ± 0.007%·h -1 ; BLEND, 0.026 ± 0.006%·h -1 ), resistance exercise and protein ingestion increased myofibrillar FSRs (time effect; P < 0.0001) over a 4-h postprandial period (MYC, 0.076 ± 0.004%·h -1 ; PEA, 0.087 ± 0.01%·h -1 ; BLEND, 0.085 ± 0.01%·h -1 ), with no differences between groups (all; P > 0.05). These data show that all three nonanimal-derived protein sources have utility in supporting postexercise muscle reconditioning. NEW & NOTEWORTHY This study provides evidence that pea protein (PEA), mycoprotein (MYC), and their blend (BLEND) can support postexercise myofibrillar protein synthesis rates following a bout of whole body resistance exercise. Furthermore, these data suggest that a methionine deficiency in pea may not limit its capacity to stimulate an acute increase in muscle protein synthesis (MPS).

Accepting a continued rise in the prevalence of vegan-type diets in the general population is also likely to occur in athletic populations, it is of importance to assess the potential impact on athletic performance, adaptation, and recovery. Nutritional consideration for the athlete requires optimization of energy, macronutrient, and micronutrient intakes, and potentially the judicious selection of dietary supplements, all specified to meet the individual athlete's training and performance goals. The purpose of this review is to assess whether adopting a vegan diet is likely to impinge on such optimal nutrition and, where so, consider evidence based yet practical and pragmatic nutritional recommendations. Current evidence does not support that a vegan-type diet will enhance performance, adaptation, or recovery in athletes, but equally suggests that an athlete can follow a (more) vegan diet without detriment. A clear caveat, however, is that vegan diets consumed spontaneously may induce suboptimal intakes of key nutrients, most notably quantity and/or quality of dietary protein and specific micronutrients (eg, iron, calcium, vitamin B12, and vitamin D). As such, optimal vegan sports nutrition requires (more) careful consideration, evaluation, and planning. Individual/seasonal goals, training modalities, athlete type, and sensory/cultural/ethical preferences, among other factors, should all be considered when planning and adopting a vegan diet., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

DNA interstrand crosslinks (ICLs) pose a major obstacle for DNA replication and transcription if left unrepaired. The cellular response to ICLs requires the coordination of various DNA repair mechanisms. Homologous recombination (HR) intermediates generated in response to ICLs, require efficient and timely conversion by structure-selective endonucleases. Our knowledge on the precise coordination of this process remains incomplete. Here, we designed complementary genetic screens to map the machinery involved in the response to ICLs and identified FIRRM/C1orf112 as an indispensable factor in maintaining genome stability. FIRRM deficiency leads to hypersensitivity to ICL-inducing compounds, accumulation of DNA damage during S-G 2 phase of the cell cycle, and chromosomal aberrations, and elicits a unique mutational signature previously observed in HR-deficient tumors. In addition, FIRRM is recruited to ICLs, controls MUS81 chromatin loading, and thereby affects resolution of HR intermediates. FIRRM deficiency in mice causes early embryonic lethality and accelerates tumor formation. Thus, FIRRM plays a critical role in the response to ICLs encountered during DNA replication.

BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes., Methods: 204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up., Results: Three distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition ( n = 76), one moderately impaired cluster ( n = 74) and one severely impaired cluster ( n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present., Conclusions: Current results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.

To mitigate the age-related decline in skeletal muscle quantity and quality, and the associated negative health outcomes, it has been proposed that dietary protein recommendations for older adults should be increased alongside an active lifestyle and/or structured exercise training. Concomitantly, there are growing environmental concerns associated with the production of animal-based dietary protein sources. The question therefore arises as to where this dietary protein required for meeting the protein demands of the rapidly aging global population should (or could) be obtained. Various non-animal-derived protein sources possess favorable sustainability credentials, though much less is known (compared with animal-derived proteins) about their ability to influence muscle anabolism. It is also likely that the anabolic potential of various alternative protein sources varies markedly, with the majority of options remaining to be investigated. The purpose of this review was to thoroughly assess the current evidence base for the utility of alternative protein sources (plants, fungi, insects, algae, and lab-grown "meat") to support muscle anabolism in (active) older adults. The solid existing data portfolio requires considerable expansion to encompass the strategic evaluation of the various types of dietary protein sources. Such data will ultimately be necessary to support desirable alterations and refinements in nutritional guidelines to support healthy and active aging, while concomitantly securing a sustainable food future., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

Introduction: Nutrition plays an essential role in the recovery of critical illness. In the post-Intensive Care Unit (ICU) period, patients typically return to oral nutrition gradually. However, studies quantifying nutritional intake in the post-ICU hospitalization period are scarce and formal guidelines are lacking. This study aims to describe energy and protein intake in detail over the entire post-ICU hospitalization period and explore associations between protein intake and clinical outcomes., Methods: A prospective observational single-center cohort study was conducted amongst post-ICU patients in general wards after a minimum ICU-stay of 72 h and who received (par)enteral feeding for ≥24 h in the ICU. Oral intake was assessed daily using food order lines and digital photography of meal leftovers. Other data, including amounts of (par)enteral nutrition, were collected from electronic medical records. The primary outcome was to identify energy and protein intake, and reached targets, in the post-ICU period. In addition, length of hospital stay after ICU discharge, readmission and mortality rates were compared between patients meeting protein targets or not., Results: In total, 48 patients were included. Complete nutritional data of 34 patients were analyzed in the current study, adding up to a total number of 484 observational days, 1681 photos and 6634 food order lines. Inter-rater agreement was excellent (ICC 0.878). Overall mean energy and protein adequacy for all nutritional groups was 82.3% (SD 18.3) and 83.1% (SD 19.8). Only 51.2% of the study participants (n = 21) reached overall >90% of prescribed protein targets during their entire post-ICU ward stay. The lowest intake was seen in the patient group with exclusively oral intake (median protein adequacy 75.5%), whereas patients with (supplemental) enteral nutrition (EN) all met >90% of their protein targets. Prescribed targets were below recommendations, and prescribed calories and proteins were neither ordered nor consumed. Discontinuation of EN resulted in immediate marked drops in energy (44.1%) and protein intake (50.7%). Subsequently, patients needed up to six days to reach protein targets again. No differences in clinical outcomes were observed., Conclusion: Most patients did not meet energy and protein targets in the post-ICU hospitalization period. Nutrition performance was highly dependent on the route of nutrition and was lowest among patients with oral intake only (despite of food fortification strategies and/or oral nutritional supplements). The best intake was observed in patients receiving (supplemental) EN. However, cessation of EN posed an immediate nutritional risk. No differences in clinical outcomes were found in this study. Our findings stress the need for follow-up studies to close the gap with individualized nutritional support in the post-ICU period to reach protein and energy targets., Competing Interests: Conflict of interest Prof. Dr A.R.H. van Zanten reported receiving honoraria for advisory board meetings, lectures, research, and travel expenses from Baxter, Braun, Cardinal Health, Danone-Nutricia, Dim-3, Fresenius Kabi, Mermaid, Lyric, and Nestle-Novartis. The other authors have nothing to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome, and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response, and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p = 0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; p = 0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample (TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes., (© 2022. The Author(s).)

Background: Gender-transformative work in the Global South often focuses on transforming 'toxic masculinities' to prevent intimate partner violence (IPV), but there has been little research on whether and how constructions of masculinities by men with disabilities shape their experiences and perpetration of violence., Methods: We used repeated in-depth interviews and content analysis to understand whether and how physical disability intersects with the construction of masculinities and experience/perpetration of violence among 15 adult men with physical disabilities participating in interventions to prevent IPV in Ghana, Rwanda, and South Africa., Results: Societal expectations and participants' aspirations around masculinity impacted their vulnerability to violence mainly by men without disabilities. Participants reported experiences of disrespect and social exclusion in their communities and felt incapable of protecting themselves when being violated. Most participants felt they were not providing for their families and perceived themselves as having lost decision-making and positions of power in their homes. They expressed their disappointment with having reduced stamina, virility, and sexual prowess in intimate partnerships as a result of their disability. While participants reported that they could not attain key markers of idealized masculinity, placed upon and often internalized by themselves, they longed to achieve these markers to facilitate their inclusion and acceptance in their communities., Conclusions: Programmers addressing violence need to engage with men with physical disabilities and consider the intersectionality of masculinities and disability, how these reinforce patriarchal norms and how men with disabilities can be included and enabled to overcome their conflict between disability and masculinities., (© 2022. The Author(s).)

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target., Competing Interests: Declaration of interests G.C.M.S. is an employee and shareholder of ArtiosPharma Ltd. and of AstraZeneca PLC. All other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has led to unprecedented societal changes limiting us in our mobility and our ability to connect with others in person. These unusual but widespread changes provide a unique opportunity for studies using digital phenotyping tools. Digital phenotyping tools, such as mobile passive monitoring platforms (MPM), provide a new perspective on human behavior and hold promise to improve human behavioral research. However, there is currently little evidence that these tools can reliably detect changes in behavior. Considering the Considering the COVID-19 pandemic as a high impact common environmental factor we studied potential impact on behavior of participants using our mobile passive monitoring platform BEHAPP that was ambulatory tracking them during the COVID-19 pandemic. We pooled data from three MPM studies involving Schizophrenia (SZ), Major Depressive Disorder (MDD) and Bipolar Disorder (BD) patients (N = 12). We compared the data collected on weekdays during three weeks prior and three weeks subsequent to the start of the quarantine. We hypothesized an increase in communication and a decrease in mobility. We observed a significant increase in the total time spent on communication applications (median 179 and 243 min per week respectively, p = 0.005), and a significant decrease in the number of unique places visited (median 6 and 3 visits per week respectively, p = 0.007), while the total time spent at home did not change significantly (median 64 and 77 h per week, respectively, p = 0.594). The data provides a proof of principle that digital phenotyping tools can identify changes in human behavior incited by a common external environmental factor., Competing Interests: Conflict of Interest Authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Background : Children with disabilities are more likely to experience violence or injury at school and at home, but there is little evidence from Central Asia. Objective : To describe the prevalence of disability and associations with peer violence perpetration and victimization, depression, corporal punishment, school performance and school attendance, among middle school children in Pakistan and Afghanistan. Method : This is a secondary analysis of data gathered in the course of evaluations of interventions to prevent peer violence conducted in Pakistan and Afghanistan as part of the 'What Works to Prevent Violence against Women and Girls Global Programme'. In Pakistan, the research was conducted in 40 schools, and disability was assessed at midline in 1516 interviews with Grade 7s. In Afghanistan, the data were from the baseline study conducted in 11 schools with 770 children. Generalized Linear Mixed Modeling was used to assess associations with disability. Results : In Afghanistan, the prevalence of disability was much higher for girls (22.1%) than boys (12.9%), while in Pakistan 6.0% of boys and girls reported a disability. Peer violence victimization was strongly associated with disability in Afghanistan and marginally associated in Pakistan. In Pakistan, perpetration of peer violence was associated with disability. In both countries, disability was significantly associated with higher depression scores. Food insecurity was strongly associated with disability in Afghanistan. Conclusion : Disability is highly prevalent in Afghanistan and Pakistan schools and this is associated with a greater risk of experiencing and perpetrating peer violence. It is important to ensure that all children can benefit from school-based prevention interventions.

Introduction: Women with disabilities experience higher rates of intimate partner violence (IPV) than women without disabilities. There remains limited evidence about whether IPV prevention interventions for the general population have benefits for women with disabilities that compare to those for women without disabilities. Using data from IPV prevention randomised controlled trials in diverse locations (Rwanda, South Africa and Afghanistan), we assess whether outcomes differed by disability status., Methods: We assessed disability at baseline in three IPV prevention trials. We performed post-hoc analysis of intervention impacts at endline (22 or 24 months post-baseline) stratified by disability status at study baseline and tested an interaction term for disability at baseline by intervention arm for three sets of outcomes: (1) past year experiences of physical, sexual and severe IPV; (2) economic and livelihood outcomes; and (3) health, mental health and substance use outcomes., Results: At baseline between 17.7% and 26.2% of women reported being disabled. For IPV prevention, in seven out of eight tests across three studies, women with and without disabilities had similar outcomes. For economic, health and substance use outcomes, there was more variation, with women with disabilities reporting both better and worse outcomes than women without disabilities; however there was no clear pattern in these differential results., Conclusion: IPV prevention programmes targeting general populations can prevent IPV among women with disabilities participants with benefits that mirror those for women without disabilities. Benefits for participants with and without disabilities on secondary programme outcomes related to economic empowerment and health may be more varied and should be explicitly monitored., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Intimate partner violence (IPV) is a serious public health and human rights violation which impacts approximately one in three women worldwide. Some existing evidence suggests that women with disabilities are at higher risk of IPV, but is largely limited in geographical scope to the Global North, and comparison across settings has been hampered by inconsistent measurement of both IPV and disability., Methods: Pooled analysis of baseline data from 8549 adult women participating in seven IPV prevention studies in five countries across Africa and Asia that used collaborative, comparative measurement strategies to assess both disability and IPV., Results: After adjusting for age, women with disabilities were more likely to experience past 12-month physical IPV (adjusted OR (aOR)=1.79; 95% CI 1.49 to 2.17), sexual IPV (aOR=1.98; 95% CI 1.36 to 2.89), emotional IPV (aOR=1.84; 95% CI 1.49 to 2.27) and economic IPV (aOR=1.66; 95% CI 1.45 to 1.89), with an overall association between disability and past 12-month physical/sexual IPV of aOR=1.93 (95% CI 1.52 to 2.46). Compared to women without disability, women with moderate and severe disability showed a trend of increasing risk of IPV in the past 12 months for each of physical, sexual, emotional and economic IPV. Overall, both women with moderate disability (aOR=1.86, 95% CI 1.57 to 2.21) and women with severe disability (aOR=2.63; 95% CI 1.95 to 3.55) were significantly more likely to experience any form of IPV when compared with women without disability., Conclusion: Women with disabilities are at increased risk of past-year IPV compared to women without disabilities across a range of settings in the Global South, and the risk of IPV increases with increasing severity of disability. IPV prevention and response efforts in these settings must find ways to include and address the needs of women with disabilities, including increased outreach and improved accessibility of programmes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway., Experimental Design: Two hundred thirty-eight BRCA1 VUS-comprising most BRCA1 VUS known in the Netherlands and Belgium-were tested for their ability to complement Brca1- deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families., Results: All three assays showed 100% sensitivity and specificity (95% confidence interval, 83%-100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 13 of these 26 variants, we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of 7 (likely) pathogenic variants., Conclusions: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays., (©2020 American Association for Cancer Research.)

Women with disabilities are more vulnerable to violence, including intimate partner violence (IPV), yet the majority of emerging IPV prevention programs fail to explicitly consider the needs of participants with disabilities. Women and men living with disabilities engaged with IPV prevention programs in four countries were interviewed to explore how disability shaped their experiences of gender, violence, IPV, and whether the programs met their disability related needs. In-depth interviews were conducted with 16 women and 15 men living with disabilities in Ghana, Rwanda, Tajikistan and South Africa. The data were analysed thematically and compared across the settings. Participants described experiencing disability-related stigma, discrimination, exclusion, and for women, increased vulnerability to IPV. Barriers to full participation in programs included limited accessibility, and lack of disability-specific materials, recruitment or outreach. Enablers of inclusion included recruitment and monitoring strategies aimed at people with disabilities, partnering with a local disabled people's organization, training staff in disability inclusion, and raising awareness of disability rights. The data encouragingly suggests that inclusion of women and men with disabilities in IPV prevention programs designed for the general population has beneficial outcomes. Inclusion can prevent violence, promote their wellbeing, support economic empowerment, and challenge disability-related stigma and discrimination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic signaling networks, is frequently activated in ILC. We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the K14-cre;Cdh1 Flox/Flox ;Trp53 Flox/Flox (KEP) mouse model of metastatic ILC. Inhibition of mTOR signaling blocked the growth of primary KEP tumors as well as the progression of metastatic disease. However, primary tumors and distant metastases eventually acquired resistance after long-term AZD8055 treatment, despite continued effective suppression of mTOR signaling in cancer cells. Interestingly, therapeutic responses were associated with increased expression of genes related to antigen presentation. Consistent with this observation, increased numbers of tumor-infiltrating major histocompatibility complex class II-positive (MHCII+) immune cells were observed in treatment-responsive KEP tumors. Acquisition of treatment resistance was associated with loss of MHCII+ cells and reduced expression of genes related to the adaptive immune system. The therapeutic efficacy of mTOR inhibition was reduced in Rag1 -/- mice lacking mature T and B lymphocytes, compared to immunocompetent mice. Furthermore, therapy responsiveness could be partially rescued by transplanting AZD8055-resistant KEP tumors into treatment-naïve immunocompetent hosts. Collectively, these data indicate that the PI3K signaling pathway is an attractive therapeutic target in invasive lobular carcinoma, and that part of the therapeutic effect of mTOR inhibition is mediated by the adaptive immune system., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer 1,2 . For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival 3 , and experimental studies have demonstrated a causal relationship between neutrophils and metastasis 4,5 . However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1β, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1β and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer.

Globally, women with disabilities experience heightened and unique forms of violence compared to men with disabilities and women without disabilities. Yet formalised guidelines for their inclusion in gender-based violence (GBV) research is lacking. This paper draws on ethical guidelines for researching violence against women, and studies on the ethicality of including people with disabilities in research, to advocate for women with disabilities' inclusion and safety in GBV research. Reflecting on lessons from a qualitative study on violence against women living with disabilities in South Africa, the paper considers what could be of value for GBV researchers and ethics review committees in low-middle income countries (LMICs). It aims to stimulate debate around the integration of reasonable accommodation, accessibility, and equal participation of women with disabilities in planning and conducting ethical GBV research. The paper recommends that considerations are practically applied and tested in other LMICs, and thereafter critiqued in consultation with a range of stakeholders and women with disabilities, to enhance best practice and form a basis for developing guidelines for undertaking ethical and inclusive GBV research in LMICs.

Notions of womanhood inculcate naturalised ideologies of femininity, sexuality, motherhood and caregiving. The paper asks how disability stigma intersects with womanhood to characterise intimate partnerships in South Africa. In-depth interviews with 30 women with a range of disabilities were conducted in informal settlements in Cape Town. Findings suggest that disability stigma may hamper attainment of normative womanhood and sexual relationships for women with disabilities in South Africa. Limited opportunities to meet potential partners, hegemonic gender expectations and restricted sexual and physical contact shape their intimate partnerships. However, women with disabilities also challenge ableist constructs of normalcy and discredit negative images of disabled womanhood. Because of this, theoretical models of intimate partner violence should consider the influence of disability on constructions of sexuality and norms in intimate partnerships. Building on women with disabilities' stigma-avoidance strategies will help facilitate better relationship outcomes. Social norms interventions with broader society, communities, women with disabilities and their partners, family and carers can help destabilise assumptions that women with disabilities are unable to have long-lasting and fulfilling sexual and intimate partnerships. Moreover, accessible and relevant sexuality education and information on relationships, intimate partner violence, maternal and sexual and reproductive health care can ensure healthy and safe intimate partnerships for women with disabilities.

South Africa has unprecedented levels of violence and many South African women are exposed to violence during their lifetime. This article explores how gender and disability intersect in women's experiences of violence during their lifetime. Repeat in-depth qualitative interviews with 30 physically disabled women in Cape Town reveal that women with physical disabilities are exposed to various forms of violence, and shows how their impairments shape their violence experiences. The most common forms of violence women with disabilities experience are psychological violence, financial abuse, neglect, and deprivation, with disability stigma playing a central role and contributing to how women with disabilities are exploited and dehumanized. Constructions of women as asexual shape their sexual relationships and experiences of sexual violence. This article identifies that women with disabilities are more at risk and experience additional layers of violence than women without disabilities. These additional risks and layers of violence need to be recognized and inform interventions to prevent and respond to violence against women with disabilities in the country. Prevention of violence against women with physical disabilities in South Africa needs to address the role of disability stigma that shapes the types of violence they experience, change gender norms, and create accessible and safe environments and economic empowerment opportunities.

Developing interventions that address psychosocial wellbeing of people living with HIV is critical to ensure strong linkages to and retention in HIV care. This paper describes the development of Sondela, an HIV adjustment and coping intervention for heterosexual men and women living with HIV, and its relevance and feasibility in the South African context. Sondela is a six three-hour, small group-based, participatory workshop series. We followed an iterative, multi-phased process of curriculum development that involved research, theoretical frameworks and piloting. A systematic review highlighted the absence of psychosocial interventions targeting heterosexual HIV positive populations living in high HIV prevalence and resource-poor settings. Formative studies demonstrated risk and social factors associated with adjustment and coping with HIV, emphasising the need for interventions that acknowledge gendered experiences. Our pilot of Sondela demonstrated high levels of relevance and feasibility. Men appreciated the workshop "space" to openly talk about their HIV positive status and what is means for their role as partners and fathers and friends. Women valued the skills and approaches because they were relevant to "real life" situations and not just about HIV. Sondela promises to be valuable in supporting health system initiatives and psychosocial support to strengthen linkages to and retention in HIV care, and this suggests a need for rigorous evaluation of Sondela to establish evidence for its effectiveness in a general population.

Background: Being diagnosed with human immunodeficiency virus (HIV), and labelled with a chronic, life-threatening, and often stigmatizing disease, can impact on a person's well-being. Psychosocial group interventions aim to improve life-functioning and coping as individuals adjust to the diagnosis., Objectives: To examine the effectiveness of psychosocial group interventions for improving the psychological well-being of adults living with HIV/AIDS., Search Methods: We searched the following electronic databases up to 14 March 2016: the Cochrane Central Register of Controlled Trials (CENTRAL) published in the Cochrane Library (Issue 2, 2016), PubMed (MEDLINE) (1996 to 14 March 2016), Embase (1996 to 14 March 2016), and Clinical Trials.gov., Selection Criteria: Randomized controlled trials (RCTs) or quasi-RCTs that compared psychosocial group interventions with versus control (standard care or brief educational interventions), with at least three months follow-up post-intervention. We included trials that reported measures of depression, anxiety, stress, or coping using standardized scales., Data Collection and Analysis: Two review authors independently screened abstracts, applied the inclusion criteria, and extracted data. We compared continuous outcomes using mean differences (MD) with 95% confidence intervals (95% CIs), and pooled data using a random-effects model. When the included trials used different measurement scales, we pooled data using standardized mean difference (SMD) values. We reported trials that we could not include in the meta analysis narratively in the text. We assessed the certainty of the evidence using the GRADE approach., Main Results: We included 16 trials (19 articles) that enrolled 2520 adults living with HIV. All the interventions were multifaceted and included a mix of psychotherapy, relaxation, group support, and education. The included trials were conducted in the USA (12 trials), Canada (one trial), Switzerland (one trial), Uganda (one trial), and South Africa (one trial), and published between 1996 and 2016. Ten trials recruited men and women, four trials recruited homosexual men, and two trials recruited women only. Interventions were conducted with groups of four to 15 people, for 90 to 135 minutes, every week for up to 12 weeks. All interventions were conducted face-to-face except two, which were delivered by telephone. All were delivered by graduate or postgraduate trained health, psychology, or social care professionals except one that used a lay community health worker and two that used trained mindfulness practitioners.Group-based psychosocial interventions based on cognitive behavioural therapy (CBT) may have a small effect on measures of depression, and this effect may last for up to 15 months after participation in the group sessions (SMD -0.26, 95% CI -0.42 to -0.10; 1139 participants, 10 trials, low certainty evidence). Most trials used the Beck Depression Inventory (BDI), which has a maximum score of 63, and the mean score in the intervention groups was around 1.4 points lower at the end of follow-up. This small benefit was consistent across five trials where participants had a mean depression score in the normal range at baseline, but trials where the mean score was in the depression range at baseline effects were less consistent. Fewer trials reported measures of anxiety, where there may be little or no effect (four trials, 471 participants, low certainty evidence), stress, where there may be little or no effect (five trials, 507 participants, low certainty evidence), and coping (five trials, 697 participants, low certainty evidence).Group-based interventions based on mindfulness have not demonstrated effects on measures of depression (SMD -0.23, 95% CI -0.49 to 0.03; 233 participants, 2 trials, very low certainty evidence), anxiety (SMD -0.16, 95% CI -0.47 to 0.15; 62 participants, 2 trials, very low certainty evidence), or stress (MD -2.02, 95% CI -4.23 to 0.19; 137 participants, 2 trials, very low certainty evidence). No mindfulness based interventions included in the studies had any valid measurements of coping., Authors' Conclusions: Group-based psychosocial interventions may have a small effect on measures of depression, but the clinical importance of this is unclear. More high quality evidence is needed to assess whether group psychosocial intervention improve psychological well-being in HIV positive adults.

Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials. It is unclear whether all pathogenic BRCA1 mutations have similar effects on the response to therapy. Here, we have investigated mammary tumorigenesis and therapy sensitivity in mice carrying the Brca1185stop and Brca15382stop alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1185delAG and BRCA15382insC. Both the Brca1185stop and Brca15382stop mutations predisposed animals to mammary tumors, but Brca1185stop tumors responded markedly worse to HRD-targeted therapy than did Brca15382stop tumors. Mice expressing Brca1185stop mutations also developed therapy resistance more rapidly than did mice expressing Brca15382stop. We determined that both murine Brca1185stop tumors and human BRCA1185delAG breast cancer cells expressed a really interesting new gene domain-less (RING-less) BRCA1 protein that mediated resistance to HRD-targeted therapies. Together, these results suggest that expression of RING-less BRCA1 may serve as a marker to predict poor response to DSB-inducing therapy in human cancer patients.