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Objectives: The purpose of the study is to investigate body awareness and body image perception of patients with type 2 diabetes mellitus (T2DM) and to explore the association between clinical parameters and body awareness. Methods: A total of 92 participants with T2DM (38 women and 54 men) aged 36–76 years were recruited. Biochemical measurements, including fasting blood glucose, postprandial blood glucose and hemoglobin A1c (HbA1c), were obtained from the patients’ blood sample records. The Body Awareness Questionnaire (BAQ), Body Cathexis Scale (BCS) and Awareness Body Chart (ABC) were filled in by all subjects. Results: Most participants had an above-average BAQ (81.5%) and BCS (87%) score. There was a significant correlation between body mass index and ABC pain subscale. HbA1c was significantly associated with the duration of diabetes and sleep-wake cycle, process domains and total BAQ score. The body awareness score for the lower leg and foot regions (ABC parts) was negatively correlated with fasting blood glucose and HbA1c levels, while body awareness in the foot region was negatively correlated with the duration of diabetes. There was no association between BCS and any clinical parameters. Conclusion: This study showed that body awareness is associated with diabetes-related clinical parameters, such as fasting blood glucose and HbA1c levels, and duration of diabetes in patients with T2DM. Following diabetes progression and an increase in blood glucose levels, body awareness tended to decrease, particularly in the lower leg and foot regions. These findings highlighted the importance of evaluating body awareness in patients with T2DM. © 2023 Elsevier Ltd

Microcystin-leucine-arginine (MC-LR) is positively linked with multiple cancers in humans. However, the association between MC-LR and the risk and prognosis of prostate cancer has not been conducted in epidemiological studies. No reported studies have linked MC-LR exposure to the poor prognosis of prostate cancer by conducting experimental studies. The content of MC-LR was detected in most of the aquatic food in wet markets and supermarkets in Nanjing and posed a health risk for consumers. MC-LR levels in both prostate cancer tissues and serum were significantly higher than controls. The adjusted odds ratio (OR) for prostate cancer risk by serum MC-LR was 1.75 (95%CI: 1.21-2.52) in the whole subjects, and a positive correlation between MC-LR and advanced tumor stage was observed. Survival curve analysis indicated patients with higher MC-LR levels in tissues exhibited poorer overall survival. Human, animal, and cell studies confirmed that MC-LR exposure increases the expression of estrogen receptor-α (ERα) and promotes epithelial-mesenchymal transition (EMT) in prostate cancer. Moreover, MC-LR-induced decreased E-cadherin levels, increased vimentin levels, and increased migratory and invasive capacities of prostate cancer cells were markedly suppressed upon ERα knockdown. MC-LR-induced xenograft tumor growth and lung metastasis in BALB/c nude mice can be effectively alleviated with ERα knockdown. Our data demonstrated that MC-LR upregulated vimentin and downregulated E-cadherin through activating ERα, promoting migration and invasion of prostate cancer cells. Our findings highlight the role of MC-LR in prostate cancer, providing new perspectives to understand MC-LR-induced prostatic toxicity.

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m 2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; pinteraction=0·71) or between-trial heterogeneity (I 2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (

Benzo[a]pyrene (BaP), a ubiquitous pollutant, raises environmental health concerns due to induction of bone toxicity in the unexposed offspring. Exposure of F0 ancestor medaka (Oryzias latipes) to 1 µg/L BaP for 21 days causes reduced vertebral bone thickness in the unexposed F3 male offspring. To reveal the inherited modifications, osteoblast (OB) abundance and molecular signaling pathways of transgenerational BaP-induced bone thinning were assessed. Histomorphometric analysis showed a reduction in OB abundance. Analyses of the miRNA and mRNA transcriptomes revealed the dysregulation of Wnt signaling (frzb/ola-miR-1-3p, sfrp5/ola-miR-96-5p/miR-455-5p) and bone morphogenetic protein (Bmp) signaling (bmp3/ola-miR-96-5p/miR-181b-5p/miR-199a-5p/miR-205-5p/miR-455-5p). Both pathways are major indicators of impaired bone formation, while the altered Rank signaling in osteoclasts (c-fos/miR-205-5p) suggests a potentially augmented bone resorption. Interestingly, a typical BaP-responsive pathway, the Nrf2-mediated oxidative stress response (gst/ola-miR-181b-5p/miR-199a-5p/miR-205), was also affected. Moreover, mRNA levels of epigenetic modification enzymes (e.g., hdac6, hdac7, kdm5b) were found dysregulated. The findings indicated that epigenetic factors (e.g., miRNAs, histone modifications) may directly regulate the expression of genes associated with transgenerational BaP bone toxicity and warrants further studies. The identified candidate genes and miRNAs may serve as potential biomarkers for BaP-induced bone disease and as indicators of historic exposures in wild fish for conservation purposes.

BACKGROUND: Heart transplantation (HTx) after donation after circulatory death (DCD) is an expanding practice but is associated with increased warm ischemic time. The impact of DCD HTx on cardiac mechanics and myocardial fibrosis has not been reported. We aimed to compare cardiac mechanics and myocardial fibrosis using cardiovascular magnetic resonance (CMR) imaging in donation after brain death (DBD) and DCD HTx recipients and healthy controls. METHODS AND RESULTS: Consecutive HTx recipients between March 2015 and March 2021 who underwent routine surveillance CMR imaging were included. Cardiac mechanics were assessed using CMR feature tracking to compute global longitudinal strain, global circumferential strain, and right ventricular free-wall longitudinal myocardial strain. Fibrosis was assessed using late gadolinium enhancement imaging and estimation of extracellular volume. There were 82 (DBD n = 42, DCD n = 40) HTx recipients (aged 53 years, interquartile range 41-59 years, 24% female) who underwent CMR imaging at median of 9 months (interquartile range 6-14 months) after transplantation. HTx recipients had increased extracellular volume (29.7 ± 3.6%) compared with normal ranges (25.9%, interquartile range 25.4-26.5). Myocardial strain was impaired after transplantation compared with controls (global longitudinal strain -12.6 ± 3.1% vs -17.2 ± 1.8%, P < .0001; global circumferential strain -16.9 ± 3.1% vs -19.2 ± 2.0%, P = .002; right ventricular free-wall longitudinal strain -15.7 ± 4.5% vs -21.6 ± 4.7%, P < .0001). There were no differences in fibrosis burden (extracellular volume 30.6 ± 4.4% vs 29.2 ± 3.2%; P = .39) or cardiac mechanics (global longitudinal strain -13.1 ± 3.0% vs -12.1 ± 3.1%, P = .14; global circumferential strain -17.3 ± 2.9% vs -16.6 ± 3.1%, P = .27; right ventricular free-wall longitudinal strain -15.9 ± 4.9% vs -15.5 ± 4.1%, P = .71) between DCD and DBD HTx. CONCLUSIONS: HTx recipients have impaired cardiac mechanics compared with controls, with increased myocardial fibrosis. There were no differences in early CMR imaging characteristics between DBD and DCD heart transplants, providing further evidence that DCD and DBD HTx outcomes are comparable.

Background: Comparative data on clinical presentation, laboratory characteristics, treatment, and outcome of neurosyphilis (NS) in people living with HIV (PLWH) and NS patients without HIV are scarce.Methods: Nationwide, population-based, prospective cohort study on all adults with NS diagnosed between 2015 and 2021 at departments of infectious diseases in Denmark.Results: We identified 108 patients with NS, which equals a yearly incidence of 0.3/100,000 adults. The median age was 49 years, 85 (79%) were male, 43 (40%) were men having sex with men and 20 (22%) were PLWH. Ninety-five (88%) had early NS, 37 (34%) had ocular or ocular and otogenic NS, and 27 (25%) had symptomatic meningitis. Most common symptoms were visual disturbance (44%), skin rash (40%), fatigue (26%) and chancre (17%). Median CSF leukocyte count was 27 × 106 cells/L. PLWH less often had neurological deficits (p = 0.02). Unfavorable outcome was observed in 23 (21%) at discharge of whom 0 were PLWH (p = 0.01). Among the 88 NS patients without HIV a CSF leukocyte count of ≥ 30 × 106 cells/L was associated with unfavorable outcome (OR = 3.3 (95% confidence interval: 1.1-10.4)).Conclusions: PLWH with NS have better outcomes than NS patients without HIV infection. Background: Comparative data on clinical presentation, laboratory characteristics, treatment, and outcome of neurosyphilis (NS) in people living with HIV (PLWH) and NS patients without HIV are scarce.Methods: Nationwide, population-based, prospective cohort study on all adults with NS diagnosed between 2015 and 2021 at departments of infectious diseases in Denmark.Results: We identified 108 patients with NS, which equals a yearly incidence of 0.3/100,000 adults. The median age was 49 years, 85 (79%) were male, 43 (40%) were men having sex with men and 20 (22%) were PLWH. Ninety-five (88%) had early NS, 37 (34%) had ocular or ocular and otogenic NS, and 27 (25%) had symptomatic meningitis. Most common symptoms were visual disturbance (44%), skin rash (40%), fatigue (26%) and chancre (17%). Median CSF leukocyte count was 27 × 106 cells/L. PLWH less often had neurological deficits (p = 0.02). Unfavorable outcome was observed in 23 (21%) at discharge of whom 0 were PLWH (p = 0.01). Among the 88 NS patients without HIV a CSF leukocyte count of ≥ 30 × 106 cells/L was associated with unfavorable outcome (OR = 3.3 (95% confidence interval: 1.1-10.4)).Conclusions: PLWH with NS have better outcomes than NS patients without HIV infection.

Introduction: Patients with advanced heart failure (HF) have high morbidity and mortality, with only a small proportion being eligible for advanced therapies. Intermittent outpatient levosimendan infusion has been shown to provide symptomatic relief and reduce the rate of HF events. Our aim was to assess the safety and efficacy of outpatient levosimendan administration in an advanced HF population. Methods: This is a report of a single-center experience of consecutive advanced HF patients referred for intermittent intravenous outpatient administration of levosimendan, between January 2018 and March 2021. Baseline and follow-up evaluation included clinical assessment, laboratory tests, transthoracic echocardiography and cardiopulmonary exercise testing. Baseline and clinical follow-up data were compared using the Wilcoxon signed-rank test. Results: A total of 24 patients (60.8 years, 83% male, mean left ventricular ejection fraction [LVEF] 24%), with a median of 1.5 HF hospitalizations in the previous six months, were referred for outpatient levosimendan pulses, the majority as a bridge to transplantation or due to clinical deterioration. At six-month follow-up there was a significant reduction in HF hospitalizations to 0.4±0.7 (p

The short-term impacts of urban air pollution on the platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) remain obscure. In this study, we included 3487 urban adults from the Wuhan-Zhuhai cohort. Individual inhalation exposure to air pollutants was estimated by combining participants' daily breath volume and ambient concentrations of six air pollutants (including fine particulate matter (PM

The contactin-associated protein-like 2 (CNTNAP2) gene encodes for the CASPR2 protein, which plays an essential role in neurodevelopment. Mutations in CNTNAP2 are associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. Rats with a loss of function mutation in the Cntnap2 gene show increased acoustic startle response (ASR) and decreased prepulse inhibition (PPI). The neural basis of this altered auditory processing in Cntnap2 knock-out rats is currently unknown. Auditory brainstem recordings previously revealed no differences between the genotypes. The next step is to investigate brainstem structures outside of the primary auditory pathway that mediate ASR and PPI, which are the pontine reticular nucleus (PnC) and pedunculopontine tegmentum (PPTg), respectively. Multi-unit responses from the PnC and PPTg in vivo of the same rats revealed sex-specific effects of loss of CASPR2 expression on PnC activity, but no effects on PPTg activity. Female Cntnap2

Microtubules are cytoskeletal elements that play key roles throughout the different steps of sperm development. As an integral part of the sperm flagellum, the molecular machine that generates sperm motility, microtubules are also essential for the progressive swimming of sperm to the oocyte, which is a prerequisite for fertilisation. Given the central role of microtubules in all steps of spermatogenesis, their functions need to be tightly controlled. Recent work has showcased tubulin posttranslational modifications as key players in sperm development and function, with aberrations often leading to male infertility with a broad spectrum of sperm defects. Posttranslational modifications are part of the tubulin code, a mechanism that can control microtubule functions by modulating the properties of their molecular building blocks, the tubulin proteins. Here we review the current knowledge on the implications of the tubulin code in sperm development and functions and its importance for male fertility.

Women who contract a viral or bacterial infection during pregnancy have an increased risk of giving birth to a child with a neurodevelopmental or psychiatric disorder. The effects of maternal infection are likely mediated by the maternal immune response, as preclinical animal models have confirmed that maternal immune activation (MIA) leads to long lasting changes in offspring brain and behavior development. The present study sought to determine the impact of MIA-exposure during the first or second trimester on neuronal morphology in dorsolateral prefrontal cortex (DLPFC) and hippocampus from brain tissue obtained from MIA-exposed and control male rhesus monkey (Macaca mulatta) during late adolescence. MIA-exposed offspring display increased neuronal dendritic branching in pyramidal cells in DLPFC infra- and supragranular layers relative to controls, with no significant differences observed between offspring exposed to maternal infection in the first and second trimester. In addition, the diameter of apical dendrites in DLPFC infragranular layer is significantly decreased in MIA-exposed offspring relative to controls, irrespective of trimester exposure. In contrast, alterations in hippocampal neuronal morphology of MIA-exposed offspring were not evident. These findings demonstrate that a maternal immune challenge during pregnancy has long-term consequences for primate offspring dendritic structure, selectively in a brain region vital for socioemotional and cognitive development.

Exposure to early life adversities (ELA) can influence a plethora of biological mechanisms leading to stress-related disorders later in life through epigenetic mechanisms, such as microRNAs (miRs). MiR-34 is a critical modulator of stress response and stress-induced pathologies and a link between ELA and miR-34a has been reported.Here using our well-established model of ELA (Repeated Cross Fostering) we investigate the behavioral long-term effects of ELA in male and female mice. We also assess basal and ELA-induced miR-34a expression in adult mice and investigate whether ELA affects the later miR-34a response to adult acute stress exposure across brain areas (medial preFrontal Cortex, Dorsal Raphe Nuclei) and peripheral organs (heart, plasma) in animals from both sexes. Finally, based on our previous data demonstrating the critical role of Dorsal Raphe Nuclei miR-34a expression in serotonin (5-HT) transmission, we also investigated prefrontal-accumbal 5-HT outflow induced by acute stress exposure in ELA and Control females by in vivo intracerebral microdialysis.ELA not just induces a depressive-like state as well as enduring changes in miR-34a expression, but also alters miR-34a expression in response to adult acute stress exclusively in females. Finally, altered DRN miR-34a expression is associated with prefrontal-accumbal 5-HT release under acute stress exposure in females.Translational study on humans is necessary to verify the results obtained in our animal models of ELA-induced depression.This is the first evidence showing long-lasting sex related effects of ELA on brain and peripheral miR-34a expression levels in an animal model of depression-like phenotype.

It is evident that sex and gender differences impact pathophysiology, disease burden, and treatment outcomes for a variety of systems and major illnesses including those affecting the unified airway. Important male-female differences in unified airway disease are driven by various intrinsic and extrinsic mechanisms including anatomic, morphometric, hormonal, genetic (and epigenetic), environmental, psycho-social, and comorbidity-related factors. This review highlights current knowledge of how patient sex influences epidemiology, diagnosis, treatment, and outcomes for diseases affecting the unified airway.

Sperm preservation is an efficient technique used for the recovery, conservation, and management of some endangered fish species. The present study was conducted to explore how preservation time would affect sperm and spawning performance in the endangered delta smelt (Hypomesus transpacificus). Sperm were preserved with the modified Hanks balanced salt solution at 14.7-16.9 °C. The Kruskal-Wallis test of sperm parameters using OpenCASA plugin in ImageJ software showed that sperm (n = 33♂) had significantly higher velocity and motility within the first 5 s after activation than that of other time points, while sperm had the lowest velocity and motility after 3 min post activation (P 0.001). The findings (n = 30♂) also showed fresh sperm had higher velocity and motility than preserved sperm, while the sperm preserved for over 24 h showed a significantly low performance (P 0.001). The nonlinear mixed effects models of fertilization results (n = 14♂ × 70♀) indicated the fresh sperm and sperm preserved for 1 h had higher fertilization rates than other preservation times (P 0.001). The hatching rate (n = 14♂ × 70♀) also showed the fresh sperm and sperm preserved for 3 min and 1 h had higher hatching rates than other preservation times (P 0.001). Overall, the study showed the best sperm performance in delta smelt was found within the first 5 s post activation, and the best fertilization and hatching rates were found when the sperm were fresh and preserved for 1 h. The findings of this study provide information for the first time about how long the delta smelt's sperm are motile for quality analysis, and how the preservation time can affect sperm quality, fertility, and hatching of this species for future applications.

Background: Although loneliness and social isolation have been linked to an increased risk of non-communicable diseases such as cardiovascular disease and dementia, their association with the risk of severe infection is uncertain. We aimed to examine the associations between loneliness and social isolation and the risk of hospital-treated infections using data from two independent cohort studies. Methods: We assessed the association between loneliness and social isolation and incident hospital-treated infections using data for participants from the UK Biobank study aged 38–73 years at baseline and participants from the nationwide population-based Finnish Health and Social Support (HeSSup) study aged 20–54 years at baseline. For inclusion in the study, participants had to be linked to national health registries, have no history of hospital-treated infections at or before baseline, and have complete data on loneliness or social isolation. Participants with missing data on hospital-treated infections, loneliness, and social isolation were excluded from both cohorts. The outcome was defined as a hospital admission with a primary diagnosis of infection, ascertained via linkage to electronic health records. Findings: After exclusion of 8·6 million participants for not responding or not providing appropriate consent, the UK Biobank cohort consisted of 456 905 participants (249 586 women and 207 319 men). 26 860 (6·2%) of 436 001 participants with available data were reported as being lonely and 40 428 (9·0%) of 448 114 participants with available data were socially isolated. During a median 8·9 years (IQR 8·0–9·6) of follow-up, 51 361 participants were admitted to hospital due to an infectious disease. After adjustment for age, sex, demographic and lifestyle factors, and morbidities, loneliness was associated with an increased risk of a hospital-treated infection (hazard ratio [HR] 1·12 [95% CI 1·07–1·16]), whereas social isolation was not (HR 1·01 [95% CI 0·97–1·04]). Of 64 797 individuals in the HeSSup cohort, 18 468 (11 367 women and 7101 men) were eligible for inclusion. 4466 (24·4%) of 18 296 were lonely and 1776 (9·7%) of 18 376 socially isolated. During a median follow-up of 10·0 years (IQR 10·0–10·1), 814 (4·4%) participants were admitted to hospital for an infectious disease. The HRs for the HeSSup study replicated those in the UK Biobank (multivariable-adjusted HR for loneliness 1·32 [95% CI 1·06–1·64]; 1·08 [0·87–1·35] for social isolation). Interpretation: Loneliness might increase susceptibility to severe infections, although the magnitude of this effect appears modest and residual confounding cannot be excluded. Interventional studies are required before policy recommendations can advance. Funding: Academy of Finland, the UK Medical Research Council, and Wellcome Trust UK. CC BY 4.0This is an Open Access article under the CC BY 4.0 license© 2023 The Author(s)Correspondence Address: M. Elovainio; Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland; email: marko.elovainio@helsinki.fiME was supported by the Academy of Finland (339390). PNS was supported by the Emil Aaltonen Foundation and Finnish Medical Foundation. JV was supported by the Academy of Finland (321409 and 329240). MK was supported by the UK Medical Research Council (S011676), Wellcome Trust UK (221854/Z/20/Z), National Institute on Aging USA (R01AG056477), and the Academy of Finland (350426). STN was supported by NordForsk (75021) and the Finnish Work Environment Fund (190424). CH was supported by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant number 101040247). This research has been done using the UK Biobank Resource under application number 14801.

Liquid biopsies such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have great potential to serve as prognostic and predictive biomarkers in urologic cancers. The possibility of using liquid biopsies for real-time noninvasive and dynamic monitoring of response to therapy has been an active area of investigation. In this brief review, we outline the evidence for the potential clinical utility of CTC and ctDNA analyses in prostate, urothelial, and renal cancers.

Component separation (CS) techniques have evolved in recent years. How surgeons apply the various CS techniques, anterior component separation (aCS) versus posterior component separation (pCS), by patient and hernia-specific factors remain unknown in the general population. Improving the quality of ventral hernia repair (VHR) on a large scale requires an understanding of current practice variations and how these variations ultimately affect patient care. In this study, we examine the application of CS techniques and the associated short-term outcomes while taking into consideration patient and hernia-specific factors.We retrospectively reviewed a clinically rich statewide hernia registry, the Michigan Surgical Quality Collaborative Hernia Registry, of persons older than 18 y who underwent VHR between January 2020 and July 2021. The exposure of interest was the use of CS. Our primary outcome was a composite end point of 30-d adverse events including any complication, emergency department visit, readmission, and reoperation. Our secondary outcome was surgical site infection (SSI). Multivariable logistic regression examined the association of CS use, 30-d adverse events, and SSI with patient-, hernia-, and operative-specific variables. We performed a sensitivity analysis evaluating for differences in application and outcomes of the posterior and aCS techniques.A total of 1319 patients underwent VHR, with a median age (interquartile range) of 55 y (22), 641 (49%) female patients, and a median body mass index of 32 (9) kg/mThis is the first population-level report of patients undergoing VHR with concurrent posterior or aCS. These data suggest wide variation in the application of CS in VHR and raises a concern for potential overutilization in smaller hernias. Continued analysis of CS application and the associated outcomes, specifically recurrence, is necessary and underway.

To determine whether the critical shoulder angle (CSA) in acute, traumatic rotator cuff tears (RCTs) is consistent with the previously described CSA in chronic degenerative RCTs.We performed a multicenter retrospective analysis of 134 patients presenting to 5 surgeons fellowship trained in shoulder and elbow or sports. Preoperative imaging was used to measure the CSA and tear characteristics. Patients were included if they had acute, traumatic full-thickness RCTs documented on advanced imaging and had preoperative Grashey radiographs. Patients were excluded if they had any history of shoulder pain, injury, surgery, or treatment prior to the current episode; were overhead athletes; or had fatty infiltration greater than Goutallier grade 1 on imaging.The mean CSA was 33.5° (standard deviation, 4.1°), and 60% of tears had a CSA of less than 35°, much below the mean of 38.0° and the threshold of greater than 35° in degenerative RCTs. The mean age was 58 years, and 70% of patients were men. Overall, 60% of tears involved the subscapularis, 49% of tears occurred in patients aged 60 years or older, and 18% of patients sustained a dislocation. Older age (β = 0.316, P = .003) and male sex (β = 5.532, P = .025) were predictive of tear size, and older age (β = 0.229, P = .011) and biceps avulsion (β = 8.822, P = .012) were predictive of tear retraction.Acute, traumatic RCTs have CSAs that are 5° smaller than those of degenerative tears, and the majority (60%) have CSAs that are below the threshold consistent with degenerative RCTs. The majority of traumatic tears (60%) involve the subscapularis.The study findings suggest that a traumatic tear is not simply the acute failure of a degenerative tendon and that it represents a distinct pathologic entity. These findings support current practice of treating traumatic RCTs differently than degenerative RCTs.

The aim of this study was to develop prediction models for total sperm motility, morphological abnormalities and sperm output based on 1,551 ejaculate records of 58 Holstein bulls. The data was collected from September 2019 to November 2020 in a single artificial insemination (AI) center located in Eastern Germany. Factors considered for the prediction models include barn climate conditions, semen collector, number of false mounts, libido, semen collection frequency, breed and age (10-74 months). In this study, the prediction models Lasso, Group Lasso and Gradient Boosting were evaluated. The best model for each sperm quality parameter was chosen using cross validation. The models were estimated with five algorithms for sperm motility and sperm morphology and three algorithms for the number of total sperm per ejaculate (sperm output). For sperm motility and morphology a binary classification algorithm was applied, reaching an accuracy of over 80% for all models. For sperm output, no such classification was used and the only variable selected by all three algorithms was age. Furthermore, for sperm morphology, climate variables were frequently selected. Additionally, network diagrams from Group Lasso show the interdependencies between the major variable groups influencing sperm motility and morphology. In conclusion, the implementation of such prediction tools could help AI centers to optimize management factors and stabilize bull semen production in the future.

Life stress has negative impacts on sleep and mental health. Little empirical work has investigated the associations between life stress, insomnia, and anxiety/depressive symptoms (ADS) in multi-wave longitudinal studies. This longitudinal study examined these associations in a large sample of adolescents.A total of 6995 adolescents (mean age = 14.86 years, 51.4 % male) participated in a 3-wave longitudinal study of behavior and health in Shandong, China. Standardized rating scales were used to assess life stress, insomnia, and ADS in 2015 (T1), 1 year later (T2), and 2 years later (T3). Three-wave longitudinal panel models were conducted to examine the prospective relationships between life stress, insomnia, and ADS.The prevalence and persistence rates of insomnia and ADS across T1-T3 significantly increased with elevated life stress score (p .001). Cross-lagged panel analysis showed that life stress, insomnia, and ADS at a later time point were significantly predicted by the same variable at earlier time points (all p .01). Life stress, insomnia, and ADS significantly predicted each other bidirectionally over time (all p .01). The relationship between life stress and ADS was partially mediated by insomnia. The relationship between life stress and insomnia was partially mediated by ADS.Life stress, insomnia, and ADS were all self-reports.Life stress, insomnia, and ADS are prospectively bidirectionally related to one another. Insomnia was a mediator of life stress and subsequent ADS and vice versa. These findings underscore the importance of sleep and mental health assessment and intervention in adolescents following life stress.

Insomnia is a risk factor for affective disorders. This study examined whether individuals with insomnia symptoms early in the pandemic, either pre-existing or new-onset, were more vulnerable to anxiety and depressive symptoms over time than those who maintained normal sleep. Additionally, sleep-related factors such as pre-sleep arousal were assessed for their influence on clinically significant anxiety and depression risk.Using a global online survey with 3-, 6-, and 12-month follow-ups between April 2020 and May 2021, data from 2069 participants (M = 46.16 ± 13.42 years; 75.3 % female) with pre-existing, new-onset, or no insomnia symptoms was examined using mixed-effects and logistic regression models.New-onset and pre-existing insomnia predicted persistent anxiety and depressive symptoms longitudinally (p's 0.001), over other known risk factors, including age, sex, and previous psychiatric diagnoses. Anxiety and depressive symptoms in both insomnia groups remained above clinically significant thresholds at most time points, whereas normal sleepers remained subclinical. Pre-sleep arousal was found to increase the risk of clinically significant anxiety (OR = 1.05) and depressive symptoms (OR = 1.09) at 12-months. Sleep effort contributed to anxiety (OR = 1.06), whereas dysfunctional sleep-related beliefs and attitudes predicted clinically significant depression (OR = 1.22).Insomnia group categorization was based on self-report at baseline supported by a validated measure. High participant attrition was observed at 3-months (53 %; n = 971), but retention remained steady till 12-months (63 %, n = 779).Insomnia is a modifiable risk factor for persistent anxiety and depressive symptoms that needs to be addressed in mental healthcare. Additionally, pre-sleep arousal may be an important transdiagnostic process linking insomnia with affective disorders.

Traumatic brain injury (TBI) can lead to neurocognitive decline, in part due to phosphorylated tau (p-tau). Whether p-tau accumulation worsens in the setting of polytrauma remains unknown. Propranolol has shown clinical benefit in head injuries; however, the underlying mechanism is also unknown. We hypothesize that hemorrhagic shock would worsen p-tau accumulation but that propranolol would improve functional outcomes on behavioral studies.A murine polytrauma model was developed to examine the accumulation of p-tau and whether it can be mitigated by early administration of propranolol. TBI was induced using a weight-drop model and hemorrhagic shock was achieved via controlled hemorrhage for 1 h. Mice were given intraperitoneal propranolol 4 mg/kg or saline control. The animals underwent behavioral testing at 30 d postinjury and were sacrificed for cerebral histological analysis. These studies were completed in male and female mice.TBI alone led to increased p-tau generation compared to sham on both immunohistochemistry and immunofluorescence (P 0.05). The addition of hemorrhage led to greater accumulation of p-tau in the hippocampus (P 0.007). In male mice, p-tau accumulation decreased with propranolol administration for both polytrauma and TBI alone (P 0.0001). Male mice treated with propranolol also outperformed saline-control mice on the hippocampal-dependent behavioral assessment (P = 0.0013). These results were not replicated in female mice; the addition of hemorrhage did not increase p-tau accumulation and propranolol did not demonstrate a therapeutic effect.Polytrauma including TBI generates high levels of hippocampal p-tau, but propranolol may help prevent this accumulation to improve both neuropathological and functional outcomes in males.

There is a scarcity of data on gender differences in outcomes during and after percutaneous coronary intervention (PCI) in the South Asian population. We assessed the gender differences in in-hospital mortality and complications in patients who underwent PCI. We conducted a cross-sectional study of 15,106 patients from the CROP (Cardiac Registry of Pakistan) CathPCI database. Logistic regression was used to determine factors associated with in-hospital mortality (primary outcome), access site hematoma, and bleeding complications. Approximately 19.6% were women. Women were older (mean age = 57.3 vs 54.4 years) and had a higher prevalence of diabetes (49.3% vs 32.6%), hypertension (72.8% vs 56.4%), peripheral arterial disease (1.5% vs 1%), and cerebrovascular accident (1.2% vs 0.8%) than men (p0.05).Unadjusted in-hospital mortality was higher in women than in men (odds ratio [OR]: 1.6, 95% confidence interval [CI] 1.1 to 2.2); however, after adjusting for age, hypertension, diabetes, history of cerebrovascular accident, and ST-elevation myocardial infarction at presentation in the multiple logistic regression model, in-hospital mortality was comparable between men and women (adjusted OR [AOR] 1.2, 95% CI 0.8 to 1.7). The results remained consistent after propensity score matching of 5,904 patients (2,952 in each group, OR 1.3, 95% CI 0.9 to 2.0 for in-hospital mortality). Bleeding complications (1.2% vs 0.4%, AOR 2.6, 95% CI 1.4 to 4.5) and access site hematoma (2% vs 0.6%, AOR 2.8, 95% CI 1.8 to 4.5) were higher in women than in men. In conclusion, the incidence of in-hospital mortality was higher for women versus men, but adjusted risks were similar, likely driven by a greater co-morbidity burden among women.

We performed a narrative review of studies that produced clinically applicable data by examining the combined use of at least one biomarker test and multiparametric MRI to predict GG ≥2 prostate cancer on biopsy and by reporting the resultant clinical outcomes (i.e, the proportion of biopsies avoided and GG ≥2 cancers missed) following the application of various testing strategies incorporating these diagnostic tests.

To compare return to sports, functional outcomes, and recurrences rates between female and male athletes following arthroscopic Bankart repair (ABR).A retrospective comparative study was performed between male and female athletes who underwent an ABR between January 2008 and December 2019. Sports practiced primarily by men in our practice (including rugby, soccer, boxing, and martial arts) were excluded. Functional outcomes included the Rowe score, visual analog scale (VAS) for pain, and shoulder-dependent sports ability measured with the Athletic Shoulder Outcome Scoring System (ASOSS). Return to sport, recurrence, and revisions were evaluated. Additionally, we assessed the period (months) between surgery and recurrence events.A total of 58 female and 106 male patients were available for analysis at a median follow-up of 60 (interquartile range [IQR], 36-84) months. Ninety-one percent of the patients (n = 150) returned to sports and 84% (n = 126) returned to their preinjury level at a median of 6 months (IQR, 5-8) postoperatively. There were no differences in the rate of return to sports between females and males (91 vs 92% respectively, P = .997). There were no differences between the groups regarding postoperative functional outcomes, with most patients achieving the minimal clinically significant difference (Rowe: 98% female and 99% male, P = .584; ASOSS: 100% female and 99% male, P = .646). The overall recurrence rate was 9.7% (n = 16), with a rate of 10.3% (n = 6) in female and 9.4% (n = 10) in male athletes (P = .851). Time to event analysis showed that the median time to recurrence was 48 months in both groups (P = .848). The overall revision rate was 3% (n = 4), without significant differences between groups (P = .556).When compared within similar sports, there does not appear to be sex-related differences in functional outcomes, recurrence, or return to play following ABR.III, retrospective comparative study.

Peripheral cytokines were found to be involved in the pathophysiology of neurocognition in individuals with major depressive disorder (MDD). However, whether there are sex differences in this association between cytokines and cognition in MDD remains unknown. Our aim is to examine sex differences in the relationship between plasma cytokines and cognition in MDD.One hundred and twenty-seven first episode drug naïve patients with MDD and sixty healthy controls (HCs) were recruited for present study. The MATRICS Consensus Cognitive Battery was administered to measure the cognition. Plasma concentrations of nineteen cytokines were measured using high sensitivity multiplex bead-based assays.Both female and male patients with MDD had significant cognitive impairment in verbal learning and visual learning and had higher levels of a range of cytokines than HCs (all p 0.05). Female patients performed worse in trail making (F = 4.442, p = 0.018) and had higher concentration of interleukin (IL)-4 (F = 7.775, p = 0.006) than males. In female MDD, a significant positive association between category frequency and level of IL-4 was observed (B = 8.040, p = 0.031). However, this association was not present in male MDD or HCs (p 0.05).Present study used a cross-sectional design.Female MDD patients had worse trail making performance and higher level of IL-4 than males. The elevated IL-4 in female MDD was positively associated with category fluency, suggesting that IL-4 may be involved in the pathophysiology related to specific cognitive domain in female MDD patients.

Anal dysplasia and anal cancer are major health problems. This study seeks to determine if inhibition of mTOR and/or PI3K pathways is effective at anal cancer prevention in mice with/without established precancerous lesions of the anus (anal dysplasia).K14E6/E7 mice were entered into the study at 5 wk, 15 wk, or 25 wk of age. Mice were treated with a topical carcinogen, 7,12-Dimethylbenz[a]anthracene (DMBA), which ensures carcinoma development within 20 wk. Treatment groups included: no treatment, DMBA only, topical Pictilisib (PI3K inhibitor) with/without DMBA, topical Sapanisertib (mTOR inhibitor) with/without DMBA, and topical Samotolisib (dual PI3K/mTOR inhibitor) with/without DMBA. Mice underwent weekly observations for anal tumor development (tumor-free survival). After 20 wk of treatment, anal tissue was harvested and evaluated histologically for squamous cell carcinoma (SqCC).All topical treatments in conjunction with DMBA increased tumor-free survival in mice that started treatment at 15 wk of age when compared to DMBA-only treatment, except for Pictilisib + DMBA in males. Topical Sapanisertib increased tumor-free survival in mice regardless of starting treatment age. When examining tissue for microscopic evidence of SqCC, only topical Samotolisib in males decreased SqCC in the 15 wk starting mice.Sapanisertib, the mTOR inhibitor, had the greatest effect, in terms of increasing tumor-free survival, regardless of starting time point or sex. Unlike the other treatments, Samotolisib, the dual PI3K/mTOR inhibitor, decreased microscopic evidence of SqCC when starting treatment at 15 wk of age but only in male mice.

The ATP binding cassette (ABC) transporter molecule ABCA1 participates in the cholesterol transport within and through cell membranes. We recently demonstrated that in dog spermatozoa, capacitation could be decreased with probucol (PRO), an ABCA1 specific antagonist. In this study, a dose-effect relationship of PRO on dog sperm capacitation, tyrosine phosphorylation and cholesterol efflux from the sperm plasma membrane was investigated. A total of 16 ejaculates from dogs of different breeds, aged 2-4 years were used. Sperm motility and membrane integrity in the main fraction was determined by CASA. Samples were stained with a boron dipyrromethene difluoride (BODIPY) fluorophore (P9672, Sigma- Aldrich, A) diluted in DMSO at a final concentration of 0.4 μM. All samples were divided into 5 aliquots, with 0, 100, 250, 500 and 1000 μM of PRO. After incubation at 37 °C for 2 h, PI was added and flow cytometry performed. All aliquots were examined for capacitation and acrosome reaction by using the CTC assay and tyrosine phosphorylation (TP). Membrane integrity was measured in all aliquots to investigate the effect of PRO on cell membranes. Membrane integrity did not differ between controls (0 μM), and 100, 250 and 500 μM PRO, but decreased with 1000 μM PRO (p 0.05). Increasing PRO concentration decreased the percentage alive cells with cholesterol efflux per PRO group (0 μM: 77.8 ± 10.6%, 100 μM: 63.7 ± 11.7%, 250 μM: 52.1 ± 12.9%, 500 μM: 37.7 ± 11.6%, 1000 μM: 33.1 ± 14.4%; p 0.05), decreased head and entire tail phosphorylated cells (0 μM: 34.6%, 1000 μM: 5.1% p 0.05); and decreased the percentage capacitated cells (maximum with PRO 500 μM: capacitated vs. control: 54.2 ± 17% vs 25 ± 7.7%, p 0.05). Conclusion: PRO decreased the cholesterol efflux, and decreased tyrosine phosphorylation and capacitation in a dose-dependent manner. This suggests a strong involvement of the ABCA1 transporter in different functional aspects of sperm capacitation in dogs.

Cardiac sarcoidosis is associated with a high mortality rate. Given multiple barriers to obtaining cardiac PET imaging, we suspect individuals with access to this imaging modality are not representative of the Sarcoid patient population, which in the United States are predominantly Black females.To evaluate the demographics of patients with cardiac PET access and the cost-effectiveness of cardiac PET/MR imaging relative to standard of care.This is a retrospective, observational study. The demographic information of patients with suspected cardiac sarcoidosis and cardiac PET/CT imaging within a national registry of sarcoidosis were reviewed (n = 4561). An individual-level, continuous, time-state transition model was used for the evaluation of long-term cost-effectiveness for the combined cardiac PET/MR compared to standard of care cardiac MR followed by cardiac PET/CT.Patients who underwent cardiac PET in the national registry had 88.35% higher odds of being male (p 0.001) and 43.82% higher odds of being White (p = 0.003) than their counterparts who did not have cardiac PET imaging. Combined cardiac PET/MR had overall lower total lifetime costs ($8761 vs $10,777) and overall improved expected quality of life-years compared to the standard of care (0.77 vs 0.69).The findings suggest that patients with access to cardiac PET/CT are not representative of the patient population most likely to have cardiac sarcoidosis in this limited study evaluation. Universal insurance coverage should be considered for Cardiac PET imaging as same day cardiac PET and MR imaging has potential long-term cost and quality of life benefit.

Background: HIV-1 infections initiated by multiple founder variants are characterised by a higher viral load and a worse clinical prognosis than those initiated with single founder variants, yet little is known about the routes of exposure through which transmission of multiple founder variants is most probable. Here we used individual patient data to calculate the probability of multiple founders stratified by route of HIV exposure and study methodology. Methods: We conducted a systematic review and meta-analysis of studies that estimated founder variant multiplicity in HIV-1 infection, searching MEDLINE, Embase, and Global Health databases for papers published between Jan 1, 1990, and Sept 14, 2020. Eligible studies must have reported original estimates of founder variant multiplicity in people with acute or early HIV-1 infections, have clearly detailed the methods used, and reported the route of exposure. Studies were excluded if they reported data concerning people living with HIV-1 who had known or suspected superinfection, who were documented as having received pre-exposure prophylaxis, or if the transmitting partner was known to be receiving antiretroviral treatment. Individual patient data were collated from all studies, with authors contacted if these data were not publicly available. We applied logistic meta-regression to these data to estimate the probability that an HIV infection is initiated by multiple founder variants. We calculated a pooled estimate using a random effects model, subsequently stratifying this estimate across exposure routes in a univariable analysis. We then extended our model to adjust for different study methods in a multivariable analysis, recalculating estimates across the exposure routes. This study is registered with PROSPERO, CRD42020202672. Findings: We included 70 publications in our analysis, comprising 1657 individual patients. Our pooled estimate of the probability that an infection is initiated by multiple founder variants was 0·25 (95% CI 0·21–0·29), with moderate heterogeneity (Q=132·3, p2=64·2%). Our multivariable analysis uncovered differences in the probability of multiple variant infection by exposure route. Relative to a baseline of male-to-female transmission, the predicted probability for female-to-male multiple variant transmission was significantly lower at 0·13 (95% CI 0·08–0·20), and the probabilities were significantly higher for transmissions in people who inject drugs (0·37 [0·24–0·53]) and men who have sex with men (0·30 [0·33–0·40]). There was no significant difference in the probability of multiple variant transmission between male-to-female transmission (0·21 [0·14–0·31]), post-partum transmission (0·18 [0·03–0·57]), pre-partum transmission (0·17 [0·08–0·33]), and intra-partum transmission (0·27 [0·14–0·45]). Interpretation: We identified that transmissions in people who inject drugs and men who have sex with men are significantly more likely to result in an infection initiated by multiple founder variants, and female-to-male infections are significantly less probable. Quantifying how the routes of HIV infection affect the transmission of multiple variants allows us to better understand how the evolution and epidemiology of HIV-1 determine clinical outcomes. Funding: Medical Research Council Precision Medicine Doctoral Training Programme and a European Research Council Starting Grant.

Cervical spine computed tomography (CSCT) scans are used to evaluate cervical spine traumatic injuries; however, recent evidence demonstrates that adult trauma centers (ATCs) overutilize CSCT when evaluating adolescent patients. This leads to unnecessary radiation exposure. The aim of this study is to review a level 1 ATC's use of CSCT in the adolescent blunt trauma population.A retrospective chart review was conducted of a level 1 ATC's trauma database. Blunt trauma patients between the ages of 11 and 18 who receive a CSCT between January 2015 to December 2019 were included. The primary outcome was the prevalence of positive findings on CSCT scans. Data were analyzed using Fischer-Exact analysis and multivariate logistic regression where appropriate.Three-hundred thirty-seven of 546 (61.7%) adolescent blunt trauma patients received CSCT. Of those, 68.2% (230) were male; the mean age was 16.6 ± 1.0 y old. Twenty-eight patients (8.3%) had a positive finding on CSCT. All patients with a positive CSCT failed the National Emergency X-Radiography Utilization study (NEXUS) criteria while 123 patients (36.5%) with a negative CSCT met NEXUS criteria.CSCT was overutilized in our trauma center. There is a low positive CSCT scan rate among adolescent patients, which aligns with the current literature. All patients with positive CSCT passed NEXUS criteria suggesting that a quality improvement project focusing on the use of the NEXUS criteria to assess the risk of cervical spine injury could potentially reduce the use of CSCT scans by nearly 40%.

Like humans, many felid species suffer from teratozoospermia and frequently produce low numbers of normal spermatozoa. Male fertility can be affected by oxidative and dicarbonyl stress. Because of the high level of glycolytic activity in testes, reactive dicarbonyl metabolites may arise as side-products of glycolysis; their generation is further promoted by oxidative stress. Alpha-oxoaldehydes, including methylglyoxal (MG), are reactive dicarbonyl metabolites and substrates for the formation of advanced glycation end products. Elevated levels of both may lead to dicarbonyl stress and cause cellular dysfunction. However, MG and other α-oxoaldehydes can be converted to less dangerous molecules via the glyoxalase pathway. In this pathway, α-oxoaldehydes react with glutathione (GSH), forming a thioacetal, which becomes metabolized by glyoxalase I (GLO I) to S-D-lactoyl-glutathione (SLG). Glyoxalase II (GLO II) converts SLG to d-lactate upon the release of GSH. Nothing is known about the glyoxalase system in the feline testis and its capacity to mitigate an excess of dicarbonyl metabolites. To study whether GLO I and GLO II are present and have a specific function in the testis of the domestic cat, the gene expression of both enzymes were analyzed in testis samples of different developmental stages (prepubertal, pubertal, postpubertal). Furthermore, the presence of GLO I and GLO II proteins was investigated via immunohistochemistry. The GLO I gene expression does not change between developmental stages. Immunohistochemistry revealed strong signals for GLO I in the cytoplasm and nuclei of Sertoli and Leydig cells during all developmental stages. GLO I was described as catalyzing the rate-limiting step in the glyoxalase pathway. This implies a function on the part of this enzyme of sustaining the homeostasis of somatic testicular cells. For GLO II, we observed stage-dependent mRNA expression, which was significantly increased after puberty. In accordance with this observation, clear immunohistochemical GLO II signals were observed in nuclei of individual germ cells. The most intense signals were visible in spermatocytes. The different localizations of the strong GLO I and GLO II signals indicate that GLO II, in addition to the classical glyoxalase pathway, may have additional functions in meiotic germ cells, for example, providing lactate as an energy substrate and/or GSH as an antioxidant. Moreover, protein functions may be modulated via S-glutathionylation.

To evaluate the efficacy of a 2-week home-based blood flow restriction (BFR) prehabiliation program on quadriceps strength and patient-reported outcomes prior to anterior cruciate ligament (ACL) reconstruction.Patients presenting with an ACL tear were randomized into two groups, BFR and control, at their initial clinic visit. Quadriceps strength was measured using a handheld dynamometer in order to calculate peak force, average force, and time to peak force during seated leg extension at the initial clinic visit and repeated on the day of surgery. All patients were provided education on standardized exercises to be performed 5 days per week for 2 weeks between the initial clinic visit and date of surgery. The BFR group was instructed to perform these exercises with a pneumatic cuff set to 80% of limb occlusion pressure placed over the proximal thigh. Patient-Reported Outcome Measurement System Physical Function (PROMIS-PF), knee range of motion, and quadriceps circumference were gathered at the initial clinic visit and day of surgery, and patients were monitored for adverse effects.A total 45 patients met inclusion criteria and elected to participate. There were 23 patients randomized to the BFR group and 22 patients randomized into the control group. No significant differences were noted between the BFR and control groups in any demographic characteristics (48% vs 64% male [P = .271] and average age 26.5 ± 12.0 vs 27.0 ± 11.0 [P = .879] in BFR and control, respectively). During the initial clinic visit, there were no significant differences in quadriceps circumference, peak quadriceps force generation, time to peak force, average force, pain, and PROMIS scales (P.05 for all). Following completion of a 2-week home prehabilitation protocol, all patients indeterminant of cohort demonstrated decreased strength loss in the operative leg compared to the nonoperative leg (P.05 for both) However, there were no significant differences in any strength or outcome measures between the BFR and control groups (P.05 for all). There were no complications experienced in either group, and both were compliant with the home-based prehabilitation program.A 2-week standardized prehabilitation protocol preceding ACL reconstruction resulted in a significant improvement in personal quadriceps peak force measurements, both with and without the use of BFR. No difference in quadriceps circumference, strength, or patient reported outcomes were found between the BFR and the control group. The home-based BFR prehabiliation protocol was found to be feasible, accessible, and well tolerated by patients.Level II, randomized controlled trial with small effect size.

Aim-\ud \ud To identify if the proportion of poor blood flow (blue) within an LDI (Laser doppler Imaging) image of a burn independently correlates with healing time.\ud \ud Methods-\ud \ud Patient age, gender, burn type, and burn surface area were collected from the IBID (International Burn Injury Database). All LDI images were copied from the MoorLDI2-BI- Laser Doppler (MLDI) Scanner, onto Adobe Photoshop® version 2020 for pixel counting analysis and calculation of % TBSA (Total Body Surface Area) blue. Multiple linear regression analysis determined if there was a proportional relationship of each parameter (age, gender, % TBSA Blue and comorbidities) with healing time.\ud \ud Results-\ud \ud 110 patients with 197 burns were scanned with MLDI. Median age was 5 years (IQR 1–6). Median burn surface area was 1.5% (IQR 1–2.4). 56.4% of patients were male and patients were scanned an average of 2.68 days (SD±1.37) following burn injury. Number of physical comorbidities and age were found to have a statistically significant relationship with healing time (p = 0.03, p = 0.002). Gender and %TBSA blue did not have a statistically significant relationship with healing time (p = 0.07 and p = 0.058 respectively). There was a statistically significant difference in the mean healing time between burns with and without blue (3.43 weeks vs. 2.80 weeks, p = 0.0001). % TBSA Blue was more than four times higher in the operated group (0.48% vs. 0.11%) and was shown to have a statistically significant relationship with decision to operate (p = 0.027). Positive predictive value for the presence of blue on operative rate was 71.6%. Age, gender and number of comorbidities did not have a statistically significant influence on operative rate (p = 0.07, p = 0.50 and p = 0.49).\ud \ud Conclusion-\ud \ud % TBSA blue was not found to be a reliable individual indicator of burn healing time, but the presence of blue within an LDI image, advanced patient age and increased number of comorbidities did have a statistically significant relationship with healing time. This suggests their standardised inclusion into management decisions regarding intermediate depth burns is warranted.

INTRODUCTION: Clinically significant prostate cancer (csCaP) with Gleason ≥3 + 4 is found in 10% negative prebiopsy multiparametric (mp) MRI cases and varies widely for equivocal mpMRI cases. The objective of this study was to investigate long-term outcomes of patients with negative and equivocal mpMRIs and to develop a predictive score for csCaP risk stratification in this group. PATIENTS AND METHODS: Patients who underwent an upfront mpMRI between May 2015 and March 2018 with an MRI score Likert 1 to 3 were included in the study. Patients had either a CaP diagnosis at MRI-targeted biopsy or were not diagnosed and attended follow-up in the community. Outcomes were analysed through the Kaplan-Meier estimator and Cox Model. Regression coefficients of significant variables were used to develop a Risk of significant Cancer of the Prostate score (RosCaP). RESULTS: At first assessment 281/469 patients had mpMRI only and 188/469 mpMRI and biopsy, 26 csCaP were found at biopsy, including 10/26 in Likert 3 patients. 12/371 patients discharged without CaP after first assessment were diagnosed with csCaP during a median of 34.2 months' follow-up, 11/12 diagnosis occurred in patients omitting initial biopsy. csCaP diagnosis-free survival was 95.7% in the MRI group and 99.1% in the biopsy group. From these outcomes, a continuous RosCaP score was developed: RosCaP = 0.083 x Age - 0.202 x (1/PSA Density) + 0.786 (if Likert 3), and 4 risk classes were proposed. Limitations include retrospective design and absence of external validation. CONCLUSION: Age, PSA Density and MRI Likert score were significantly associated to the risk of csCaP and utilised to devise the novel RosCap predictive score focused to support risk assessment in patients with negative or equivocal mpMRI results.

Subtotal laparoscopic cholecystectomy (SUB) is an alternative to total laparoscopic cholecystectomy (TOT) when the critical view of safety (CVS) cannot be achieved. Little is known about the clinical factors and postoperative outcomes associated with SUB. The objective was to determine predictive factors and outcomes of SUB as compared to TOT.Clinical data from patients admitted from our emergency department to the acute care surgery service who underwent SUB or TOT by an acute care surgery surgeon for acute biliary disease (2017-2019) were reviewed. Wilcoxon rank-sum and Fisher's exact tests were used.355 patients underwent cholecystectomy for acute cholecystitis; 28 were SUB (7.9%). SUB patients were more likely to be older (57 versus 43 y; P = 0.015), male (60.7% versus 39.3%; P 0.001), have a history of cirrhosis or liver disease (14.3% versus 2.1%; P = 0.007), and have a higher Charlson-Comorbidity Index (1 versus 0, P = 0.041). SUB had greater leukocytosis (14.6 versus 10.9; P 0.001), higher total bilirubin (0.9 versus 0.6; P = 0.021), and a higher Tokyo grade (2 versus 1; P 0.001), and had operative findings including gallbladder decompression (82.1% versus 23.2%; P 0.001) and inability to achieve the CVS (78.6% versus 3.4%; P 0.001). SUB patients had an increased length of stay (4 versus 2 d; P 0.001) and more 1-y readmissions. No major vascular injuries occurred in either group with one biliary injury in the TOT group.SUB patients present with more significant markers of biliary disease and have more complicated intraoperative and postoperative courses. However, the lack of biliary or vascular injuries suggests that SUB may represent a safe alternative when the CVS cannot be achieved.

The general aggression model has shown that both individual and situational factors can predict aggression. However, past research has tended to discuss these two factors separately, which might lead to inconsistency. This study addresses this gap by examining the importance of each predictor of aggression in a Chinese compulsory drug treatment population and further explores the predictors of aggression in various substance use disorder populations.Analyses were conducted using a sample of 894 male participants (mean = 38.30, SD = 8.38) in Chinese compulsory drug rehab. A machine learning model named LightGBM was employed to make predictions. We then used a game-theoretic explanatory technique, SHAP, to estimate the effect of predictors.In the full-sample model, psychological security, parental conflict, and impulsivity were the top 3 predictors. Depression, childhood abuse, and alexithymia positively predicted aggression, whereas psychological security, family cohesion, and gratitude negatively predicted aggression. There were significant differences in the predictive effects of depressants and stimulants. Although the importance of predictors varied between drug-use groups, several individual and situational factors were consistently the most important predictors.All participants in this study were male, and the data were acquired through self-reports from the participants. Domestic and nondomestic aggression are not distinguished. Additionally, our findings cannot support causal conclusions.This study tested a series of classical theories of the predictors of aggression in China's compulsory drug treatment context and extended the ideas of the GAM to various substance use disorder groups. The findings have important implications for aggression treatment.

Although gender-related disparities in intermediate-term outcomes have been reported after transcatheter aortic valve implantation (TAVI), disparate predictors of mortality in men and women who underwent TAVI have not been well studied. This prospective institutional registry study included 297 consecutive patients (153 men, 144 women) who underwent transfemoral TAVI from December 2015 to June 2018 at an academic tertiary medical center. Baseline and clinical characteristics, procedural data, and clinical outcomes at 1 year were recorded. Mortality rates at 1 year were 11.1% and 20.3% in women and men, respectively (p = 0.033). Risk-adjusted mortality was significantly higher in men who underwent TAVI than in women (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.24 to 4.87, p = 0.010). Gender-specific risk-adjusted predictors of 1-year mortality post-TAVI included the presence of atrial fibrillation (OR 4.20, 95% CI 1.31 to 13.46, p = 0.016) and peripheral artery disease (OR 4.64, 95% CI 1.04 to 20.71, p = 0.044) in women and presence of chronic obstructive pulmonary disease (OR 3.14, 95% CI 1.13 to 8.72, p = 0.029), higher serum creatinine (OR 1.57, 95% CI 1.15 to 2.15, p = 0.004), and lower body mass index (OR 0.88, 95% CI 0.80 to 0.97, p = 0.008) in men. In this prospective institutional registry of adults who underwent TAVI, risk-adjusted 1-year mortality is significantly lower in women, and disparate predictors of risk-adjusted 1-year mortality exist in men and women.

For many heart failure patients, a heart transplant is required. Few hospitals in Canada perform heart transplants; thus, patients and caregivers must relocate to access transplant care.This study explores Canadian patients' and caregivers' experiences of to access transplant care and how patients and caregivers define home. The study's goal is to gain insights from the patient and caregiver experience and identify opportunities to improve the experience for those who relocate to access heart transplants. The research question was: How is the concept of home connected to the heart transplant journey?We conducted 18 interviews with advanced heart failure patients and caregivers, to explore patient and caregiver experiences of relocating to access transplant care. Patients and caregivers ranged in ages from 20's to 60's and had left their home of origin to move to a new location where medical care was available. 7 patients were male, 3 were female. All caregivers were female.Patients and caregivers identified three supports during relocation: other patients and caregivers, medical team and family. Patients and caregivers defined home as friends, family, community, warmth, safety, belonging and comfort.During relocation, patients and caregivers were supported by: other patients and caregivers, their medical team and family, and how these people made them feel: safe, warm, comfortable and that they belonged is how they defined home. The supports and definitions of home are connected; thus, a sense of home is inextricably linked to the transplant journey for patients and caregivers.

Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular events. Although the association between NAFLD and aortic valve sclerosis has been described, the prevalence and prognostic implications of NAFLD among patients with severe aortic stenosis (AS) have not been described. In addition, the effect of the presence of severe tricuspid regurgitation (TR) on the prevalence of NAFLD remains unexplored. Accordingly, we investigated the prognostic implications of NAFLD among patients with severe AS with and without concomitant significant TR. A total of 538 patients (aged 80 ± 7 y, 49.6% men) who underwent noncontrast computed tomography before transcatheter aortic valve implantation (TAVI) between 2007 and 2019 were included. NAFLD was defined as a liver-to-spleen attenuation ratio1.0 on noncontrast computed tomography. NAFLD was present in 118 patients (21.9%). There were no significant differences in pulmonary arterial pressure, right atrial pressure, or the prevalence of significant TR between patients with and without NAFLD. During a median follow-up of 47 months (interquartile range 20 to 70 months), 224 patients (41.6%) died. Univariate Cox regression analysis demonstrated that NAFLD was not significantly associated with all-cause death among patients treated with TAVI (hazard ratio 1.32, 95% confidential interval 0.97 to 1.79, p = 0.07). In conclusion, among patients with severe AS who underwent TAVI, the prevalence of significant TR and the clinical outcomes were similar in patients with and without NAFLD.

Despite evidence that early-stage male breast cancer (MBC) can be treated the same as in females, we hypothesized that men undergo more extensive surgery.Patients with clinical T1-2 breast cancer were identified in the National Cancer Database 2004-2016. Trends in surgery type and overall survival were compared between sexes.Of 9,782 males and 1,078,105 females, most were cN0 with AJCC stage I/II disease. Unilateral mastectomy was most common in men (67.1% vs. 24.1%, p 0.001) and partial mastectomy in women (64.7% vs. 26.4%, p 0.001), with no significant change over time. Over 1/3 of men received ALND in 2016. While overall survival was superior in females (HR 0.83, 95% CI 0.73-0.94, p = 0.003), partial mastectomy was associated with a 42% reduction in mortality risk for males (HR 0.58, 95% CI 0.4-0.8, p = 0.003).De-escalation of surgery could be considered for MBC to improve survival and align with current standards of care.

A hyperdynamic heart is defined as a left ventricular (LV) with an ejection fraction (EF) above the normal range. Is this favorable? We looked at the diastolic properties of subjects with a hyperdynamic heart and its impact on outcome. Consecutive echocardiography examinations during 5 years were evaluated by EF subgroups, including a hyperdynamic heart (EF70%). All examinations with significant LV hypertrophy or valve disease were excluded. The study included 16,994 subjects. A total of 720 subjects (4.2%) had a hyperdynamic heart. Subjects with a hyperdynamic heart were older, more likely to be women, and more likely to have hypertension, diabetes, and obesity. A total of 20% of patients had a diagnosis of heart failure. This group had a higher heart rate, smaller ventricular size, and the highest relative wall thickness. All indexes of diastolic dysfunction were significantly more prevalent in the hyperdynamic group. This included a higher LV mass, larger left atrial volume, reduced relaxation (smaller mitral e'), longer deceleration time, and higher LV end-diastolic pressures (high mitral E/e' ratio) and peak tricuspid regurgitation gradient. Diastolic dysfunction, defined by an abnormal functional or structural parameter, was present in 78% of the subjects. Survival was significantly lower in the group with a hyperdynamic heart. The Cox regression analysis after adjustment demonstrated reduced survival during a median 9-year follow-up in the hyperdynamic group compared with those with a normal EF (hazard ratio 1.56, 95% confidence interval 1.38 to 1.76, p0.001). In conclusion, subjects with a hyperdynamic systolic function have increased prevalence of diastolic dysfunction and reduced survival. A hyperdynamic heart is not a normally functioning heart.

The effect of reductions in homocysteine (Hcy) on cardiovascular disease (CVD) was suggested to be modified by platelet activation, but the interaction between Hcy and platelet activation on CVD events is not well studied. Here, we aimed to examine the interaction between Hcy and platelet activation on CVD in a large, real-world population.A total of 27,234 patients with hypertension (mean 63 years, 48% male) who were registered in Taicang city and free of CVD were prospectively followed up for new CVD events from 2017 to 2020. Hcy and platelet indices including mean platelet volume (MPV) were assayed at baseline. A total of 1063 CVD events were recorded during follow-up. Hcy at baseline was significantly associated with a higher risk of CVD (HR = 1.85, P 0.001 for log-transformed Hcy). MPV showed a significant interaction effect with Hcy on CVD (HR = 1.20, P = 0.030 for the interaction term). The association between Hcy and CVD was significantly stronger in participants with a large (vs. small) MPV (HR = 2.71 vs. 1.32, P = 0.029 for log-transformed Hcy). For participants with both elevated Hcy and a large MPV, the attributable proportion of CVD events due to their interaction was 0.26 (95% CI: 0.06-0.45).The association between Hcy and CVD was significantly stronger in patients with hypertension with a larger MPV. MPV may modify the contribution of Hcy to CVD events through synergistic interactions with Hcy. These findings suggest that MPV could be monitored and controlled in the prevention of CVD.

We conducted a retrospective study to determine the incidence and frequency of different subtypes of encephalitis in patients aged 15 and older in the Auckland and Northland regions of New Zealand between 2009 and 2018. Residents in Auckland and Northland presenting with encephalitis between 2009 and 2018 were identified from three overlapping databases: positive cerebrospinal fluid (CSF) viral polymerase chain reaction (PCR) tests, CSF neuronal antibody requests, and CSF neuronal antibody tests sent overseas. A diagnosis of autoimmune encephalitis required fulfilment of diagnostic criteria published by Graus and colleagues (2016). One hundred and thirty-six (69, 50.7% female) patients met study inclusion criteria. The median age was 59 (range 15-92). The annual incidence was 1.10 cases per 100,000 person-years. Of these 136 patients, 56 (41.2%) had an infectious aetiology, with varicella zoster (26, 46.4%) and herpes simplex (23, 41.1%) being the most common agents. Autoimmune encephalitis was diagnosed in 32 patients (23.5%). LGI-1 antibody was the most commonly identified neuronal autoantibody (10 patients, 13.2%). Forty-eight patients (35.3%) had encephalitis of unknown cause. In-hospital mortality for infectious encephalitis was 12.5%, autoimmune encephalitis 6.3%, and encephalitis of unknown cause 10.4%. Compared to a previous analysis of encephalitis in adults in Auckland, the incidence of encephalitis and autoimmune encephalitis had increased. The proportion of patients with an unknown cause for encephalitis had decreased.

Social and interpersonal context are associated with the onset and persistence of psychiatric disorders. We compared the effects of short-term interpersonal psychotherapy (IPT) on weight loss, binge eating behaviors, and depressive symptoms against cognitive-behavioral therapy (CBT), health education (HE), and behavioral weight loss (BWL).We searched until May 28th, 2022 following databases: PubMed, CINAHL, Science Direct, Web of Science, EMBASE, and Scopus. Articles on parallel randomized clinical trials were included. Outcomes were body mass index (BMI), binge days (bulimic episode), and depressive symptoms. These outcomes were self-reported or measured with specific scales (BMI) or instrument (depressive symptoms).The initial search retrieved 820 articles, a total of 10 studies met the eligibility criteria, and seven were included in the meta-analysis. Participants with overweight/obesity were women (62-100 %), aged between 11 and 50 years. There was a trivial to small effect on BMI favoring IPT over other interventions (standardized mean difference [SMD] = -0.10; 95%CI: -0.27 to 0.07, ISmall number of studies, the discrepancy in age cohorts, and racial diversity. Psychotherapeutic protocols and assessment tools had to be adapted across studies.Patients with overweight/obesity and depression had some benefit from IPT when compared with other interventions. In view of existing evidence, an IPT program adapted to obesity could help to achieve reliable and long-term effects.

The optimal treatment strategy after syndesmotic injuries is still controversial. In our study, we aimed to evaluate ideal fixation method in syndesmotic injury by using finite element analysis method. A 3D SolidWorks model file was created by taking computed tomography (CT) images of the area from the right foot base to the knee joint level of a healthy adult male. The intact model, injury model, and 8 different fixation models were created that 3.5 mm screw and suture-button were used in. The models were compared in terms of lateral fibular translation, posterior fibular translation and external rotation of fibula compared to tibia and stress values occurred on screws and suture-buttons. In the hybrid-1 model, lateral fibular translation and external fibular rotation values were obtained as close to the intact model. Von Mises stresses occurred in the screw (435.7 MPa) and suture-button (424.7 MPa) that used in hybrid-1 model was more than single screw at 4 cm model (316.8 MPa) and single suture-button at 2 cm model (160.7 MPa). In the Hybrid-1 model, the screw compensates for posterior fibular translation and external fibular rotation, while the suture-button compensates for lateral fibular translation. Also, the effect of the distal suture-button preventing diastasis in case of proximal screw failure, it was concluded that the hybrid-1 model can be used as a good treatment alternative in the surgical treatment of distal tibiofibular syndesmotic injuries.

The U.S. Food and Drug Administration (FDA) Biologics Effectiveness and Safety (BEST) Initiative conducts active surveillance of adverse events of special interest (AESI) after COVID-19 vaccination. Historical incidence rates (IRs) of AESI are comparators to evaluate safety.We estimated IRs of 17 AESI in six administrative claims databases from January 1, 2019, to December 11, 2020: Medicare claims for adults ≥ 65 years and commercial claims (Blue Health Intelligence®, CVS Health, HealthCore Integrated Research Database, IBM® MarketScan® Commercial Database, Optum pre-adjudicated claims) for adults 65 years. IRs were estimated by sex, age, race/ethnicity (Medicare), and nursing home residency (Medicare) in 2019 and for specific periods in 2020.The study included100 million enrollees annually. In 2019, rates of most AESI increased with age. However, compared with commercially insured adults, Medicare enrollees had lower IRs of anaphylaxis (11 vs 12-19 per 100,000 person-years), appendicitis (80 vs 117-155), and narcolepsy (38 vs 41-53). Rates were higher in males than females for most AESI across databases and varied by race/ethnicity and nursing home status (Medicare). Acute myocardial infarction (Medicare) and anaphylaxis (all databases) IRs varied by season. IRs of most AESI were lower during March-May 2020 compared with March-May 2019 but returned to pre-pandemic levels after May 2020. However, rates of Bell's palsy, Guillain-Barré syndrome, narcolepsy, and hemorrhagic/non-hemorrhagic stroke remained lower in multiple databases after May 2020, whereas some AESI (e.g., disseminated intravascular coagulation) exhibited higher rates after May 2020 compared with 2019.AESI background rates varied by database and demographics and fluctuated in March-December 2020, but most returned to pre-pandemic levels after May 2020. It is critical to standardize demographics and consider seasonal and other trends when comparing historical rates with post-vaccination AESI rates in the same database to evaluate COVID-19 vaccine safety.

Although the Wistar Kyoto (WKY) rat has been consistently recognized as an animal model with endogenous depression, the exact molecular mechanisms underlying its genetic susceptibility to depression remain undetermined.Compared with the Wistar rats, the depression-like behaviors of the male WKY ones were evaluated by both the sucrose preference test and forced swimming test. Golgi staining analysis was conducted to access the dendritic morphology. TMT-labelled quantitative proteomics analyses were respectively performed in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and hippocampus (Hip), followed by KEGG enrichment-based clustering analysis, Venn diagram analysis, and Pearson correlation analysis.The WKY strain showed significant differences in both the depression-like behaviors and synaptic plasticity. Moreover, the WKY model displayed markedly distinct differentially-expressed protein (DEP) profiles, with minor differences between the WKY subgroups. A cerebral regional commonality and specificity were evident in the signaling pathways enriched in the WKY model, and a total of 15 brain region-specific DEPs were identified to closely correlate with the depression-like phenotypes (in the mPFC: Lrrc8d, Dcun1d2, and Mtnd5; in the NAc: Ccdc154, Sec14l2, Kif2a, LOC680322, Me1, Mknk1, and Ret7; in the Hip: Sec14l2, Serpinf2, LOC103694855, Fam13c, and Loxl1). Data were available via ProteomeXchange with identifier PXD029079.Female WKY rats are not included, and the roles of these candidate DEPs in depression remain further elucidation.The present study further evidences the brain region-specific protein signatures in the male WKY model with endogenous depression, providing novel insights into the pathogenesis of depression in males.

Female patients are underrepresented in randomized controlled clinical trials and registries of ventricular arrhythmia (VA). Personalized prevention and therapies require an understanding of sex differences in risk factors and prognosis of VA.We aimed to assess sex differences in the incidence, risk factors, and mortality of VA in congestive heart failure (HF) patients.This study included 10,889 patients (mean [SD] age, 73.8 [13.4] years; 5917 [53.8%] male) with congestive HF, of which 1555 (14.3%) patients developed VA during hospitalization. VA incidence, potential risk factors, and in-hospital mortality were evaluated in both sexes.Men were more strongly associated with incident VA compared with women (odds ratio [OR]: 2.006, 95% CI: 1.790-2.248, p 0.001). Thirteen potential predictors, which accounted for 91.0% of the risk of VA in men and 88.2% in women, were included in this study. There were significant interactions by sex in the association between incident VA, atrial fibrillation (AF) (relative risk ratio = 0.730, 95% CI: 0.571-0.933, interaction p = 0.012), and non-ischemic cardiomyopathy (NICM) (relative risk ratio = 1.391, 95% CI: 1.029-1.872, interaction p = 0.030). Congestive HF patients developed with VA had an approximately 1.5-fold risk of in-hospital mortality, which was not affected by sex.In congestive HF patients, incident VA was an independent risk factor of in-hospital mortality, and male sex was strongly associated with an increased risk of VA. Awareness of sex differences in the association of AF and NICM with VA may enhance therapeutic decisions, thus improving their clinical outcomes.

BACKGROUND: Observations in people with cerebral cavernous malformations, and in preclinical models of this disorder, suggest that the β-blocker propranolol might reduce the risk of intracerebral haemorrhage. We aimed to evaluate the safety and efficacy of prolonged treatment with propranolol to reduce the incidence of symptomatic intracerebral haemorrhage or focal neurological deficit in people with familial cerebral cavernous malformations.METHODS: We conducted a randomised, open-label, blinded-endpoint, phase 2 pilot trial (Treat_CCM) at six national reference centres for rare diseases in Italy. People aged 18 years or older with symptomatic familial cerebral cavernous malformation were eligible for enrolment. Participants were randomly assigned (2:1) to receive either oral propranolol (20-320 mg daily) plus standard care (intervention group), or standard care alone (control group), for 24 months. Participants, caregivers, and investigators were aware of treatment group assignment. Participants had clinical assessments and 3 T brain MRI at baseline and at 12 and 24 months. The primary outcome was new occurrence of symptomatic intracerebral haemorrhage or focal neurological deficit attributable to cerebral cavernous malformation over 24 months. Outcome assessors were masked to treatment group assignment. The primary analysis was done in the intention-to-treat population. Because of the pilot study design, we chose a one-sided 80% CI, which could either exclude a clinically meaningful effect or show a signal of efficacy. This trial is registered with EudraCT, 2017-003595-30, and ClinicalTrials.gov, NCT03589014, and is closed to recruitment.FINDINGS: Between April 11, 2018, and Dec 5, 2019, 95 people were assessed for eligibility and 83 were enrolled, of whom 57 were assigned to the propranolol plus standard care group and 26 to the standard care alone group. The mean age of participants was 46 years (SD 15); 48 (58%) were female and 35 (42%) were male. The incidence of symptomatic intracerebral haemorrhage or focal neurological deficit was 1·7 (95% CI 1·4-2·0) cases per 100 person-years (two [4%] of 57 participants) in the propranolol plus standard care group and 3·9 (3·1-4·7) per 100 person-years (two [8%] of 26) in the standard care alone group (univariable hazard ratio [HR] 0·43, 80% CI 0·18-0·98). The univariable HR showed a signal of efficacy, according to predefined criteria. The incidence of hospitalisation did not differ between groups (8·2 cases [95% CI 7·5-8·9] per 100 person-years in the propranolol plus standard care group vs 8·2 [95% CI 7·1-9·3] per 100 person-years in the standard care alone group). One participant in the standard care alone group died of sepsis. Three participants in the propranolol plus standard care group discontinued propranolol due to side-effects (two reported hypotension and one reported weakness).INTERPRETATION: Propranolol was safe and well tolerated in this population. Propranolol might be beneficial for reducing the incidence of clinical events in people with symptomatic familial cerebral cavernous malformations, although this trial was not designed to be adequately powered to investigate efficacy. A definitive phase 3 trial of propranolol in people with symptomatic familial cerebral cavernous malformations is justified.FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro, Swedish Science Council, Knut and Alice Wallenberg Foundation, CARIPLO Foundation, Italian Ministry of Health.