Candesartan restores blood-brain barrier dysfunction, mitigates aberrant gene expression, and extends lifespan in a knockin mouse model of epileptogenesis.

Blockade of Angiotensin type 1 receptor (AT1R) has potential therapeutic utility in the treatment of numerous detrimental consequences of epileptogenesis, including oxidative stress, neuroinflammation, blood-brain barrier (BBB) dysfunction. We have recently shown that many of these pathological processes played a critical role in seizure onset and propagation in the Scn8a-N1768D mouse model. Here we investigate the efficacy and potential mechanism(s) of action of candesartan (CND), an FDA-approved angiotensin receptor blocker (ARB) indicated for hypertension, in improving outcomes in this model of pediatric epilepsy. We compared length of lifespan, seizure frequency, and BBB permeability in juvenile (D/D) and adult (D/+) mice treated with CND at times after seizure onset. We performed RNAseq on hippocampal tissue to quantify differences in genome-wide patterns of transcript abundance and inferred beneficial and detrimental effects of canonical pathways identified by enrichment methods in untreated and treated mice. Our results demonstrate that treatment with CND gives rise to increased survival, longer periods of seizure freedom, and diminished BBB permeability, as well as partially reversed or "normalized" disease-induced genome-wide gene expression profiles associated with inhibition of NF-κB, TNFα, IL-6, and TGF-ß signaling in juvenile and adult mice. Pathway analyses reveal that efficacy of CND is due to its known dual mechanism of action as both an AT1R antagonist and a PPARγ agonist. The robust efficacy of CND across ages, sexes and mouse strains is a positive indication for its translation to humans and its suitability of use for clinical trials in children with SCN8A epilepsy.

Close approximations to the sound of a cochlear implant.

Cochlear implant (CI) systems differ in terms of electrode design and signal processing. It is likely that patients fit with different implant systems will experience different percepts when presented speech via their implant. The sound quality of speech can be evaluated by asking single-sided-deaf (SSD) listeners fit with a cochlear implant (CI) to modify clean signals presented to their typically hearing ear to match the sound quality of signals presented to their CI ear. In this paper, we describe very close matches to CI sound quality, i.e., similarity ratings of 9.5 to 10 on a 10-point scale, by ten patients fit with a 28 mm electrode array and MED EL signal processing. The modifications required to make close approximations to CI sound quality fell into two groups: One consisted of a restricted frequency bandwidth and spectral smearing while a second was characterized by a wide bandwidth and no spectral smearing. Both sets of modifications were different from those found for patients with shorter electrode arrays who chose upshifts in voice pitch and formant frequencies to match CI sound quality. The data from matching-based metrics of CI sound quality document that speech sound-quality differs for patients fit with different CIs and among patients fit with the same CI.

Patient perspective on adapting to bowel dysfunction after rectal cancer surgery.

AIM: Bowel dysfunction continues to be a clinically significant consequence of rectal cancer surgery, affecting quality of life. Rectal cancer patients value self-empowerment and adaptation to change to improve their quality of life in the context of bowel dysfunction. There are limited qualitative data addressing patients' perspectives on adapting to bowel dysfunction. The aim of this study is to evaluate patients' perspectives on adapting to bowel dysfunction after rectal cancer surgery. METHOD: Adult patients who underwent rectal cancer surgery with sphincter preservation at a single colorectal referral centre from July 2017 to July 2020 were included. Patients were excluded if they had surgery <1 year since recruitment, received a permanent stoma or developed recurrence or metastasis. Semistructured interviews were held by phone and transcribed verbatim. Bowel dysfunction was assessed via the low anterior resection syndrome (LARS) score. Thematic analysis was used to identify adaptations which patients found helpful for improving bowel dysfunction after rectal cancer surgery. RESULTS: A total of 54 patient interviews were included. The distribution of patients with no, minor and major LARS was 39%, 22% and 39%, respectively. Four main themes were conceived from the analysis: implementing lifestyle changes, fostering supportive relationships and self-compassion, communication and access to resources, and adapting to social and cultural challenges. Associated subthemes were identified, namely forward planning, self-compassion and addressing social stigma. CONCLUSION: Patients' valuable perspective on adapting to bowel dysfunction involve subtle themes which expand the existing literature. These themes inform a patient-centred approach, which may improve outcomes and quality of care for rectal cancer patients.

Novel Osteomyocutaneous Flap Model for Vascularized Composite Allotransplantation.

Background: Vascularized composite allotransplantation (VCA) has become a viable option for restoration of devastating injuries that are not amenable to conventional reconstructive techniques. However, the relative scarcity of procedures performed worldwide, as well as the potential for iatrogenic injury with biopsies, makes studying the immunopathogenesis of acute rejection challenging. Translational VCA research focuses on developing strategies to overcome these barriers with the use of animal models can be technically challenging and difficult to replicate without highly trained microsurgeons. Methods: We describe a modified model of a femur-based composite tissue allograft using an adapted vascular cuff anastomotic technique with a tunneled skin flap in a rodent model. Results: The use of a heterotopic osteomyocutaneous flap with a subcutaneously tunneled-skin paddle to the posterolateral aspect of the recipient rodent allows for ease of flap monitoring and reduces the risk of self-mutilation. A total of six transplantations were conducted with no signs of self-mutilation. Operative time decreased as our surgical technique improved, and long-term graft tolerance was possible under our immunosuppressive regimen. Additionally, we demonstrate cases of successful transplantation in both an allogeneic and syngeneic rodent model. Conclusion: Animal models, although technically challenging, are a reliable and reproducible modality that has been used to investigate various aspects of VCA immunology. We describe the success of an osteomyocutaneous flap with a modified vascular cuff anastomosis that can be used by investigators with less experience in microsurgical techniques to further our understanding of VCA physiology. Furthermore, tunneling of the skin paddle reduces the risk of self-mutilation and other external factors affecting the graft.

Mental health and well-being of elite youth athletes: a scoping review.

BACKGROUND: There is increasing recognition of the prevalence and risk factors for mental health symptoms and disorders among adult elite athletes, with less research involving elite youth athletes. This scoping review aimed to characterise the mental health and well-being of elite youth athletes who travel internationally and compete for their sport. METHOD: Four databases were searched in March 2023. Inclusion criteria were studies with elite youth athlete populations (mean age 12-17 years) reporting mental health and well-being outcomes. Data from included studies were charted by outcome, and risk/protective factors identified. RESULTS: Searches retrieved 3088 records, of which 33 studies met inclusion criteria, encapsulating data from 5826 athletes (2538 males, 3288 females). The most frequently studied issue was disordered eating (k=16), followed by anxiety (k=7), depression (k=5) and mixed anxiety/depression (k=2). Caseness estimates (a symptom level where mental health treatment is typically indicated) for disordered eating were wide ranging (0%-14% for males; 11%-41% for females), whereas only two studies estimated caseness for depression (7% in a mixed-sex sample; 14% for males, 40% for females) and one for anxiety (8% for males, 28% for females). Common risk factors for mental ill-health included sex, athlete status (compared with non-athletes) and social/relationship factors (with coaches/parents/peers). Contradictory evidence was observed for elite/competition level, which was associated with higher and lower rates of disordered eating. CONCLUSION: Further representative research into the mental health and well-being of elite youth athletes is needed to enhance understanding and guide prevention and intervention measures.

Transfusion Camp: The UK experience and its value in improving knowledge of transfusion medicine among postgraduate trainees.

OBJECTIVES: To report the UK experience of rolling out Transfusion Camp. BACKGROUND: Transfusion Camp is a structured education programme developed in Toronto, with the aim of reducing knowledge gaps in transfusion medicine in postgraduate trainees. It consists of didactic lectures viewed online by the participants, then interactive, locally delivered seminars. Since 2015, it has been rolled out in the United Kingdom, and is now available in four centres. Here, we report the UK experience of Transfusion Camp and outcomes. METHODS: Trainees are recruited via the training programme directors in each region. Pre- and post-course assessments are administered using the validated BEST (Biomedical Excellence for Safer Transfusion) test, with possible scores 0-20, and confidence measured on an A-E Likert scale. RESULTS: Since 2015, 130 trainees have participated in Transfusion Camp in the United Kingdom. Trainees from all specialties significantly improved their BEST-test scores after attending the course (mean score 11.6/20 before the course, compared with 14.3/20 after the course), and confidence in managing transfusion-related issues was also significantly improved. CONCLUSION: We recommend that all centres consider offering Transfusion Camp to trainees in haematology and other specialties that frequently use blood transfusions, such as anaesthesia/ICU, Internal Medicine and others.

Clinical applications of 3D printing in colorectal surgery: A systematic review.

BACKGROUND: The utilization of three-dimensional printing has grown rapidly within the field of surgery over recent years. Within the subspecialty of colorectal surgery, the technology has been used to create personalized anatomical models for preoperative planning, models for surgical training, and occasionally customized implantable devices and surgical instruments. We aim to provide a systematic review of the current literature discussing clinical applications of three-dimensional printing in colorectal surgery. METHODS: Full-text studies published in English which described the application of 3D printing in pre-surgical planning, advanced surgical planning, and patient education within the field of colorectal surgery were included. Exclusion criteria were duplicate articles, review papers, studies exclusively dealing with surgical training and/or education, studies which used only virtual models, and studies which described colorectal cancer only as it pertained to other organs. RESULTS: Eighteen studies were included in this review. There were two randomized controlled trials, one retrospective outcomes study, five case reports/series, one animal model, and nine technical notes/feasibility studies. There were three studies on advanced surgical planning/device manufacturing, six on pre-surgical planning, two on pelvic anatomy modeling, eight on various types of anatomy modeling, and one on patient education. CONCLUSIONS: While more studies with a higher level of evidence are needed, the findings of this review suggest many promising applications of three-dimensional printing within the field of colorectal surgery with the potential to improve patient outcomes and experiences.

IOC consensus statement on elite youth athletes competing at the Olympic Games: essentials to a healthy, safe and sustainable paradigm.

With the pronounced ongoing growth of global youth sports, opportunities for and participation of youth athletes on the world sports stage, including the Olympic Games, are expected to escalate. Yet, adolescence is a vulnerable period of development and inherently dynamic, with non-linear and asynchronous progression of physical, physiological, psychological and social attributes. These non-concurrent changes within and between individuals are accompanied by irregular and unpredictable threats and impediments. Likewise, the evident age-based criteria and conventional path for those youth athletes deemed eligible candidates for the Olympic Games are not well or consistently defined. Furthermore, the unstructured and largely varying policies and practices across the sporting International Federations specific to youth participation underscore the need to establish a contemporary universal paradigm that would enable elite youth athletes to navigate an individualised healthy pathway to personal, athletic and sport success. First, we reviewed and summarised key challenges facing elite youth athletes and the relevant evidence fundamental to facilitating and supporting central aspects of health and well-being, while empowering safe, sustainable and positive engagement during athletic and personal advancement and competition. Second, we developed and present a modern elite youth athlete model that emphasises a child-centred, practical framework with corresponding guidelines and recommendations to protect health and well-being while safely and favourably managing international sport competition. Our proposed evidence-informed paradigm will enable and support individualised pathways for healthy, well-rounded and sustainable positive engagement while achieving sport success for youth contending or aiming to compete at world-class international sporting events.

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. OBJECTIVES: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

Child maltreatment as a transdiagnostic risk factor for the externalizing dimension: a Mendelian randomization study.

Observational studies suggest that child maltreatment increases the risk of externalizing spectrum disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), antisocial personality disorder (ASPD), and substance use disorder (SUD). Yet, only few of such associations have been investigated by approaches that provide strong evidence for causation, such as Mendelian Randomization (MR). Establishing causal inference is essential given the growing recognition of gene-environment correlations, which can confound observational research in the context of childhood maltreatment. Evaluating causality between child maltreatment and the externalizing phenotypes, we used genome-wide association study (GWAS) summary data for child maltreatment (143,473 participants), ADHD (20,183 cases; 35,191 controls), CD (451 cases; 256,859 controls), ASPD (381 cases; 252,877 controls), alcohol use disorder (AUD; 13,422 cases; 244,533 controls), opioid use disorder (OUD; 775 cases; 255,921 controls), and cannabinoid use disorder (CUD; 14,080 cases; 343,726 controls). We also generated a latent variable 'common externalizing factor' (EXT) using genomic structural equation modeling. Genetically predicted childhood maltreatment was consistently associated with ADHD (odds ratio [OR], 10.09; 95%-CI, 4.76-21.40; P = 1.63 × 10-09), AUD (OR, 3.72; 95%-CI, 1.85-7.52; P = 2.42 × 10-04), and the EXT (OR, 2.64; 95%-CI, 1.52-4.60; P = 5.80 × 10-04) across the different analyses and pleiotropy-robust methods. A subsequent GWAS on childhood maltreatment and the externalizing dimension from Externalizing Consortium (EXT-CON) confirmed these results. Two of the top five genes with the strongest associations in EXT GWAS, CADM2 and SEMA6D, are also ranked among the top 10 in the EXT-CON. The present results confirm the existence of a common externalizing factor and an increasing vulnerability caused by child maltreatment, with crucial implications for prevention. However, the partly diverging results also indicate that specific influences impact individual phenotypes separately.

Adaptation and validation of a suicide-focused Word Sentence Association Paradigm to assess suicide-specific interpretation biases.

The cognitive model of suicide proposes that biased cognitive processes contribute to suicidal thoughts and behaviors, and initial evidence suggests that attentional bias to suicide-congruent cues may predict suicidal behavior beyond established clinical risk factors. To date, much less work has explored the potential role of interpretation biases in the development and prediction of suicide risk. The present study assessed the psychometric properties, including reliability, concurrent validity, and predictive validity, of a novel adaptation of the Word Sentence Association Paradigm (WSAP) to assess suicide-suicide interpretation biases. In a sample of 239 psychiatric inpatients, including patients with no recent suicidal ideation or lifetime attempts (n = 35), those with recent suicide attempts (n = 29), and those with recent suicidal ideation (n = 174), participants completed the modified WSAP as well as self-reported suicidal ideation and attempts for the subsequent 6 months. Although the WSAP demonstrated good reliability, evidence of concurrent and prospective validity (in terms of self-reported suicidal ideation and attempts) was limited. Specifically, the clinical groups did not differ from one another on any measure of interpretation bias, nor did suicide-specific interpretation endorsements predict concurrent or future suicidal ideation when controlling for dysphoric interpretation bias. However, suicide-specific interpretation biases were uniquely associated with a history of a lifetime suicide attempt. Future work should further clarify the extent and specificity of the relationship between suicide-specific interpretation biases and clinical outcomes.

Virtual reality gameplay classification illustrates the multidimensionality of visuospatial neglect.

Brain injuries can significantly impact mental processes and lead to hidden disabilities not easily detectable. Traditional methods for assessing these impacts are imprecise, leading to unreliable prevalence estimates and treatments with uncertain effectiveness. Immersive virtual reality has shown promise for assessment, but its use as a standalone tool is rare. Our research focused on developing and validating a standalone immersive virtual reality classification system for unilateral spatial neglect, a condition common following brain injury characterized by inattention to one side of space. Our study involved 51 brain injury inpatients and 30 controls, all engaging with 'The Attention Atlas', an immersive virtual reality game for testing visual search skills. Our classification system aimed to identify patients with neglect, 'minor atypicality' (indicative of inattention not consistent enough to be labelled as neglect) or non-neglect. This categorization was based on a simple mathematical definition, utilizing gameplay to describe spatial orientation (to the left or right side) and attentional challenge (indicative of search inefficiency). These metrics were benchmarked against a normative model to detect atypical visual search, which refers to gameplay beyond the usual bounds. The combination of neglected side, orientation and challenge factors was used to categorize neglect. We discovered a strong correlation between atypical visual search patterns and neglect risk factors, such as middle cerebral artery stroke, parietal injuries and existing neglect diagnoses (Poisson regression incidence rate ratio = 7.18, 95% confidence interval = 4.41-11.90). In our study, immersive virtual reality-identified neglect in one-fourth of the patients (n = 13, 25.5%), minor atypicality in 17.6% (n = 9) and non-neglect in the majority, 56.9% (n = 29). This contrasts with standard assessments, which detected neglect in 17.6% (n = 9) of cases and had no intermediate category. Our analysis determined six categories of neglect, the most common being left hemispace neglect with above-median orientation and challenge scores. Traditional assessments were not significantly more accurate (accuracy = 84.3%, P = 0.06) than a blanket assumption of non-neglect. Traditional assessments were also relatively insensitive in detecting immersive virtual reality-identified neglect (53.8%), particularly in less severe cases and those involving right-side inattention. Our findings underline the effectiveness of immersive virtual reality in revealing various dimensions of neglect, surpassing traditional methods in sensitivity and detail and operating independently from them. To integrate immersive virtual reality into real-world clinical settings, collaboration with healthcare professionals, patients and other stakeholders is crucial to ensure practical applicability and accessibility.

Hyperthermia and radiotherapy: physiological basis for a synergistic effect.

In cancer treatment, mild hyperthermia (HT) represents an old, but recently revived opportunity to increase the efficacy of radiotherapy (RT) without increasing side effects, thereby widening the therapeutic window. HT disrupts cellular homeostasis by acting on multiple targets, and its combination with RT produces synergistic antitumoral effects on specific pathophysiological mechanisms, associated to DNA damage and repair, hypoxia, stemness and immunostimulation. HT is furthermore associated to direct tumor cell kill, particularly in higher temperature levels. A phenomenon of temporary resistance to heat, known as thermotolerance, follows each HT session. Cancer treatment requires innovative concepts and combinations to be tested but, for a meaningful development of clinical trials, the understanding of the underlying mechanisms of the tested modalities is essential. In this mini-review, we aimed to describe the synergistic effects of the combination of HT with RT as well as the phenomena of thermal shock and thermotolerance, in order to stimulate clinicians in new, clinically relevant concepts and combinations, which become particularly relevant in the era of technological advents in both modalities but also cancer immunotherapy.

Opioid Dose Variation in Cardiac Surgery: A Multicenter Study of Practice.

BACKGROUND: Although high-opioid anesthesia was long the standard for cardiac surgery, some anesthesiologists now favor multimodal analgesia and low-opioid anesthetic techniques. The typical cardiac surgery opioid dose is unclear, and the degree to which patients, anesthesiologists, and institutions influence this opioid dose is unknown. METHODS: We reviewed data from nonemergency adult cardiac surgeries requiring cardiopulmonary bypass performed at 30 academic and community hospitals within the Multicenter Perioperative Outcomes Group registry from 2014 through 2021. Intraoperative opioid administration was measured in fentanyl equivalents. We used hierarchical linear modeling to attribute opioid dose variation to the institution where each surgery took place, the primary attending anesthesiologist, and the specifics of the surgical patient and case. RESULTS: Across 30 hospitals, 794 anesthesiologists, and 59,463 cardiac cases, patients received a mean of 1139 (95% confidence interval [CI], 1132-1146) fentanyl mcg equivalents of opioid, and doses varied widely (standard deviation [SD], 872 µg). The most frequently used opioids were fentanyl (86% of cases), sufentanil (16% of cases), hydromorphone (12% of cases), and morphine (3% of cases). 0.6% of cases were opioid-free. 60% of dose variation was explainable by institution and anesthesiologist. The median difference in opioid dose between 2 randomly selected anesthesiologists across all institutions was 600 µg of fentanyl (interquartile range [IQR], 283-1023 µg). An anesthesiologist's intraoperative opioid dose was strongly correlated with their frequency of using a sufentanil infusion (r = 0.81), but largely uncorrelated with their use of nonopioid analgesic techniques (|r| < 0.3). CONCLUSIONS: High-dose opioids predominate in cardiac surgery, with substantial dose variation from case to case. Much of this variation is attributable to practice variability rather than patient or surgical differences. This suggests an opportunity to optimize opioid use in cardiac surgery.

They are still children: a scoping review of conditions for positive engagement in elite youth sport.

OBJECTIVE: The objective of this study is to characterise the key factors that influence positive engagement and desirable developmental outcomes in sport among elite youth athletes by summarising the methods, groups and pertinent topical areas examined in the extant published research. DESIGN: Scoping review. DATA SOURCES: We searched the databases SPORTDiscus, APA PsycINFO, Web of Science and Sports Medicine & Education Index for peer-reviewed, published in English articles that considered the factors influencing positive developmental outcomes for athletes under 18 years competing at a national and/or international level. RESULTS: The search returned 549 articles, of which 43 met the inclusion criteria. 16 studies used a qualitative approach, 14 collected quantitative data, 2 adopted mixed methods and 11 were reviews. Seven articles involved athletes competing in absolute skill contexts (ie, against the best athletes of any age) while the majority involved athletes competing in relative skill contexts (ie, against the best in a specific age or developmental group). The studies described the characteristics of the athletes, as well as their training, relationships with others, social and physical environments, and/or their overall developmental pathways. CONCLUSION: Existing research on positive engagement in elite youth sport aligned with and mapped onto established models of positive development in youth sport more generally. Our findings further support that, while certain youth athletes may demonstrate extraordinary performance capabilities, they are still children who benefit from positive engagement prompted and reinforced by developmentally appropriate and supportive activities, relationships and environments.

Fasciotomy and Occupational Separation among US Service Members with Lower Extremity Chronic Exertional Compartment Syndrome.

PURPOSE: Lower extremity chronic exertional compartment syndrome (LE-CECS) can limit rigorous physical activity, particularly in the US military, and fasciotomy is a potential treatment. Associations between LE-CECS, fasciotomy, and occupational outcomes appear understudied. We studied active-duty US service members to identify whether LE-CECS diagnoses and fasciotomy for LE-CECS predict military service separation. METHODS: We conducted a retrospective cohort study of 1,103,417 individuals who entered service during 2011 to 2017. Distributions of separation statuses and independent variables were tabulated, and sex-specific multivariable regression models were computed for separation outcomes. RESULTS: LE-CECS was associated with a 474% medical service separation risk in men (95% confidence interval (CI) for adjusted risk ratio: 5.21 to 6.33) and a 282% increase in women (CI: 2.99 to 4.88). Among 1947 patients with LE-CECS, men saw a 57% nonmedical separation risk increase (CI: 1.27 to 1.93) and women had a 119% increase (CI: 1.10 to 4.35) when anterior and/or lateral compartment procedures occurred. Men with LE-CECS and any posterior procedures saw a 47% nonmedical separation risk increase (CI: 1.17 to 1.86). Men with anterior and/or lateral procedures and any posterior procedures experienced 36% (CI: 1.09 to 1.71) and 78% (CI: 1.40 to 2.26) medical separation risk increases, respectively. No statistically significant risk increases for the outcomes were otherwise seen for women. CONCLUSIONS: LE-CECS was associated with increased military service discharge risks. Among the affected patients, positive effects on career longevity were not seen in association with fasciotomy. However, fasciotomy could simply serve as a marker of the most refractory cases that are least likely to continue service. More study is needed to clarify causal pathways and identify patients who may derive career benefits from surgical treatment.

DNA liquid biopsy-based prediction of cancer-associated venous thromboembolism.

Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying high-risk patients for prophylactic anticoagulation is challenging and adds to clinician burden. Circulating tumor DNA (ctDNA) sequencing assays ('liquid biopsies') are widely implemented, but their utility for VTE prognostication is unknown. Here we analyzed three plasma sequencing cohorts: a pan-cancer discovery cohort of 4,141 patients with non-small cell lung cancer (NSCLC) or breast, pancreatic and other cancers; a prospective validation cohort consisting of 1,426 patients with the same cancer types; and an international generalizability cohort of 463 patients with advanced NSCLC. ctDNA detection was associated with VTE independent of clinical and radiographic features. A machine learning model trained on liquid biopsy data outperformed previous risk scores (discovery, validation and generalizability c-indices 0.74, 0.73 and 0.67, respectively, versus 0.57, 0.61 and 0.54 for the Khorana score). In real-world data, anticoagulation was associated with lower VTE rates if ctDNA was detected (n = 2,522, adjusted hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.30-0.81); ctDNA- patients (n = 1,619) did not benefit from anticoagulation (adjusted HR = 0.89, 95% CI: 0.40-2.0). These results provide preliminary evidence that liquid biopsies may improve VTE risk stratification in addition to clinical parameters. Interventional, randomized prospective studies are needed to confirm the clinical utility of liquid biopsies for guiding anticoagulation in patients with cancer.

Identifying Suicide-Related Predictors Using Overseas Airborne Infantry Brigade Serious Incident Reports.

INTRODUCTION: Suicidal ideation and attempts are considered to be graduated risks for suicide, yet they remain under studied. Suicide is among the leading causes of death in the U.S. for all individuals between the ages of 10 and 64 years. Suicide is a critical problem in the U.S. Military. The U.S. Army suicide rates surpassed civilian rates in 2008 and continue to climb steadily; with U.S. Army soldiers at more than twice the risk than U.S. civilians, and enlisted personnel at more than twice the risk of officers. Suicidal ideation and attempts are routinely reported within U.S. Army brigades using suicide-related serious incident reports (SR-SIRs). These reports could form a useful source of information for prevention planning, but to date there have been no efforts to summary these reports. This paper analyzes SR-SIRs among enlisted personnel for a 4-year period for 1 Army brigade, to test the usefulness of this information and to explore whether risk factors for attempts compared to ideation can be identified. MATERIALS AND METHODS: This report analyzes 130 de-identified reports of suicidal ideation (n = 102) and suicide attempts (n = 28) reported as SR-SIRs from August 2018 to June 2022 among enlisted personnel in an airborne infantry brigade combat team (BCT) outside the continental U.S. Analysis of de-identified data was not considered research by brigade and university human subject/IRB authorities. Fourteen soldier characteristics and context factors were examined to determine if they differentiate the two types of incidents, suicidal ideations and suicide attempts. RESULTS: Unit location and alcohol use at the time of the incident were strongly associated with suicide attempts compared to ideation. Attempts occurred disproportionately during off duty hours, and attempters were more likely to have had prior contact with behavioral health services than ideators; however, these differences did not attain conventional statistical significance. CONCLUSIONS: The study can help inform unit-specific suicide prevention and intervention strategies. Off duty hours and alcohol use are risk factors for attempts, particularly among soldiers who have sought behavioral health care. Plans to engage and support soldiers who have sought behavioral health care during off duty hours, and information regarding the risks of alcohol use, could meaningfully reduce their risk. This is the first known attempt to examine active duty U.S. Army brigade combat team SR-SIRs, and they are a potentially valuable source of health and mental health-related information.

Tight junctions control lumen morphology via hydrostatic pressure and junctional tension.

Formation of fluid-filled lumina by epithelial tissues is essential for organ development. How cells control the hydraulic and cortical forces to control lumen morphology is not well understood. Here, we quantified the mechanical role of tight junctions in lumen formation using MDCK-II cysts. We found that the paracellular ion barrier formed by claudin receptors is not required for the hydraulic inflation of a lumen. However, the depletion of the zonula occludens scaffold resulted in lumen collapse and folding of apical membranes. Combining quantitative measurements of hydrostatic lumen pressure and junctional tension with modeling enabled us to explain lumen morphologies from the pressure-tension force balance. Tight junctions promote lumen inflation by decreasing cortical tension via the inhibition of myosin. In addition, our results suggest that excess apical area contributes to lumen opening. Overall, we provide a mechanical understanding of how epithelial cells use tight junctions to modulate tissue and lumen shape.

Adversarial Learning for MRI Reconstruction and Classification of Cognitively Impaired Individuals.

Game theory-inspired deep learning using a generative adversarial network provides an environment to competitively interact and accomplish a goal. In the context of medical imaging, most work has focused on achieving single tasks such as improving image resolution, segmenting images, and correcting motion artifacts. We developed a dual-objective adversarial learning framework that simultaneously 1) reconstructs higher quality brain magnetic resonance images (MRIs) that 2) retain disease-specific imaging features critical for predicting progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). We obtained 3-Tesla, T1-weighted brain MRIs of participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI, N=342) and the National Alzheimer's Coordinating Center (NACC, N = 190) datasets. We simulated MRIs with missing data by removing 50% of sagittal slices from the original scans (i.e., diced scans). The generator was trained to reconstruct brain MRIs using the diced scans as input. We introduced a classifier into the GAN architecture to discriminate between stable (i.e., sMCI) and progressive MCI (i.e., pMCI) based on the generated images to facilitate encoding of disease-related information during reconstruction. The framework was trained using ADNI data and externally validated on NACC data. In the NACC cohort, generated images had better image quality than the diced scans (Structural similarity (SSIM) index: 0.553 ± 0.116 versus 0.348 ± 0.108). Furthermore, a classifier utilizing the generated images distinguished pMCI from sMCI more accurately than with the diced scans (F1-score: 0.634 ± 0.019 versus 0.573 ± 0.028). Competitive deep learning has potential to facilitate disease-oriented image reconstruction in those at risk of developing Alzheimer's disease.