Prophylactic Antibiotic Choice and Deep Infection in Lower Extremity Endoprosthetic Reconstruction: Comparison of Cefazolin, Cefazolin-Vancomycin, and Alternative Regimens.

INTRODUCTION: Infection is a common mode of failure in lower extremity endoprostheses. The Prophylactic Antibiotic Regimens in Tumor Surgery trial reported that 5 days of cefazolin had no difference in surgical site infection compared with 24 hours of cefazolin. Our purpose was to evaluate infection rates of patients receiving perioperative cefazolin monotherapy, cefazolin-vancomycin dual therapy, or alternative antibiotic regimens. METHODS: A single-center retrospective review was conducted on patients who received lower extremity endoprostheses from 2008 to 2021 with minimum 1-year follow-up. Three prophylactic antibiotic regimen groups were compared: cefazolin monotherapy, cefazolin-vancomycin dual therapy, and alternative regimens. The primary outcome was deep infection, defined by a sinus tract, positive culture, or clinical diagnosis. Secondary outcomes were revision surgery, microorganisms isolated, and superficial wound issues. RESULTS: The overall deep infection rate was 10% (30/294) at the median final follow-up of 3.0 years (IQR 1.7 to 5.4). The deep infection rates in the cefazolin, cefazolin-vancomycin, and alternative regimen groups were 8% (6/72), 10% (18/179), and 14% (6/43), respectively (P = 0.625). Patients not receiving cefazolin had an 18% deep infection rate (6/34) and 21% revision surgery rate (7/34) compared with a 9% deep infection rate (24/260) (P = 0.13) and 12% revision surgery rate (31/260) (P = 0.17) in patients receiving cefazolin. In those not receiving cefazolin, 88% (30/34) were due to a documented penicillin allergy, only two being anaphylaxis. All six patients in the alternative regimen group who developed deep infections did not receive cefazolin secondary to nonanaphylactic penicillin allergy. CONCLUSION: The addition of perioperative vancomycin to cefazolin in lower extremity endoprosthetic reconstructions was not associated with a lower deep infection rate. Patients who did not receive cefazolin trended toward higher rates of deep infection and revision surgery, although not statistically significant. The most common reason for not receiving cefazolin was a nonanaphylactic penicillin allergy, highlighting the continued practice of foregoing cefazolin unnecessarily.

Induction cyclophosphamide with maintenance immunosuppression in high-risk myasthenia gravis: long-term follow-up and safety profile.

BACKGROUND: Patients with refractory or high-risk myasthenia gravis (MG) respond poorly to conventional immunosuppressive therapy, requiring rescue therapies and often experiencing treatment toxicity. Rescue and injectable therapies do not induce remission and require repetitive administration leading to significant constraints on patients and the healthcare system. This long-term follow-up study demonstrates cyclophosphamide as a rapidly effective and safe treatment in patients with refractory or high-risk MG. METHODS: Retrospective cohort study of MG patients treated with cyclophosphamide between January 2000 and June 2022 conducted at a quaternary neuroimmunology clinic in New South Wales, Australia. RESULTS: 31 patients were treated: mean age of 64 years; median follow-up 3.6 years (5 months to 11 years); 94% seropositive to acetylcholine receptor (AChR) antibodies and 45% had thymoma. A reduced intensity cyclophosphamide induction protocol followed by oral antiproliferative maintenance is described.Median myasthenia gravis composite scores reduced by >50% after the third cycle of cyclophosphamide. Complete cessation of prednisolone was possible in 11 patients while 20 remained on prednisolone with a median daily dose of 5 mg. Plasma exchange was ceased in 62% of patients and intravenous immunoglobulin ceased in 55%. Cyclophosphamide was generally well tolerated with mild cytopenias. There were no malignancies or cases of haemorrhagic cystitis. CONCLUSION: We describe a large cohort of high-risk MG patients treated with cyclophosphamide in a retrospective single-clinic cohort. We suggest cyclophosphamide should be considered for rapid remission induction, corticosteroid reduction and long-term freedom from recurrent injectable therapies in selected patients, typically those with AChR antibodies.

Head Contact and Suspected Concussion Rates in Youth Basketball: Time to Target Head Contact Penalties for Prevention.

OBJECTIVE: To compare game events, head contact (HC) rates, and suspected concussion incidence rates (IRs) in boys' and girls' youth basketball. DESIGN: Cross-sectional. SETTING: Canadian club basketball teams (U16-U18). PARTICIPANTS: Players from 24 boys' and 24 girls' Canadian club basketball teams during the 2022 season. ASSESSMENT OF RISK FACTORS: Recorded games were analyzed using Dartfish video analysis software to compare sexes. MAIN OUTCOME MEASURES: Poisson regression analyses were used to estimate HCs [direct (HC1) and indirect (HC2)], suspected concussion IRs, and IR ratios (IRRs). Game event, court location, and HC1 fouls were reported. RESULTS: Division 1 HC rates did not differ between boys (n = 238; IR = 0.50/10 player-minutes; 95% confidence interval [CI], 0.43-0.56) and girls (n = 220; IR = 0.46/10 player-minutes; 95% CI, 0.40-0.52). Division 2 boys experienced 252 HCs (IR = 0.53/10 player-minutes; 95% CI, 0.46-0.59); girls experienced 192 HCs (IR = 0.40/10 player-minutes; 95% CI, 0.35-0.46). Division 2 boys sustained higher HC1 IRs compared with Division 2 girls (IRR = 1.42; 95% CI, 1.15-1.74). Head contacts, rates did not differ between boys and girls in either Division. Suspected concussion IRs were not significantly different for boys and girls in each Division. Head contacts occurred mostly in the key for boys and girls in each Division. Despite illegality, HC1 penalization ranged from 3.9% to 19.7%. Head contact mechanisms varied across Divisions and sexes. CONCLUSIONS: Despite current safety measures, both HCs and suspected concussions occur in boys' and girls' basketball. Despite the illegality and potential danger associated with HC, only a small proportion of direct HCs were penalized and therefore targeting greater enforcement of these contacts may be a promising prevention target.

Use of Medications for Opioid Use Disorder and Child Welfare Outcomes.

This cohort study investigates whether use of medications for opioid use disorder in pregnancy is associated with higher rates of infants discharge home with their mothers after birth.

Functional architecture of intracellular oscillations in hippocampal dendrites.

Fast electrical signaling in dendrites is central to neural computations that support adaptive behaviors. Conventional techniques lack temporal and spatial resolution and the ability to track underlying membrane potential dynamics present across the complex three-dimensional dendritic arbor in vivo. Here, we perform fast two-photon imaging of dendritic and somatic membrane potential dynamics in single pyramidal cells in the CA1 region of the mouse hippocampus during awake behavior. We study the dynamics of subthreshold membrane potential and suprathreshold dendritic events throughout the dendritic arbor in vivo by combining voltage imaging with simultaneous local field potential recording, post hoc morphological reconstruction, and a spatial navigation task. We systematically quantify the modulation of local event rates by locomotion in distinct dendritic regions, report an advancing gradient of dendritic theta phase along the basal-tuft axis, and describe a predominant hyperpolarization of the dendritic arbor during sharp-wave ripples. Finally, we find that spatial tuning of dendritic representations dynamically reorganizes following place field formation. Our data reveal how the organization of electrical signaling in dendrites maps onto the anatomy of the dendritic tree across behavior, oscillatory network, and functional cell states.

Tomographic three-dimensional ultrasound imaging improves spatial visualization and management of varicose veins.

Tomographic three-dimensional ultrasound using handsfree electromagnetic tracking is an important adjunct to traditional two-dimensional duplex ultrasound examination. This technique allows vascular surgeons to better orientate and visualize the often complex anatomy along the entire length of the target vein. This paper reports a novel technique in preoperative and postoperative acquisition of superficial incompetent veins, thereby providing a comprehensive three-dimensional orientation of different pathological patterns of incompetence.

An integrated clinical approach to children at genetic risk for neurodevelopmental and psychiatric conditions: interdisciplinary collaboration and research infrastructure.

BACKGROUND: A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary 'genetic-diagnosis-first' clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians. METHODS: We retrieved data on referral sources and indications, genetic and NPD diagnoses and recommendations for children seen at DAGSY between 2018 and 2022. Through a survey, we obtained feedback from twenty families and eleven referring clinicians. RESULTS: 159 children (mean age 10.2 years, 57.2% males) completed an interdisciplinary (psychiatry, psychology, genetic counselling) DAGSY assessment during this period. Of these, 69.8% had a pathogenic microdeletion or microduplication, 21.5% a sequence-level variant, 4.4% a chromosomal disorder, and 4.4% a variant of unknown significance with emerging evidence of pathogenicity. One in four children did not have a prior NPD diagnosis, and referral to DAGSY was motivated by their genetic vulnerability alone. Following assessment, 76.7% received at least one new NPD diagnosis, most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) and specific learning (16.4%) disorder. Both families and clinicians responding to our survey expressed satisfaction, but also highlighted some areas for potential improvement. CONCLUSIONS: DAGSY addresses an unmet clinical need for children identified with genetic variants that confer increased vulnerability for NPD and provides a crucial platform for research in this area. DAGSY can serve as a model for interdisciplinary clinics integrating child psychiatry, psychology and genetics, addressing both clinical and research needs for this emerging population.

Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes.

BACKGROUND: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches. METHODS: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme. RESULTS: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes. CONCLUSIONS: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

Are we tackle ready? Cross-sectional video analysis of match tackle characteristics in elite women's Rugby Union.

The tackle contest is the most common and most injurious match contact event in rugby and is an indicator of performance. Tackle Ready is World Rugby's tackle technique education program. Limited research has characterized the tackle contest in women's rugby. The purpose of this study is to: (1) identify the match situational characteristics, ball-carrier and tackler technical actions demonstrated in elite women's Rugby Union and (2) to determine the extent to which Tackle Ready recommended tackle techniques were exhibited. Technical characteristics for 1500 tackle events in the 2022-2023 Women's Six Nations Championship were visually assessed according to a predefined coding framework and the Tackle Ready program. Tackles lacked full completion (0.2%) of the 22 coded Tackle Ready techniques with 47% of the recommended techniques demonstrated in each tackle on average (range 15%-98%). A high proportion of tackles involved two defenders (48%), approaching ball-carriers from the side (38%) or oblique angles (39%), in an upright position (30%), and with initial contact made with the arm (51%). Incorrect pre-contact head positioning and head placement upon contact accounted for 50% and 15% of tackles, respectively, and there was a mean of 14 (95% CI 11-18) head and neck contacts to a tackler and 18 (95% CI 14-22) head and neck contacts to a ball-carrier per game. Targeted interventions to encourage adoption of recommended techniques are needed to reduce tackle-related injury risk in women's rugby. This study provides valuable context for future discussion across law enforcement, coach education and gender-specific tackle coaching in the women's game.

Long-term effects of once-only flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: 21-year follow-up of the UK Flexible Sigmoidoscopy Screening randomised controlled trial.

BACKGROUND: Flexible sigmoidoscopy screening reduces colorectal cancer incidence and mortality; however, uncertainty exists about the duration of protection and differences by sex and age. We assessed effects of once-only flexible sigmoidoscopy screening after 21 years' follow-up. METHODS: The UK Flexible Sigmoidoscopy Screening Trial is a multicentre randomised controlled trial that recruited men and women aged 55-64 years from general practices serving 14 hospitals. Among participants indicating that they would attend flexible sigmoidoscopy screening if invited, randomisation (2:1) to the control (no further contact) or intervention (invited to once-only flexible sigmoidoscopy screening) group was performed centrally in blocks of 12, stratified by centre, general practice, and household type. Masking of intervention was infeasible. Primary outcomes were colorectal cancer incidence and mortality. The Kaplan-Meier method estimated cumulative incidence. Primary analyses estimated intention-to-treat hazard ratios (HRs) and risk differences, overall and stratified by subsite, sex, and age. The trial is registered with ISRCTN, number 28352761. FINDINGS: Among participants recruited between Nov 14, 1994, and March 30, 1999, 170 432 were eligible and 113 195 were randomly assigned to the control group and 57 237 were randomly assigned to the intervention group. 406 participants were excluded from analyses (268 in the control group and 138 in the intervention group), leaving 112 927 participants in the control group (55 336 [49%] men and 57 591 [51%] women) and 57 099 in the intervention group (27 966 [49%] men and 29 103 [51%] women). Of participants who were invited to be screened, 40 624 (71%) attended screening. Median follow-up was 21·3 years (IQR 18·0-22·2). In the invited-to-screening group, colorectal cancer incidence was reduced compared with the control group (1631 vs 4201 cases; cumulative incidence at 21 years was 3·18% [95% CI 3·03 to 3·34] vs 4·16% [4·04 to 4·29]; HR 0·76 [95% CI 0·72 to 0·81]) with 47 fewer cases per 100 000 person-years (95% CI -56 to -37). Colorectal cancer mortality was also reduced in the invited-to-screening group compared with the control group (502 vs 1329 deaths; cumulative incidence at 21 years was 0·97% [0·88 to 1·06] vs 1·33% [1·26 to 1·40]; HR 0·75 [0·67 to 0·83]) with 16 fewer deaths per 100 000 person-years (-21 to -11). Effects were particularly evident in the distal colorectum (726 incident cancer cases in the invited-to-screening group vs 2434 cases in the control group; HR 0·59 [0·54 to 0·64]; 47 fewer cases per 100 000 person-years [-54 to -41]; 196 cancer deaths in the invited-to-screening group vs 708 deaths in the control group; HR 0·55 [0·47 to 0·64]; 15 fewer deaths per 100 000 person-years [-19 to -12]) and not the proximal colon (871 incident cancer cases in the invited-to-screening group vs 1749 cases in the control group; HR 0·98 [0·91 to 1·07]; one fewer case per 100 000 person-years [-8 to 5]; 277 cancer deaths in the invited-to-screening group vs 547 deaths in the control group; HR 1·00 [0·86 to 1·15]; zero fewer deaths per 100 000 person-years [-4 to 4]). The HR for colorectal cancer incidence was lower in men (0·70 [0·65-0·76]) than women (0·86 [0·79 to 0·93]; pinteraction=0·0007) but there was no difference by age. INTERPRETATION: We show that once-only flexible sigmoidoscopy screening reduces colorectal cancer incidence and mortality for two decades and provide important data to inform colorectal cancer screening guidelines. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme and the Medical Research Council.

Ways to think about vasculitic neuropathy.

PURPOSE OF REVIEW: Vasculitis as a pathomechanism for neuropathy can be isolated to the peripheral nervous system, a part of a systemic autoimmune condition or a component of another syndrome. This review aims to discuss the broad range of diagnoses in which vasculitic neuropathy can be encountered, highlight the progress in imaging techniques in identifying vasculitis, and the new drugs developed for other autoimmune diseases that may be applied to neurological conditions. RECENT FINDINGS: Advances in imaging modalities, ultrasound, MRI and FDG-PET scanning for neuromuscular applications has redefined many aspects of vasculitic neuropathies. The benefit of dividing vasculitides by vessel size is becoming less absolute as diagnostic approaches advance. MRI and FDG-PET are widely used in diagnosis, defining extent of involvement of disease and monitoring. In neuralgic amyotrophy, the identification of hourglass-like constrictions on imaging has changed the treatment paradigm to include surgical interventions. These diagnostic approaches are supported by new immunomodulating and immunosuppression techniques. SUMMARY: Vasculitic neuropathies are a broad group of conditions with a range of causes and associations. Increased use of imaging techniques impacts our traditional definitions and classifications. The growth in treatment options for other autoimmune conditions are likely to infiltrate the neurological landscape.

Dietary exposure to polyaromatic hydrocarbons of the Hong Kong population.

Polyaromatic hydrocarbons (PAHs) are ubiquitous in the environment and food. The Joint FAO/WHO Expert Committee on Food Additives concluded 13 individual PAHs are carcinogenic and genotoxic in vitro and in vivo. Food is recognized as the main source of exposure to PAHs for adult non-smokers, which contributed to more than 90% of total exposure. In this study, 300 food samples were collected in Hong Kong, analysed the levels of 16 European Union priority PAHs, the dietary exposure to these PAHs by the local adult population from these food items, and the associated health risk. The most predominant detectable PAH was chrysene (CHR) (14.4%), followed by benzo[c]fluorene (11.2%), benzo[a]anthracene (BaA) (10.6%) and benzo[b]fluoranthene (BbFA) (7.8%). The dietary exposures for average consumers of benzo[a]pyrene (BaP) and PAH4 (sum of BaP, CHR, BaA and BbFA) were 0.13-0.90 and 1.4-4.2 ng/kg bw/day respectively for lower and upper bound approaches. Cereal and its products contributed more than 50% to BaP and PAH4 for average consumers in a lower-bound approach. The margin of exposure (MOE) approach was used to assess the health risks of consumers. The calculated MOE values for both BaP and PAH4 of the average and high consumers (90th percentile) were >50,000, indicating a low concern for the health of the Hong Kong population.

A novel animal model of symptomatic neuroma for assessing neuropathic pain.

INTRODUCTION: Following amputation, peripheral nerves lack distal targets for regeneration, often resulting in symptomatic neuromas and debilitating neuropathic pain. Animal models can establish a practical method for symptomatic neuroma formation for better understanding of neuropathic pain pathophysiology through behavioral and histological assessments. We created a clinically translatable animal model of symptomatic neuroma to mimic neuropathic pain in patients and assess sexual differences in pain behaviors. METHODS: Twenty-two male and female rats were randomly assigned to one of two experimental groups: (1) neuroma surgery, or (2) sham surgery. For the neuroma experimental group, the tibial nerve was transected in the thigh, and the proximal segment was placed under the skin for mechanical testing at the site of neuroma. For the sham surgery, rats underwent tibial nerve isolation without transection. Behavioral testing consisted of neuroma-site pain, mechanical allodynia, cold allodynia, and thermal hyperalgesia at baseline, and then weekly over 8 weeks. RESULTS: Male and female neuroma rats demonstrated significantly higher neuroma-site pain response compared to sham groups starting at weeks 3 and 4, indicating symptomatic neuroma formation. Weekly assessment of mechanical and cold allodynia among neuroma groups showed a significant difference in pain behavior compared to sham groups (p < 0.001). Overall, males and females did not display significant differences in their pain responses. Histology revealed a characteristic neuroma bulb at week 8, including disorganized axons, fibrotic tissue, Schwann cell displacement, and immune cell infiltration. CONCLUSION: This novel animal model is a useful tool to investigate underlying mechanisms of neuroma formation and neuropathic pain.

Uptake of COVID-19 vaccination among community-dwelling individuals receiving healthcare for substance use disorder and major mental illness: a matched retrospective cohort study.

Introduction: Patients with major mental illness (MMI) and substance use disorders (SUD) face barriers in accessing healthcare. In this population-based retrospective cohort study, we investigated the uptake of COVID-19 vaccination in Ontario, Canada among community-dwelling individuals receiving healthcare for major mental illness (MMI) and/or substance use disorders (SUD), comparing them to matched general population controls. Methods: Using linked health administrative data, we identified 337,290 individuals receiving healthcare for MMI and/or SUD as of 14 December 2020, matched by age, sex, and residential geography to controls without such healthcare. Follow-up extended until 31 December 2022 to document vaccination events. Results: Overall, individuals receiving healthcare for MMI and/or SUD (N = 337,290) had a slightly lower uptake of first (cumulative incidence 82.45% vs. 86.44%; hazard ratio [HR] 0.83 [95% CI 0.82-0.83]) and second dose (78.82% vs. 84.93%; HR 0.77 [95% CI 0.77-0.78]) compared to matched controls. Individuals receiving healthcare for MMI only (n = 146,399) had a similar uptake of first (87.96% vs. 87.59%; HR 0.97 [95% CI 0.96-0.98]) and second dose (86.09% vs. 86.05%, HR 0.94 [95% CI 0.93-0.95]). By contrast, individuals receiving healthcare for SUD only (n = 156,785) or MMI and SUD (n = 34,106) had significantly lower uptake of the first (SUD 78.14% vs. 85.74%; HR 0.73 [95% CI 0.72-0.73]; MMI & SUD 78.43% vs. 84.74%; HR 0.76 [95% CI 0.75-0.77]) and second doses (SUD 73.12% vs. 84.17%; HR 0.66 [95% CI 0.65-0.66]; MMI & SUD 73.48% vs. 82.93%; HR 0.68 [95% CI 0.67-0.69]). Discussion: These findings suggest that effective strategies to increase vaccination uptake for future COVID-19 and other emerging infectious diseases among community-dwelling people with SUD are needed.

Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications.

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function.

Genomics of Natural Populations: Gene Conversion Events Reveal Selected Genes within the Inversions of Drosophila pseudoobscura.

When adaptive phenotypic variation or QTLs map within an inverted segment of a chromosome, researchers often despair because the suppression of crossing over will prevent the discovery of selective target genes that established the rearrangement. If an inversion polymorphism is old enough, then the accumulation of gene conversion tracts offers the promise that QTLs or selected loci within inversions can be mapped. The inversion polymorphism of Drosophila pseudoobscura is a model system to show that gene conversion analysis is a useful tool for mapping selected loci within inversions. D. pseudoobscura has over 30 different chromosomal arrangements on the third chromosome (Muller C) in natural populations and their frequencies vary with changes in environmental habitats. Statistical tests of five D. pseudoobscura gene arrangements identified outlier genes within inverted regions that had potentially heritable variation, either fixed amino acid differences or differential expression patterns. We use genome sequences of the inverted third chromosome (Muller C) to infer 98,443 gene conversion tracts for a total coverage of 142 Mb or 7.2 x coverage of the 19.7 Mb chromosome. We estimated gene conversion tract coverage in the 2,668 genes on Muller C and tested whether gene conversion coverage was similar among arrangements for outlier versus non-outlier loci. Outlier genes had lower gene conversion tract coverage among arrangements than the non-outlier genes suggesting that selection removes exchanged DNA in the outlier genes. These data support the hypothesis that the third chromosome in D. pseudoobscura captured locally adapted combinations of alleles prior to inversion mutation events.

Beyond STEMI-NSTEMI Paradigm: Dante Pazzanese's Proposal for Occlusion Myocardial Infarction Diagnosis. / Além do Paradigma IAMCSST-IAMSSST: Proposta do Instituto Dante Pazzanese para o Diagnóstico de Oclusão Coronariana Aguda.

Although the existing framework for classifying acute myocardial infarction (AMI) into STEMI and NSTEMI has been beneficial, it is now considered to be falling short in addressing the complexity of acute coronary syndromes. The study aims to scrutinize the current STEMI-NSTEMI paradigm and advocate for a more nuanced framework, termed as occlusion myocardial infarction (OMI) and non-occlusion myocardial infarction (NOMI), for a more accurate diagnosis and management of AMI. A comprehensive analysis of existing medical literature was conducted, with a focus on the limitations of the STEMI-NSTEMI model. The study also outlines a new diagnostic approach for patients presenting with chest pain in emergency settings. The traditional STEMI-NSTEMI model falls short in diagnostic precision and effective treatment, especially in identifying acute coronary artery occlusions. The OMI-NOMI framework offers a more anatomically and physiologically accurate model, backed by a wealth of clinical research and expert opinion. It underscores the need for quick ECG assessments and immediate reperfusion therapies for suspected OMI cases, aiming to improve patient outcomes. The OMI-NOMI framework offers a new avenue for future research and clinical application. It advocates for a more comprehensive understanding of the underlying mechanisms of acute coronary syndromes, leading to individualized treatment plans. This novel approach is expected to ignite further scholarly debate and research, particularly in the Brazilian cardiology sector, with the goal of enhancing diagnostic accuracy and treatment effectiveness in AMI patients.

Embora o modelo existente de classificação do infarto agudo do miocárdio (IAM) em IAMCSST e IAMSSST tenha sido benéfico, considera-se hoje que ele falha em abordar a complexidade das síndromes coronarianas agudas. O estudo tem como objetivo examinar o atual paradigma IAMCSST-IAMSSST e defender um modelo mais detalhado, chamado de oclusão coronariana aguda (OCA) e Ausência de Oclusão Coronária Aguda (NOCA), para um diagnóstico e um manejo do IAM mais precisos. Realizou-se uma análise abrangente da literatura médica existente, com foco nas limitações do modelo IAMCSST-IAMSSST. O estudo também descreve uma nova abordagem diagnóstica para pacientes apresentando do torácica nos departamentos de emergência. O modelo IAMCSST-IAMSSST tradicional falha em prover um diagnóstico preciso e um tratamento efetivo, principalmente na identificação de oclusões da artéria coronária. O modelo OCA-NOCA é mais preciso em termos anatômicos e fisiológicos, e apoiado por pesquisa clínica extensa e opiniões de especialistas. Ele destaca a necessidade de rápida realização de eletrocardiogramas (ECGs) e terapias de reperfusão para casos suspeitos de OCA, visando melhorar os desfechos dos pacientes. O modelo OCA-NOCA abre um novo caminho para pesquisas e aplicações clínicas futuras. Ele defende um entendimento mais abrangente dos mecanismos subjacentes das síndromes coronarianas agudas, levando a planos individualizados de tratamentos. Espera-se que essa nova abordagem incite novos debates e pesquisas acadêmicas, principalmente na área de cardiologia no Brasil, com o objetivo de aumentar a precisão diagnóstica e a eficácia do tratamento de pacientes com IAM.

Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors.

The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we show that exosomes (EXs) derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

Biomolecular condensates as drivers of membrane trafficking and remodelling.

Membrane remodelling is essential for the trafficking of macromolecules throughout the cell, a process that regulates various aspects of cellular health and pathology. Recent studies implicate the role of biomolecular condensates in regulating multiple steps of the membrane trafficking pathway including but not limited to the organization of the trafficking machinery, dynamic remodeling of membranes, spatial and functional regulation, and response to cellular signals. The implicated proteins contain key structural elements, most notably prion-like domains within intrinsically disordered regions that are necessary for biomolecular condensate formation at fusion sites in processes like endocytic assembly, autophagy, organelle biosynthesis and synaptic vesicle fusion. Experimental and theoretical advances in the field continue to demonstrate that protein condensates can perform mechanical work, the implications of which can be extrapolated to diverse areas of membrane biology.

Mitochondria and cell death.

Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation.