Reproductive Risk Factor Patterns in Caribbean Women With Breast Cancer Across 4 Generations.

Importance: Breast cancer (BC) is commonly diagnosed among Caribbean women. Shifts in reproductive patterns modify the incidence of BC diagnosis and age at BC diagnosis in population-based studies; however, reproductive patterns in Caribbean women remain understudied. Objective: To describe the temporal trends in reproductive patterns and age at BC diagnosis in Caribbean-born women. Design, Setting, and Participants: A cross-sectional observational study-the Caribbean Women's Cancer Study-was conducted, with data on reproductive patterns known to affect BC risk collected in The Bahamas, Barbados, Cayman Islands, Dominica, Haiti, Jamaica, and Trinidad and Tobago. Participants were recruited prospectively. The sample included women born in Caribbean countries and diagnosed with invasive BC and/or ovarian cancer from June 1, 2010, to June 30, 2018, and was divided into 4 birth cohorts (born before 1950, 1950-1959, 1960-1969, and in or after 1970). Data were analyzed between August 1, 2023, and July 31, 2024. Exposures: Receipt of a BC diagnosis and birth in a Caribbean country. Main Outcomes and Measures: Change in reproductive patterns between birth cohorts, including age at BC diagnosis, family history of cancer, age at first pregnancy, number of pregnancies, number of full-term pregnancies, number of siblings, age at menarche and menopause, estrogen receptor status, and germline pathogenic/likely pathogenic variants. Results: Of 1015 participants diagnosed with BC and ovarian cancer, 995 women (mean [SD] age, 46.6 [10.8] years; 605 [81.8%] Afro-Caribbean, 98 [13.2%] East Indian, 22 [3.0%] White, and 12 [1.6%] >1 race) received a diagnosis of invasive BC. Comparison from older to younger birth cohorts (presented in the order of born before 1950, 1950-1959, 1960-1969 and in or after 1970) showed an increased proportion of women experiencing menarche at age 12 years or younger (33.0% vs 47.3% vs 45.5% vs 57.9%; P < .001), women with no pregnancies (6.8% vs 6.8% vs 10.5% vs 22.8%; P < .001), and nulliparous women (8.6% vs 9.2% vs 13.9% vs 27.6%; P < .001). Younger age at BC diagnosis was observed in women experiencing menarche at age 12 years or younger (mean [SD], 45.0 [10.5] years) vs 15 years or older (mean [SD], 49.1 [11.2] years) and in nulliparous women (mean [SD], 42.1 [11.2] years) vs 3 or more full-term pregnancies (mean [SD], 49.9 [10.6] years; P < .001). For every year of first pregnancy delay, women had a 4% increased chance of being diagnosed with estrogen receptor-positive tumors (odds ratio, 1.04; 95% CI, 1.01-1.08; P = .02). Conclusions and Relevance: In this cross-sectional study, between each 10-year birth cohort, women diagnosed with BC had a lower age at menarche, number of pregnancies, and number of full-term pregnancies. These findings suggest that interventions targeting other BC risk factors need to be implemented.

Cardiac Hepatoma: An Unlikely Cause of Malignant Cardiac Metastatic Disease.

Cardiac hepatoma is an extremely rare presentation of tumor metastasis. We present a case of an 80-year-old male who presented with symptoms of heart failure and was subsequently diagnosed with cardiac metastatic tumors. This case report highlights the diagnostic challenges and management options associated with this rare entity.

Proteogenomic analysis integrated with electronic health records data reveals disease-associated variants in Black Americans.

BACKGROUND: Most genome wide association studies (GWAS) of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry enriched protein quantitative loci (pQTL). METHODS: We conducted a discovery GWAS of ~3,000 plasma proteins measured by the antibody based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS), and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs were further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome wide association study (PheWAS) across two large multi-ethnic electronic health record (EHR) systems in All of Us and BioMe. RESULTS: We identified 1002 pQTLs for 925 proteins. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for Cathepsin L (CTSL) and Siglec-9 that were linked with sarcoidosis and non-Hodgkin's lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, white blood cell count, and multiple sclerosis. CONCLUSIONS: Our findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.

Presentation and outcomes of Lassa fever in children in Nigeria: a prospective cohort study (LASCOPE).

BACKGROUND: Data on the presentation, management and outcomes of Lassa fever (LF) in children are limited. METHODS: Description of the clinical and biological features, treatment and outcomes of RT-PCR-confirmed LF in children aged under 15, enrolled in the LASCOPE prospective cohort study in Nigeria between April 2018 and February 2023. RESULTS: 124 children (aged under 12 months: 19; over 12 months: 105) were hospitalized with RT-PCR-confirmed LF. All received intravenous ribavirin. During follow-up, 99/124 (80%) had fever; 71/124 (57%) had digestive symptoms, vomiting (n = 56/122, 46%) and abdominal pain (n = 34/78 aged ≥ 5 years, 44%) more often than diarrhea (n = 19/124, 15%); 17/124 (14%) had hemorrhagic signs; 44/112 (39%) had a hematocrit lower than 25%, of whom 32/44 (73%) received transfusions; 44/88 (50%) developed hypotension; 18/112 (16.1%) developed KDIGO ≥ 2 acute kidney injury; 10/112 (8.9%) had KDIGO 3 acute kidney failure; 4/124 (3.2%) underwent renal replacement therapy. 7 children died, including 4 aged under 12 months (case fatality rate: under 12 months - 22%, 95% CI 7 - 48%; over 12 months - 2.9%, 95% CI 0.7 - 8.7%). In univariable analysis, age (p=0.003), impaired consciousness (p=0.026), and Lassa RT-PCR Ct value (p=0.006) were associated to Day 30 mortality. CONCLUSIONS: The fatality rate for children over 12 months hospitalized with LF was lower than that previously reported for adults. Hypotension and acute kidney injury were the most frequent organ dysfunctions. Bleeding was relatively infrequent. Anemia and the need for transfusion were common, the relative contribution of ribavirin-induced hemolysis being unknown.

Effects of mediolateral whole-body vibration during gait with additional cognitive load.

Whole-body vibration (WBV) may increase musculoskeletal disorder risk among workers standing on vibrating surfaces for prolonged periods. Limited studies were conducted to comprehend WBV impact on individuals engaged in dynamic activities. This study explored the effects of different horizontal WBV frequencies on gait parameters, lower limb kinematics, and the cognitive response of healthy subjects. Forty participants walked at constant speed on a treadmill mounted on a horizontal shaker providing harmonic vibration with an amplitude of 1 m/s2 and frequencies 2-10 Hz, with inversely proportional amplitudes. A Psychomotor Vigilance Test measured reaction time while a motion capture system recorded walking kinematics. ANOVA results revealed no significant impact of vibration frequencies on the reaction time. At 2 Hz, alterations in gait spatiotemporal parameters were significant, with reduced stride length, stride time, step length, and stance time and increased step width and cadence. Similarly, gait variability measured by standard deviation and coefficient of variation significantly increased at 2 Hz compared to the other conditions. Comparably, kinematic time series analyzed through statistical parametric mapping showed significant adjustments in different portions of the gait cycle at 2 Hz, including increased hip abduction and flexion, greater knee flexion around the heel strike, and augmented ankle dorsiflexion. Participants exhibited gait kinematic variations, mainly at 2 Hz, where the associated mediolateral displacement was higher, as a plausible strategy to maintain stability and postural control during perturbed locomotion. These findings highlight individuals' complex biomechanical adaptations in response to horizontal WBV, especially at lower frequencies, under dual-task conditions.

Morphologic Spectrum of HPV-associated Sinonasal Carcinomas.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection has been increasingly recognized as a risk factor for sinonasal tract carcinomas. However the prevalence and prognostic significance of HPV-associated sinonasal carcinomas is not well known due to limited studies and inconsistency in HPV testing modalities in literatures. Morphologically, HPV-associated sinonasal carcinomas encompass a diverse group of tumors. HPV-associated sinonasal adenocarcinoma has not been reported. The purpose of this study was to determine the prevalence, morphologic spectrum and prognostic implication of HPV-associated sinonasal carcinomas. METHODS: This cohort included 153 sinonasal carcinomas. Tissue microarrays were constructed. P16 immunohistochemistry and HR-HPV E6/7 in-situ Hybridization (ISH) were performed. Carcinomas were deemed HPV-associated based on a positive ISH testing. Clinicopathologic data was collected. RESULTS: 28/153 (18%) sinonasal carcinomas were HPV-associated. HPV-associated carcinomas consisted of 26 (93%) squamous cell carcinomas and variants, 1 (3.5%) HPV-related multiphenotypic sinonasal carcinoma and 1 (3.5%) adenocarcinoma. The HPV-associated adenocarcinoma closely resembled HPV-associated endocervical adenocarcinoma morphologically. HPV-associated carcinomas occurred in 8 (29%) women and 20 (71%) men with a median age of 66 years old. HPV-associated carcinomas were predominantly located at nasal cavity. A trend toward improved overall survival and progression free survival in HPV-associated carcinomas patients was observed, yet without statistical significance. CONCLUSION: Our study identifies a novel HPV-associated sinonasal adenocarcinoma subtype, highlights the broad morphologic spectrum of HPV-associated sinonasal carcinomas, and supports routine p16 testing during pathology practice regardless of tumor subtype followed by a confirmatory HR-HPV testing. This practice is critical for studying the clinical behavior of HPV-associated sinonasal carcinomas.

Effect of General Surgery Resident Participation in Thoracic Surgery on Oncologic Outcomes: An Observational Cohort Study.

Background: Despite increasing sub-specialization, general surgeons continue to perform oncologic thoracic surgeries. Our objective was to determine whether general surgery resident participation in thoracic surgery affects surgical quality or oncologic outcomes. We hypothesized that patient outcomes with and without resident participation would be similar. Methods: We retrospectively reviewed the electronic health records of patients with stage 0-IV lung cancer undergoing oncologic pulmonary resection at BLINDED FOR REVIEW during an 11-year period (2012-2022). Patients younger than 18 years or older than 85 years were excluded, as were those who had incomplete follow-up data or were unregistered in our institutional cancer registry. Patients were divided into groups based on whether residents or staff surgeons completed >50% of the critical portions of the operation. We compared 30-day morbidity outcomes, overall survival (OS), and disease-free survival (DFS). Results: Three hundred thirteen patients met inclusion criteria. Demographic and clinical characteristics were similar between groups, as were types of surgical resection and median operative times. A statistical difference was found in the distribution of surgical approach. The odds of morbidity were 65% higher in the Staff group (OR=1.65; 95% CI, 1.007-2.71). Resident participation was not significantly associated with OS or DFS (P =.32 and P =.54, respectively). Discussion: General surgery resident involvement in lung cancer operations is not associated with longer operative times but is associated with a higher likelihood of a thoracotomy. General surgery resident involvement was associated with decreased postoperative morbidity and did not significantly affect OS or DFS.

Tropine exacerbates the ventilatory depressant actions of fentanyl in freely-moving rats.

Our lab is investigating the efficacy profiles of tropine analogs against opioid-induced respiratory depression. The companion manuscript reports that the cell-permeant tropeine, tropine ester (Ibutropin), produces a rapid and sustained reversal of the deleterious actions of fentanyl on breathing, alveolar-arterial (A-a) gradient (i.e., index of alveolar gas exchange), and arterial blood-gas (ABG) chemistry in freely-moving male Sprague Dawley rats, while not compromising fentanyl analgesia. We report here that in contrast to Ibutropin, the injection of the parent molecule, tropine (200 µmol/kg, IV), worsens the adverse actions of fentanyl (75 µg/kg, IV) on ventilatory parameters (e.g., frequency of breathing, tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives), A-a gradient, ABG chemistry (e.g., pH, pCO2, pO2, and sO2), and sedation (i.e., the righting reflex), while not affecting fentanyl antinociception (i.e., the tail-flick latency) in freely-moving male Sprague Dawley rats. These data suggest that tropine augments opioid receptor-induced signaling events that mediate the actions of fentanyl on breathing and alveolar gas exchange. The opposite effects of Ibutropin and tropine may result from the ability of Ibutropin to readily enter peripheral and central cells. Of direct relevance is that tropine, resulting from the hydrolysis of Ibutropin, would combat the Ibutropin-induced reversal of the adverse effects of fentanyl. Because numerous drug classes, such as cocaine, atropine, and neuromuscular blocking drugs contain a tropine moiety, it is possible that their hydrolysis to tropine has unexpected/unintended consequences. Indeed, others have found that tropine exerts the same behavioral profile as cocaine upon central administration. Together, these data add valuable information about the pharmacological properties of tropine.

Genetic risk for trait aggression and alcohol use predict unique facets of alcohol-related aggression.

OBJECTIVE: A propensity for aggression or alcohol use may be associated with alcohol-related aggression. Previous research has shown genetic overlap between alcohol use and aggression but has not looked at how alcohol-related aggression may be uniquely influenced by genetic risk for aggression or alcohol use. The present study examined the associations of genetic risk for trait aggression, alcohol use, and alcohol use disorder (AUD) with alcohol-related aggression using a polygenic risk score (PRS) approach. METHOD: Using genome-wide association study summary statistics, PRSs were created for trait aggression, alcohol consumption, and AUD. These PRSs were used to predict the phenotype of alcohol-related aggression among drinkers in two independent samples: the University of California at San Francisco (UCSF) Family Alcoholism Study (n = 1,162) and the National Longitudinal Study of Adolescent to Adult Health (Add Health; n = 4,291). RESULTS: There were significant associations between the AUD PRS and lifetime alcohol-related aggression in the UCSF study sample. Additionally, the trait aggression PRS was associated with three or more experiences of hitting anyone else and getting into physical fights while under the influence of alcohol, along with a composite score of three or more experiences of alcohol-related aggression, in the UCSF study sample. No significant associations were observed in the Add Health sample. Limited sex-specific genetic effects were observed. CONCLUSIONS: These results provide preliminary evidence that genetic influences underlying alcohol use and aggression are uniquely associated with alcohol-related aggression and suggest that these associations may differ by type and frequency of alcohol-related aggression incidents. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Gut microbial features and dietary fiber intake predict gut microbiota response to resistant starch supplementation.

Resistant starch (RS) consumption can have beneficial effects on metabolic health, but the response, in terms of effects on the gut microbiota and host physiology, varies between individuals. Factors predicting the response to RS are not yet established and would be useful for developing precision nutrition approaches that maximize the benefits of dietary fiber intake. We sought to identify predictors of gut microbiota response to RS supplementation. We enrolled 76 healthy adults into a 7-week crossover study with 59 individuals completing the study. Participants consumed RS type 2 (RS2), RS type 4 (RS4), and digestible starch, for 10 d each with 5-d washout periods in between. We collected fecal and saliva samples and food records during each treatment period. We performed 16S rRNA gene sequencing and measured fecal short-chain fatty acids (SCFAs), salivary amylase (AMY1) gene copy number, and salivary amylase activity (SAA). Dietary fiber intake was predictive of the relative abundance of several amplicon sequence variants (ASVs) at the end of both RS treatments. AMY1-related metrics were not predictive of response to RS. SAA was only predictive of the relative abundance of one ASV after digestible starch supplementation. Interestingly, SCFA concentrations increased the most during digestible starch supplementation. Treatment order (the order of consumption of RS2 and RS4), alpha diversity, and a subset of ASVs were predictive of SCFA changes after RS supplementation. Based on our findings, dietary fiber intake and gut microbiome composition would be informative if assessed prior to recommending RS supplementation because these data can be used to predict changes in specific ASVs and fecal SCFA concentrations. These findings lay a foundation to support the premise that using a precision nutrition approach to optimize the benefits of dietary fibers such as RS could be an effective strategy to compensate for the low consumption of dietary fiber nationwide.

Re-assessing viologens for modern bio-electrocatalysis.

Viologens, 1,1'-disubstituted-4,4'-bipyridinium salts, are organic redox species that can be used in place of NADPH as mediators for redox enzymes. In this study, using the reduction of oxidized glutathione by glutathione reductase as a model system, a rationally designed library of viologens covering a range of polarities and functional groups were explored as electron transfer mediators for bio-electrocatalysis. Through a series of electrochemical investigations, the reduction potential was found to be the primary determining factor for electron transfer between the viologen and enzyme. Through enhancing the solubility of viologen such that the fully reduced state remained soluble, we demonstrate a much-widened window of useable viologen potentials. In doing so, we describe for the first time a highly efficient electron transfer to a flavoenzyme promoting the catalytic reaction in the absence of co-factors. As such, our study provides a platform for broadening the scope for using viologens as mediating agents for electrochemically-driven enzymatic processes.

Carbazole-embedded p-benziporphyrinoid: synthesis, structure and a reversible chemodosimeter for mercury(II) ions.

The first carbazole-embedded p-benziporphyrinoid is synthesized by a [3+1] acid-catalyzed condensation between appropriate coupling partners. The macrocycle 1 exhibited orange emission and showed a large Stokes shift of 5831 cm-1. Intriguingly, it shows a selective affinity towards Hg2+ ions over other metal-ions in a reversible manner. Job's plot confirmed the 1 : 1 stoichiometry with unambiguous confirmation of both 1 and 1-Hg by single crystal X-ray analysis.

Generalized genetic liability to substance use disorders.

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.

Advanced Critical Care Techniques in the Field.

Critical care principles and techniques continue to hold promise for improving patient outcomes in time-dependent diseases encountered by emergency medical services such as cardiac arrest, acute ischemic stroke, and hemorrhagic shock. In this review, the authors discuss several current and evolving advanced critical care modalities, including extracorporeal cardiopulmonary resuscitation, resuscitative endovascular occlusion of the aorta, prehospital thrombolytics for acute ischemic stroke, and low-titer group O whole blood for trauma patients. Two important critical care monitoring technologies-capnography and ultrasound-are also briefly discussed.

A Multimodal Exertional Test for concussion: a pilot study in healthy athletes.

Introduction: Exertional tests have become a promising tool to assist clinicians in the management of concussions, however require expensive equipment, extensive spaces, and specialized clinician expertise. As such, we developed a test with minimal resource requirements encompassing key elements of sport and physical activity. The purpose of this study was to pilot test the Multimodal Exertional Test (MET) protocol in a sample of healthy interuniversity athletes. Methods: The MET comprises four stages, each featuring three distinct tasks. The test begins with engaging in squats, alternating reverse lunges, and hip hinges (Stage 1). The next stage progressively evolves into executing these tasks within specified time limits (Stage 2). Following this, the test advances to a stage that incorporates cognitive tasks (Stage 3), and the final stage demands greater levels of physical exertion, cognition, and multi-directional movements (Stage 4). Heart rate (HR) was obtained during each stage of the MET and participants' symptom severity scores were recorded following each task. Results: Fourteen healthy interuniversity athletes (n = 8 female, n = 6 male) participated in the study. HR was obtained for 10 of the 14 athletes (females: n = 6, males: n = 4). Increases in average and maximum HR were identified between pre-MET and Stage 1, and between Stages 3 and 4. Consistent with the tasks in each stage, there were no increases in average and maximum HR observed between MET Stages 1 to 3. Female athletes exhibited higher average and maximum HRs compared to male athletes during all four stages. All 14 athletes reported minimal changes in symptom severity following each task. Conclusion: Among healthy athletes, the MET elicits an increase in average and maximum HR throughout the protocol without symptom provocation. Female athletes exhibit higher HRs during all four stages in comparison to male athletes.

Reactivity of amino acids and short peptide sequences: identifying bioactive compounds via DFT calculations.

Bioactive peptides are short amino acid sequences that play important roles in various physiological processes, including antioxidant and protective effects. These compounds can be obtained through protein hydrolysis and have a wide range of potential applications in a variety of areas. However, despite the potential of these compounds, more in-depth knowledge is still necessary to better understand details regarding their chemical reactivity and electronic properties. In this study, we used molecular modeling techniques to investigate the electronic structure of isolated amino acids (AA) and short peptide sequences. Details on the relative alignments between the frontier electronic levels, local chemical reactivity and donor-acceptor properties of the 20 primary amino acids and some di- and tripeptides were evaluated in the framework of the density functional theory (DFT). Our results suggest that the electronic properties of isolated amino acids can be used to interpret the reactivity of short sequences. We found that aromatic and charged amino acids, as well as Methionine, play a key role in determining the local reactivity of peptides, in agreement with experimental data. Our analyses also allowed us to identify the influence of the relative position of AA and terminations on the local reactivity of the sequences, which can guide experimental studies and help to propose/evaluate possible mechanisms of action. In summary, our data indicate that the position of active sites of polypeptides can be predicted from short sequences, providing a promising strategy for the synthesis and bioprospection of new optimized compounds.

Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.