Recent breakthroughs in genetic and brain structural correlates of suicidal behaviours: A short review.

Suicide accounts for more than 700,000 deaths annually and is the fourth leading cause of death among individuals aged 15 to 29. Despite years of research to understand the aetiology and pathophysiology of suicidal behaviour, many questions remain unresolved; for example, whether suicidal behaviour has a unique genetic or neurobiological basis and how these differ from related psychiatric conditions, such as depression, bipolar disorder, schizophrenia, etc. Identifying these biological correlates is paramount to advancing our understanding of the underlying mechanisms of suicidal behaviour. This literature review delves into the complex nature of suicidal thoughts and behaviours, integrating insights from recent large-scale genetic and neuroimaging studies published between 2018 and 2023. Recent genome-wide association studies have uncovered specific genomic loci associated with specific suicidal behaviours. However, there is a need for larger and more diverse samples in these studies to overcome challenges in replicability and generalisability. Neuroimaging studies have also revealed structural brain differences associated with suicidal behaviour, thanks to international consortium-level efforts that have enabled data sharing, collaboration, and coordinated analyses that improve the robustness and reliability of findings. Despite promising progress in identifying the genetic and neurobiological underpinnings of suicidal behaviour, the translation of these advances and findings into effective suicide prevention strategies and clinical tools remains a crucial challenge; consequently, future studies must focus on integrating biological elements into an improved mechanistic understanding of the aetiology of suicidal behaviour, which in turn can translate into new strategies for early detection, intervention and treatment.

Health sciences graduates: perception of their professional training and job placement.

BACKGROUND: The follow-up of health sciences graduates is relevant due to the commitment of universities to train professionals who contribute to solve the country's health problems. The National Autonomous University of Mexico (UNAM) has health sciences graduates who join the workforce every year. OBJECTIVE: To identify the perception of health sciences graduates regarding the curriculum and their incorporation into the labor market from 1994 to 2015, and compare it according to the degree program and campus. MATERIAL AND METHODS: Observational, cross-sectional, comparative, quantitative study. The sample of 26,866 graduates was obtained from information of three decades of the institutional questionnaire for graduates applied by the General Directorate of Planning of the UNAM. RESULTS: Most graduates were females (68.4%), with admission to the degree course at between 19 and 20 years of age (65.4%). At least 47% had a job; incorporation into the labor market depended on not having an income, a higher grade point average, not having presented extraordinary exams, or failed subjects, among others. CONCLUSIONS: Adequate job insertion is associated with starting the degree course at age 18, having financial support, having an average of 8.1 or higher and perceiving low academic and teaching training.

ANTECEDENTES: El seguimiento de egresados en ciencias de la salud es de relevancia debido al compromiso de las universidades de formar profesionales que contribuyan a resolver los problemas de salud del país. La Universidad Nacional Autónoma de Mexico (UNAM) cuenta con egresados en ciencias de la salud que cada año se incorporan al campo laboral. OBJETIVO: Identificar la percepción de los egresados de ciencias de la salud de 1994 a 2015 respecto su formación académica y su incorporación laboral, y compararla según licenciatura y plantel. MATERIAL Y MÉTODOS: Estudio observacional, transversal, comparativo y cuantitativo. La muestra de 26 866 graduados se obtuvo de la información de tres décadas del cuestionario institucional para egresados de la Dirección General de Planeación de la UNAM. RESULTADOS: La mayoría de los egresados fue del sexo femenino (68.4 %), con ingreso a la licenciatura entre los 19 y 20 años (65.4 %). Al menos 47 % trabajaba; la incorporación laboral dependió de no contar con ingresos, mayor promedio, no haber presentado exámenes extraordinarios ni recursado materias, entre otros. CONCLUSIONES: La inserción laboral adecuada se asocia a iniciar la licenciatura a los 18 años, contar con apoyo económico, tener promedio de 8.1 o más y percibir la formación académica y docente baja.

Preparedness of Filipino Neurologists on the Provision of Medical Care Toward Patients of the Lesbian, Gay, Bisexual, Transgender, Queer Plus Community.

The study aimed to describe the preparedness of active members of the Philippine Neurological Association (PNA) in providing medical care to LGBTQ+ patients. We electronically sent out a 21-item self-administered online survey adapted from the 2019 American Academy of Neurology LGBTQ+ Survey Task Force to 511 active members of PNA that included questions about demographic information, knowledge, attitude, and clinical practices. Descriptive statistics were used to analyze variables. Text responses were transcribed and summarized. Seventy-nine (15.5%) of 511 PNA members participated. Most participants were aware of local (53%) and national (56%) barriers that preclude patients in the LGBTQ+ sector from accessing quality health care. The majority (90%) of participants agreed that LGBTQ+ patients experience disproportionate levels of physical and psychological problems. Forty-two percent (42%) of respondents believed that sexual and gender issues have no bearing on neurological management, although a majority (53%) reported individualizing their management considering these issues. The majority were cognizant of the challenges that LGBTQ+ patients face in the health care system. However, awareness has not translated into modifications in neurological management. The openness of the participants to educational opportunities concerning health care related to LGBTQ+ can be leveraged to address this gap.

Clinical outcomes of patients with seizure admitted for COVID-19: Findings from the Philippine CORONA study.

Objective: Seizure is one of the neurologic manifestations of coronavirus disease 2019 (COVID-19) infection. There are few studies focused on the outcome of hospitalized patients with COVID-19 and seizure. Methods: This was a subgroup analysis of patients with seizure based on a nationwide, multicenter, retrospective study of COVID-19 patients admitted in 37 hospitals in the Philippines. Results: A total of 10,881 patients with COVID-19 infection were included. Among these, 27 (0.2 %) patients had pre-existing seizure/epilepsy and 125 (1.1 %) had new-onset seizure. The patients with pre-existing seizure/epilepsy had a mean age of 49 years and majority were males (63.0 %). The patients with new-onset seizure had a mean age of 57 years and majority were males (60.5 %). Among patients with pre-existing seizure/epilepsy, there were no significant differences in the proportion of severe/critical COVID-19 (p = 0.131), all-cause mortality (p = 0.177), full/partial neurologic recovery (p = 0.190), ventilator use (p = 0.106), length of intensive care unit stay (p = 0.276), and length of hospitalization (p = 0.591). Patients with new-onset seizure were 2.65 times more likely to have severe/critical COVID-19 infection (p < 0.001), 3.12 times more likely to die (p < 0.001), and 3.51 times more likely to require a ventilator (p < 0.001) than those without new-onset seizure. New-onset seizure, however, was not significantly associated with full/partial neurologic recovery (p = 0.184) and prolonged length of hospitalization (p = 0.050). Conclusion: Severe/critical COVID-19 infection, higher mortality rate, and use of a ventilator were significantly higher among patients with new-onset seizure but not among patients with pre-existing seizure/epilepsy.

Analysis and interpretation of Coronavirus infection children's incidence, contributing factors, risks of complications and their relationship.

OBJECTIVE: Aim: To study and investigate the incidence of Coronavirus infection in children, the course of the disease, the risks of complications and their interrelationships. PATIENTS AND METHODS: Materials and Methods: Study included the analysis and observation of children (n=55, aged 14.36±3.62 years) with confirmed Coronerovirus infection, who were observed in the CNE ≪CMCH≫ in Uzhgorod in outpatient conditions. A study of clinical presentations, a clinical and laboratory examination followed by a mathematical analysis of the symptoms data in children with an identified Coronavirus infection and in the dynamics up to week 30 (with survey intervals in 3 weeks) from the diagnosis verification was carried out. RESULTS: Results: A dynamic analysis of the clinical manifestation of symptoms in children with an identified Corona virus infection and within 30 weeks (with survey intervals of 3 weeks) from the beginning of the diagnosis verification was carried out. Complaints from the respiratory system were prevailed. The most long-lasting complaint was observed ≪changes in the sense of taste and smell≫ (from 35(63.6%) to 6(10.9%) up to 18 weeks inclusive. Other complaints ≪Cough, Rhinitis, Shortness of breath, Pain in the chest≫ was observed for 6 weeks. Sore throat, muscular and joint pain were persisted for 3 weeks. Fever was not identified at week 3. Illness with other viral respiratory diseases started at week 9 and was observed until week 30 (from 10(18.2%) to 19(34.5%)) with varying levels. A decrease in cases of IgM identification was observed within 6 weeks (from 55, 100% to 20, 36, 4%). On the 9th week, the presence of IgM was not established. There is also an increase in the number of cases of detection of IgG in patients with a level maximum of 6 weeks. CONCLUSION: Conclusions: There is a positive effect of the CRP level on the occurrence of symptoms of cough, rhinitis, shortness of breath, chest pain, change in taste and smell, muscle and joint pain (r=0.33-0.55), with the most significant data for the symptom of pain in chest (p=0.00001). Ferritin level interactions mostly had a negative direction (r=-0.35-0.48, p=0.02-0.00001) on the development of symptoms, with the exception of rhinorrhea (r=0.48, p=0.00002) and chest pains (r=0.39, 0.003). According to multiple logistic regression analysis the chance of the symptom of a change in taste and smell increases due to an increasing in the level of Procalcitonin in 1.48 times. The chance of the symptom of shortness of breath increased due to an increasing in the Ferritin level in 1.025 times.

Comparing Redox and Intracellular Signalling Responses to Cold Plasma in Wound Healing and Cancer.

Cold plasma (CP) is an ionised gas containing excited molecules and ions, radicals, and free electrons, and which emits electric fields and UV radiation. CP is potently antimicrobial, and can be applied safely to biological tissue, birthing the field of plasma medicine. Reactive oxygen and nitrogen species (RONS) produced by CP affect biological processes directly or indirectly via the modification of cellular lipids, proteins, DNA, and intracellular signalling pathways. CP can be applied at lower levels for oxidative eustress to activate cell proliferation, motility, migration, and antioxidant production in normal cells, mainly potentiated by the unfolded protein response, the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)-activated antioxidant response element, and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, which also activates nuclear factor-kappa B (NFκB). At higher CP exposures, inactivation, apoptosis, and autophagy of malignant cells can occur via the degradation of the PI3K/Akt and mitogen-activated protein kinase (MAPK)-dependent and -independent activation of the master tumour suppressor p53, leading to caspase-mediated cell death. These opposing responses validate a hormesis approach to plasma medicine. Clinical applications of CP are becoming increasingly realised in wound healing, while clinical effectiveness in tumours is currently coming to light. This review will outline advances in plasma medicine and compare the main redox and intracellular signalling responses to CP in wound healing and cancer.

Self-reported cognitive function mediates the relationship between employment status and cognitive functioning in persons with multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) is common in people with MS (PwMS). Evidence is lacking for the self-reported CI's mediation effect on employment status and objective cognitive performance. Self-reported CI was found to be unreliable and seemed to be more associated with depression rather than formal cognitive performance. We hypothesized that the link between subjective and objective assessments of cognitive functions, mood, and employment status may be more complex in PwMS than previously reported. OBJECTIVE: The aims of this study are the following: (Romero-Pinel et al., 2022) to determine whether employment status could affect performance in cognitive function testing and (Rao et al., 1991) whether their relationship may be mediated by self-reported CI; and (Deluca et al., 2013) to determine whether self-reported depression interacts with self-reported CI in influencing performance in various cognitive domains in PwMS. METHODOLOGY: A retrospective study was performed involving PwMS who completed the self-report Multiple Sclerosis Neuropsychological Questionnaire (MSNQ), Hospital Anxiety and Depression Scale-depression scale (HADS-D), Minimal Assessment of Cognitive Function in MS (MACFIMS) and had data regarding employment status. Included PwMS were classified as employed or unemployed. A structural equation modeling (SEM) approach was taken due to the advantage of examining multiple cognitive outcomes simultaneously while accounting for shared associations. First, a latent factor of memory and executive functioning modeled the error-free associations between both factors and a processing speed task (SDMT). Next, the model tested for the indirect effect of self-reported cognition (MSNQ) on employment status differences in each outcome (memory, speed, and executive functioning). Finally, we tested interactions between MSNQ and HADS-D on each of the outcomes. RESULTS: We included 590 PwMS: 72.5% female, mean age 44.2 years (SD = 10.5), mean disease duration 8.6 years (SD 9.0). The majority (n = 455, 77.1%) had relapsing MS; 357 (60.5%) were employed. About half (n = 301, 51%) did not report CI on the MSNQ; of those, 213 (70.8%) were employed. The mean MSNQ for employed PwMS was 24.5 (SD = 10.7) and 29.8 (SD = 11.2) for unemployed PwMS. Employed PwMS had significantly better memory (ß = .16, p < .05), executive functioning (ß = .25, p < .05), and processing speed (ß = .22, p < .05). MSNQ partially indirectly mediated the effect of employment status on memory (Δß = .03, p < .05) and executive functioning (Δß = .03, p < .05) and processing speed (Δß = .04, p < .05), indicating that self-report CI partially explains the influence of employment status on these cognitive domains. The association between MSNQ with both memory and executive functioning was moderated by depression, meaning that in PwMS with high HADS-D scores, MSNQ was more strongly related to worse memory and executive functioning. The final model was an acceptable fit to the data (χ2(87) = 465.07, p < .05; CFI = .90, RMSEA = .08, 90% CI [.06, .09], SRMR = .05) explaining 41.20%, 38.50% and 33.40% of the variability in memory, executive functioning, and processing speed, respectively. CONCLUSION: Self-reported CI partially explains the associations between employment status and objective cognitive assessment in PwMS. Depression may moderate the relationship between self-reported cognitive assessment and objective cognitive performance. Thus, employment status and mood may guide the interpretation of self-reported CI.

Cardiometabolic biomarker patterns associated with cardiac MRI defined fibrosis and microvascular dysfunction in patients with heart failure with preserved ejection fraction.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a complex disease process influenced by metabolic disorders, systemic inflammation, myocardial fibrosis, and microvascular dysfunction. The goal of our study is to identify potential relationships between plasma biomarkers and cardiac magnetic resonance (CMR) imaging markers in patients with HFpEF. Methods: Nineteen subjects with HFpEF and 15 age-matched healthy controls were enrolled and underwent multiparametric CMR and plasma biomarker analysis using the Olink® Cardiometabolic Panel (Olink Proteomics, Uppsala, Sweden). Partial least squares discriminant analysis (PLS-DA) was used to characterize CMR and biomarker variables that differentiate the subject groups into two principal components. Orthogonal projection to latent structures by partial least squares (OPLS) analysis was used to identify biomarker patterns that correlate with myocardial perfusion reserve (MPR) and extracellular volume (ECV) mapping. Results: A PLS-DA could differentiate between HFpEF and normal controls with two significant components explaining 79% (Q2 = 0.47) of the differences. For OPLS, there were 7 biomarkers that significantly correlated with ECV (R2 = 0.85, Q = 0.53) and 6 biomarkers that significantly correlated with MPR (R2 = 0.92, Q2 = 0.32). Only 1 biomarker significantly correlated with both ECV and MPR. Discussion: Patients with HFpEF have unique imaging and biomarker patterns that suggest mechanisms associated with metabolic disease, inflammation, fibrosis and microvascular dysfunction.

A Semi-Selective Medium to Evaluate Over-Summering Survival of Neopestalotiopsis sp. in Florida Strawberry Fields.

Devastating disease outbreaks with leaf spot symptoms and fruit rot caused by a fungus identified as a cryptic species of Neopestalotiopsis have generated concern in the Florida strawberry industry. Some Neopestalotiopsis species are saprobes in soil and plant debris, but the ability of the new Neopestalotiopsis sp. to survive in strawberry debris was unknown. Therefore, the objectives of this study were to develop a semiselective medium for isolation of Neopestalotiopsis spp. and to evaluate Neopestalotiopsis sp. survival in soil and strawberry plant debris over the summer in Florida. The Neopestalotiopsis semiselective medium (NSM) inhibited growth of most fungal species pathogenic to strawberry in Florida, except Neopestalotiopsis rosae, Neopestalotiopsis sp., and Phomopsis obscurans, in addition to Penicillium spp., which are nonpathogenic. However, Neopestalotiopsis species, P. obscurans, and Penicillium spp. could be distinguished in the medium through morphological characteristics. Soil samples arbitrarily collected from six commercial fields toward the end of the season (May) and before (July) and after (September) preplant soil fumigation in the following season were processed with NSM, and Neopestalotiopsis spp. populations were calculated as CFU per gram of soil. CFU ranged from 48.3 to 2,410.8 at the end of the season and from 1.7 to 630.8 before soil fumigation, but Neopestalotiopsis spp. were not recovered after soil treatment. However, 1.7 to 25 CFU were obtained from the nontreated areas in the row middles. Neopestalotiopsis sp. survival was also evaluated on diseased strawberry plants (leaves and crowns) exposed to the environment for 17 months. On leaves, Neopestalotiopsis spp. were recovered for 6 months before leaf decomposition, whereas the number of CFU on crowns declined monthly, but colonies were still recovered during the final evaluation months. A high-resolution melting analysis confirmed most of the colonies from soil and crowns were the new Neopestalotiopsis sp. Our results show Neopestalotiopsis sp. can survive in soil and strawberry debris under Florida summer conditions and may serve as a source of inoculum for the subsequent season.

Limited utility of adding 3T cervical spinal cord MRI to monitor disease activity in multiple sclerosis.

BACKGROUND: Performing routine brain magnetic resonance imaging (MRI) is widely accepted as the standard of care for disease monitoring in multiple sclerosis (MS), but the utility of performing routine spinal cord (SC) MRI for this purpose is still debatable. OBJECTIVE: This study aimed to measure the frequency of new isolated cervical spinal cord lesions (CSLs) in people with MS (pwMS) undergoing routine brain and cervical SC-MRI for disease monitoring and determine the factors associated with the development of new CSLs and their prognostic value. METHODS: We retrospectively identified 1576 pwMS who underwent follow-up 3T brain and cervical SC-MRI over a 9-month period. MRI was reviewed for the presence of new brain lesions (BLs) and CSLs. Clinical records were reviewed for interval relapses between sequential scans and subsequent clinical relapse and disability worsening after the follow-up MRI. RESULTS: In 1285 pwMS (median interval: 13-14 months) who were clinically stable with respect to relapses, 73 (5.7%) had new CSLs, of which 49 (3.8%) had concomitant new BLs and 24 (1.9%) had new isolated CSLs only. New asymptomatic CSLs were associated with ⩾ 3 prior relapses (p = 0.04), no disease-modifying therapy (DMT) use (p = 0.048), and ⩾ 3 new BLs (p < 0.001); ⩾ 3 new BLs (OR: 7.11, 95% CI: 4.3-11.7, p < 0.001) remained independently associated with new CSLs on multivariable analysis. Having new asymptomatic CSLs was not independently associated with subsequent relapse or disability worsening after the follow-up MRI (median follow-up time of 26 months). CONCLUSION: Routine brain and cervical SC-MRI detected new isolated CSLs in only < 2% of clinically stable pwMS. Developing new asymptomatic CSLs was associated with concomitant new BLs and did not confer an independent increased risk of relapse or disability worsening. Performing SC-MRI may not be warranted for routine monitoring in most pwMS, and performing only brain MRI may be sufficient to capture the vast majority of clinically silent disease activity.

Outcomes of patients with COVID-19 and coronary artery disease and heart failure: findings from the Philippine CORONA study.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) and coronary artery disease (CAD) or heart failure (HF) are more likely to have poor outcomes. This study aimed to determine the characteristics and outcomes of COVID-19 patients with CAD/HF across various institutions in the Philippines. METHODS: We utilized the data from the Philippine CORONA Study and compared the outcomes of admitted COVID-19 patients with CAD/HF versus those without. The Student's t test, Mann-Whitney U test, binary logistic regression and multivariate regression analysis were utilized. Odds ratios (OR) and Kaplan-Meier curves were generated. RESULTS: We included a total of 512 patients with COVID-19 had CAD/HF and 10,369 were without. CAD/HF was significantly associated with COVID severity, all-cause mortality, death from cardiac causes, respiratory failure, and prolonged hospitalization. After adjusting for confounders, the presence of CAD/HF was still associated with death from a cardiac cause (OR 2.22, 95% CI 1.49-3.3, p < 0.01). CONCLUSIONS: The presence of CAD or HF was significantly associated with severity of COVID disease, all-cause mortality, death from cardiac causes, respiratory failure, and prolonged hospitalization.

Longitudinal Functional Connectome in Pediatric Concussion: An Advancing Concussion Assessment in Pediatrics Study.

Advanced magnetic resonance imaging (MRI) techniques indicate that concussion (i.e., mild traumatic brain injury) disrupts brain structure and function in children. However, the functional connectivity of brain regions within global and local networks (i.e., functional connectome) is poorly understood in pediatric concussion. This prospective, longitudinal study addressed this gap using data from the largest neuroimaging study of pediatric concussion to date to study the functional connectome longitudinally after concussion as compared with mild orthopedic injury (OI). Children and adolescents (n = 967) 8-16.99 years with concussion or mild OI were recruited from pediatric emergency departments within 48 h post-injury. Pre-injury and 1-month post-injury symptom ratings were used to classify concussion with or without persistent symptoms based on reliable change. Subjects completed a post-acute (2-33 days) and chronic (3 or 6 months via random assignment) MRI scan. Graph theory metrics were derived from 918 resting-state functional MRI scans in 585 children (386 concussion/199 OI). Linear mixed-effects modeling was performed to assess group differences over time, correcting for multiple comparisons. Relative to OI, the global clustering coefficient was reduced at 3 months post-injury in older children with concussion and in females with concussion and persistent symptoms. Time post-injury and sex moderated group differences in local (regional) network metrics of several brain regions, including degree centrality, efficiency, and clustering coefficient of the angular gyrus, calcarine fissure, cuneus, and inferior occipital, lingual, middle occipital, post-central, and superior occipital gyrus. Relative to OI, degree centrality and nodal efficiency were reduced post-acutely, and nodal efficiency and clustering coefficient were reduced chronically after concussion (i.e., at 3 and 6 months post-injury in females; at 6 months post-injury in males). Functional network alterations were more robust and widespread chronically as opposed to post-acutely after concussion, and varied by sex, age, and symptom recovery at 1-month post-injury. Local network segregation reductions emerged globally (across the whole brain network) in older children and in females with poor recovery chronically after concussion. Reduced functioning between neighboring regions could negatively disrupt specialized information processing. Local network metric alterations were demonstrated in several posterior regions that are involved in vision and attention after concussion relative to OI. This indicates that functioning of superior parietal and occipital regions could be particularly susceptibile to the effects of concussion. Moreover, those regional alterations were especially apparent at later time periods post-injury, emerging after post-concussive symptoms resolved in most and persisted up to 6 months post-injury, and differed by biological sex. This indicates that neurobiological changes continue to occur up to 6 months after pediatric concussion, although changes emerge earlier in females than in males. Changes could reflect neural compensation mechanisms.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Risk of COVID-19 outcomes among healthcare workers: Findings from the Philippine CORONA retrospective cohort study

Objectives@#While many healthcare workers (HCWs) contracted COVID-19 during the pandemic, more information is needed to fully understand the potential for adverse health effects in this population segment. The aim of the present study is to examine the association between healthcare worker status and neurologic and clinical outcomes in COVID-19 infected inpatients.@*Methods@#Using the nationwide database provided by the retrospective cohort Philippine CORONA study, we extracted relevant data and performed a secondary analysis primarily focusing on the presentation and outcomes of healthcare workers. Propensity score matching in a 3:1 ratio was performed to match HCWs and non-HCWs. We performed multiple logistic and Cox regression analyses to determine the relationship between HCWs and COVID-19 clinical outcomes.@*Results@#We included 3,362 patients infected with COVID-19; of which, 854 were HCWs. Among the HCWs, a total of 31 (3.63%) and 45 (5.27%) had the primary outcomes of in-hospital mortality and respiratory failure, respectively. For both overall and 3:1 propensity-matched cohorts, being an HCW significantly decreased the odds of the following outcomes: severe/critical COVID-19 at nadir; in-hospital mortality; respiratory failure; intensive care unit admission; and hospital stay >14 days.@*Conclusion@#We found that being an HCW is not associated with worse neurologic and clinical outcomes among patients hospitalized for COVID-19.

RESPIRATORY MICROBIOME AND ITS RELATIONSHIP WITH INFLAMMATORY MARKERS.

OBJECTIVE: The aim: This study aims to investigate and analyze the microbiome of the nasopharyngeal zone in acute respiratory infections (ARI) and their relationship with inflammatory markers. PATIENTS AND METHODS: Materials and methods: Examination of 112 children (10-14 years old) with acute respiratory infections (ARI) of the upper respiratory tract was carried out. The control group consisted of 25 healthy children identical in age and examination parameters. RESULTS: Results: When analyzing the microflora of the nasopharynx of patients, 29,0% of strains were gram-positive bacteria and 71,0% were gram-negative bacteria (Escherichia coli representing 37,0%). Biochemical examination of the biomaterial revealed the presence of sucrase (n=69), maltase (n=87), lactorepoxidase (n-89) and alcohols - sorbitol (hexahydric alcohol, n=102), mannitol (hexahydric alcohol, n=84), xylitol (pentahydric alcohol, n=86). Regarding the markers of inflammatory response, the following dynamics was noted: increase in the level of IgM (3,91 ± 1,79 g/l, p<0,01) by 2,2 times, elevation of Ig G level by 10 times (145, 91 ± 53,04 g/l, p< 0,01), slightly higher than the reference values IgE level. In addition, increased IL-1, IL-4, IL-6, γ-IFN, TNF-α, Neopterin levels were detected. The level of Thyroid stimulating hormone (TSH) was significantly different compared to the control group (0,62 ± 0,57 vs. 1,98 ± 0,30 mIU/ ml, p< 0,01), but within the reference values. CONCLUSION: Conclusions: Predominance of Gram-negative bacteria in the nasopharyngeal microflora of patients along with elevated inflammatory markers and lactop-eroxydase enzyme predominance was detected in the study.

Geraniol attenuates behavioral and neurochemical impairments by inhibitions of HPA-axis and oxido-inflammatory perturbations in mice exposed to post-traumatic stress disorder.

Geraniol is an acyclic isoprenoid monoterpenoid analogue that has been shown to elicit neuroprotective functions, primarily through its ability to stimulate antioxidant and anti-inflammatory systems. An increase in inflammatory cytokines and oxidative stress exacerbate activation hypothalamic-pituitary-adrenal axis (HPA), leading to neurochemical dysfunction, which has important roles in the pathogenesis of post-traumatic disorder (PTSD), a mental health disorder characterized of post-trauma-induced intense fear. The aim of this study was to evaluate the anti-PTSD-like effects and underlying mechanisms of geraniol against single-prolonged-stress (SPS)-induced PTSD in mice. Following concomitant exposure to SPS (triple-paradigm traumatic events) and isolation for 7 days, mice (n = 9) were treated with geraniol (50 and 100 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.) from days 8-21. Mice were assessed for behavioral changes. Neurochemical changes, inflammatory, oxido-nitrergic markers, adrenal weight, serum glucose and corticosterone concentrations were assayed. Geraniol inhibits SPS-induced anxiety- and depressive-like features as well as behavioral despair in the depression paradigms. SPS-induced locomotor and memory impairments were also abated by geraniol treatment similarly to fluoxetine. SPS-induced adrenal hypertrophy and increased blood glucose and corticosterone concentrations, were attenuated by the geraniol treatment. Elevated levels of TNF-α and IL-6, and malondialdehyde, nitrite, acetylcholinesterase enzyme were reduced by geraniol. Geraniol also increased glutathione, superoxide-dismutase, and catalase levels as well as dopamine, serotonin concentrations and GABAergic glutamic acid decarboxylase enzyme activity in the striatum, prefrontal cortex and hippocampus in the PTSD-mice relative to SPS control. In conclusion, geraniol attenuates behavioral impairments and neurochemical dysregulations by inhibitions of HPA-axis and oxido-inflammatory perturbations in mice exposed to PTSD.

Clinical Outcomes of COVID-19 Infection among Patients with Chronic Obstructive Pulmonary Disease: Findings from the Philippine CORONA Study.

BACKGROUND: The global pandemic caused by the coronavirus disease 2019 (COVID-19) resulted in many deaths from fulminant respiratory failure. Chronic obstructive pulmonary disease (COPD) is the leading cause of morbidity and mortality worldwide. There has been great concern regarding the impact of COPD on the COVID-19 illness. METHODS: Data from the Philippine CORONA study were analyzed to determine the association of COPD and COVID-19 in terms of mortality, disease severity, respiratory failure, mechanical ventilation, and lengths of stay in the intensive care unit (ICU) and hospital. RESULTS: A total of 10,881 patients were included in this study, and 156 (1.4%) patients had been diagnosed with COPD. A majority of COVID-19 patients with COPD had other existing comorbidities: hypertension, diabetes mellitus, chronic cardiac disease, and chronic kidney disease. COPD patients were 2.0× more likely to present with severe to critical COVID-19 disease. COVID-19 patients with COPD in our study have a 1.7× increased mortality, 1.6× increased respiratory failure, and 2.0× increased risk for ICU admission. Smokers with COVID-19 were 1.8× more likely to present with more severe disease and have a 1.9× increased mortality. CONCLUSION: Our study supports the growing evidence that COPD among COVID-19 patients is a risk factor for higher mortality, more severe form of COVID-19, higher ICU admission, and higher respiratory failure needing ventilatory support.

Repetitive transcranial magnetic stimulation for apathy in patients with neurodegenerative conditions, cognitive impairment, stroke, and traumatic brain injury: a systematic review.

Background: We aimed to determine the effects and tolerability of repetitive transcranial magnetic stimulation (rTMS) on apathy in patients with neurodegenerative conditions, mild cognitive impairment (MCI), stroke, and traumatic brain injury (TBI) via systematic review. Methods: We conducted a systematic search in major electronic health databases, including PubMed, Scopus, and PsycINFO, covering the period from inception to June 2023. Comparative clinical trials and cohort studies, and studies with before-after designs were considered for inclusion. We used the Cochrane Risk of Bias and the National Institutes of Health (NIH) tools to assess methodological quality. Results: Out of 258 records identified, 14 studies met our eligibility criteria (11 randomized controlled trials (RCT) and 3 studies utilized before-and-after designs) with a total of 418 patients (overall female-to-male ratio 1:1.17) included in the review. The overall methodological quality of the included studies was assessed to be fair to good. The stimulation parameters used varied considerably across the studies. The summary findings of our review indicate the following observations on the effects of rTMS on apathy: (1) the results of all included studies in Alzheimer's disease investigating the effects of rTMS on apathy have consistently shown a positive impact on apathy; (2) the majority of studies conducted in Parkinson's disease have not found statistically significant results; (3) a single study (RCT) on patients with primary progressive aphasia demonstrated significant beneficial effects of rTMS on apathy; (4) the trials conducted on individuals with MCI yielded varying conclusions; (5) one study (RCT) in chronic stroke suggested that rTMS might have the potential to improve apathy; (6) one study conducted on individuals with mild TBI did not find a significant favorable association on apathy; and (7) the use of different rTMS protocols on the populations described is generally safe. Conclusion: The feasibility of utilizing rTMS as a treatment for apathy has been suggested in this review. Overall, limited evidence suggests that rTMS intervention may have the potential to modify apathy among patients with AD, PPA, MCI and chronic stroke, but less so in PD and mild TBI. These findings require confirmation by larger, well-designed clinical trials.

Discontinuation of antidepressant treatment: a retrospective cohort study on more than 20,000 participants.

BACKGROUND: Factors influencing antidepressant treatment discontinuation are poorly understood. In the present study, we aimed to estimate the prevalence of antidepressant treatment discontinuation and identify demographic characteristics, psychiatric comorbidities, and specific side effects associated with treatment discontinuation. METHODS: We leveraged data from the Australian Genetics of Depression Study (AGDS; N = 20,941) to perform a retrospective cohort study on antidepressant treatment discontinuation. Participants were eligible if they were over 18 years of age, had taken antidepressants in the past 4 years, and provided informed consent. RESULTS: Among the ten antidepressants studied, the highest discontinuation rates were observed for Mirtazapine (57.3%) and Amitriptyline (51.6%). Discontinuation rates were comparable across sexes except for Mirtazapine, for which women were more likely to discontinue. The two most common side effects, reduced sexual function and weight gain, were not associated with increased odds of treatment discontinuation. Anxiety, agitation, suicidal thoughts, vomiting, and rashes were associated with higher odds for treatment discontinuation, as were lifetime diagnoses of PTSD, ADHD, and a higher neuroticism score. Educational attainment showed a negative (protective) association with discontinuation across medications. CONCLUSIONS: Our study suggests that not all side effects contribute equally to discontinuation. Common side effects such as reduced sexual function and weight gain may not necessarily increase the risk of treatment discontinuation. Side effects linked to discontinuation can be divided into two groups, psychopathology related and allergy/intolerance.

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.