Brain-derived neurotrophic factor Val66Met and CYP2B6 polymorphisms as predictors for ketamine effectiveness in patients with treatment-resistant depression.

BACKGROUND: Converging lines of evidence indicate that ketamine is a rapid antidepressant for individuals with treatment-resistant depression. Hitherto, no reliable a priori predictors of ketamine response have been reported. Pharmacogenetic biomarkers have yielded mixed results regarding potential candidate genes associated with ketamine's biochemistry as reliable predictors of response. AIMS: No studies have examined the effects of Val66Met and CYP2B6 genotypes on patients receiving repeated infusions of intravenous ketamine. METHODS: In all, 85 participants with major depressive disorder who had previously received four infusions of intravenous ketamine were recruited to the foregoing study. Buccal swabs were collected and genotype variants across the Val66Met and CYP2B6 genes were analyzed. A repeated measures mixed linear model was used to assess change in depressive symptoms, suicidality, and anxiety, correcting for sex and age. Multiple regression was run to determine whether these genetic markers were associated with treatment efficacy for depressive severity, suicidal ideation, anxiolytic response, and degree of dissociation to intravenous ketamine. RESULTS: Participants experienced significant overall reductions in depression, suicide, and anxiety. Overall, 25% met the response criteria and 15% met the remission criteria. However, Val66Met and CYP2B6 did not significantly predict changes in symptoms of depression, suicide, anxiety, or average dissociation. CONCLUSIONS: This study contributes to the growing literature that ketamine efficacy is unlikely to be predicted by single genes, and a pleiotropic approach may likely be necessary for developing reliable predictors of clinical benefits.

Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Monitoring arthropods under the scope of LIFE-SNAILS project: I - Santa Maria Island baseline data with implementation of the Index of Biotic Integrity.

Background: The database we introduce is a pivotal component of the LIFE SNAILS project (Support and Naturalisation in Areas of Importance for Land Snails). This initiative is dedicated to safeguarding three endangered species of terrestrial molluscs, specifically, two snails (Oxychilusagostinhoi Martins 1981 and Leptaxisminor Backhuys, 1975) and a semi-slug (Plutoniaangulosa (Morelet, 1860)), all of which are single island endemics from Santa Maria Island and face significant threats towards their populations.In this study, we established a comprehensive database derived from a long-term arthropod monitoring campaign utilising SLAM (Sea, Land, Air, Malaise) traps. Although molluscs were not the primary focus, our findings serve as a credible proxy for evaluating the overall habitat quality for endemic invertebrates, with arthropods serving as principal indicators. From September to December of 2022, a total of 11 SLAM traps were installed and monitored monthly in eleven sites of mixed forests of Santa Maria Island. New information: Based on the 33 available samples (11 sites x 3 sampling periods), we recorded a total of 118 taxa of arthropods (of which 94 were identified at species or subspecies level), belonging to three classes, 14 orders and 62 families. From the 94 identified taxa, a total of 21 species were endemic, 31 native non-endemic, 32 introduced and 10 indeterminate. We also provide additional information of the habitat quality (Index of Biotic Integrity), including general habitat and dominant species composition.We registered three new records to the Island, the native bug Piezodoruslituratus (Fabricius, 1794) (Hemiptera, Pentatomidae), the Azorean endemic beetle Phloeosinusgillerforsi Bright, 1987 (Coleoptera, Curculionidae) and the exotic ant Hypoponerapunctatissima (Roger, 1859) (Hymenoptera, Formicidae) and one new record for the Azores Archipelago, the native beetle Cephenniumvalidum Assing & Meybohm, 2021 (Coleoptera, Staphylinidae, Scydmaeninae).This publication not only contributes to the conservation of highly threatened endemic molluscs, through an assessment of habitat quality, based on arthropod communities and habitat description (e.g. native or exotic vegetation), but also provides an updated inventory of arthropods from Santa Maria Island.

Associations between disturbed sleep and attenuated psychotic experiences in people at clinical high risk for psychosis.

BACKGROUND: Pre-diagnostic stages of psychotic illnesses, including 'clinical high risk' (CHR), are marked by sleep disturbances. These sleep disturbances appear to represent a key aspect in the etiology and maintenance of psychotic disorders. We aimed to examine the relationship between self-reported sleep dysfunction and attenuated psychotic symptoms (APS) on a day-to-day basis. METHODS: Seventy-six CHR young people completed the Experience Sampling Methodology (ESM) component of the European Union Gene-Environment Interaction Study, collected through PsyMate® devices, prompting sleep and symptom questionnaires 10 times daily for 6 days. Bayesian multilevel mixed linear regression analyses were performed on time-variant ESM data using the brms package in R. We investigated the day-to-day associations between sleep and psychotic experiences bidirectionally on an item level. Sleep items included sleep onset latency, fragmentation, and quality. Psychosis items assessed a range of perceptual, cognitive, and bizarre thought content common in the CHR population. RESULTS: Two of the seven psychosis variables were unidirectionally predicted by previous night's number of awakenings: every unit increase in number of nightly awakenings predicted a 0.27 and 0.28 unit increase in feeling unreal or paranoid the next day, respectively. No other sleep variables credibly predicted next-day psychotic symptoms or vice-versa. CONCLUSION: In this study, the relationship between sleep disturbance and APS appears specific to the item in question. However, some APS, including perceptual disturbances, had low levels of endorsement amongst this sample. Nonetheless, these results provide evidence for a unidirectional relationship between sleep and some APS in this population.

Dexterous helical magnetic robot for improved endovascular access.

Treating vascular diseases in the brain requires access to the affected region inside the body. This is usually accomplished through a minimally invasive technique that involves the use of long, thin devices, such as wires and tubes, that are manually maneuvered by a clinician within the bloodstream. By pushing, pulling, and twisting, these devices are navigated through the tortuous pathways of the blood vessels. The outcome of the procedure heavily relies on the clinician's skill and the device's ability to navigate to the affected target region in the bloodstream, which is often inhibited by tortuous blood vessels. Sharp turns require high flexibility, but this flexibility inhibits translation of proximal insertion to distal tip advancement. We present a highly dexterous, magnetically steered continuum robot that overcomes pushability limitations through rotation. A helical protrusion on the device's surface engages with the vessel wall and translates rotation to forward motion at every point of contact. An articulating magnetic tip allows for active steerability, enabling navigation from the aortic arch to millimeter-sized arteries of the brain. The effectiveness of the magnetic continuum robot has been demonstrated through successful navigation in models of the human vasculature and in blood vessels of a live pig.

Geospatial investigations in Colombia reveal variations in the distribution of mood and psychotic disorders.

BACKGROUND: Geographical variations in mood and psychotic disorders have been found in upper-income countries. We looked for geographic variation in these disorders in Colombia, a middle-income country. We analyzed electronic health records from the Clínica San Juan de Dios Manizales (CSJDM), which provides comprehensive mental healthcare for the one million inhabitants of Caldas. METHODS: We constructed a friction surface map of Caldas and used it to calculate the travel-time to the CSJDM for 16,295 patients who had received an initial diagnosis of mood or psychotic disorder. Using a zero-inflated negative binomial regression model, we determined the relationship between travel-time and incidence, stratified by disease severity. We employed spatial scan statistics to look for patient clusters. RESULTS: We show that travel-times (for driving) to the CSJDM are less than 1 h for ~50% of the population and more than 4 h for ~10%. We find a distance-decay relationship for outpatients, but not for inpatients: for every hour increase in travel-time, the number of expected outpatient cases decreases by 20% (RR = 0.80, 95% confidence interval [0.71, 0.89], p = 5.67E-05). We find nine clusters/hotspots of inpatients. CONCLUSIONS: Our results reveal inequities in access to healthcare: many individuals requiring only outpatient treatment may live too far from the CSJDM to access healthcare. Targeting of resources to comprehensively identify severely ill individuals living in the observed hotspots could further address treatment inequities and enable investigations to determine factors generating these hotspots.

The frequencies of mental disorders vary by geographic region. Investigating such variations may lead to more equitable access to mental healthcare and to scientific discoveries that reveal specific localized factors that contribute to the causes of mental illness. This study examined the frequency of three disorders with a major impact on public health ­ schizophrenia, bipolar disorder, and major depressive disorder ­ by analyzing electronic health records from a hospital providing comprehensive mental health care for a large region in Colombia. We show that individuals receiving outpatient care mainly live relatively near the facility. Those receiving inpatient care live throughout the region, but cluster in a few scattered locations. Future research could lead to strategies for more equitable provision of mental healthcare in Colombia and identify environmental or genetic factors that affect the likelihood that someone will develop one of these disorders.

Complete genome sequence of Brucella abortus isolated from a human blood culture sample in Tanzania.

Brucella abortus causes infections in humans and livestock. Bacterial isolates are challenging to obtain, and very little is known about the genomic epidemiology of this species in Africa. Here, we report the complete genome sequence of a Brucella abortus isolate cultured from a febrile human in northern Tanzania.

Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci.

Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.

Potential endpoints for assessment of bone health in persons with neurofibromatosis type 1.

Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field.

Implementation of extreme ultraviolet spectroscopy on a sheared-flow-stabilized Z pinch.

A diagnostic for extreme ultraviolet spectroscopy was fielded on the sheared-flow-stabilized (SFS) fusion Z-pinch experiment (FuZE-Q) for the first time. The spectrometer collected time-gated plasma emission spectra in the 5-40 nm wavelength (30-250 eV) range for impurity identification, radiative power studies, and for plasma temperature and density measurements. The unique implementation of the diagnostic included fast (10 ns risetime) pulsed high voltage electronics and a multi-stage differential pumping system that allowed the vacuum-coupled spectrometer to collect three independently timed spectra per FuZE-Q shot while also protecting sensitive internal components. Analysis of line emission identifies oxygen (N-, C-, B-, Be-, Li-, and He-like O), peaking in intensity shortly after maximum current (>500 kA). This work provides a foundation for future high energy spectroscopy experiments on SFS Z-pinch devices.

Predicting diagnostic conversion from major depressive disorder to bipolar disorder: an EHR based study from Colombia.

Bipolar Disorder (BD) is a severe and chronic disorder characterized by recurrent episodes of depression, mania, and/or hypomania. Most BD patients initially present with depressive symptoms, resulting in a delayed diagnosis of BD and poor clinical outcomes. This study leverages electronic health record (EHR) data from the Clínica San Juan de Dios Manizales in Colombia to identify features predictive of the transition from Major Depressive Disorder (MDD) to BD. Analyzing EHR data from 13,607 patients diagnosed with MDD over 15 years, we identified 1,610 cases of conversion to BD. Using a multivariate Cox regression model, we identified severity of the initial MDD episode, the presence of psychosis and hospitalization at first episode, family history of mood or psychotic disorders, female gender to be predictive of the conversion to BD. Additionally, we observed associations with medication classes (prescriptions of mood stabilizers, antipsychotics, and antidepressants) and clinical features (delusions, suicide attempt, suicidal ideation, use of marijuana and alcohol use/abuse) derived from natural language processing (NLP) of clinical notes. Together, these risk factors predicted BD conversion within five years of the initial MDD diagnosis, with a recall of 72% and a precision of 38%. Our study confirms many previously identified risk factors identified through registry-based studies (such as female gender and psychotic depression at the index MDD episode), and identifies novel ones (specifically, suicidal ideation and suicide attempt extracted from clinical notes). These results simultaneously demonstrate the validity of using EHR data for predicting BD conversion as well as underscore its potential for the identification of novel risk factors and improving early diagnosis.

Cerebral Venous Thrombosis in a 17-Year-Old Female Patient: A Case Report.

Cerebral venous thrombosis (CVT) is a rare disorder predominantly affecting young women. Clinical presentation is not specific and varies depending on the location of the thrombus. The diagnosis requires clinical suspicion with confirmation by images. Guidelines for treatment recommend heparin during the acute phase even in patients with intraparenchymal hemorrhage. It is associated with a good prognosis when diagnosed and treated promptly. We present a case of CVT and intraparenchymal hemorrhage in a 17-year-old female with severe headache, nausea, vomiting, and altered mental status. The patient was diagnosed with CVT secondary to systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). She showed improvement after anticoagulation and corticosteroids.

The relationship between subjective sleep disturbance and attenuated psychotic symptoms after accounting for anxiety and depressive symptoms.

BACKGROUND AND HYPOTHESES: Sleep disturbances are increasingly recognized as cooccurring with psychotic symptoms. The potential importance of this relationship is complicated when considering the effects of anxiety and depressive symptoms which commonly present in early-stage illness states. This study aimed to investigate the relationship between self-reported sleep disturbance on the development of attenuated psychotic symptoms (APS) cross-sectionally and longitudinally while adjusting for roles of anxiety and depressive symptoms. DESIGN: Eight-hundred and two help-seeking young people aged 12 to 25 years who engaged with our Australian early intervention services were included in the study (the "Transitions" cohort). Cross sectional mediation and cross-lagged longitudinal (12-month) mediation models were developed with outcomes being different APS domains. RESULTS: Only baseline excessive daytime sleepiness predicted later APS when accounting for previous APS, anxiety and depressive symptomatology. Cross sectionally, self-reported sleep disturbance showed both direct and indirect predictive relationships with all APS domains. Partial mediation through anxiety and depression was shown for unusual thought content, perceptual abnormalities, and disorganised speech, while full mediation through depression was shown for non-bizarre ideas. CONCLUSIONS: The specificity of the relationship between self-reported sleep disturbance on APS highlights the potential for different roles in mechanistic models of psychotic symptom expression. This further indicates the need for further experimental research to illuminate potential causal pathways. Future research should continue to use continuous, symptom level approaches across a range of timeframes to more accurately model the complex dynamics present in the sleep-psychosis relationship.

Stroke in mitral valve prolapse: risk factors and left atrial function in cryptogenic versus non-cryptogenic ischemic subtypes.

Background and purpose: Mitral valve prolapse (MVP) has been associated with an increased risk of ischemic stroke. Older age, thicker mitral leaflets, and significant mitral regurgitation (MR) leading to atrial fibrillation have been traditionally considered risk factors for ischemic stroke in MVP. However, specific risk factors for MVP-stroke subtypes are not well defined. The aim of this study is to evaluate clinical and echocardiographic parameters, including left atrial (LA) function, in MVP with cryptogenic (C) vs. non-cryptogenic (NC) stroke. Methods: In this case-control matched study, MVPs were identified in consecutive echocardiograms obtained after a stroke from January 2013 to December2016 at the University of California, San Francisco. MVP was defined as leaflet displacement ≥2 mm in the parasternal long-axis view at end-systole. Age/gender matched MVPs without stroke and healthy controls without MVP were also identified. We analyzed LA end-systolic/diastolic volume index, emptying fraction (LAEF), function index (LAFI), and global longitudinal strain in all MVPs and controls. We also measured left ventricular (LV) volume indexes, mass index, ejection fraction (EF), degree of MR and leaflet thickness. Results: We identified a total of 30 MVPs (age 70 ± 12, 50% females) with stroke (11 with C- and 19 with NC-stroke), 20 age/gender matched MVPs without a stroke and 16 controls. MVPs without stroke had lower BMI, less hypertension but more MR (≥moderate in 45% vs. 17%), more abnormal LA function (lower LAEF, LAFI) and larger LV volumes/mass (all p < 0.05) when compared to MVPs with stroke. Leaflet thickness was overall mild (<3 mm) and similar in the 2 groups. Within the MVP stroke group, NC-stroke had higher BMI, more hypertension and more atrial fibrillation compared to C-stroke. In the variables tested, patients with C-stroke did not differ from controls. Conclusions: MVP-related MR may be protective against stroke despite abnormal LA function. Risk of NC-stroke in MVP is related to common stroke risk factors rather than mitral valve leaflet thickness. The etiology of C-stroke in MVP warrants further studies.

The AUX1-AFB1-CNGC14 module establishes a longitudinal root surface pH profile.

Plant roots navigate in the soil environment following the gravity vector. Cell divisions in the meristem and rapid cell growth in the elongation zone propel the root tips through the soil. Actively elongating cells acidify their apoplast to enable cell wall extension by the activity of plasma membrane AHA H+-ATPases. The phytohormone auxin, central regulator of gravitropic response and root development, inhibits root cell growth, likely by rising the pH of the apoplast. However, the role of auxin in the regulation of the apoplastic pH gradient along the root tip is unclear. Here, we show, by using an improved method for visualization and quantification of root surface pH, that the Arabidopsis thaliana root surface pH shows distinct acidic and alkaline zones, which are not primarily determined by the activity of AHA H+-ATPases. Instead, the distinct domain of alkaline pH in the root transition zone is controlled by a rapid auxin response module, consisting of the AUX1 auxin influx carrier, the AFB1 auxin co-receptor, and the CNCG14 calcium channel. We demonstrate that the rapid auxin response pathway is required for an efficient navigation of the root tip.

Evaluating the mouse neural precursor line, SN4741, as a suitable proxy for midbrain dopaminergic neurons.

To overcome the ethical and technical limitations of in vivo human disease models, the broader scientific community frequently employs model organism-derived cell lines to investigate disease mechanisms, pathways, and therapeutic strategies. Despite the widespread use of certain in vitro models, many still lack contemporary genomic analysis supporting their use as a proxy for the affected human cells and tissues. Consequently, it is imperative to determine how accurately and effectively any proposed biological surrogate may reflect the biological processes it is assumed to model. One such cellular surrogate of human disease is the established mouse neural precursor cell line, SN4741, which has been used to elucidate mechanisms of neurotoxicity in Parkinson disease for over 25 years. Here, we are using a combination of classic and contemporary genomic techniques - karyotyping, RT-qPCR, single cell RNA-seq, bulk RNA-seq, and ATAC-seq - to characterize the transcriptional landscape, chromatin landscape, and genomic architecture of this cell line, and evaluate its suitability as a proxy for midbrain dopaminergic neurons in the study of Parkinson disease. We find that SN4741 cells possess an unstable triploidy and consistently exhibits low expression of dopaminergic neuron markers across assays, even when the cell line is shifted to the non-permissive temperature that drives differentiation. The transcriptional signatures of SN4741 cells suggest that they are maintained in an undifferentiated state at the permissive temperature and differentiate into immature neurons at the non-permissive temperature; however, they may not be dopaminergic neuron precursors, as previously suggested. Additionally, the chromatin landscapes of SN4741 cells, in both the differentiated and undifferentiated states, are not concordant with the open chromatin profiles of ex vivo, mouse E15.5 forebrain- or midbrain-derived dopaminergic neurons. Overall, our data suggest that SN4741 cells may reflect early aspects of neuronal differentiation but are likely not a suitable proxy for dopaminergic neurons as previously thought. The implications of this study extend broadly, illuminating the need for robust biological and genomic rationale underpinning the use of in vitro models of molecular processes.

Country-level gender inequality is associated with structural differences in the brains of women and men.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.