Neurophysiological and other features of working memory in older adults at risk for dementia.

Theta-gamma coupling (TGC) is a neurophysiological process that supports working memory. Working memory is associated with other clinical and biological features. The extent to which TGC is associated with these other features and whether it contributes to working memory beyond these features is unknown. Two-hundred-and-three older participants at risk for Alzheimer's dementia-98 with mild cognitive impairment (MCI), 39 with major depressive disorder (MDD) in remission, and 66 with MCI and MDD (MCI + MDD)-completed a clinical assessment, N-back-EEG, and brain MRI. Among them, 190 completed genetic testing, and 121 completed [11C] Pittsburgh Compound B ([11C] PIB) PET imaging. Hierarchical linear regressions were used to assess whether TGC is associated with demographic and clinical variables; Alzheimer's disease-related features (APOE ε4 carrier status and ß-amyloid load); and structural features related to working memory. Then, linear regressions were used to assess whether TGC is associated with 2-back performance after accounting for these features. Other than age, TGC was not associated with any non-neurophysiological features. In contrast, TGC (ß = 0.27; p = 0.006), age (ß = - 0.29; p = 0.012), and parietal cortical thickness (ß = 0.24; p = 0.020) were associated with 2-back performance. We also examined two other EEG features that are linked to working memory-theta event-related synchronization and alpha event-related desynchronization-and found them not to be associated with any feature or performance after accounting for TGC. Our findings suggest that TGC is a process that is independent of other clinical, genetic, neurochemical, and structural variables, and supports working memory in older adults at risk for dementia. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09938-y.

Endovascular Treatment to Improve Outcomes for Medium Vessel Occlusions: The ESCAPE-MeVO trial.

RATIONALE: Clinical outcomes in acute ischemic stroke due to medium vessel occlusion (MeVO) are often poor when treated with best medical management. Data from non-randomized studies suggest that endovascular treatment (EVT) may improve outcomes in MeVO stroke, but randomized data on potential benefits and risks are hitherto lacking. Thus, there is insufficient evidence to guide endovascular treatment decision-making in MeVO stroke. AIM: The primary aim of the ESCAPE-MeVO trial is to demonstrate that acute, rapid EVT in patients with acute ischemic stroke due to MeVO results in better clinical outcomes compared to best medical management. Secondary outcomes are to demonstrate the safety of EVT, its impact on self-reported health-related quality of life, and cost-effectiveness. SAMPLE SIZE ESTIMATES: Based on previously published data, we estimate a sample size of 500 subjects to achieve a power of 85% with a two-sided alpha of 0.05. To account for potential loss to follow-up, 530 subjects will be recruited. METHODS AND DESIGN: ESCAPE-MeVO is a multicenter, prospective, randomized, open-label study with blinded endpoint evaluation (PROBE design), clinicaltrials.gov: NCT05151172. Subjects with acute ischemic stroke due to MeVO meeting the trial eligibility criteria will be allocated in a 1:1 ratio to best medical care plus EVT vs. best medical care only. Patients will be screened only at comprehensive stroke centers to determine if they are eligible for the trial, regardless of whether they were previously treated at a primary care center. Key eligibility criteria are 1) acute ischemic stroke due to MeVO that is clinically and technically eligible for EVT, 2) last-known well within the last 12 hours, 3) National Institutes of Health Stroke Scale >5 or 3-5 with disabling deficit, 4) high likelihood of salvageable tissue on non-invasive neuroimaging. STUDY OUTCOMES: The primary outcome is the modified Rankin scale 90 days after randomization (shift analysis), whereby modified Rankin Score 5 and 6 will be collapsed into one category. Secondary outcomes include dichotomizations of the modified Rankin Score at 90 days, 24-hour National Institutes of Health Stroke Score, difference between 24-hour and baseline National Institutes of Health Stroke Score, mortality at 90 days, health-related quality of life (EQ-5D-5L), Lawton scale of instrumental activities of daily living score, reperfusion quality (MeVO expanded Thrombolysis in Cerebral Infarction Score) and infarct volume at 24 hours, and cost-effectiveness of endovascular recanalization. Safety outcomes include symptomatic and asymptomatic intracranial hemorrhage and procedural complications. DISCUSSION: The ESCAPE-MeVO trial will demonstrate the effect of endovascular thrombectomy in addition to best medical management vis-à-vis best medical management in patients with acute ischemic stroke due to MeVO and provide data for evidence-based treatment decision-making in acute MeVO stroke.

Napa Valley Cabernet Sauvignon Proanthocyanidin Changes During Fruit Ripening: A Multi-Appellation Survey.

In 2015, an experiment was designed to investigate the distribution and variance of in winegrape flavonoids across the ripening phase in the Napa Valley. This Cabernet Sauvignon experiment was intended to evaluate the polyphenol differences across Napa Valley in order to understand parameters controlling "proanthocyanidin activity." This method has shown promise in understanding proanthocyanidin (PA) astringency based on size distribution, pigmentation, conformation, and composition. Results from whole berry partial extractions showed that seed PA material was driving PA activity early in the ripening phase, while the formation of the pigmented polymer led to a decrease later in the growing season. Multivariate analysis showed that the main drivers of changes across the ripening phase were the molecular masses of PAs and the amount of pigmentation. Given the high amount of variability seen in the experiment between sites in such a small geographical area, the results suggest that manipulation of PA activity may be possible in the vineyard, perhaps explaining variations in wine mouthfeel attributes between locations. These results can be used to develop furthermore controlled experiments targeting the variables responsible for PA activity changes.

Genetic and polygenic investigation of heart rate variability to identify biomarkers associated with Anxiety disorders.

Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into anxiety etiology. This study used polygenic risk scores (PRS) to explore the genetic overlap between AD and HRV, and investigated whether HRV-related polymorphisms influence anxiety risk. Resting vagally-mediated HRV was measured using a wearable device in 188 European individuals (AD=101, healthy controls=87). AD PRS was tested for association with resting HRV, and HRV PRS for association with AD. We also investigated 15 significant hits from an HRV genome-wide association study (GWAS) for association with resting HRV and AD and if this association is mediated through resting HRV. The AD PRS and HRV PRS showed nominally significant associations with resting HRV and anxiety disorders, respectively. HRV GWAS variants associated with resting HRV were rs12980262 (NDUFA11), rs2680344 (HCN4), rs4262 and rs180238 (GNG11), and rs10842383 (LINC00477). Mediation analyses revealed that NDUFA11 rs12980262 A-carriers and GNG11 rs180238 and rs4262 C-carriers had higher anxiety risk through lower HRV. This study supports an anxiety-HRV genetic relationship, with HRV-related genetic variants translating to AD. This study encourages exploration of HRV genetics to understand mechanisms and identify novel treatment targets for anxiety.

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Immune checkpoint inhibitor associated diarrhoea.

A man in his 80s was undergoing immunotherapy with pembrolizumab, an anti-PD-1 monoclonal antibody, following his diagnosis of adenocarcinoma of primary lung origin. 24 weeks into treatment, the patient reported experiencing loose stools associated with malaise and poor appetite but no further symptoms. This progressed in frequency and a clinical diagnosis of grade 2 immune checkpoint inhibitor colitis was made. Management with oral prednisolone was commenced but symptoms persisted. Common enteric infections had been ruled out, as were coeliac disease and hyperthyroidism. Flexible sigmoidoscopy and colonoscopy results were not in keeping with colitis, having revealed normal looking mucosa. Following this, a faecal elastase level was found to be low. A diagnosis of pembrolizumab-induced pancreatic exocrine insufficiency was made, and stool frequency and consistency swiftly improved following the use of pancreatic enzyme replacement therapy.

Organ-on-a-chip for studying immune cell adhesion to liver sinusoidal endothelial cells: the potential for testing immunotherapies and cell therapy trafficking.

Immunotherapy has changed the landscape of treatment options for patients with hepatocellular cancer. Checkpoint inhibitors are now standard of care for patients with advanced tumours, yet the majority remain resistant to this therapy and urgent approaches are needed to boost the efficacy of these agents. Targeting the liver endothelial cells, as the orchestrators of immune cell recruitment, within the tumour microenvironment of this highly vascular cancer could potentially boost immune cell infiltration. We demonstrate the successful culture of primary human liver endothelial cells in organ-on-a-chip technology followed by perfusion of peripheral blood mononuclear cells. We confirm, with confocal and multiphoton imaging, the capture and adhesion of immune cells in response to pro-inflammatory cytokines in this model. This multicellular platform sets the foundation for testing the efficacy of new therapies in promoting leukocyte infiltration across liver endothelium as well as a model for testing cell therapy, such as chimeric antigen receptor (CAR)-T cell, capture and migration across human liver endothelium.

Discovery of Potent Glycosidases Enables Quantification of Smoke-Derived Phenolic Glycosides through Enzymatic Hydrolysis.

When grapes are exposed to wildfire smoke, certain smoke-related volatile phenols (VPs) can be absorbed into the fruit, where they can be then converted into volatile-phenol (VP) glycosides through glycosylation. These volatile-phenol glycosides can be particularly problematic from a winemaking standpoint as they can be hydrolyzed, releasing volatile phenols, which can contribute to smoke-related off-flavors. Current methods for quantitating these volatile-phenol glycosides present several challenges, including the requirement of expensive capital equipment, limited accuracy due to the molecular complexity of the glycosides, and the utilization of harsh reagents. To address these challenges, we proposed an enzymatic hydrolysis method enabled by a tailored enzyme cocktail of novel glycosidases discovered through genome mining, and the generated VPs from VP glycosides can be quantitated by gas chromatography-mass spectrometry (GC-MS). The enzyme cocktails displayed high activities and a broad substrate scope when using commercially available VP glycosides as the substrates for testing. When evaluated in an industrially relevant matrix of Cabernet Sauvignon wine and grapes, this enzymatic cocktail consistently achieved a comparable efficacy of acid hydrolysis. The proposed method offers a simple, safe, and affordable option for smoke taint analysis.

Hydrophilic Modification of Dialysis Membranes Sustains Middle Molecule Removal and Filtration Characteristics.

While efficient removal of uremic toxins and accumulated water is pivotal for the well-being of dialysis patients, protein adsorption to the dialyzer membrane reduces the performance of a dialyzer. Hydrophilic membrane modification with polyvinylpyrrolidone (PVP) has been shown to reduce protein adsorption and to stabilize membrane permeability. In this study we compared middle molecule clearance and filtration performance of nine polysulfone-, polyethersulfone-, and cellulose-based dialyzers over time. Protein adsorption was simulated in recirculation experiments, while ß2-microglobulin clearance as well as transmembrane pressure (TMP) and filtrate flow were determined over time. The results of this study showed that ß2-microglobulin clearance (-7.2 mL/min/m2) and filtrate flow (-54.4 mL/min) decreased strongly during the first 30 min and slowly afterwards (-0.7 mL/min/m2 and -6.8 mL/min, respectively, for the next 30 min); the TMP increase (+37.2 mmHg and +8.6 mmHg, respectively) showed comparable kinetics. Across all tested dialyzers, the dialyzer with a hydrophilic modified membrane (FX CorAL) had the highest ß2-microglobulin clearance after protein fouling and the most stable filtration characteristics. In conclusion, hydrophilic membrane modification with PVP stabilizes the removal capacity of middle molecules and filtration performance over time. Such dialyzers may have benefits during hemodiafiltration treatments which aim to achieve high exchange volumes.

Analysis of schizophrenia-associated genetic markers in the HLA region as risk factors for tardive dyskinesia.

OBJECTIVES: The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia-associated HLA-region single-nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. METHODS: The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. RESULTS: The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. CONCLUSION: Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD.

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. METHODS: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. FINDINGS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. INTERPRETATION: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. FUNDING: None.

When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population.

Mental illnesses are one of the biggest contributors to the global disease burden. Despite the increased recognition, diagnosis and ongoing research of mental health disorders, the etiology and underlying molecular mechanisms of these disorders are yet to be fully elucidated. Moreover, despite many treatment options available, a large subset of the psychiatric patient population is nonresponsive to standard medications and therapies. There has not been a comprehensive study to date examining the burden and impact of treatable genetic disorders (TGDs) that can present with neuropsychiatric features in psychiatric patient populations. In this study, we test the hypothesis that TGDs that present with psychiatric symptoms are more prevalent within psychiatric patient populations compared to the general population by performing targeted next-generation sequencing of 129 genes associated with 108 TGDs in a cohort of 2301 psychiatric patients. In total, 48 putative affected and 180 putative carriers for TGDs were identified, with known or likely pathogenic variants in 79 genes. Despite screening for only 108 genetic disorders, this study showed a two-fold (2.09%) enrichment for genetic disorders within the psychiatric population relative to the estimated 1% cumulative prevalence of all single gene disorders globally. This strongly suggests that the prevalence of these, and most likely all, genetic diseases is greatly underestimated in psychiatric populations. Increasing awareness and ensuring accurate diagnosis of TGDs will open new avenues to targeted treatment for a subset of psychiatric patients.

Functional Outcomes of Congenital Scoliosis at a Mean 35-Year Follow-up Post In Situ Fusion. Revisiting Patients From the 2002 Goldberg et al Study.

BACKGROUND: The management of congenital scoliosis poses a significant challenge for treating surgeons. The aim of our study was to provide insight into the long-term clinical results of spinal fusion in congenital scoliosis. METHODS: We performed a retrospective review of the scoliosis database in our institution for the period 1976 until 2002 identifying 43 patients with congenital scoliosis who underwent spinal fusion. Patient demographics, diagnosis, levels fused, and radiographs were evaluated. Patients were evaluated for unplanned return to the operating room (UPROR) via SRS 22, EQ5D-5L, and Oswestry Disability Index (ODI). RESULTS: Of the 43 patients who fulfilled the inclusion criteria, 22 patients agreed to participate, 3 patients were known to be deceased and 18 patients were lost to follow-up or declined to participate and were excluded. The mean age of the respondents was 40.7 years (range, 30 to 47 y) with a mean follow-up from index surgery of 35 years (range, 20 to 44 y). At most recent follow-up, 12 patients (54%) underwent UPROR. The mean age at diagnosis was 3.4 years (range, birth to 11.5 y), and the mean age for first surgery was 5.8 years (range, 1 to 13 y). As regards radiologic follow-up; the mean number of levels fused was 5.2 (range, 2 to 12). Thoracic fusion was performed in 17 patients (77%). The mean T1 to T12 height at index surgery and maturity was 166 mm (range, 130 to 240 mm) and 202 mm (range, 125 to 270 mm), respectively. The mean functional scores at follow-up were SRS 22: 4.5 (range, 2.4 to 5), cumulative EQ5D-5L score 7.2 (range, 5 to 15), and ODI: 8% (range, 2 to 30%). All respondents completed high school, 10 patients (45%) completed university, and 2 patients were awarded doctorates. Currently, 17 patients (77%) are in paid employment. CONCLUSIONS: This report constitutes the largest series of patients treated by spinal arthrodesis for congenital scoliosis followed into maturity. We demonstrate the thorax continues to grow after index fusion, patient-reported outcomes were satisfactory with superior educational and employment rates and unplanned return to theatre is rare in adult life. LEVEL OF EVIDENCE: Therapeutic Level IV.

Comparison of prebiotic candidates in ulcerative colitis using an in vitro fermentation model.

AIMS: This study explored the effect of three different prebiotics, the human milk oligosaccharide 2'-fucosyllactose (2'-FL), an oligofructose-enriched inulin (fructo-oligosaccharide, or FOS), and a galacto-oligosaccaride (GOS) mixture, on the faecal microbiota from patients with ulcerative colitis (UC) using in vitro batch culture fermentation models. Changes in bacterial groups and short-chain fatty acid (SCFA) production were compared. METHODS AND RESULTS: In vitro pH controlled batch culture fermentation was carried out over 48 h on samples from three healthy controls and three patients with active UC. Four vessels were run, one negative control and one for each of the prebiotic substrates. Bacterial enumeration was carried out using fluorescence in situ hybridization with flow cytometry. SCFA quantification was performed using gas chromatography mass spectrometry. All substrates had a positive effect on the gut microbiota and led to significant increases in total SCFA and propionate concentrations at 48 h. 2'-FL was the only substrate to significantly increase acetate and led to the greatest increase in total SCFA concentration at 48 h. 2'-FL best suppressed Desulfovibrio spp., a pathogen associated with UC. CONCLUSIONS: 2'FL, FOS, and GOS all significantly improved the gut microbiota in this in vitro study and also led to increased SCFA.

Psychiatric Polygenic Risk Scores Across Youth With Bipolar Disorder, Youth at High Risk for Bipolar Disorder, and Controls.

OBJECTIVE: There is a pronounced gap in knowledge regarding polygenic underpinnings of youth bipolar disorder (BD). This study aimed to compare polygenic risk scores (PRSs) in youth with BD, youth at high clinical and/or familial risk for BD (HR), and controls. METHOD: Participants were 344 youths of European ancestry (13-20 years old), including 136 youths with BD, 121 HR youths, and 87 controls. PRSs for BD, schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder were constructed using independent genome-wide summary statistics from adult cohorts. Multinomial logistic regression was used to examine the association between each PRS and diagnostic status (BD vs HR vs controls). All genetic analyses controlled for age, sex, and 2 genetic principal components. RESULTS: The BD group showed significantly higher BD-PRS than the control group (odds ratio = 1.54, 95% CI = 1.13-2.10, p = .006), with the HR group numerically intermediate. BD-PRS explained 7.9% of phenotypic variance. PRSs for schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder were not significantly different among groups. In the BD group, BD-PRS did not significantly differ in relation to BD subtype, age of onset, psychosis, or family history of BD. CONCLUSION: BD-PRS derived from adult genome-wide summary statistics is elevated in youth with BD. Absence of significant between-group differences in PRSs for other psychiatric disorders supports the specificity of BD-PRS in youth. These findings add to the biological validation of BD in youth and could have implications for early identification and diagnosis. To enhance clinical utility, future genome-wide association studies that focus specifically on early-onset BD are warranted, as are studies integrating additional genetic and environmental factors. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Association study of the complement component C4 gene and suicide risk in schizophrenia.

Schizophrenia is a severe mental illness and a major risk factor for suicide, with approximately 50% of schizophrenia patients attempting and 10% dying from suicide. Although genetic components play a significant role in schizophrenia risk, the underlying genetic risk factors for suicide are poorly understood. The complement component C4 gene, an immune gene involved in the innate immune system and located in the major histocompatibility complex (MHC) region, has been identified to be strongly associated with schizophrenia risk. In addition, recent findings have also suggested that the MHC region has been associated with suicide risk across disorders, making C4 a potential candidate of interest for studying suicidality in schizophrenia patients. Despite growing interest in investigating the association between the C4 gene and schizophrenia, to our knowledge, no work has been done to examine the potential of C4 variants as suicide risk factors in patients with schizophrenia. In this study, we investigated the association between different C4 copy number variants and predicted C4 brain expression with suicidal outcomes (suicide attempts/suicidal ideation). We directly genotyped 434 schizophrenia patients to determine their C4A and C4B copy number variants. We found the C4AS copy number to be marginally and negatively associated with suicide risk, potentially being protective against suicide attempts (OR = 0.49; p = 0.05) and suicidal ideation (OR = 0.65; p = 0.07). Furthermore, sex-stratified analyses revealed that there are no significant differences between males and females. Our preliminary findings encourage additional studies of C4 and potential immune dysregulation in suicide.

Outcomes of intensive and nonintensive blast-reduction strategies in accelerated and blast-phase MPN.

ABSTRACT: Transformation of BCR::ABL1-negative myeloproliferative neoplasms (MPN) to an accelerated or blast phase is associated with poor outcomes. The efficacy of acute myeloid leukemia (AML)-type intensive and nonintensive hypomethylating agent-based regimens is not well studied. We therefore performed a retrospective analysis of patients with MPN-AP/BP (N = 138) treated with intensive (N = 81) and nonintensive (N = 57) blast-reduction strategies. We used clinically relatable response criteria developed at the Princess Margaret Cancer Centre. The overall best response, comprising complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and reversion to chronic phase MPN (cMPN), in the intensive and nonintensive groups was 77% (62 of 81) and 39% (21 of 54), respectively. Similar overall best response rates were observed in patients receiving induction with daunorubicin combined with cytarabine arabinoside (daunorubicin + ara-C) (74% [23 of 31]) or FLAG-IDA/NOVE-HiDAC (78% [39 of 50], P = .78). However, patients receiving daunorubicin + ara-C more often required second inductions (29% [9 of 31] vs 4% [2 of 50], P = .002). Most responses in the entire cohort were reversions to cMPN (55 of 83 [66%]). CR and CRi comprised 30% (25 of 83) and 4% (3 of 83) of responses, respectively. Mutations in TP53 (overall response [OR] 8.2 [95% confidence interval [CI] 2.01, 37.1], P = .004) and RAS pathway (OR 5.1 [95%CI 1.2, 23.7], P = .03) were associated with inferior treatment response for intensively treated patients, and poorer performance status (Eastern Cooperative Oncology Group) was associated with inferior treatment response in both intensively (OR 10.4 [95% CI 2.0, 78.5], P = .009) and nonintensively treated groups (OR 12 [95% CI 2.04, 230.3], P = .02). In patients with paired samples before and after therapy (N = 26), there was a significant residual mutation burden remaining irrespective of response to blast-reduction therapy.

Nesting behavior of greater eelpout (Lycodes esmarkii), identified through a predation event by spotted wolffish (Anarhichas minor).

The stomach of a spotted wolffish (Anarhichas minor) caught in Icelandic waters was found to contain ~727 greater eelpout larvae (Lycodes esmarkii). All the larvae were of similar size and at a similar state of digestion, indicating they were all consumed together. The likely explanation for this observation is that greater eelpout lay their eggs in a nest, with the larvae remaining in the nest for a short period after hatching. The larvae were then predated upon by the spotted wolffish while still in the nest. This study sheds new light on greater eelpout in Icelandic waters, with recently hatched larvae being present in March, breeding at a depth of ~200-250 m, and likely exhibiting nesting behavior, which has not previously been documented.

Investigating the association of anxiety disorders with heart rate variability measured using a wearable device.

BACKGROUND: Reduced vagally-mediated heart rate variability (HRV) has been associated with anxiety disorders (AD). The aim of this study was to use a wearable device and remote study design to re-evaluate the association of HRV with ADs, anxiety-related traits, and confounders. METHODS: 240 individuals (AD = 120, healthy controls = 120) completed an at-home assessment of their short-term resting vagally-mediated HRV using a wristband, monitored over videoconference. Following quality control, analyses were performed investigating differences in HRV between individuals with AD (n = 119) and healthy controls (n = 116), associations of HRV with anxiety-related traits and confounders, and antidepressants effects on HRV in patients, including analyses stratified by ancestry (i.e., European, East Asian, African). RESULTS: Among the confounders investigated, only age had a significant association with HRV. Patients with an AD had significantly lower vagally-mediated HRV than healthy controls in the European subsample, with a trend of significance in the whole sample. HRV was significantly associated with the Hamilton Anxiety Rating Scale (HAM-A) but not with antidepressant use in the European subsample. LIMITATIONS: The study measures occurred in a non-standardized at-home setting, and the three ancestry group sample sizes were unequal. CONCLUSIONS: This study demonstrates reduced vagally-mediated HRV among patients with ADs compared to healthy controls. Results also point to low HRV being related to more physical anxiety symptoms (measured via HAM-A), suggesting a possible anxiety subtype. Overall, this study highlights the feasibility of using wearables for patients and encourages exploration of the biological and clinical utility of HRV as a risk factor for ADs.

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression.

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine.