Excessive left anterior hippocampal and caudate activation in schizophrenia underlie cognitive underperformance in a virtual navigation task.

We used a virtual navigation paradigm in a city environment to assess neuroanatomical correlates of cognitive deficits in schizophrenia spectrum disorders (SSD). We studied a total of N = 36 subjects: 18 with SSD and 18 matched unaffected controls. Participants completed 10 rapid, single-trial navigation tasks within the virtual city while undergoing functional magnetic resonance imaging (fMRI). All trials tested ability to find different targets seen earlier, during the passive viewing of a path around different city blocks. SSD patients had difficulty finding previously-encountered targets, were less likely to find novel shortcuts to targets, and more likely to attempt retracing of the path observed during passive viewing. Based on a priori region-of-interest analyses, SSD participants had hyperactivation of the left hippocampus when passively viewing turns, hyperactivation of the left caudate when finding targets, and hypoactivation of a focal area of the dorsolateral prefrontal cortex when targets were initially shown during passive viewing. We propose that these brain-behaviour relations may bias or reinforce stimulus-response navigation approaches in SSD and underlie impaired performance when allocentric spatial memory is required, such as when forming efficient shortcuts. This pattern may extend to more general cognitive impairments in SSD that could be used to design remediation strategies.

EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. There is no specific treatment for FXS due to the lack of therapeutic targets. We report here that Elongation Factor 1α (EF1α) forms a complex with two other proteins: Tripartite motif-containing protein 3 (TRIM3) and Murine double minute (Mdm2). Both EF1α-Mdm2 and EF1α-TRIM3 protein complexes are increased in the brain of Fmr1 knockout mice as a result of FMRP deficiency, which releases the normal translational suppression of EF1α mRNA and increases EF1α protein levels. Increased EF1α-Mdm2 complex decreases PSD-95 ubiquitination (Ub-PSD-95) and Ub-PSD-95-C1q interaction. The elevated level of TRIM3-EF1α complex is associated with decreased TRIM3-Complement Component 3 (C3) complex that inhibits the activation of C3. Both protein complexes thereby contribute to a reduction in microglia-mediated phagocytosis and dendritic spine pruning. Finally, we created a peptide that disrupts both protein complexes and restores dendritic spine plasticity and behavioural deficits in Fmr1 knockout mice. The EF1α-Mdm2 and EF1α-TRIM3 complexes could thus be new therapeutic targets for FXS.

Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis.

While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the autoimmune response. Hence, glutamate receptor antagonists preventing excitotoxicity showed promise in MS animal models, though blocking glutamate signaling prevents critical neuronal functions. This study reports the discovery of a small molecule that prevents AMPA-mediated excitotoxicity by targeting an allosteric binding site. A machine learning approach was used to screen for small molecules targeting the AMPA receptor GluA2 subunit. The lead candidate has potent effects in restoring neurological function and myelination while reducing the immune response in experimental autoimmune encephalitis and cuprizone MS mouse models without affecting basal neurotransmission or learning and memory. These findings facilitate development of a treatment for MS with a different mechanism of action than current immune modulatory drugs and avoids important off-target effects of glutamate receptor antagonists. This class of MS therapeutics could be useful as an alternative or complementary treatment to existing therapies.

Care Pathways and Initial Engagement in Early Psychosis Intervention Services Among Youths and Young Adults.

Importance: Broad efforts to improve access to early psychosis intervention (EPI) services may not address health disparities in pathways to care and initial engagement in treatment. Objective: To understand factors associated with referral from acute hospital-based settings and initial engagement in EPI services. Design, Setting, and Participants: This retrospective cohort study used electronic medical record data from all patients aged 16 to 29 years who were referred to a large EPI program between January 2018 and December 2019. Statistical analysis was performed from March 2022 to February 2023. Exposures: Patients self-reported demographic information in a structured questionnaire. The main outcome for the first research question (referral source) was an exposure for the second research question (initial attendance). Main Outcomes and Measures: Rate of EPI referral from acute pathways compared with other referral sources, and rate of attendance at the consultation appointment. Results: The final study population included 999 unique patient referrals. At referral, patients were a mean (SD) age of 22.5 (3.5) years; 654 (65.5%) identified as male, 323 (32.3%) female, and 22 (2.2%) transgender, 2-spirit, nonbinary, do not know, or prefer not to answer; 199 (19.9%) identified as Asian, 176 (17.6%) Black, 384 (38.4%) White, and 167 (16.7%) other racial or ethnic groups, do not know, or prefer not to answer. Participants more likely to be referred to EPI services from inpatient units included those who were older (relative risk ratio [RRR], 1.10; 95% CI, 1.05-1.15) and those who identified as Black (RRR, 2.11; 95% CI, 1.38-3.22) or belonging to other minoritized racial or ethnic groups (RRR, 1.79; 95% CI, 1.14-2.79) compared with White participants. Older patients (RRR, 1.16; 95% CI, 1.11-1.22) and those who identified as Black (RRR, 1.67; 95% CI, 1.04-2.70) or belonging to other minoritized racial or ethnic groups (RRR, 2.11; 95% CI, 1.33-3.36) were more likely to be referred from the emergency department (ED) compared with White participants, whereas participants who identified as female (RRR, 0.51 95% CI, 0.34-.74) had a lower risk of ED referral compared with male participants. Being older (odds ratio [OR], 0.95; 95% CI, 0.90-1.00) and referred from the ED (OR, 0.40; 95% CI, 0.27-0.58) were associated with decreased odds of attendance at the consultation appointment. Conclusions and relevance: In this cohort study of patients referred to EPI services, disparities existed in referral pathways and initial engagement in services. Improving entry into EPI services may help facilitate a key step on the path to recovery among youths and young adults with psychosis.

A catalytically active oscillator made from small organic molecules.

Oscillatory systems regulate many biological processes, including key cellular functions such as metabolism and cell division, as well as larger-scale processes such as circadian rhythm and heartbeat1-4. Abiotic chemical oscillations, discovered originally in inorganic systems5,6, inspired the development of various synthetic oscillators for application as autonomous time-keeping systems in analytical chemistry, materials chemistry and the biomedical field7-17. Expanding their role beyond that of a pacemaker by having synthetic chemical oscillators periodically drive a secondary function would turn them into significantly more powerful tools. However, this is not trivial because the participation of components of the oscillator in the secondary function might jeopardize its time-keeping ability. We now report a small molecule oscillator that can catalyse an independent chemical reaction in situ without impairing its oscillating properties. In a flow system, the concentration of the catalytically active product of the oscillator shows sustained oscillations and the catalysed reaction is accelerated only during concentration peaks. Augmentation of synthetic oscillators with periodic catalytic action allows the construction of complex systems that, in the future, may benefit applications in automated synthesis, systems and polymerization chemistry and periodic drug delivery.

Integrating stay-green and PIN-FORMED genes: PIN-FORMED genes as potential targets for designing climate-resilient cereal ideotypes.

Plant architecture modification (e.g. short-stature crops) is one of the key outcomes of modern crop breeding for high-yielding crop varieties. In cereals, delayed senescence, or stay-green, is an important trait that enables post-anthesis drought stress adaptation. Stay-green crops can prolong photosynthetic capacity during grain-filling period under post-anthesis drought stress, which is essential to ensure grain yield is not impacted under drought stress conditions. Although various stay-green quantitative trait loci have been identified in cereals, the underlying molecular mechanisms regulating stay-green remain elusive. Recent advances in various gene-editing technologies have provided avenues to fast-track crop improvement, such as the breeding of climate-resilient crops in the face of climate change. We present in this viewpoint the focus on using sorghum as the model cereal crop, to study PIN-FORMED (PIN) auxin efflux carriers as means to modulate plant architecture, and the potential to employ it as an adaptive strategy to address the environmental challenges posed by climate uncertainties.

Evaluating the effect of electroconvulsive therapy (ECT) on post-traumatic stress disorder (PTSD): A systematic review and meta-analysis of five studies.

ECT has been proposed as a potential treatment for PTSD. There is a small number of clinical studies to date, but no quantitative review of the efficacy has been conducted. We performed a systematic review and meta-analysis to evaluate the effect of ECT in reducing PTSD symptoms. We followed the PICO and the PRISMA guidelines and searched PubMed, MEDLINE (Ovid), EMBASE (Ovid), Web of Science, and the Cochrane Central Register of Controlled Trials (PROSPERO No: CRD42022356780). A random effects model meta-analysis was conducted with the pooled standard mean difference, applying Hedge's adjustment for small sample sizes. Five within-subject studies met the inclusion criteria, containing 110 patients with PTSD symptoms receiving ECT (mean age 44.13 ± 15.35; 43.4% female). ECT had a small but significant pooled effect on reducing PTSD symptoms (Hedges' g = -0.374), reducing intrusion (Hedges' g = -0.330), avoidance (Hedges' g = -0.215) and hyperarousal (Hedges' g = -0.171) symptoms. Limitations include the small number of studies and subjects and the heterogeneity of study designs. These results provide preliminary quantitative support for the use of ECT in the treatment of PTSD.

The Bigger Fish: A Comparison of Meta-Learning QSAR Models on Low-Resourced Aquatic Toxicity Regression Tasks.

Toxicological information as needed for risk assessments of chemical compounds is often sparse. Unfortunately, gathering new toxicological information experimentally often involves animal testing. Simulated alternatives, e.g., quantitative structure-activity relationship (QSAR) models, are preferred to infer the toxicity of new compounds. Aquatic toxicity data collections consist of many related tasks─each predicting the toxicity of new compounds on a given species. Since many of these tasks are inherently low-resource, i.e., involve few associated compounds, this is challenging. Meta-learning is a subfield of artificial intelligence that can lead to more accurate models by enabling the utilization of information across tasks. In our work, we benchmark various state-of-the-art meta-learning techniques for building QSAR models, focusing on knowledge sharing between species. Specifically, we employ and compare transformational machine learning, model-agnostic meta-learning, fine-tuning, and multi-task models. Our experiments show that established knowledge-sharing techniques outperform single-task approaches. We recommend the use of multi-task random forest models for aquatic toxicity modeling, which matched or exceeded the performance of other approaches and robustly produced good results in the low-resource settings we studied. This model functions on a species level, predicting toxicity for multiple species across various phyla, with flexible exposure duration and on a large chemical applicability domain.

Predicting self-perceived general health status using machine learning: an external exposome study.

BACKGROUND: Self-perceived general health (SPGH) is a general health indicator commonly used in epidemiological research and is associated with a wide range of exposures from different domains. However, most studies on SPGH only investigated a limited set of exposures and did not take the entire external exposome into account. We aimed to develop predictive models for SPGH based on exposome datasets using machine learning techniques and identify the most important predictors of poor SPGH status. METHODS: Random forest (RF) was used on two datasets based on personal characteristics from the 2012 and 2016 editions of the Dutch national health survey, enriched with environmental and neighborhood characteristics. Model performance was determined using the area under the curve (AUC) score. The most important predictors were identified using a variable importance procedure and individual effects of exposures using partial dependence and accumulated local effect plots. The final 2012 dataset contained information on 199,840 individuals and 81 variables, whereas the final 2016 dataset had 244,557 individuals with 91 variables. RESULTS: Our RF models had overall good predictive performance (2012: AUC = 0.864 (CI: 0.852-0.876); 2016: AUC = 0.890 (CI: 0.883-0.896)) and the most important predictors were "Control of own life", "Physical activity", "Loneliness" and "Making ends meet". Subjects who felt insufficiently in control of their own life, scored high on the De Jong-Gierveld loneliness scale or had difficulty in making ends meet were more likely to have poor SPGH status, whereas increased physical activity per week reduced the probability of poor SPGH. We observed associations between some neighborhood and environmental characteristics, but these variables did not contribute to the overall predictive strength of the models. CONCLUSIONS: This study identified that within an external exposome dataset, the most important predictors for SPGH status are related to mental wellbeing, physical exercise, loneliness, and financial status.

Corrections to "Prevalence of persistent symptoms after treatment for lyme borreliosis: a prospective observational cohort study" [The Lancet Regional Health - Europe 6 (2021) 100142].

[This corrects the article DOI: 10.1016/j.lanepe.2021.100142.].

Predictors of healthy physiological aging across generations in a 30-year population-based cohort study: the Doetinchem Cohort Study.

BACKGROUND: Predicting healthy physiological aging is of major interest within public health research. However, longitudinal studies into predictors of healthy physiological aging that include numerous exposures from different domains (i.e. the exposome) are scarce. Our aim is to identify the most important exposome-related predictors of healthy physiological aging over the life course and across generations. METHODS: Data were used from 2815 participants from four generations (generation 1960s/1950s/1940s/1930s aged respectively 20-29/30-39/40-49/50-59 years old at baseline, wave 1) of the Doetinchem Cohort Study who were measured every 5 years for 30 years. The Healthy Aging Index, a physiological aging index consisting of blood pressure, glucose, creatinine, lung function, and cognitive functioning, was measured at age 46-85 years (wave 6). The average exposure and trend of exposure over time of demographic, lifestyle, environmental, and biological exposures were included, resulting in 86 exposures. Random forest was used to identify important predictors. RESULTS: The most important predictors of healthy physiological aging were overweight-related (BMI, waist circumference, waist/hip ratio) and cholesterol-related (using cholesterol lowering medication, HDL and total cholesterol) measures. Diet and educational level also ranked in the top of important exposures. No substantial differences were observed in the predictors of healthy physiological aging across generations. The final prediction model's performance was modest with an R2 of 17%. CONCLUSIONS: Taken together, our findings suggest that longitudinal cardiometabolic exposures (i.e. overweight- and cholesterol-related measures) are most important in predicting healthy physiological aging. This finding was similar across generations. More work is needed to confirm our findings in other study populations.

Introduction of a newly created AW stereotactic frame: a phantom-based accuracy evaluation and an initial experience in clinical usage.

BACKGROUND: A new stereotactic frame was created in 2015, based on a linear algorithm. It is called Albert Wong (AW) frame. A simple AW stereo-calculator was also designed based on Excel® (Microscoft Corporation, Redmond, WA) programme for the frame. OBJECTIVE: The aim of this study is to test the accuracy of the AW frame by a direct head to head comparison with CRW® frame (Integra Life Sciences, Plainsboro, NJ) on a phantom. METHODS: This is a prospective pilot cross-sectional phantom study with a total of 42 (21 for AW and 21 for CRW®) laboratory testings performed in 2017 at our institute to compare the accuracies of both frames in a consecutive manner. A phantom (BL phantom) was newly created, where targets can be placed at different heights and positions on a platform attached under the frame for accuracy testing comparing between the AW and CRW® frames. RESULTS: A comparable accuracy testing results were observed between the AW and CRW® frames of 0.64 mm versus 1.07 mm respectively. Approval from the local ethics committee for a clinical trial was obtained. We report on three case illustrations who had the AW frame-based biopsies with definitive diagnoses and without any post-biopsy related complication. CONCLUSION: AW frame successfully demonstrated a good accuracy of 0.64 mm in phantom testing using the BL phantom by a linear algorithmic calculation. The clinical trial with three patients demonstrated definitive diagnoses and safety with its use.

Prevalence and Severity of Symptoms 3 Months After Infection With SARS-CoV-2 Compared to Test-Negative and Population Controls in the Netherlands.

BACKGROUND: This prospective study assesses symptoms 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection compared to test-negative and population controls, and the effect of vaccination prior to infection. METHODS: Participants enrolled after a positive (cases) or negative (test-negative controls) SARS-CoV-2 test, or after invitation from the general population (population controls). After 3 months, participants indicated presence of 41 symptoms and severity of 4 symptoms. Permutation tests were used to select symptoms significantly elevated in cases compared to controls and to compare symptoms between cases that were vaccinated or unvaccinated prior to infection. RESULTS: In total, 9166 cases, 1698 symptomatic but test-negative controls, and 3708 population controls enrolled. At 3 months, 13 symptoms, and severity of fatigue, cognitive impairment, and dyspnea were significantly elevated incases compared to controls. Of cases, 48.5% reported ≥1 significantly elevated symptom compared to 29.8% of test-negative controls and 26.0% of population controls. Effect of vaccination could be determined for cases aged <65 years, and was significantly protective for loss of smell and taste but not for other symptoms. DISCUSSION: Three months after SARS-CoV-2 infection, almost half of cases report symptoms, which was higher than background prevalence and test-negative prevalence. Vaccination prior to infection was protective against loss of smell and taste in cases aged <65 years.

Estimating healthcare expenditures after becoming divorced or widowed using propensity score matching.

Becoming divorced or widowed are stressful life events experienced by a substantial part of the population. While marital status is a significant predictor in many studies on healthcare expenditures, effects of a change in marital status, specifically becoming divorced or widowed, are less investigated. This study combines individual health claims data and registered sociodemographic characteristics from all Dutch inhabitants (about 17 million) to estimate the differences in healthcare expenditure for individuals whose marital status changed (n = 469,901) compared to individuals who remained married, using propensity score matching and generalized linear models. We found that individuals who were (long-term) divorced or widowed had 12-27% higher healthcare expenditures (RR = 1.12, 95% CI 1.11-1.14; RR = 1.27, 95% CI 1.26-1.29) than individuals who remained married. Foremost, this could be attributed to higher spending on mental healthcare and home care. Higher healthcare expenditures are observed for both divorced and widowed individuals, both recently and long-term divorced/widowed individuals, and across all age groups, income levels and educational levels.

Serum amyloid P component (SAP) modulates antidepressant effects through promoting membrane insertion of the serotonin transporter.

Serum amyloid P component (SAP) is a universal constituent of human amyloid deposits including those in Alzheimer's disease. SAP has been observed to be elevated in patients with depression, and higher SAP levels are associated with better response to the antidepressant escitalopram. The mechanisms underlying these clinical observations remain unclear. We examined the effect of SAP on serotonin transporter (SERT) expression and localization using Western blot, confocal microscopy, and positron emission tomography with the radioligand [11C]DASB. We also investigated the effect of SAP on treatment response to escitalopram in mice with the forced swim test (FST), a classical behaviour paradigm to assess antidepressant effects. SAP reduced [11C]DASB binding as an index of SERT levels, consistent with Western blots showing decreased total SAP protein because of increased protein degradation. In conjunction with the global decrease in SERT levels, SAP also promotes VAMP-2 mediated SERT membrane insertion. SAP levels are correlated with behavioural despair and SSRI treatment response in mice with FST. In MDD patients, the SAP and membrane SERT levels are correlated with response to SSRI treatment. SAP has complex effects on SERT levels and localization, thereby modulating the effect of SSRIs, which could partially explain clinical variability in antidepressant treatment response. These results add to our understanding of the mechanism for antidepressant drug action, and with further work could be of clinical utility.

Measuring Nursing Home Performance Using Administrative Data.

To improve the quality of nursing home care, reliable estimates of outcomes are essential. Obtaining such estimates requires optimal use of limited data, especially for small homes. We analyze the variation in mortality and hospital admissions across nursing homes in the Netherlands during the years 2010-2013. We use administrative data on all nursing home clients. We apply mixed-effects survival models, empirical Bayes estimation, and machine-learning techniques to optimally use the available longitudinal data. We find large differences in both outcomes across nursing homes, yet the estimates are surrounded by substantial uncertainty. We find no correlation between performance on mortality and avoidable hospital admissions, suggesting that these are related to different aspects of quality. Hence, caution is needed when evaluating the performance of individual nursing homes, especially when the number of outcome indicators is limited.

The APOE locus is linked to decline in general cognitive function: 20-years follow-up in the Doetinchem Cohort Study.

Cognitive decline is part of the normal aging process. However, some people experience a more rapid decline than others due to environmental and genetic factors. Numerous single nucleotide polymorphisms (SNPs) have been linked to cognitive function, but only a few to cognitive decline. To understand whether cognitive function and cognitive decline are driven by the same mechanisms, we investigated whether 433 SNPs previously linked to cognitive function and 2 SNPs previously linked to cognitive decline are associated with both general cognitive functioning at baseline and general cognitive decline up to 20-years follow-up in the Doetinchem Cohort Study (DCS). The DCS is a longitudinal population-based study that enrolled men and women aged 20-59 years between 1987-1991, with follow-up examinations every 5 years. We used data of rounds 2-6 (1993-2017, n = 2559). General cognitive function was assessed using four cognition tests measuring memory, speed, fluency and flexibility. With these test scores, standardized residuals (adjusted for sex, age and examination round) were calculated for each cognition test at each round and subsequently combined into one general cognitive function measure using principal component analyses. None of the 435 previously identified variants were associated with baseline general cognitive function in the DCS. But rs429358-C, a coding apolipoprotein E (APOE) SNP and one of the variants previously associated with cognitive decline, was associated with general cognitive decline in our study as well (p-value = 1 × 10-5, Beta = -0.013). These findings suggest that decline of general cognitive function is influenced by other mechanisms than those that are involved in the regulation of general cognitive function.

Challenges and Controversies in the Management of Tuberculous Meningitis with Hydrocephalus: A Systematic Review and Sarawak Institution's Experience.

Introduction To date, there are no standard practice guidelines available and no universal consensus regarding treatment protocol in management of tuberculous meningitis (TBM) with hydrocephalus. Over the years, diverse views have existed in neurosurgical management of TBM with hydrocephalus. Some authors advocate ventriculo-peritoneal (VP) shunt, while others suggest that external ventricular drainage (EVD) may be the preferable neurosurgical procedure for a poor-grade patient. Method We systematically reviewed published literature and presented our institution's experience. We performed a retrospective case study in our Sarawak neurosurgical center from 2018 to 2020. We tabulated the outcome according to preoperative classifications, which were Vellore Grading (VG), Modified Vellore Grading (MVG), British Medical Research Council Classification (MRC), and others: author-defined. Result In our center, there were 20 cases of TBM with hydrocephalus treated by EVD and VP shunt from 2018 to 2020. We systematically searched published medical literature, and 23 articles were retrieved and analyzed. Poor outcomes were observed in poor-grade patients, especially VG/MVG 3/4 and MRC 3, from both institution and systemic review data. Shunt complication rate was lower in our center as compared with published literature. Conclusion Unfortunately, morbidity and mortality were approximately twofold higher in poor-grade as compared with good-grade patients. However, about one-third of poor-grade patients achieved a good outcome. Cerebrospinal fluid (CSF) diversion would be an unavoidable treatment for hydrocephalus. Poor-grade patients tend to have cerebral infarcts in addition to hydrocephalus. An extended duration of EVD placement could be a potential measure to assess Glasgow coma scale recovery and monitor serial CSF samples.

Propylthiouracil-Induced Antineutrophil Cytoplasmic Antibodies-Associated Vasculitis with Renal and Lung Involvement.

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a rare and heterogeneous disease. Moreover, optimal treatment is still lacking. We described the case of a 44-year-old lady with underlying Graves' disease who had cough, blood-streaked sputum, and impaired renal function. A strongly positive anti-myeloperoxidase antibody (>200 U/mL) along with pauci-immune glomerulonephritis and pulmonary hemorrhage resulted in the diagnosis of PTU-induced AAV, given that the patient had been on PTU for 3 years. PTU withdrawal, therapeutic plasma exchanges, and oral cyclophosphamide provided favorable clinical and biochemical outcomes. She remained well on azathioprine 50 mg daily as maintenance therapy and clinically euthyroid with carbimazole 2.5 mg daily. The effective treatment for drug-induced ANCA vasculitis remains controversial, but rapid withdrawal of the offending medication should be the mainstay of treatment. In severe drug-induced ANCA vasculitis with pulmonary hemorrhage and/or life-threatening organ involvement such as kidney failure requiring dialysis, therapeutic plasma exchange with immunosuppressants is often required. In this case, we have shown that patient achieved remission after therapeutic plasma exchange with cyclophosphamide in the acute stage of treatment and remained symptom-free with azathioprine in the maintenance phase of treatment for 24 months.