Sodium valproate and clozapine induced neutropenia: A case control study using register data

BACKGROUND: The use of clozapine is limited due to the occurrence of neutropenia, and the rare but life threatening adverse event of agranulocytosis. There is little epidemiological research into clinical factors that may impact on this risk. We conducted a case control study examining the clinical risk factors for neutropenia patients treated with clozapine. METHOD: A case-control study was conducted within a database of anonymised electronic clinical records. All patients who discontinued clozapine due to a neutropenic event were included as cases. Matched controls were selected from patients with a documented clozapine exposure at the time of the clozapine neutropenic event of the case patient, matched by duration of clozapine treatment. RESULTS: 136 cases and 136 controls were included. In multivariable analysis, the concurrent use of sodium valproate was associated with neutropenia (Odds Raito (OR) 2.28, 95%CI: 1.27–4.11, p = 0.006). There was a dose-response effect, with greater associations for higher doses. Patients who discontinued clozapine due to neutropenia were more likely to be of black ethnicity (OR 2.99, p < 0.001), were younger (t = 5.86, df = 267, p < 0.001), and received lower doses of clozapine (t = − 2.587, p = 0.01) than those who did not develop neutropenia. CONCLUSION: We identified an association between the concurrent use of sodium valproate and an increased risk of clozapine associated neutropenia. These results, taken in combination with the results from previous case series, suggest that the risk of clozapine associated neutropenia could be reduced by avoiding concurrent valproate treatment

Traumatic brain injury: a comparison of diffusion and volumetric magnetic resonance imaging measures

Cognitive impairment after traumatic brain injury remains hard to predict. This is partly because axonal injury, which is of fundamental importance, is difficult to measure clinically. Advances in MRI allow axonal injury to be detected after traumatic brain injury, but the most sensitive approach is unclear. Here, we compare the performance of diffusion tensor imaging, neurite orientation dispersion and density-imaging and volumetric measures of brain atrophy in the identification of white-matter abnormalities after traumatic brain injury. Thirty patients with moderate-severe traumatic brain injury in the chronic phase and 20 age-matched controls had T1-weighted and diffusion MRI. Neuropsychological tests of processing speed, executive functioning and memory were used to detect cognitive impairment. Extensive abnormalities in neurite density index and orientation dispersion index were observed, with distinct spatial patterns. Fractional anisotropy and mean diffusivity also indicated widespread abnormalities of white-matter structure. Neurite density index was significantly correlated with processing speed. Slower processing speed was also related to higher mean diffusivity in the corticospinal tracts. Lower white-matter volumes were seen after brain injury with greater effect sizes compared to diffusion metrics; however, volume was not sensitive to changes in cognitive performance. Volume was the most sensitive at detecting change between groups but was not specific for determining relationships with cognition. Abnormalities in fractional anisotropy and mean diffusivity were the most sensitive diffusion measures; however, neurite density index and orientation dispersion index may be more spatially specific. Lower neurite density index may be a useful metric for examining slower processing speed

Routine Modeling with Time Series Metric Learning

version éditeur : https://rd.springer.com/chapter/10.1007/978-3-030-30484-3_47International audienceTraditionally, the automatic recognition of human activities is performed with supervised learning algorithms on limited sets of specific activities. This work proposes to recognize recurrent activity patterns, called routines, instead of precisely defined activities. The modeling of routines is defined as a metric learning problem, and an architecture, called SS2S, based on sequence-to-sequence models is proposed to learn a distance between time series. This approach only relies on inertial data and is thus non intrusive and preserves privacy. Experimental results show that a clustering algorithm provided with the learned distance is able to recover daily routines

Applied Interventions in the Prevention and Treatment of Obesity Through the Research of Professor Jane Wardle

Purpose of Review Obesity presents a challenge for practitioners, policy makers, researchers and for those with obesity themselves. This review focuses on psychological approaches to its management and prevention in children and adults. Recent Findings Through exploring the work of the late Professor Jane Wardle, we look at the earliest behavioural treatment approaches and how psychological theory has been used to develop more contemporary approaches, for example incorporating genetic feedback and habit formation theory into interventions. We also explore how Jane has challenged thinking about the causal pathways of obesity in relation to eating behaviour. Beyond academic work, Jane was an advocate of developing interventions which had real-world applications. Summary Therefore, we discuss how she not only developed new interventions but also made these widely available and the charity that she established

An outbreak of intestinal schistosomiasis, alongside increasing urogenital schistosomiasis prevalence, in primary school children on the shoreline of Lake Malawi, Mangochi District, Malawi

Background: Intestinal schistosomiasis was not considered endemic in Lake Malawi until 14 November 2017 when populations of Biomphalaria pfeifferi were first reported; in May 2018, emergence of intestinal schistosomiasis was confirmed. This emergence was in spite of ongoing control of urogenital schistosomiasis by preventive chemotherapy. Our current study sought to ascertain whether intestinal schistosomiasis is transitioning from emergence to outbreak, to judge if stepped-up control interventions are needed. Methods: During late-May 2019, three cross-sectional surveys of primary school children for schistosomiasis were conducted using a combination of rapid diagnostic tests, parasitological examinations and applied morbidity-markers; 1) schistosomiasis dynamics were assessed at Research Article IDOP Samama (n = 80) and Mchoka (n = 80) schools, where Schistosoma mansoni was first reported, 2) occurrence of S. mansoni was investigated at two non-sampled schools, Mangochi Orphan Education and Training (MOET) (n = 60) and Koche (n = 60) schools, where B. pfeifferi was nearby, and 3) rapid mapping of schistosomiasis, and B. pfeifferi, conducted across a further 8 shoreline schools (n = 240). After data collection, univariate analyses and Chi-square testing were performed, followed by binary logistic regression using generalized linear models, to investigate epidemiological associations. Results: In total, 520 children from 12 lakeshore primary schools were examined, mean prevalence of S. mansoni by ‘positive’ urine circulating cathodic antigen (CCA)-dipsticks was 31.5% (95% Confidence Interval (CI): 27.5–35.5). Upon comparisons of infection prevalence in May 2018, significant increases at Samama (Relative Risk (RR) = 1.7, 95% CI: 33 1.4–2.2) and Mchoka (RR = 2.7, 95% CI: 1.7–4.3) schools were observed. Intestinal schistosomiasis was confirmed at MOET (18.3%) and Koche (35.0%) schools, and in all rapid mapping schools, ranging from 10.0% to 56.7%. Several populations of B. pfeifferi were confirmed, with two new eastern shoreline locations noted. Mean prevalence of urogenital schistosomiasis was 24.0% (95% CI: 20.3–27.7). Conclusions: We notify that intestinal schistosomiasis, once considered non-endemic in Lake Malawi, is now transitioning from emergence to outbreak. Once control interventions can resume after coronavirus disease 2019 (COVID-19) suspensions, we recommend stepped-up preventive chemotherapy, with increased community-access to treatments, alongside renewed efforts in appropriate environmental control

Pulmonary Outcomes of Congenital Diaphragmatic Hernia Patients Based on Defect Size (CDH Study Group Stage)

BACKGROUND: Congenital diaphragmatic hernia (CDH) is associated with significant pulmonary morbidity. Previous investigation has shown that postnatal inpatient morbidity is linked to diaphragmatic defect size. The objective of this study was to evaluate long-term pulmonary outcomes by CDH study group defect size. METHODS: A retrospective analysis was conducted for CDH patients (n=133) managed in a neonatal intensive care unit (NICU) at a single children\u27s hospital within an adult hospital system and subsequently followed up at a comprehensive multidisciplinary CDH clinic (n=102) from January 2012 to April 2022. CDH patients were stratified according to Congenital Diaphragmatic Hernia Study Group (CDHSG) Stage, and then categorized as low-risk (LR), defect size A and B, or high-risk (HR), defect size C and D. Inpatient data, including the presence of pulmonary hypertension, extracorporeal life support (ECLS) utilization, and mechanical ventilation days, were collected. Post-discharge data including the prevalence of asthma, pulmonary hypertension, emergency department visits, the total number of hospitalizations, and average rehospitalization days were collected. Frequentist analysis was used. RESULTS: The outcomes for 133 NICU patients were analyzed (HR: n=54, LR: n=79). During NICU stay, the prevalence of pulmonary hypertension [HR: 16/54 (30%) CONCLUSIONS: HR CDHSG Stage is associated with worse inpatient and long-term pulmonary outcomes

Miscellaneous Problems

Contains reports on eight research projects

Clozapine-Associated Agranulocytosis Treatment With Granulocyte Colony-Stimulating Factor/Granulocyte-Macrophage Colony-Stimulating Factor:A Systematic Review

PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis. METHODS/PROCEDURES: We conducted a systematic review of published interventional and observational studies, case series, and case reports where G-CSF/GM-CSF was used to treat clozapine-associated agranulocytosis. FINDINGS/RESULTS: We identified 29 reports (40 patients). The median duration of neutrophil recovery time after stopping clozapine and starting cytokine treatment was 7 days (range, 2-13 days) for those with agranulocytosis (absolute neutrophil count IMPLICATIONS/CONCLUSIONS: Our findings indicate that G-CSF/GM-CSF use is well tolerated and suggest that G-CSF can sometimes be safely used to reduce the duration of neutropenia associated with clozapine use. However, the interpretation of this outcome is difficult, given the likely publication bias for positive outcomes in case reports.</p

Longitudinal changes in DNA methylation associated with clozapine use in treatment-resistant schizophrenia from two international cohorts

The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle the effects of diagnosis and medication. We therefore profiled DNA methylation in sequential blood samples (n = 126) from two independent cohorts of patients (n = 38) with treatment-resistant schizophrenia spectrum disorders who commenced clozapine after study enrolment and were followed up for up to six months. We identified significant non-linear changes in cell-type proportion estimates derived from DNA methylation data - specifically B-cells - associated with time on clozapine. Mixed effects regression models were used to identify changes in DNA methylation at specific sites associated with time on clozapine, identifying 37 differentially methylated positions (DMPs) (p < 5 × 10-5) in a linear model and 90 DMPs in a non-linear quadratic model. We compared these results to data from our previous epigenome-wide association study (EWAS) meta-analysis of psychosis, finding evidence that many previously identified DMPs associated with schizophrenia and treatment-resistant schizophrenia might reflect exposure to clozapine. In conclusion, our results indicate that clozapine exposure is associated with changes in DNA methylation and cellular composition. Our study shows that medication effects might confound many case-control studies of neuropsychiatric disorders performed in blood