Search

Automation of surveillance of infectious diseases—where algorithms are applied to routine care data to replace manual decisions—likely reduces workload and improves quality of surveillance. However, various barriers limit large-scale implementation of automated surveillance (AS). Current implementation strategies for AS in surveillance networks include central implementation (i.e. collecting all data centrally, and central algorithm application for case ascertainment) or local implementation (i.e. local algorithm application and sharing surveillance results with the network coordinating center). In this perspective, we explore whether current challenges can be solved by federated AS. In federated AS, scripts for analyses are developed centrally and applied locally. We focus on the potential of federated AS in the context of healthcare associated infections (AS-HAI) and of severe acute respiratory illness (AS-SARI). AS-HAI and AS-SARI have common and specific requirements, but both would benefit from decreased local surveillance burden, alignment of AS and increased central and local oversight, and improved access to data while preserving privacy. Federated AS combines some benefits of a centrally implemented system, such as standardization and alignment of an easily scalable methodology, with some of the benefits of a locally implemented system including (near) real-time access to data and flexibility in algorithms, meeting different information needs and improving sustainability, and allowance of a broader range of clinically relevant case-definitions. From a global perspective, it can promote the development of automated surveillance where it is not currently possible and foster international collaboration.The necessary transformation of source data likely will place a significant burden on healthcare facilities. However, this may be outweighed by the potential benefits: improved comparability of surveillance results, flexibility and reuse of data for multiple purposes. Governance and stakeholder agreement to address accuracy, accountability, transparency, digital literacy, and data protection, warrants clear attention to create acceptance of the methodology. In conclusion, federated automated surveillance seems a potential solution for current barriers of large-scale implementation of AS-HAI and AS-SARI. Prerequisites for successful implementation include validation of results and evaluation requirements of network participants to govern understanding and acceptance of the methodology. [ABSTRACT FROM AUTHOR]

This work describes a competing activation network, which is regulated by chemical feedback at the liquid‐surface interface. Feedback loops dynamically tune the concentration of chemical components in living systems, thereby controlling regulatory processes in neural, genetic, and metabolic networks. Advances in systems chemistry demonstrate that chemical feedback could be designed based on similar concepts of using activation and inhibition processes. Most efforts, however, are focused on temporal feedback whereas biological networks are maintained by the interplay between temporal and spatial organization. Here, we designed a feedback system comprising a simple acid‐base equilibrium that can be perturbed by two opposing activation processes. Crucially, one of the processes is immobilized on the surface of a microfluidic channel using poly‐l‐lysine (PLL). We measured the capacity of the PLL‐coated channels to resist changes in pH in flow using a pH‐sensitive indicator, phenol red, and showed that this capacity can be increased by employing polyelectrolyte multilayers. Specifically, we found that the rate of local activation (i. e., the deprotonation of the immobilized lysine residues) could be significantly increased to delay the otherwise fast equilibrium. This effect allowed for encoding read and write operations, providing the potential to bestow CRNs with the capacity of molecular information processing. [ABSTRACT FROM AUTHOR]

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 CRW1® frames. Results: A comparable accuracy testing results were observed between the AW and CRW1® 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 0.64mm 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The stay-green trait is recognized as a key drought adaptation mechanism in cereals worldwide. Stay-green sorghum plants exhibit delayed senescence of leaves and stems, leading to prolonged growth, a reduced risk of lodging, and higher grain yield under end-of-season drought stress. More than 45 quantitative trait loci (QTL) associated with stay-green have been identified, including two major QTL (Stg1 and Stg2). However, the contributing genes that regulate functional stay-green are not known. Here we show that the PIN FORMED family of auxin efflux carrier genes induce some of the causal mechanisms driving the stay-green phenotype in sorghum, with SbPIN4 and SbPIN2 located in Stg1 and Stg2 , respectively. We found that nine of 11 sorghum PIN genes aligned with known stay-green QTL. In transgenic studies, we demonstrated that PIN genes located within the Stg1 (SbPIN4), Stg2 (SbPIN2), and Stg3b (SbPIN1) QTL regions acted pleiotropically to modulate canopy development, root architecture, and panicle growth in sorghum, with SbPIN1 , SbPIN2 , and SbPIN4 differentially expressed in various organs relative to the non-stay-green control. The emergent consequence of such modifications in canopy and root architecture is a stay-green phenotype. Crop simulation modelling shows that the SbPIN2 phenotype can increase grain yield under drought. [ABSTRACT FROM AUTHOR]

The postprandial glycemic response is an important metabolic health factor, which, from laboratory studies, is known to change from low to high over the course of the day, and from which negative health outcomes have been linked to nightly eating. We applied interstitial continuous glucose monitoring to examine the glycemic response to a standardized carbohydrate-rich snack (198 kcal) across the day in a real-life setting. Twenty-four healthy participants (12 men, 12 women, 27–61 y old) consumed the snack nine times during 6 d in a crossover design, altering the time of consumption between morning, afternoon and evening. The snack was consumed in the participant's own environment with a preceding fast of at least 2.5 h between their customary main meals and practices. Linear mixed models were used with fixed effect of timing, and participant as random effect, to assess incremental area under the curve, peak value and time-to-peak of the glycemic response. Overall, the highest glycemic excursions were observed in the morning, while a more dampened but prolonged response was observed in the evening. These findings do not concur with previously published laboratory studies. This implies that results obtained under controlled experimental conditions in laboratories cannot be generalized directly to predict chrononutritional effects on the glycemic response in healthy individuals and their daily routines. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that has caused a global pandemic Coronavirus Disease 2019 (COVID-19). Currently, there are no effective treatments specifically for COVID-19 infection. The initial step in SARS-CoV-2 infection is attachment to the angiotensin-converting enzyme 2 (ACE2) on the cell surface. We have developed a protein peptide that effectively disrupts the binding between the SARS-CoV-2 spike protein and ACE2. When delivered by nasal spray, our peptide prevents SARS-CoV-2 spike protein from entering lung and olfactory bulb cells of mice expressing human ACE2. Our peptide represents a potential novel treatment and prophylaxis against COVID-19. [ABSTRACT FROM AUTHOR]

Background: Urban renewal traditionally involves policy sectors such as housing, transport, and employment, which potentially can enhance the health of residents living in deprived areas. Additional involvement of the public health sector might increase the health impact of these urban renewal activities. This study evaluates the health impact of an additional focus on health, under the heading of Healthy District Experiments (HDE), within districts where an urban renewal programme was carried out. Methods: We evaluated changes in health outcomes before the start of the HDE and after implementation, and compared these changes with health changes in control areas, e.g. districts from the urban renewal programme where no additional HDE was implemented. Additionally, we gathered information on the content of the experiments to determine what types of activities have been implemented. Results: The additional activities from the HDE were mostly aimed at strengthening the health care in the districts and at promoting physical activity. When we compared the prevalence in general health, mental health, overweight, obesity, smoking, and physical activity during the study period between the HDE districts and control districts, we found no significant differences in the rate of change. The study is limited by a small sample size and the cross-sectional nature of the data. These and other limitations are discussed. Conclusion: We found no evidence for a beneficial health impact of the activities that were initiated with a specific focus on health, within a Dutch urban renewal programme. Specific attention for network management and the integration of such activities in the wider programme, as well as an allocated budget might be needed in order to sort a health impact. [ABSTRACT FROM AUTHOR]

Due to the wealth of exposome data from longitudinal cohort studies that is currently available, the need for methods to adequately analyze these data is growing. We propose an approach in which machine learning is used to identify longitudinal exposome-related predictors of health, and illustrate its potential through an application. Our application involves studying the relation between exposome and self-perceived health based on the 30-year running Doetinchem Cohort Study. Random Forest (RF) was used to identify the strongest predictors due to its favorable prediction performance in prior research. The relation between predictors and outcome was visualized with partial dependence and accumulated local effects plots. To facilitate interpretation, exposures were summarized by expressing them as the average exposure and average trend over time. The RF model's ability to discriminate poor from good self-perceived health was acceptable (Area-Under-the-Curve = 0.707). Nine exposures from different exposome-related domains were largely responsible for the model's performance, while 87 exposures seemed to contribute little to the performance. Our approach demonstrates that ML can be interpreted more than widely believed, and can be applied to identify important longitudinal predictors of health over the life course in studies with repeated measures of exposure. The approach is context-independent and broadly applicable. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In most agriculture farmlands, weed management is predominantly reliant on integrated weed management (IWM) strategies, such as herbicide application. However, the overuse and misuse of herbicides, coupled with the lack of novel active ingredients, has resulted in the uptrend of herbicide-resistant weeds globally. Moreover, weedy traits that contribute to weed seed bank persistence further exacerbate the challenges in weed management. Despite ongoing efforts in identifying and improving current weed management processes, the pressing need for novel control techniques in agricultural weed management should not be overlooked. The advent of CRISPR/Cas9 gene-editing systems, coupled with the recent advances in "omics" and cheaper sequencing technologies, has brought into focus the potential of managing weeds in farmlands through direct genetic control approaches, but could be achieved stably or transiently. These approaches encompass a range of technologies that could potentially manipulate expression of key genes in weeds to reduce its fitness and competitiveness, or, by altering the crop to improve its competitiveness or herbicide tolerance. The push for reducing or circumventing the use of chemicals in farmlands has provided an added incentive to develop practical and feasible molecular approaches for weed management, although there are significant technical, practical, and regulatory challenges for utilizing these prospective molecular technologies in weed management. [ABSTRACT FROM AUTHOR]

The objective of this study is to determine the factors that are associated with the diagnostic yield of stereotactic brain biopsy. A retrospective analysis was performed on 50 consecutive patients who underwent stereotactic brain biopsies in a single institute from 2014 to 2019. Variables including age, gender, lesion topography and characteristics, biopsy methods, and surgeon's experience were analyzed along with diagnostic rate. This study included 31 male and 19 female patients with a mean age of 48.4 (range: 1–76). Of these, 25 underwent frameless brain-suite stereotactic biopsies, 15 were frameless Portable Brain-lab® stereotactic biopsies and 10 were frame-based CRW® stereotactic biopsies. There was no statistical difference between the diagnostic yield of the three methods. The diagnostic yield in our series was 76%. Age, gender, and biopsy methods had no impact on diagnostic yield. Periventricular and pineal lesion biopsies were significantly associated with negative diagnostic yield (p = 0.01) whereas larger lesions were significantly associated with a positive yield (p = 0.01) with the mean volume of lesions in the positive yield group (13.6 cc) being higher than the negative yield group (7 cc). The diagnostic yields seen between senior and junior neurosurgeons in the biopsy procedure were 95% and 63%, respectively (p = 0.02). Anatomical location of the lesion, volume of the lesion, and experience of the surgeon have significant impacts on the diagnostic yield in stereotactic brain biopsy. There was no statistical difference between the diagnostic yield of the three methods, age, gender, and depth of lesion. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Co‐payments for long‐term care (LTC) can impose a substantial financial burden on the elderly. How this burden is distributed across income groups depends on the design of the co‐payment. We estimate the lifecycle dynamics of LTC using Dutch administrative data. These estimates are inputs in a stochastic lifecycle decision model. Using the model, we analyze the welfare effects of the Dutch income‐ and wealth‐dependent co‐payment system and compare it to alternative systems. We find that the Dutch co‐payment system redistributes income to low‐income groups, who use the most care over their life but contribute the least co‐payments, from high‐income groups, who pay the most. Moreover, the Dutch system protects the middle‐income groups relatively well against financial risk: although alternative co‐payment systems hardly affect these groups average payments, they induce welfare losses of 2% to 4% due to an increased risk of very high co‐payments. [ABSTRACT FROM AUTHOR]

Background For decades, the dopamine D2 receptor (D2R) has been known as the main target of antipsychotic medications, but the mechanism for antipsychotic effects beyond this pharmacological target remains unclear. Disrupted-in-schizophrenia 1 (DISC1) is a gene implicated in the etiology of schizophrenia, and we have found elevated levels of the D2R-DISC1 complex in the postmortem brain tissue of patients with schizophrenia. Methods We used coimmunoprecipitation to measure D2R-DISC1 complex levels in peripheral blood samples from patients with schizophrenia and unaffected controls in 3 cohorts (including males and females) from different hospitals. We also used label-free mass spectrometry to conduct proteomic analysis of these samples. Results Levels of the D2R-DISC1 complex were elevated in the peripheral blood samples of patients with schizophrenia from 3 independent cohorts, and were normalized with antipsychotic treatment. Proteomic analysis of the blood samples from patients with high D2R-DISC1 complex levels that were normalized with antipsychotic treatment revealed a number of altered proteins and pathways associated with D2R, DISC1 and the D2R-DISC1 complex. We identified additional proteins and pathways that were associated with antipsychotic treatment in schizophrenia, and that may also be novel targets for schizophrenia treatment. Limitations Sample sizes were relatively small, but were sufficient to detect associations between D2R-DISC1 levels, schizophrenia and treatment response. The relevance of leukocyte changes to the symptoms of schizophrenia is unknown. The coimmunoprecipitation lanes included several nonspecific bands. Conclusion Levels of the D2R-DISC1 complex were elevated in patients with schizophrenia and reduced with antipsychotic treatment. This finding reinforces the independent role of each protein in schizophrenia. Our results enhanced our understanding of the molecular pathways involved in schizophrenia and in antipsychotic medications, and identified novel potential molecular targets for treating schizophrenia. [ABSTRACT FROM AUTHOR]

The front cover artwork is provided by the Chemical Reaction Network lab at the University of Twente. The image shows a microfluidic channel with multilayer polylysine surfaces, which provide the potential to bestow an acid‐base equilibrium with the capacity of signal transduction. Read the full text of the Research Article at 10.1002/syst.202300030.“Localized reactions provide the potential to bestow chemical reaction networks with the capacity of signal transduction. This work demonstrates that a microfluidic channel with polylysine‐coated surfaces could be used to delay an otherwise fast acid‐base equilibrium. Control over the rates of protonation and deprotonation allows for molecular information processing…” This and more about the story behind the front cover can be found in the Research Article at 10.1002/syst.202300030. [ABSTRACT FROM AUTHOR]

The front cover artwork is provided by the Chemical Reaction Network lab at the University of Twente. The image shows a microfluidic channel with multilayer polylysine surfaces, which provide the potential to bestow an acid‐base equilibrium with the capacity of signal transduction. Read the full text of the Research Article at 10.1002/syst.202300030. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is associated with significant morbidity and mortality. Most antidepressant medications target the serotonin and norepinephrine transporters, but a significant minority of patients do not respond to treatment and novel therapeutic targets are needed. We previously identified a protein complex composed of the α7 nicotinic acetylcholine receptor (nAChR) and NMDA glutamate receptors (NMDARs), through which α7nAChR upregulates NMDAR function. Disruption of the α7nAChR–NMDAR complex with an interfering peptide blocked α7nAChR-mediated upregulation of NMDAR function and cue-induced reinstatement of nicotine seeking in rat models of relapse. Here we report that disrupting the α7nAChR–NMDAR complex with the interfering peptide also has antidepressant-like effects in the forced swim test (FST), a common rat behaviour screening test for antidepressant effects. Furthermore, the interfering peptide significantly increases extracellular signal-regulated kinase (ERK) activity in the animals subjected to the FST. Our results provide a novel potential therapeutic target for the development of new antidepressant medications. [ABSTRACT FROM AUTHOR]

Background: Worldwide, socioeconomic differences in health and use of healthcare resources have been reported, even in countries providing universal healthcare coverage. However, it is unclear how large these socioeconomic differences are for different types of care and to what extent health status plays a role. Therefore, our aim was to examine to what extent healthcare expenditure and utilization differ according to educational level and income, and whether these differences can be explained by health inequalities.Methods: Data from 18,936 participants aged 25-79 years of the Dutch Health Interview Survey were linked at the individual level to nationwide claims data that included healthcare expenditure covered in 2017. For healthcare utilization, participants reported use of different types of healthcare in the past 12 months. The association of education/income with healthcare expenditure/utilization was studied separately for different types of healthcare such as GP and hospital care. Subsequently, analyses were adjusted for general health, physical limitations, and mental health.Results: For most types of healthcare, participants with lower educational and income levels had higher healthcare expenditure and used more healthcare compared to participants with the highest educational and income levels. Total healthcare expenditure was approximately between 50 and 150 % higher (depending on age group) among people in the lowest educational and income levels. These differences generally disappeared or decreased after including health covariates in the analyses. After adjustment for health, socioeconomic differences in total healthcare expenditure were reduced by 74-91 %.Conclusions: In this study among Dutch adults, lower socioeconomic status was associated with increased healthcare expenditure and utilization. These socioeconomic differences largely disappeared after taking into account health status, which implies that, within the universal Dutch healthcare system, resources are being spent where they are most needed. Improving health among lower socioeconomic groups may contribute to decreasing health inequalities and healthcare spending. [ABSTRACT FROM AUTHOR]

The value of optimization: Glioblastoma (GBM) is one of the most malignant types of tumors of the central nervous system with an average survival time of only 12 to 18 months. The synthetic peptide vaccine pepVIII, targeting EGFRvIII, has shown promising results in patients. Here, Fidanza et al. developed an optimization strategy and characterized several peptides derived from pepVIII in GBM murine models. The authors found that a tyrosine substitution (Y6-pepVIII) improved the efficacy of the vaccine in mice by increasing proteasome cleavage. Y6-pepVIII in combination with anti–PD-1 therapy increased survival compared to the checkpoint blockade therapy alone. The results suggest that similar optimization strategy could be effective in improving treatment efficacy of other peptide vaccines. Despite its essential role in antigen presentation, enhancing proteasomal processing is an unexploited strategy for improving vaccines. pepVIII, an anticancer vaccine targeting EGFRvIII, has been tested in several trials for glioblastoma. We examined 20 peptides in silico and experimentally, which showed that a tyrosine substitution (Y6-pepVIII) maximizes proteasome cleavage and survival in a subcutaneous tumor model in mice. In an intracranial glioma model, Y6-pepVIII showed a 62 and 31% improvement in median survival compared to control animals and pepVIII-vaccinated mice. Y6-pepVIII vaccination altered tumor-infiltrating lymphocyte subsets and expression of PD-1 on intratumoral T cells. Combination with anti–PD-1 therapy cured 45% of the Y6-pepVIII–vaccinated mice but was ineffective for pepVIII-treated mice. Liquid chromatography–tandem mass spectrometry analysis of proteasome-digested pepVIII and Y6-pepVIII revealed that most fragments were similar but more abundant in Y6-pepVIII digests and 77% resulted from proteasome-catalyzed peptide splicing (PCPS). We identified 10 peptides that bound human and murine MHC class I. Nine were PCPS products and only one peptide was colinear with EGFRvIII, indicating that PCPS fragments may be a component of MHC class I recognition. Despite not being colinear with EGFRvIII, two of three PCPS products tested were capable of increasing survival when administered independently as vaccines. We hypothesize that the immune response to a vaccine represents the collective contribution from multiple PCPS and linear products. Our work suggests a strategy to increase proteasomal processing of a vaccine that results in an augmented immune response and enhanced survival in mice. [ABSTRACT FROM AUTHOR]

Key message: Integrating CRISPR/Cas9 genome editing into modern breeding programs for crop improvement in cereals. Global climate trends in many agricultural regions have been rapidly changing over the past decades, and major advances in global food systems are required to ensure food security in the face of these emerging challenges. With increasing climate instability due to warmer temperatures and rising CO2 levels, the productivity of global agriculture will continue to be negatively impacted. To combat these growing concerns, creative approaches will be required, utilising all the tools available to produce more robust and tolerant crops with increased quality and yields under more extreme conditions. The integration of genome editing and transgenics into current breeding strategies is one promising solution to accelerate genetic gains through targeted genetic modifications, producing crops that can overcome the shifting climate realities. This review focuses on how revolutionary genome editing tools can be directly implemented into breeding programs for cereal crop improvement to rapidly counteract many of the issues affecting agriculture production in the years to come. [ABSTRACT FROM AUTHOR]

Chordomas are rare and slow-growing locally destructive bone tumors that can develop in the craniospinal axis. It is commonly found in the sacrococcygeal region whereas only 25–35% are found in the clival region. Headache with neurological deficits are the most common clinical presentations. Complete surgical resection either via open or endoscopic endonasal approaches are the main mode of treatment. Here, we report a series of 5 cases of clival chordomas which was managed via endoscopic endonasal approaches in our center. A retrospective analysis of patients who had undergone endoscopic endonasal resection of clival chordoma in Sarawak General Hospital from 2014 to 2018. A total of 5 cases were operated on endoscopically via a combine effort of both the otorhinolaryngology team and the neurosurgical team during the study period from year 2013 to 2018. From our patient, 2 were female and 3 were male patients. The main clinical presentation was headache, squinting of eye and nasopharyngeal fullness. All our patient had endoscopic endonasal debulking of clival tumor done, with average of hospital stay from 9 – 23 days. Pos-operatively, patients were discharged back well. Endoscopic endonasal resection of clival chordomas gives good surgical resection results with low morbidity rates and therefore can be considered as a surgical option in centers where the surgical specialties are available. [ABSTRACT FROM AUTHOR]

The World Health Organization characterized COVID-19 (coronavirus disease 2019) as a pandemic on March 11, 2020 (WHO). Within a couple of days, all Canadian provinces announced the implementation of social distancing measures. We evaluated the immediate effect of COVID-19 on psychiatric emergency and inpatient services in Canada's largest psychiatric hospital in the first month of the pandemic. We extracted data from the electronic medical records of the Center for Addiction and Mental Health in Toronto, Canada. We compared emergency department visits, inpatient occupancy rates, and length of stay in March 2019 and March 2020, and during the first and second half of March 2020. There was a decrease in the number of emergency department visits and inpatient occupancy rates in March 2020 compared to March 2019. There was also a significant decrease in the number of emergency department visits and inpatient occupancy rates in the second half of March 2020 compared to the first half. Our findings suggest that the pandemic was followed by a rapid decrease in the usage of psychiatric emergency and inpatient services in a large mental health hospital. Future studies will need to assess whether this decrease will be followed by a return to baseline or an increase in need for these services. [ABSTRACT FROM AUTHOR]

Uterine Leiomyosarcoma (uLMS) is an aggressive tumor with poor clinical outcome. Skull and dural metastasis from uterine uLMS is exceptionally rare. We report a 60-year-old woman who had a 6 months' history of per vaginal bleed and abdominal pain who presented to us in a confused state and raised intracranial pressure symptoms with swelling over her right frontal-temporal region. She underwent excision of the right frontal-temporal tumor and evacuation of a right subdural hematoma (SDH), which greatly improved her condition. Postoperatively, she underwent adjuvant radiotherapy and chemotherapy. This case highlights the importance of clinical suspicion to diagnose patients with this rare metastasis to this region and the appropriate subsequent treatment. We herein report a rare case of metastatic uLMS with skull and dural metastasis that presented with SDH. [ABSTRACT FROM AUTHOR]

To control the rise in Neisseria meningitidis strain W infections, during 2018-2019, the Netherlands launched a catch-up meningococcal conjugate (MenACWY) vaccination campaign for teenagers (13-18 years of age). Applying a mental models approach, we surveyed teenagers and their parents about their knowledge and beliefs about meningococcal disease, the MenACWY vaccination, vaccinations in general, and their MenACWY vaccination intentions. Using random forest analysis, we studied predictions of vaccination intentions by knowledge and beliefs. Survey response rate was 52.8% among teenagers and 59.4% among parents. MenACWY vaccination intentions were best predicted by knowledge and beliefs about vaccinations in general, surpassing knowledge and beliefs about meningococcal disease and the MenACWY vaccination. For teenagers, their parents' intention that the teenager be vaccinated was a strong predictor of the teenagers' own vaccination intention. To optimize vaccination uptake during future outbreaks, we recommend that communications emphasize the effectiveness and safety of vaccines and continue to focus on parents. [ABSTRACT FROM AUTHOR]

Background: Poisoning in pregnancy can cause maternal and neonatal morbidity and mortality, but few data detail such events. Herein, we describe poisoning exposures in pregnant women identified by a large Canadian Poison Centre. Methods: This retrospective study evaluated poisoning exposures in pregnant women aged 12–60 years, reported to the Ontario Poison Centre from 2010 to 2017. Exposures were identified from the Poison Centre database by calls received, in which the patient was also reported to be pregnant. We collected patient demographics (age, trimester, and location), as well as information about the poisoning exposure (number and type of substances, route of exposure, reason for exposure, decontamination, and treatment recommendations). Results: There were 1716 cases of poisoning exposures during pregnancy over the eight-year study period, representing 0.28% of all 619,539 calls over the period. Median maternal age was 29 years (IQR 25–33), and exposures were most frequent in the second trimester of pregnancy (41%). Unintentional exposures (n = 1397) accounted for 81% of all calls. Of the 18% of calls (n = 305) for intentional exposures, 71% (n = 219) were suspected attempted suicides. Intentional exposures were more frequent in the first (OR 2.64, 95% CI 1.85–3.76) and second trimesters (OR 1.61, 95% CI 1.13–2.28), relative to third trimester. The associated risk of intentional exposures was more likely in women aged ≤19 years (OR 21.41, 95% CI 12.75–35.94) and 20–29 years (OR 3.72, 95% CI 2.70–5.14), relative to women ≥30 years old. Conclusions: Intentional poisoning exposures in pregnancy most commonly involve young women in the first two trimesters. Population-based studies are needed to further examine risk factors for overdose, poisoning, and self-harm in pregnancy, as well as perinatal outcomes. [ABSTRACT FROM AUTHOR]

The Disrupted in schizophrenia 1 (DISC1) gene encodes a scaffolding protein that is involved in many neural functions such as neurogenesis, neural differentiation, embryonic neuron migration and neurotransmitter signalling. DISC1 was originally implicated in schizophrenia in a single family with a drastic mutation, a chromosomal translocation severing the mid-point of the gene (aa 598). Some common DISC1 variants have also been associated with schizophrenia in the general population, but those located far from the chromosomal translocation breakpoint likely have a different functional impact. We previously reported that DISC1 forms a protein complex with dopamine D2 receptor (D2R), the main target for antipsychotic medications. The D2R-DISC1 complex is elevated in brain tissue from schizophrenia patients and facilitates glycogen synthase kinase (GSK)-3 signaling. The DISC1 R264Q variant is located within the region that binds the D2R, and we found that this polymorphism increases the affinity of DISC1 for the D2R and promotes GSK3 activity. Our results suggest a possible mechanism by which this common polymorphism could affect aspects of brain function that are relevant to psychosis and schizophrenia. This provides additional insight into molecular mechanisms underlying schizophrenia that could be exploited in the development of novel pharmacological treatments. [ABSTRACT FROM AUTHOR]

Complex systems such as ecosystems, the climate and stock markets produce emergent behaviour which is capable of undergoing dramatic change when pushed beyond a tipping point. Such complex systems display Early Warning Signals in their behaviour when they are close to a tipping point. Here we show that a complex chemical reaction network can also display early warning signals when it is in close proximity to the boundary between oscillatory and steady state concentration behaviours. We identify early warning signals using both an active sensing method, based on the recovery time of an oscillatory response after a perturbation in temperature, and a passive sensing method, based upon a change in the shape of the oscillations. The presence of the early warning signals indicates that complex, dissipative chemical networks can intrinsically sense their proximity to a boundary between behaviours. [ABSTRACT FROM AUTHOR]

Background: We developed a system to automatically classify stance towards vaccination in Twitter messages, with a focus on messages with a negative stance. Such a system makes it possible to monitor the ongoing stream of messages on social media, offering actionable insights into public hesitance with respect to vaccination. At the moment, such monitoring is done by means of regular sentiment analysis with a poor performance on detecting negative stance towards vaccination. For Dutch Twitter messages that mention vaccination-related key terms, we annotated their stance and feeling in relation to vaccination (provided that they referred to this topic). Subsequently, we used these coded data to train and test different machine learning set-ups. With the aim to best identify messages with a negative stance towards vaccination, we compared set-ups at an increasing dataset size and decreasing reliability, at an increasing number of categories to distinguish, and with different classification algorithms.Results: We found that Support Vector Machines trained on a combination of strictly and laxly labeled data with a more fine-grained labeling yielded the best result, at an F1-score of 0.36 and an Area under the ROC curve of 0.66, considerably outperforming the currently used sentiment analysis that yielded an F1-score of 0.25 and an Area under the ROC curve of 0.57. We also show that the recall of our system could be optimized to 0.60 at little loss of precision.Conclusion: The outcomes of our study indicate that stance prediction by a computerized system only is a challenging task. Nonetheless, the model showed sufficient recall on identifying negative tweets so as to reduce the manual effort of reviewing messages. Our analysis of the data and behavior of our system suggests that an approach is needed in which the use of a larger training dataset is combined with a setting in which a human-in-the-loop provides the system with feedback on its predictions. [ABSTRACT FROM AUTHOR]

Current efforts to design functional molecular systems have overlooked the importance of coupling out‐of‐equilibrium behaviour with changes in the environment. Here, the authors use an oscillating reaction network and demonstrate that the application of environmental forcing, in the form of periodic changes in temperature and in the inflow of the concentration of one of the network components, removes the dependency of the periodicity of this network on temperature or flow rates and enforces a stable periodicity across a wide range of conditions. Coupling a system to a dynamic environment can thus be used as a simple tool to regulate the output of a network. In addition, the authors show that coupling can also induce an increase in behavioural complexity to include quasi‐periodic oscillations. [ABSTRACT FROM AUTHOR]

Background Aggregated claims data on medication are often used as a proxy for the prevalence of diseases, especially chronic diseases. However, linkage between medication and diagnosis tend to be theory based and not very precise. Modelling disease probability at an individual level using individual level data may yield more accurate results. Methods Individual probabilities of having a certain chronic disease were estimated using the Random Forest (RF) algorithm. A training set was created from a general practitioners database of 276 723 cases that included diagnosis and claims data on medication. Model performance for 29 chronic diseases was evaluated using Receiver-Operator Curves, by measuring the Area Under the Curve (AUC). Results The diseases for which model performance was best were Parkinson's disease (AUC =.89, 95% CI =.77–1.00), diabetes (AUC =.87, 95% CI =.85–.90), osteoporosis (AUC =.87, 95% CI =.81–.92) and heart failure (AUC =.81, 95% CI =.74–.88). Five other diseases had an AUC >.75: asthma, chronic enteritis, COPD, epilepsy and HIV/AIDS. For 16 of 17 diseases tested, the medication categories used in theory-based algorithms were also identified by our method, however the RF models included a broader range of medications as important predictors. Conclusion Data on medication use can be a useful predictor when estimating the prevalence of several chronic diseases. To improve the estimates, for a broader range of chronic diseases, research should use better training data, include more details concerning dosages and duration of prescriptions, and add related predictors like hospitalizations. [ABSTRACT FROM AUTHOR]

Dietary supplements are products that are widely used for instance as energisers or to lose weight. There have been cases reported where undeclared ingredients present in such supplements have caused adverse effects on the health of the user. As there are many different products to choose from, it seems impossible to predict which might contain harmful components and to ban them from the market. Nonetheless, the use of dietary supplements and the experiences of users are shared in online discussions. We describe the development of a search engine to retrieve products associated with certain effects. Upon application we were able to retrieve a list of dietary supplements that are repeatedly associated with excessive effects by users on public fora. The top of the list contains supplements that have previously been banned because they contained undeclared harmful components. The use of the search engine as described here is a powerful method for making a risk-based selection of dietary supplements which can then be analysed for the presence of illegal or other unwanted components. [ABSTRACT FROM AUTHOR]

Respondent-driven detection is a chain recruitment method used to sample contact persons of infected persons in order to enhance case finding. It starts with initial individuals, so-called seeds, who are invited for participation. Afterwards, seeds receive a fixed number of coupons to invite individuals with whom they had contact during a specific time period. Recruitees are then asked to do the same, resulting in successive waves of contact persons who are connected in one recruitment tree. However, often the majority of participants fail to invite others, or invitees do not accept an invitation, and recruitment stops after several waves. A mathematical model can help to analyse how various factors influence peer recruitment and to understand under which circumstances sustainable recruitment is possible. We implemented a stochastic simulation model, where parameters were suggested by empirical data from an online survey, to determine the thresholds for obtaining large recruitment trees and the number of waves needed to reach a steady state in the sample composition for individual characteristics. We also examined the relationship between mean and variance of the number of invitations sent out by participants and the probability of obtaining a large recruitment tree. Our main finding is that a situation where participants send out any number of coupons between one and the maximum number is more effective in reaching large recruitment trees, compared to a situation where the majority of participants does not send out any invitations and a smaller group sends out the maximum number of invitations. The presented model is a helpful tool that can assist public health professionals in preparing research and contact tracing using online respondent-driven detection. In particular, it can provide information on the required minimum number of successfully sent invitations to reach large recruitment trees, a certain sample composition or certain number of waves. [ABSTRACT FROM AUTHOR]