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Background. Single Assessment Numeric Evaluation (SANE) Score is a single-answer scale widely used within the global medical community. However, to date, it has not been adapted and validated into Russian, particularly as a tool to assess orthopedic shoulder conditions. The aim of the study is to conduct a cross-cultural adaptation and validation of the Russian version of the SANE score as an assessment tool of orthopedic shoulder conditions. Methods. The study included a total of 160 patients with various shoulder pathologies, of which 101 (63%) males and 59 (37%) females. The median age was 45 (37-52) years. At the first stage of the study, we performed cross-cultural adaptation of the SANE score into Russian. The second stage was the validation of the obtained score. Its reliability, validity and responsiveness were evaluated. Reliability was assessed by “test-retest” method. It allowed to measure an intra-class correlation coefficient (ICC) between the SANE score results obtained at the time of the first appointment and again in 14 days. The validity assessment was based on the comparison of the SANE and ASES (have already been adapted into Russian) score results. Responsiveness was assessed using statistical analysis for two dependent samples and calculation of the Guyatt’s Responsivity Index (GRI). Floor and ceiling effects were evaluated as the percentage of patients who reported either minimum or maximum scores. Results. The psychometric properties assessment has revealed good indicators of reliability (ICC = 0.77), validity (a strong direct correlation between SANE and ASES scores = 0.707; a moderate strength inverse correlation with ASES “Intensity of pain” subsection = 0.542) and responsiveness (GRI = 1.861). Floor and ceiling effects accounted for 1% and 3%, respectively, (all below 15%). Conclusions. Adapted to assess the shoulder conditions, the Russian version of the SANE score has good psychometric properties. Its advantage is the combination of completion speed and ease of use with a high-quality integrated subjective assessment of the patients’ set of complaints.

Objective: The aim of this scoping review on infant oral mutilation (IOM) was to study the prevalence, dental complications, and immediate and long-term effects of this practice, in addition to providing a systematic overview on existing knowledge and analysis of identified knowledge gaps on IOM. Methods: Five electronic bibliographic databases (OVID/Medline, Embase.com, Clarivate Analytics/Web of Science Core Collection, SCOPUS, and Global Index Medicus) were searched for relevant studies. Data were entered in a bespoke data-charting form. The risk of bias was assessed by 2 independent reviewers. Results: A total of 478 studies were identified from the search, out of which 42 studies were included in this review. Of the 42 studies, 19 were prevalence studies published between 1969 and 2019 which were additionally assessed for the risk of bias. We found the prevalence of IOM in Uganda was 2% to 30%; Ethiopia, 12% to 86%; Sudan, 10%; Kenya, 61% to 87%; and Tanzania 0% to 24%. Based on the prevalence studies, we observed that the most common factor motivating IOM was diarrhoea. The immediate effects of IOM were found to be infection, bleeding, anaemia, pneumonia, septicaemia, osteomyelitis, meningitis, tetanus, and blood-borne diseases, with some infants dying from these effects. Missing canines, enamel hypoplasia, malformations, abnormal eruption of permanent teeth, occlusal discrepancies, midline shift, chronic periapical infections, rotations, canine transposition, or odontomas were the long-term effects found in relation to IOM. Conclusions: IOM is a practice with serious immediate and long-term consequences that is mainly performed in East Africa (or by people originated from this region) in children aged 4 to 8 months. Most frequently affected are the deciduous canines and mostly the mandibular teeth. It is important to create professional and public awareness of the procedure in low- and high-income countries. Furthermore, there is a need for more research on the prevalence of IOM in Africa and other areas of the world to determine the long-term consequences of the practice.

Literary reading is an interactive process between a reader and a text that depends on a balance between cognitive effort and emotional rewards. By studying both the crucial features of the text and of the subjective reader reception, a better understanding of this interactive process can be reached. In the present study, subjects (N=31) read and rated a work of narrative fiction that was written in a poetic style, thereby offering the readers two pathways to cognitive rewards: Aesthetic appreciation and narrative immersion. Using purely text-based quantitative descriptors, we were able to independently and accurately predict the subjective ratings in the dimensions comprehensibility, valence, arousal, and liking across roughly 140 pages of naturalistic text. The specific text features that were most important in predicting each rating dimension are discussed in detail. In addition, the implications of the findings are discussed more generally in the context of existing models of literary processing and future research avenues for empirical literary studies.

Background Worldwide, there are concerns about declining mental health of children and young people (CYP).Objectives To examine trends in GP consultation rates for psychosocial problems and the impact of the COVID-19 pandemic.Methods We performed a population-based cohort study using electronic GP records of CYP (0–24 years) living in the Rotterdam metropolitan area between 2016 and 2021. We calculated monthly consultation rates for psychosocial problems, stratified by age group and sex. We used negative binomial models to model the pre-COVID-19 trend, and estimate expected rates post-COVID-19 onset. We modelled the effect of COVID-19 infection rate and school closure on consultation rates per sex and age group.Results The cohort increased from 64801 to 92093 CYP between January 2016 and December 2021. Median age was 12.5 years and 49.3% was female. Monthly consultation rates increased from 2,443 to 4,542 consultations per 100,000 patient months over the six years. This trend (RR 1.009, 95%CI 1.008–1.011) started well before the COVID-19 pandemic. Consultation rates of adolescent girls and young women increased most strongly. Between March and May 2020, there was a temporary reduction in consultation rates, whereupon these returned to expected levels. COVID-19 infection rate and school closures showed small but significant associations with consultation rates for psychosocial problems but this did not affect the overall trend. Although consultation rates for psychosocial problems increased, this increment was stable over the entire study period.Conclusion The COVID-19 pandemic did not significantly increase consultation rates for psychosocial problems in CYP. The consultation rates increased, especially in adolescent girls and young women.

Introduction Clinical assessment in emergency departments (EDs) for possible acute myocardial infarction (AMI) requires at least one cardiac troponin (cTn) blood test. The turn-around time from blood draw to posting results in the clinical portal for central laboratory analysers is ~1–2 hours. New generation, high-sensitivity, point-of-care cardiac troponin I (POC-cTnI) assays use whole blood on a bedside (or near bedside) analyser that provides a rapid (8 min) result. This may expedite clinical decision-making and reduce length of stay. Our purpose is to determine if utilisation of a POC-cTnI testing reduces ED length of stay. We also aim to establish an optimised implementation process for the amended clinical pathway.Methods and analysis This quality improvement initiative has a pragmatic multihospital stepped-wedge cross-sectional cluster randomised design. Consecutive patients presenting to the ED with symptoms suggestive of possible AMI and having a cTn test will be included. Clusters (comprising one or two hospitals each) will change from their usual-care pathway to an amended pathway using POC-cTnI—the ‘intervention’. The dates of change will be randomised. Changes occur at 1 month intervals, with a minimum 2 month ‘run-in’ period. The intervention pathway will use a POC-cTnI measurement as an alternate to the laboratory-based cTn measurement. Clinical decision-making steps and logic will otherwise remain unchanged. The POC-cTnI is the Siemens (Erlangen Germany) Atellica VTLi high-sensitivity cTnI assay. The primary outcome is ED length of stay. The safety outcome is cardiac death or AMI within 30 days for patients discharged directly from the ED.Ethics and dissemination Ethics approval has been granted by the New Zealand Southern Health and Disability Ethics Committee, reference 21/STH/9. Results will be published in a peer-reviewed journal. Lay and academic presentations will be made. Māori-specific results will be disseminated to Māori stakeholders.Trial registration number ACTRN12619001189112.

Abstract Background In the adult population, about 50% have hypertension, a risk factor for cardiovascular disease and subsequent premature death. Little is known about the quality of the methods used to diagnose hypertension in primary care. Objectives The objective was to assess the frequency of use of recognized methods to establish a diagnosis of hypertension, and specifically for OBPM, whether three distinct measurements were taken, and how correctly the blood pressure levels were interpreted. Methods A retrospective population-based cohort study using electronic medical records of patients aged between 40 and 70 years, who visited their general practitioner (GP) with a new-onset of hypertension in the years 2012, 2016, 2019, and 2020. A visual chart review of the electronic medical records was used to assess the methods employed to diagnose hypertension in a random sample of 500 patients. The blood pressure measurement method was considered complete if three or more valid office blood pressure measurements (OBPM) were performed, or home-based blood pressure measurements (HBPM), the office- based 30-minute method (OBP30), or 24-hour ambulatory blood pressure measurements (24 H-ABPM) were used. Results In all study years, OBPM was the most frequently used method to diagnose new-onset hypertension in patients. The OBP-30 method was used in 0.4% (2012), 4.2% (2016), 10.6% (2019), and 9.8% (2020) of patients respectively, 24 H-ABPM in 16.0%, 22.2%, 17.2%, and 19.0% of patients and HBPM measurements in 5.4%, 8.4%, 7.6%, and 7.8% of patients, respectively. A diagnosis of hypertension based on only one or two office measurements occurred in 85.2% (2012), 87.9% (2016), 94.4% (2019), and 96.8% (2020) of all patients with OBPM. In cases of incomplete measurement and incorrect interpretation, medication was still started in 64% of cases in 2012, 56% (2016), 60% (2019), and 73% (2020). Conclusion OBPM is still the most often used method to diagnose hypertension in primary care. The diagnosis was often incomplete or misinterpreted using incorrect cut-off levels. A small improvement occurred between 2012 and 2016 but no further progress was seen in 2019 or 2020. If hypertension is inappropriately diagnosed, it may result in under treatment or in prolonged, unnecessary treatment of patients. There is room for improvement in the general practice setting.

Background The Rotterdam Eczema Study was an observational cohort study with an embedded pragmatic randomised controlled open-label trial. It was conducted in children with atopic dermatitis (AD) in the Dutch primary care system. The objective of the trial was to determine whether a potent topical corticosteroid (TCS) is more effective than a low-potency TCS.Objective We are aiming to communicate transparently about the poor recruitment for the trial part and to explore the reasons why recruitment was weak.Design We used a survey to find out what patients in the cohort did when they experienced a flare-up.Methods Descriptive statistics were used to present the baseline characteristics of participants in the trial and the results of the survey.Results In total, 367 patients were included in the cohort. Of these, 32 were randomly assigned to a trial treatment; they had a median age of 4.0 years (IQR 2.0–9.8). A total of 69 of the 86 children (80.2%) who could participate in the survey responded. 39 (56.5%) suffered a flare-up during the follow-up (making them potentially eligible for inclusion in the trial). 26 out of 39 (66.7%) increased their use of an emollient and/or TCS themselves. Only 12 of the 39 (30.7%) contacted their general practitioner (GP) as instructed in the study protocol, but 8 out of these 12 did not meet the inclusion criteria for the trial.Conclusion The main reason why cohort participants did not take part in the trial was that they did not contact their GPs when they experienced an AD flare-up. Furthermore, the majority of patients who contacted their GPs did not match the inclusion criteria of the trial. We expect that the lessons learnt from this study will be useful when developing future studies of children with AD in primary care.

Background: This article attempts to make a reasoned case for re-thinking and repositioning public administration education curriculum in South Africa considering the emerging ‘consultocratic’ regime in the public service. It appears that public managers are determined to outsource private knowledge and expertise with little efforts made to build their own internal capacity. Aim: To establish ways in which the higher education sector can help in preparing future public servants in South Africa. Setting: The article is an extract of the study that was conducted in 13 Limpopo-based municipalities, including provincial Co-operative Governance and Traditional Affairs (COGTA) and South African local government association. Methods: Qualitative methods were used to obtain perspectives from officials and practitioners involved in local government in order to establish reasons why public institutions over-consult. Results: The main finding of this study shows that public institutions, municipalities in this case, over consult because of limited inhouse talent and skills shortage. Participants agreed that while municipalities take blame for ineffective recruitment strategies, higher education sector can play a bigger role in building future skilled graduates. A lack of critical thinking skills was said to be the main problem. With the backup from critical thinking theory, the study proved the need for revised Public Administration (PA) curricula. Conclusion: The repositioning of PA education is encouraged considering that the public sector governance approach is said to be inspired by the market – oriented ideology, the New Public Management, which favours outsourcing against the central role of government. Contribution: Inclusion of critical thinking as module in the PA discourse is recommended. Public sector is also urged to ease legislative red tapes to encourage innovation in the public service. This will guarantee skilled and readily available recruitment pool from which public sector can source talent from, but most significantly, a cultivation of tactical, critical, and strategic thinkers will positively challenge the prevailing consultocratic regime.

BackgroundConducting oral treatment early in the disease course, is encouraged for better health outcomes. Obtaining informed consent is an essential part of medical practice, protecting the legal rights of patients and guiding the ethical practice of medicine. In practice, consent means different things in different contexts. Silver Diamine Fluoride (SDF) and Silver Fluoride (SF) is becoming popular and cost effective methods to manage carious lesions, however, cause black discolouration of lesions treated. Obtaining informed consent and assent is crucial for any dental treatment—and has specific relevance with SDF/ SF treatments.MethodsThe aim of this paper is to describe informed consent regulations for dental care in a selection of countries, focusing on children and patients with special health care needs. An online survey was shared with a convenience sample of dental professionals from 13 countries. The information was explored and the processes of consent were compared.ResultsFindings suggest that there are variations in terms of informed consent for medical practice. In Tanzania, South Africa, India, Kenya, Malaysia and Brazil age is the determining factor for competence and the ability to give self-consent. In other countries, other factors are considered alongside age. For example, in Singapore, the United Kingdom, and the United States the principle of Gillick Competence is applied. Many countries' laws and regulations do not specify when a dentist may overrule general consent to act in the “best interest” of the patient.ConclusionIt is recommended that it is clarified globally when a dentist may act in the “best interest” of the patient, and that guidance is produced to indicate what constitutes a dental emergency. The insights gathered provide insights on international practice of obtaining informed consent and to identify areas for change, to more efficient and ethical treatment for children and patients with special needs. A larger follow up study is recommended to include more or all countries.

Introduction. The modern development of Russia is based on the priority development of high-tech industries and the corresponding infrastructure as prerequisites for achieving technical and technological leadership in the global economy. The innovative development of the country largely depends on the success of scientific and technological policy at the regional level. The purpose of the study is to analyze the spatial regularities of the functioning of innovative territorial clusters to justify promising directions of state cluster policy. Materials and Methods. The study was carried out on the basis of official statistical information of the Federal State Statistics Service, information and analytical reports of the Association of Clusters, Technoparks and Special Economic Zones of Russia, official ratings of innovative development of regions, legislative acts of the federal and regional levels. Based on geo-information technologies, a series of analytical maps have been created that reflect and visualize various aspects of the functioning of innovative territorial clusters in the context of all regions of the Russian Federation. Results. Spatial patterns of the formation of innovative territorial clusters in the regions of Russia have been identified. It is noted that the implementation of the cluster policy contributes to a more rational use of federal budget funds by determining priority investment areas and establishing on this basis the recipients of state support in the cluster with the greatest potential in the context of limited financial resources. This is especially promising when justifying the stimulation of new high-tech industries and enterprises. The patterns of functioning and development trends of innovative territorial clusters are identified. Promising directions for improving Russia’s cluster policy are formulated. Discussion and Conclusion. The author considers that the main purpose of the emerging innovative territorial clusters is the saturation of the domestic market with high-tech goods, services and technologies to achieve the technological independence of the country. The results of the study can be used by organizations and decision makers to substantiate ways to improve cluster policy in the regions of the country.

“Are you LISTENING?” may be one of the most frequent questions preschoolers hear from their parents and teachers, but can children be taught to listen carefully—and thus better comprehend language—and if so, what changes occur in their brains? Twenty-seven four- and five-year-old children were taught a language simulation strategy to use while listening to stories: first, they practiced moving graphics on an iPad to correspond to the story actions, and then they practiced imagining the movements. Compared to a control condition, children in the intervention answered comprehension questions more accurately when imagining moving the graphics and on a measure of transfer using a new story without any instruction and with only immovable graphics. Importantly, for children in the intervention, the change in comprehension from the first to the sixth day was strongly correlated with changes in EEG mu and alpha desynchronization, suggesting changes in motor and visual processing following the intervention. Thus, the data are consistent with our hypothesis that a language simulation listening comprehension intervention can improve children’s listening comprehension by teaching children to align visual and motor processing with language comprehension.

Este artigo procura analisar a relação entre loucos e não-loucos em São João del-Rei entre o fim do século XIX e o começo do século XX a partir da análise da figura dos “tipos de rua”, loucos geralmente ligados ao universo do não-trabalho e de alguma forma marcantes para o cotidiano da cidade. Essas personagens, parte da paisagem urbana brasileira, se tornaram objeto de intervenção do poder-saber psiquiátrico com a ascensão de discursos e práticas alienistas no Brasil desde meados do Oitocentos. Por meio principalmente do exame de periódicos, procuramos entender como a população, dentro dela, as elites letradas locais compreendiam e lidavam com a presença desses sujeitos, em particular, e dos loucos e pobres, em geral, num contexto de normatização do espaço urbano e dos habitantes sob os conceitos de “trabalho” e “civilização”. A relação entre a cidade e seus loucos mostrava-se complexa na medida em que dela faziam parte atores leigos, não-especializados, marcada ainda por mostras de simpatia para com os tipos de rua e de agência desses sujeitos.

Abstract Several questionnaires are used to measure asthma control in children. The most appropriate tool for use in primary care is not defined. In this systematic review, we evaluated questionnaires used to measure asthma control in children in primary care and determined their usefulness in asthma management. Searches were performed in the MEDLINE, Embase, Web of Science, Google Scholar and Cochrane databases with end date 24 June 2022. The study population comprised children aged 5–18 years with asthma. Three reviewers independently screened studies and extracted data. The methodological quality of the studies was assessed, using the COSMIN criteria for the measurement properties of health status questionnaires. Studies conducted in primary care were included if a minimum of two questionnaires were compared. Studies in secondary or tertiary care and studies of quality-of-life questionnaires were excluded. Heterogeneity precluded meta-analysis. Five publications were included: four observational studies and one sub-study of a randomized controlled trial. A total of 806 children were included (aged 5–18 years). We evaluated the Asthma Control Test (ACT), childhood Asthma Control Test (c-ACT), Asthma APGAR system, NAEPP criteria and Royal College of Physicians’ ‘3 questions’ (RCP3Q). These questionnaires assess different symptoms and domains. The quality of most of the studies was rated ‘intermediate’ or ‘poor’. The majority of the evaluated questionnaires do not show substantial agreement with one another, which makes a comparison challenging. Based on the current review, we suggest that the Asthma APGAR system seems promising as a questionnaire for determining asthma control in children in primary care.

Background COVID-19 is a highly challenging infectious disease. Research ethics committees (RECs) have challenges reviewing research on this new pandemic disease under a tight timeline and public pressure. This study aimed to assess RECs’ responses and review during the outbreak in seven Asian countries where the Strategic Initiative for Developing Capacity in Ethical Review (SIDCER) networks are active. Methods The online survey was conducted in seven Asian countries from April to August 2021. Two sets of online questionnaires were developed, one set for the chairs/secretaries and another set for the REC members. The REC profiles obtained from the REC members are descriptive in nature. Data from the chairs/secretaries were compared between the RECs with external quality assessment (SIDCER-Recognized RECs, SR-RECs) and non-external quality assessment (Non-SIDCER-Recognized RECs, NSR-RECs) and analyzed using a Chi-squared test. Results A total of 688 REC members and 197 REC chairs/secretaries participated in the survey. Most RECs have standard operating procedures (SOPs), and have experience in reviewing all types of protocols, but 18.1% had no experience reviewing COVID-19 protocols. Most REC members need specific training on reviewing COVID-19 protocols (93%). In response to the outbreak, RECs used online reviews, increased meeting frequency and single/central REC. All SR-RECs had a member composition as required by the World Health Organisation ethics guidelines, while some NSR-RECs lacked non-affiliated and/or layperson members. SR-RECs reviewed more COVID-related product development protocols and indicated challenges in reviewing risk/benefit and vulnerability (0.010), informed consent form (0.002), and privacy and confidentiality (P = 0.020) than NSR-RECs. Conclusions Surveyed RECs had a general knowledge of REC operation and played a significant role in reviewing COVID-19-related product development protocols. Having active networks of RECs across regions to share updated information and resources could be one of the strategies to promote readiness for future public health emergencies.

Background Mutations to the co‐chaperone protein BAG3 (B‐cell lymphoma‐2–associated athanogene‐3) are a leading cause of dilated cardiomyopathy (DCM). These mutations often impact the C‐terminal BAG domain (residues 420–499), which regulates heat shock protein 70‐dependent protein turnover via autophagy. While mutations in other regions are less common, previous studies in patients with DCM found that co‐occurrence of 2 BAG3 variants (P63A, P380S) led to worse prognosis. However, the underlying mechanism for dysfunction is not fully understood. Methods and Results In this study, we used proteomics, Western blots, and myofilament functional assays on left ventricular tissue from patients with nonfailing, DCM, and DCM with BAG363/380 to determine how these mutations impact protein quality control and cardiomyocyte contractile function. We found dysregulated autophagy and increased protein ubiquitination in patients with BAG363/380 compared with nonfailing and DCM, suggesting impaired protein turnover. Expression and myofilament localization of BAG3‐binding proteins were also uniquely altered in the BAG3,63/380 including abolished localization of the small heat shock protein CRYAB (alpha‐crystallin B chain) to the sarcomere. To determine whether these variants impacted sarcomere function, we used cardiomyocyte force‐calcium assays and found reduced maximal calcium‐activated force in DCM and BAG363/380. Interestingly, myofilament calcium sensitivity was increased in DCM but not with BAG363/380, which was not explained by differences in troponin I phosphorylation. Conclusions Together, our data support that the disease‐enhancing mechanism for BAG3 variants outside of the BAG domain is through disrupted protein turnover leading to compromised sarcomere function. These findings suggest a shared mechanism of disease among pathogenic BAG3 variants, regardless of location.

Abstract Background Allergic rhinitis (AR) affects 10–15% of children. Symptoms in seasonal AR are influenced by pollen exposure. Pollen counts vary throughout the pollen season and therefore, symptom severity fluctuates. This study investigates the correlation between pollen concentration and symptom load in children with AR in The Netherlands. Methods A secondary analysis was performed in a study determining the most effective treatment for children with seasonal AR. Symptoms were measured during three months in 2013 and 2014 using a daily symptom diary. The pollen concentration was measured with a Hirst type volumetric spore trap sampler. A correlation coefficient was calculated for the correlation between the pollen concentration and the mean daily symptom score. The study protocol was approved by the medical ethical review committee of the Erasmus MC and is incorporated in the International Clinical Trials Registry Platform (EUCTR2012-001,591–11-NL). Results In 2014, the correlation coefficient for birch pollen concentration and symptom score was 0.423 (p = 0.000). The correlation coefficient for grass pollen concentration and symptom score was 0.413 (p = 0.000) and 0.655 (p = 0.000) in 2013 and 2014, respectively. A delayed correlation between the birch pollen concentration and the symptom scores was seen up to two days after the pollen measurement (0.151, p = 0.031). For grass pollen this effect lasted up to three days after the pollen measurement (0.194, p = 0.000). Conclusion We found comparable correlations between symptom score and pollen concentration as found by EAACI. Birch and grass pollen have an elongated influence on symptom score of several days. This implies patients need to continue on demand medication longer after a measured pollen peak.

The utilization of phase change materials (PCMs) in solar water heating systems (SWHS) has undergone notable advancements, driven by a rising demand for systems delivering superior performance and efficiency. Extensive research suggests that enhancing heat transfer (HTE) in storage systems is crucial for achieving these improvements. This review employs a bibliometric analysis to track the evolution of HTE methods within this field. While current literature underscores the necessity for further exploration into hot water generation applications, several methodologies exhibit significant promise. Particularly, strategies such as fins, encapsulation, and porous media emerge as prominent HTE techniques, alongside nanofluids, which hold the potential for augmenting solar water heating systems. This review also identifies numerous unexplored techniques awaiting investigation, aiming to pave new paths in research and application within the field of hot water generation. It highlights methods that could be used independently or alongside predominantly used techniques.

This paper explores methods to enhance the reproducibility of Josephson junctions, which are crucial elements in superconducting quantum technologies, when employing the Dolan technique in 30 kV e-beam processes. The study explores the influence of dose distribution along the bridge area on reproducibility, addressing challenges related to fabrication sensitivity. Experimental methods include e-beam lithography, with electron trajectory simulations shedding light on the behavior of backscattered electrons. Wedescribe the fabrication of various Josephson junction geometries and analyze the correlation between the success rates of different lithography patterns and the simulated distribution of backscattered electrons. Our findings demonstrate a success rate of up to 96.3% for the double-resist 1-step low-energy e-beam lithography process. As a means of implementation strategy, we provide a geometric example that takes advantage of simulated stability regions to administer a controlled, uniform dose across the junction area, introducing novel features to overcome the difficulties associated with fabricating bridge-like structures.

Schizophrenia is a significant worldwide health concern, affecting over 20 million individuals and contributing to a potential reduction in life expectancy by up to 14.5 years. Despite its profound impact, the precise pathological mechanisms underlying schizophrenia continue to remain enigmatic, with previous research yielding diverse and occasionally conflicting findings. Nonetheless, one consistently observed phenomenon in brain imaging studies of schizophrenia patients is the disruption of white matter, the bundles of myelinated axons that provide connectivity and rapid signalling between brain regions. Myelin is produced by specialised glial cells known as oligodendrocytes, which have been shown to be disrupted in post-mortem analyses of schizophrenia patients. Oligodendrocytes are generated throughout life by a major population of oligodendrocyte progenitor cells (OPC), which are essential for white matter health and plasticity. Notably, a decline in a specific subpopulation of OPC has been identified as a principal factor in oligodendrocyte disruption and white matter loss in the aging brain, suggesting this may also be a factor in schizophrenia. In this review, we analysed genomic databases to pinpoint intersections between aging and schizophrenia and identify shared mechanisms of white matter disruption and cognitive dysfunction.

Summary: Understanding the cell biological mechanisms that enable tumor cells to persist after therapy is necessary to improve the treatment of recurrent disease. Here, we demonstrate that transient receptor potential channel 6 (TRPC6), a channel that mediates calcium entry, contributes to the properties of breast cancer stem cells, including resistance to chemotherapy, and that tumor cells that persist after therapy are dependent on TRPC6. The mechanism involves the ability of TRPC6 to regulate integrin α6 mRNA splicing. Specifically, TRPC6-mediated calcium entry represses the epithelial splicing factor ESRP1 (epithelial splicing regulatory protein 1), which enables expression of the integrin α6B splice variant. TRPC6 and α6B function in tandem to facilitate stemness and persistence by activating TAZ and, consequently, repressing Myc. Therapeutic inhibition of TRPC6 sensitizes triple-negative breast cancer (TNBC) cells and tumors to chemotherapy by targeting the splicing of α6 integrin mRNA and inducing Myc. These data reveal a Ca2+-dependent mechanism of chemotherapy-induced persistence, which is amenable to therapy, that involves integrin mRNA splicing.

Over the last years many companies and national agencies in different countries have been involved in development of various technical aspects of on-orbit-servicing (OOS). US and Russian OOS experiences are described. The problem of OOS in general is considered as a bit wider. It is shown that OOS relates to development of the next-generation space infrastructure and the solution of the problem of OOS, to a great extent, predetermines the characteristics of the next-generation space systems. Two equally important directions are stressed for OOS activities: first, making satellites serviceable, and the second, creating directly servicing systems. Implementation of each direction includes a wide range of developments. In the first case, we have to consider a capability of docking with the serviced satellite, a guaranteed access to the satellite components, block-modular structure of the serviced satellite, standardization of hardware and connectors, etc. Implementation of the second direction varies from the development of servicing methods and servicing systems to satellite orbits and constellation optimization. The existing and perspective key technologies for serviceable and servicing satellite are presented. It is shown, that the economic benefit of OOS must be justified by more thoroughly from an end-to-end perspective taking into account the features of the future space infrastructure. Servicing allows extending operational lifetime of satellites and thus reducing lifecycle cost, or moreover enable for entirely new systems and mission. These effects could be achieved not only through refuelling or repairing of the satellites, but also through satellite orbit correction. OOS creates a prospect of establishing a commercial servicing and debris removal network lending form the same technology base, which constitutes, however, separate technological problems, which are closely connected with OOS.

Various applications would benefit from the ability to continuously measure biomolecules. Here the authors describe a biosensing technology based on the free diffusion of biofunctionalized particles hovering over a sensor surface, which enables monitoring of analytes (pM-µM) over long timespans.

Abstract Background Anxiety problems are common in both children and adolescents, and many affected children do not receive appropriate treatment. Understaffing of mental healthcare services and long waiting lists form major barriers. In the Netherlands, practice nurses have been introduced into general practice to support general practitioners (GPs) in the management of psychosocial problems. In this study we investigated the views of GPs and practice nurses on their management of paediatric anxiety problems. Methods We performed an exploratory study using semi-structured interviews with 13 GPs and 13 practice nurses in the greater Rotterdam area in 2021. Interviews were transcribed and coded into topics, which were categorized per research question. Results In their management of paediatric anxiety problems, both GPs and practice nurses try to explore the case and the needs of affected children and their parents. GPs rarely follow up affected children themselves. They often refer the child, preferably to their practice nurse. Practice nurses regularly initiate follow-up consultations with affected children themselves. Practice nurses reported using a variety of therapeutic techniques, including elements of cognitive behavioural therapy. In more severe cases, practice nurses refer the child to external mental healthcare services. GPs reported being satisfied with their collaboration with practice nurses. Both GPs and practice nurses experience significant barriers in the management of paediatric anxiety problems. Most importantly, long waiting lists for external mental health care were reported to be a major difficulty. Improving cooperation with external mental healthcare providers was reported to be an important facilitator. Conclusions In their management of paediatric anxiety problems, GPs and practice nurses experience major challenges in the cooperation with external mental healthcare providers and in the long waiting lists for these services. GPs and practice nurses believe that thanks to their shared approach more children with anxiety problems can remain treated in general practice. Future research is needed to evaluate the treatment outcomes of the shared efforts of GPs and practice nurses in their management of paediatric anxiety problems.

ABSTRACT Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm; whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute Plasmodium infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma. Metabolomic assessments confirmed substantial alterations to the plasma of LPS-conditioned and acutely infected mice, and identified a small number of candidate inhibitory metabolites. Finally, we confirmed rapid parasite responses to systemic host inflammation in vivo using parasite scRNA-seq, noting broad impairment in transcriptional activity and translational capacity specifically in trophozoites but not rings or schizonts. Thus, we provide evidence that systemic host inflammation rapidly triggered transcriptional alterations in circulating blood-stage Plasmodium trophozoites and predict candidate inhibitory metabolites in the plasma that may impair parasite maturation in vivo. IMPORTANCE Malaria parasites cyclically invade, multiply, and burst out of red blood cells. We found that a strong inflammatory response can cause changes to the composition of host plasma, which directly slows down parasite maturation. Thus, our work highlights a new mechanism that limits malaria parasite growth in the bloodstream.

O presente artigo tem a finalidade de analisar, seguindo lições de Stanley Paulson, os fundamentos metaéticos do Positivismo Jurídico de Kelsen, procurando identificar três níveis presentes na sua obra, a saber: (i) sua posição não cognitivista acerca do conhecimento moral, no que diz respeito ao status epistêmico dos juízos de bom/correto/justo; (ii) sua posição cognitivista em relação ao conhecimento científico em si, em referência a juízos de veracidade e falsidade no âmbito da Teoria do Direito; e (iii) a sua posição não cognitivista relativamente à dimensão da aplicação das leis e da tomada de decisão pelos tribunais. Esse esclarecimento teórico dos níveis metaéticos no pensamento de Kelsen ajudará a melhor compreender os méritos e os equívocos contidos em sua produção científica.

Background: Kenya has a remarkably high burden of oral diseases, especially in vulnerable communities like persons with HIV (PWH). In the last few decades, the National AIDS & STI Control Programme has efficiently and successfully provided care and prevention against HIV for people living in Kenya. Objective: To assess the feasibility of integrating oral health into HIV research and policy structures in Kenya. Methods: The study took place between November 2021 and April 2022 in the cities of Nairobi, Kisumu, Mombasa, and Eldoret town. Using a semi-structured interview, three remote and 14 in-person sessions were conducted. Participants included individuals with professional experience in HIV and/or oral health such as researchers, potential mentors, institutional administrators, and other grant-funded experts. A qualitative analysis of recordings was performed by nine pretested independent reviewers, all with qualitative data analysis experience. Areas of interest included research, motivation, obstacles, and support. The free coding phase as well as an iterative grouping analysis (MIRO) was used. Findings: Of the 22 stakeholders interviewed in the study, researchers accounted for the majority (48%) of stakeholders, with the rest composed of practitioners (29%), university administrators (19%), and one public health administrator. University administrators were identified as having the most ability for resource mobilization followed by researchers and practitioners. All participants desired improved health outcomes using an evidence-based approach. The primary motivators were increased networks, collaborations, publications, and bridging the gap between oral health and HIV. While the obstacles to their desires included time and lack of funding, Institutional support through recruitment of qualified personnel, mentors, and mentees was their major desirable support. Conclusion: Stakeholders were unanimous in supporting integrating oral health within the current research and policy environment to address the gap between oral health and HIV, and to improve health outcomes through evidence-based interventions.

Introduction: Handheld echocardiography (echo) is the tool of choice for rheumatic heart disease (RHD) screening. We aimed to assess the agreement between screening and standard echo for latent RHD diagnosis in schoolchildren from an endemic setting. Methods: Over 14 months, 3 nonphysicians used handheld machines and the 2012 WHF Criteria to determine RHD prevalence in consented schoolchildren from Brazilian low-income public schools. Studies were interpreted by telemedicine by 3 experts (Brazil, US). RHD-positive children (borderline/definite) and those with congenital heart disease (CHD) were referred for standard echo, acquired and interpreted by a cardiologist. Agreement between screening and standard echo, by WHF subgroups, was assessed. Results: 1390 students were screened in 6 schools, with 110 (7.9%, 95% CI 6.5–9.5) being screen positive (14 ± 2 years, 72% women). Among 16 cases initially diagnosed as definite RHD, 11 (69%) were confirmed, 4 (25%) reclassified to borderline, and 1 to normal. Among 79 cases flagged as borderline RHD, 19 (24%) were confirmed, 50 (63%) reclassified to normal, 8 (10%) reclassified as definite RHD, and 2 had mild CHD. Considering the 4 diagnostic categories, kappa was 0.18. In patients with borderline RHD reclassified to non-RHD, the most frequent WHF criterion was B (isolated mitral regurgitation, 64%), followed by A (2 mitral valve morphological features, 31%). In 1 patient with definite RHD reclassified to normal, the WHF criterion was D (borderline RHD in aortic and mitral valves). After standard echo, RHD prevalence was 3.2% (95% CI 2.3–4.2). Conclusions: Although practical, RHD screening with handheld devices tends to overestimate prevalence.

Summary: Monocytes are abundant immune cells that infiltrate inflamed organs. However, the majority of monocyte studies focus on circulating cells, rather than those in tissue. Here, we identify and characterize an intravascular synovial monocyte population resembling circulating non-classical monocytes and an extravascular tissue-resident monocyte-lineage cell (TR-MC) population distinct in surface marker and transcriptional profile from circulating monocytes, dendritic cells, and tissue macrophages that are conserved in rheumatoid arthritis (RA) patients. TR-MCs are independent of NR4A1 and CCR2, long lived, and embryonically derived. TR-MCs undergo increased proliferation and reverse diapedesis dependent on LFA1 in response to arthrogenic stimuli and are required for the development of RA-like disease. Moreover, pathways that are activated in TR-MCs at the peak of arthritis overlap with those that are downregulated in LFA1−/− TR-MCs. These findings show a facet of mononuclear cell biology that could be imperative to understanding tissue-resident myeloid cell function in RA.

IntroductionMost predictive biomarkers approved for clinical use measure single analytes such as genetic alteration or protein overexpression. We developed and validated a novel biomarker with the aim of achieving broad clinical utility. The Xerna™ TME Panel is a pan-tumor, RNA expression-based classifier, designed to predict response to multiple tumor microenvironment (TME)-targeted therapies, including immunotherapies and anti-angiogenic agents.MethodsThe Panel algorithm is an artificial neural network (ANN) trained with an input signature of 124 genes that was optimized across various solid tumors. From the 298-patient training data, the model learned to discriminate four TME subtypes: Angiogenic (A), Immune Active (IA), Immune Desert (ID), and Immune Suppressed (IS). The final classifier was evaluated in four independent clinical cohorts to test whether TME subtype could predict response to anti-angiogenic agents and immunotherapies across gastric, ovarian, and melanoma datasets.ResultsThe TME subtypes represent stromal phenotypes defined by angiogenesis and immune biological axes. The model yields clear boundaries between biomarker-positive and -negative and showed 1.6-to-7-fold enrichment of clinical benefit for multiple therapeutic hypotheses. The Panel performed better across all criteria compared to a null model for gastric and ovarian anti-angiogenic datasets. It also outperformed PD-L1 combined positive score (>1) in accuracy, specificity, and positive predictive value (PPV), and microsatellite-instability high (MSI-H) in sensitivity and negative predictive value (NPV) for the gastric immunotherapy cohort.DiscussionThe TME Panel’s strong performance on diverse datasets suggests it may be amenable for use as a clinical diagnostic for varied cancer types and therapeutic modalities.

Cancer is the second leading cause of death for children and one of the treatment options for this disease is radiotherapy. Children treated with radiotherapy using photon beams are more likely to develop secondary neoplasms. Proton therapy can reduce the probability of neoplasm formation by up to 50%. Recent studies propose the use of ultra high dose rates as a treatment option. From the threshold of 40 Gy/s it is possible to reach the FLASH effect. This technique protects healthy tissue while maintaining tumor control. The effect was validated in vivo using a proton beam and, therefore, it will be available as a new treatment option. On the other hand, the proposal for FLASH treatment with a proton beam would not use the Bragg peak located in the target volume, which is the differential of proton radiotherapy. In addition, the increase in the intensity of the beam and the energy of the particles, lead to the generation of a greater amount of neutrons. The objective of this work is to evaluate the dose due to the neutrons generated in the interaction with the accelerator components in FLASH proton therapy in relation to conventional proton therapy. The dose evaluation was performed through Monte Carlo simulations, using a water phantom, with the code TOPAS MC. The results found show that the dose of neutrons in the FLASH technique would be about 100 times greater than the dose in the conventional technique. Still, it would be below 1% of the prescribed dose.

Introduction: Vidutolimod, a CpG-A TLR9 agonist, was investigated in a phase 1b study (CMP-001-003; ClinicalTrials.gov, NCT03438318) in combination with atezolizumab with and without radiation therapy (RT) in patients with advanced NSCLC. Methods: Patients with progressive disease after anti–programmed cell death protein 1 or programmed death-ligand 1 therapy received either vidutolimod and atezolizumab (part A) or vidutolimod, atezolizumab, and RT (part B). The primary objective was to evaluate the safety of vidutolimod and atezolizumab with and without RT. Key secondary end point was best objective response rate per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Between March 28, 2018, and July 25, 2019, a total of 29 patients were enrolled and received at least one dose of vidutolimod (part A, n = 13; part B, n = 16). Intratumoral injections of vidutolimod were administered successfully, including injection of visceral lesions. The most common treatment-related adverse events (≥30%) were flu-like symptoms and hypotension. No objective responses were observed; 23.1% and 50.0% of the patients in parts A and B, respectively, had stable disease as best response. In parts A and B, 15.4% and 25.0% of the patients, respectively, had tumor shrinkage (

The finite element method (FEM) was used to investigate the optical–mechanical behavior of a Fabry–Perot Interferometer (FPI) composed of a capillary segment spliced between two sections of standard optical fiber. The developed FEM model was validated by comparing it with theory and with previously published experimental data. The model was then used to show that the absolute strain on the host substrate is usually smaller than the strain measurement obtained with the sensor. Finally, the FEM model was used to propose a cavity geometry that can be produced with repeatability and that yields the correct absolute strain experienced by the host substrate, without requiring previous strain calibration.

Language processing is influenced by sensorimotor experiences. Here, we review behavioral evidence for embodied and grounded influences in language processing across six linguistic levels of granularity. We examine (a) sub-word features, discussing grounded influences on iconicity (systematic associations between word form and meaning); (b) words, discussing boundary conditions and generalizations for the simulation of color, sensory modality, and spatial position; (c) sentences, discussing boundary conditions and applications of action direction simulation; (d) texts, discussing how the teaching of simulation can improve comprehension in beginning readers; (e) conversations, discussing how multi-modal cues improve turn taking and alignment; and (f) text corpora, discussing how distributional semantic models can reveal how grounded and embodied knowledge is encoded in texts. These approaches are converging on a convincing account of the psychology of language, but at the same time, there are important criticisms of the embodied approach and of specific experimental paradigms. The surest way forward requires the adoption of a wide array of scientific methods. By providing complimentary evidence, a combination of multiple methods on various levels of granularity can help us gain a more complete understanding of the role of embodiment and grounding in language processing.

Up-to-date knowledge of key epidemiological aspects of each Plasmodium species is necessary for making informed decisions on targeted interventions and control strategies to eliminate each of them. This study aims to describe the epidemiology of plasmodial species in Mali, where malaria is hyperendemic and seasonal. Data reports collected during high-transmission season over six consecutive years were analyzed to summarize malaria epidemiology. Malaria species and density were from blood smear microscopy. Data from 6870 symptomatic and 1740 asymptomatic participants were analyzed. The median age of participants was 12 years, and the sex ratio (male/female) was 0.81. Malaria prevalence from all Plasmodium species was 65.20% (95% CI: 60.10–69.89%) and 22.41% (CI: 16.60–28.79%) for passive and active screening, respectively. P. falciparum was the most prevalent species encountered in active and passive screening (59.33%, 19.31%). This prevalence was followed by P. malariae (1.50%, 1.15%) and P. ovale (0.32%, 0.06%). Regarding frequency, P. falciparum was more frequent in symptomatic individuals (96.77% vs. 93.24%, p = 0.014). In contrast, P. malariae was more frequent in asymptomatic individuals (5.64% vs. 2.45%, p < 0.001). P. ovale remained the least frequent species (less than 1%), and no P. vivax was detected. The most frequent coinfections were P. falciparum and P. malariae (0.56%). Children aged 5–9 presented the highest frequency of P. falciparum infections (41.91%). Non-falciparum species were primarily detected in adolescents (10–14 years) with frequencies above 50%. Only P. falciparum infections had parasitemias greater than 100,000 parasites per µL of blood. P. falciparum gametocytes were found with variable prevalence across age groups. Our data highlight that P. falciparum represented the first burden, but other non-falciparum species were also important. Increasing attention to P. malariae and P. ovale is essential if malaria elimination is to be achieved.

O ensino de Física Médica evolui a cada ano no Brasil. A necessidade de métodos didáticos e interativos cresce de maneira proporcional visando uma maior motivação e melhor aprendizagem por parte dos alunos. Nos cursos de graduação em Física Médica no Brasil, a disciplina de Física das Radiações é fundamental para a formação profissional do estudante. O objetivo deste trabalho é utilizar o código de Monte Carlo TOPAS para simular experimentos que possibilitem a discussão de conteúdos abordados na disciplina de Física das Radiações. A ferramenta poderá ser utilizada por docentes ao ministrar essa disciplina e por alunos que queiram aprofundar seus conhecimentos e serem introduzidos ao método de Monte Carlo. Inicialmente, foi realizada a validação do TOPAS para os espectros de fótons utilizados através da comparação com dados da literatura. Com isso, foi possível elaborar os arquivos de entrada e realizar a análise de dados dos arquivos de saída para diferentes configurações de irradiação abordadas academicamente de modo a evidenciar a influência de fatores como: estatística das curvas pelo número de histórias; tamanho do campo de irradiação; meios homogêneos e heterogêneos; feixes incidentes de diferentes naturezas. Os resultados obtidos mostram que as simulações elaboradas possibilitam uma análise correta e dinâmica dos processos de interação da radiação com a matéria abordados em Física das Radiações.