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Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a rare genetic disorder caused by deleterious genetic variation in the prolyl endopeptidase-like (PREPL) gene. Previous reports have described patients with deletions and nonsense variants in PREPL, but nothing is known about the effect of missense variants in the pathology of CMS22. In this study, we have functionally characterized missense variants in PREPL from 3 patients with CMS22, all with hallmark phenotypes. Biochemical evaluation revealed that these missense variants do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria and disease mechanism. Structural analysis showed that the variants affect regions most likely involved in intraprotein or protein-protein interactions. Indeed, binding to a selected group of known interactors was differentially reduced for the 3 variants. The importance of nonhydrolytic functions of PREPL was investigated in catalytically inactive PREPL p.Ser559Ala cell lines, which showed that hydrolytic activity of PREPL is needed for normal mitochondrial function but not for regulating AP1-mediated transport in the transgolgi network. In conclusion, these studies showed that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense variants that do not necessarily result in a loss of hydrolytic activity of PREPL.

There is an urgent need for new antifungal drugs to treat invasive fungal diseases. Unfortunately, the echinocandin drugs that are fungicidal against other important fungal pathogens are ineffective against Cryptococcus neoformans , the causative agent of life-threatening meningoencephalitis in immunocompromised people. Contributing mechanisms for echinocandin tolerance are emerging with connections to calcineurin signaling, the cell wall, and membrane composition. In this context, we discovered that a defect in phosphate uptake impairs the tolerance of C. neoformans to the echinocandin caspofungin. Our previous analysis of mutants lacking three high affinity phosphate transporters revealed reduced elaboration of the polysaccharide capsule and attenuated virulence in mice. We investigated the underlying mechanisms and found that loss of the transporters and altered phosphate availability influences the cell wall and membrane composition. These changes contribute to the shedding of capsule polysaccharide thus explaining the reduced size of capsules on mutants lacking the phosphate transporters. We also found an influence of the calcineurin pathway including calcium sensitivity and an involvement of the endoplasmic reticulum in the response to phosphate limitation. Furthermore, we identified membrane and lipid composition changes consistent with the role of phosphate in phospholipid biosynthesis and with previous studies implicating membrane integrity in caspofungin tolerance. Finally, we discovered a contribution of phosphate to titan cell formation, a cell type that displays modified cell wall and capsule composition. Overall, our analysis reinforces the importance of phosphate as a regulator of cell wall and membrane composition with implications for capsule attachment and antifungal drug susceptibility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Qu, Bhalla, Horianopoulos, Hu, Alcázar Magaña, Foster, Roque da Silva, Kretschmer and Kronstad.)

Context: Epilepsy is one of the most common chronic neurological disorders in childhood. Structural malformations of the cerebral cortex are an important cause of developmental disabilities and epilepsy; this leads to a significant amount of psychological burden on parents of such children. Despite being a common and debilitating neurological illness, there is a paucity of data on the burden of stress and depression in parents of such children., Aims: The objective was to find out the burden of these illnesses on caregivers of such children., Settings and Design: This was a hospital-based cross-sectional, questionnaire-based study conducted in the Department of Pediatrics (both inpatient and outpatient), PGIMS Rohtak, during the period of June-September 2023. Parents of children with structural epilepsy (age: 2-14 years) were study subjects., Methods and Material: A cross-sectional study involving parents of 100 children with structural epilepsy (aged 2-14 years) was conducted using Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HAM-A)., Statistical Analysis Used: Data were recorded in Microsoft Office Excel. Statistical analysis was performed using Statistical Package for Social Sciences v22. Statistical significance was checked by P value (two-tailed) considering value < 0.05 as significant., Results: Higher levels of anxiety and depression were seen in parents of children having structural epilepsy. Relatively higher levels were seen in parents of such children who were receiving polytherapy (HDRS (P = 0.002); HAM-A (0.001))., Conclusions: This study shows a higher prevalence of anxiety and depression among caregivers of children having structural epilepsy. Parents of such children require extra support as they appear to be a population prone to illnesses that will hinder the proper care of children with structural epilepsy and their quality of life. This circle has to be broken for better upbringing and treatment compliance for such children. Preventive and therapeutic interventions need to be taken to reduce the burden of such psychiatric illness at the community level., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Small GTPases of the Rab family coordinate multiple membrane fusion and trafficking events in eukaryotes. In fungi, the Rab GTPase, Ypt7, plays a critical role in late endosomal trafficking, and is required for homotypic fusion events in vacuole biogenesis and inheritance. In this study, we identified a putative YPT7 homologue in Cryptococcus neoformans , a fungal pathogen causing life threatening meningoencephalitis in immunocompromised individuals. As part of an ongoing effort to understand mechanisms of iron acquisition in C. neoformans , we established a role for Ypt7 in growth on heme as the sole iron source. Deletion of YPT7 also caused abnormal vacuolar morphology, defective endocytic trafficking and autophagy, and mislocalization of Aph1, a secreted vacuolar acid phosphatase. Ypt7 localized to the vacuolar membrane and membrane contact sites between the vacuole and mitochondria (vCLAMPs), and loss of the protein impaired growth on inhibitors of the electron transport chain. Additionally, Ypt7 was required for robust growth at 39°C, a phenotype likely involving the calcineurin signaling pathway because ypt7 mutants displayed increased susceptibility to the calcineurin-specific inhibitors, FK506 and cyclosporin A; the mutants also had impaired growth in either limiting or high levels of calcium. Finally, Ypt7 was required for survival during interactions with macrophages, and ypt7 mutants were attenuated for virulence in a mouse inhalation model thus demonstrating the importance of membrane trafficking functions in cryptococcosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hu, Qu, Bhalla, Xue, Bakkeren, Lee and Kronstad.)

Cryptococcus neoformans causes cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug against C. neoformans . BRI can affect the organization of the cell membrane, increasing the fungal cell permeability. We also investigated the effects of BRI against the model system Saccharomyces cerevisiae by analyzing libraries of mutants grown in the presence of BRI. In S. cerevisiae , BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. In vivo experiments show BRI significantly reduces C. neoformans survival inside macrophages and partially clears C. neoformans lung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action against C. neoformans . BRI + CAS affects endocytic movement, calcineurin, and mitogen-activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis., Importance: Invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Cryptococcosis, one of the most prevalent fungal diseases, is generally characterized by meningitis and is mainly caused by two closely related species of basidiomycetous yeasts, Cryptococcus neoformans and Cryptococcus gattii . There are few therapeutic options for treating cryptococcosis, and searching for new antifungal agents against this disease is very important. Here, we present brilacidin (BRI) as a potential antifungal agent against C. neoformans . BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammatory activity against bacteria and viruses. BRI alone was shown to inhibit the growth of C. neoformans , acting as a fungicidal drug, but surprisingly also potentiated the activity of caspofungin (CAS) against this species. We investigated the mechanism of action of BRI and BRI + CAS against C. neoformans . We propose BRI as a new antifungal agent against cryptococcosis., Competing Interests: Gustavo H. Goldman is a member of the scientific advisory board of Innovation Pharmaceuticals, a company that is conducting clinical trials on brilacidin. Other authors have no conflict of interest.

Loss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic Syndrome-22 (CMS22). It is characterized by severe neonatal hypotonia, feeding problems, growth retardation, and hyperphagia leading to rapid weight gain later in childhood. The phenotypic similarities with Prader-Willi syndrome (PWS) are striking, suggesting that similar pathways are affected. The aim of this study was to identify changes in the hypothalamic-pituitary axis in mouse models for both disorders and to examine mitochondrial function in skin fibroblasts of patients and knockout cell lines. We have demonstrated that Prepl is downregulated in the brains of neonatal PWS-IC -p/+m mice. In addition, the hypothalamic-pituitary axis is similarly affected in both Prepl -/- and PWS-IC -p/+m mice resulting in defective orexigenic signaling and growth retardation. Furthermore, we demonstrated that mitochondrial function is altered in PREPL knockout HEK293T cells and can be rescued with the supplementation of coenzyme Q10. Finally, PREPL-deficient and PWS patient skin fibroblasts display defective mitochondrial bioenergetics. The mitochondrial dysfunction in PWS fibroblasts can be rescued by overexpression of PREPL. In conclusion, we provide the first molecular parallels between CMS22 and PWS, raising the possibility that PREPL substrates might become therapeutic targets for treating both disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: International and observational epidemiological studies provide evidence that vitamin D deficiency may confer increased risk of influenza and respiratory tract infection. This study was undertaken to evaluate the prevalence of vitamin D deficiency in pneumonia in children, and to assess its relationship with the severity., Methods: Study group included children aged between 2 months to 5 years of age admitted as inpatients who presented with clinical features of pneumonia as per WHO Classification. Detailed clinical assessment and physical examination was done at the time of admission and patients were enrolled and relevant findings were noted in prestructured proforma. Vitamin D levels <30 nmol/L (<12 ng/mL) were defined as deficient, 30-50 nmol/L (12-20 ng/mL) as insufficient, and >125 nmol/L (>50 ng/mL) as sufficient. Outcomes of the patients admitted were recorded in terms of duration of hospitalization, Intensive Care Unit (ICU) stay, oxygen requirement, antibiotic need and duration, need for upgradation of antibiotics, nebulization need with drugs used, ventilator need and other parameters. Statistical analysis was performed using statistical package for social sciences software (SPSS Inc., Chicago, IL, USA). A P value of <0.05 was considered statistically significant., Results: Out of 101 patients, 100% presented with fever, cough and fast breathing, 42.6% with grunting, 41 (40.5%) with noisy breathing, 5.7% with bluish discoloration, and 4.3% with apnea. Forty-one (40.5%) patients had crepitation, 53 (52.4%) patients had rhonchi, while 7 (6%) presented with bronchial breathing. Chest radiography features at admission helped to differentiate between presumed viral and presumed bacterial infection. Vitamin D deficient patients had significantly longer duration of hospital stay as compared to vitamin D sufficient group (P<0.001). The need for upgradation of antibiotics between the three groups were found to be significant (P<0.001). This showed that vitamin D deficiency is directly proportional to the need of upgradation of antibiotics. Bacterial pneumonia presents mostly as alveolar infiltrates and/or pleural effusion while viral pneumonia presents as interstitial infiltrates and/or hyperinflation. Cases with presumed bacterial pneumonia (based on X-ray, 38 out of 48, 79.1%) were more often vitamin D deficient as compared to case with presumed viral pneumonia (32 out of 52, 61.5%, P=0.05)., Conclusions: Vitamin D is widely prevalent in Indian children with pneumonia. Vitamin D deficient patients needed a longer duration of hospitalization, more upgradation of antibiotics, and PICU admissions; moreover, it had more CPAP requirement, longer duration of PICU stay and longer duration of CPAP requirements as compared to vitamin D sufficient group.

Aim The aim of this study was to investigate the utility of serum resistin levels as a prognostic indicator for mortality in neonates diagnosed with sepsis. Methodology This one-year prospective study at Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences (PGIMS), Rohtak, India, included 151 neonates categorized into two groups based on blood culture results: group 1 (n=86) included those with culture-negative, probable sepsis and group 2 (n=65) included those with culture-positive, proven sepsis. Blood samples obtained pre-treatment underwent comprehensive analysis, including complete blood count, C-reactive protein assessment, micro-erythrocyte sedimentation rate, and resistin level measurement via enzyme-linked immunosorbent assay. The comparison between groups was conducted using either the Student t-test or the Mann-Whitney U test, while correlations were assessed using the Spearman correlation. These analyses were employed to identify the optimal resistin cut-off for distinguishing patients with sepsis. A p-value of <0.05 was considered statistically significant. Results This study with 151 neonates diagnosed with sepsis found a significant association (p < 0.05) between elevated serum resistin levels and increased mortality risk. Multivariate analysis confirmed an independent predictive role of resistin. Elevated resistin levels correlate with higher chances of requiring mechanical ventilation and prolonged hospital stays. These findings highlight serum resistin's potential as a prognostic tool for the early identification of high-risk neonatal sepsis patients. Conclusion This study highlights the link between elevated serum resistin levels and increased mortality risk in neonatal sepsis, supported by strong multivariate analysis, indicating an independent predictive role. Additionally, resistin correlates with higher chances of mechanical ventilation and prolonged hospitalization, suggesting its potential as a prognostic marker for early identification of high-risk neonatal sepsis cases., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Jain et al.)

Utilizing a novel microsimulation approach, this study evaluates the impact of fixed and average point-to-point Speed Enforcement Cameras (SEC) on driving safety. Using the SUMO software, agent-based models for a 6-km highway without exits or obstacles were created. Telematics data from 93,160 trips were used to determine the desired free-flow speed. A total of 13,860 scenarios were simulated with 30 random seeds. The ratio of unsafe driving (RUD) is the spatial division of the total distance travelled at an unsafe speed by the total travel distance. The study compared different SEC implementations under different road traffic and community behaviours using the Power Model and calculated crash risk changes. Results showed that adding one or two fixed SECs reduced RUD by 0.20% (0.18-0.23) and 0.57% (0.54-0.59), respectively. However, average SECs significantly lowered RUD by 10.97% (10.95-10.99). Furthermore, a 1% increase in telematics enforcement decreased RUD by 0.22% (0.21-0.22). Point-to-point cameras effectively reduced crash risk in all implementation scenarios, with reductions ranging from - 3.44 to - 11.27%, pointing to their superiority as speed enforcement across various scenarios. Our cost-conscious and replicable approach can provide interim assessments of SEC effectiveness, even in low-income countries., (© 2024. The Author(s).)

Background: Road Traffic injuries (RTI) are among the top ten leading causes of death in the world resulting in 1.35 million deaths every year, about 93% of which occur in low- and middle-income countries (LMICs). Despite several global resolutions to reduce traffic injuries, they have continued to grow in many countries. Many high-income countries have successfully reduced RTI by using a public health approach and implementing evidence-based interventions. As many LMICs develop their highway infrastructure, adopting a similar scientific approach towards road safety is crucial. The evidence also needs to be evaluated to assess external validity because measures that have worked in high-income countries may not translate equally well to other contexts. An evidence gap map for RTI is the first step towards understanding what evidence is available, from where, and the key gaps in knowledge., Objectives: The objective of this evidence gap map (EGM) is to identify existing evidence from all effectiveness studies and systematic reviews related to road safety interventions. In addition, the EGM identifies gaps in evidence where new primary studies and systematic reviews could add value. This will help direct future research and discussions based on systematic evidence towards the approaches and interventions which are most effective in the road safety sector. This could enable the generation of evidence for informing policy at global, regional or national levels., Search Methods: The EGM includes systematic reviews and impact evaluations assessing the effect of interventions for RTI reported in academic databases, organization websites, and grey literature sources. The studies were searched up to December 2019., Selection Criteria: The interventions were divided into five broad categories: (a) human factors (e.g., enforcement or road user education), (b) road design, infrastructure and traffic control, (c) legal and institutional framework, (d) post-crash pre-hospital care, and (e) vehicle factors (except car design for occupant protection) and protective devices. Included studies reported two primary outcomes: fatal crashes and non-fatal injury crashes; and four intermediate outcomes: change in use of seat belts, change in use of helmets, change in speed, and change in alcohol/drug use. Studies were excluded if they did not report injury or fatality as one of the outcomes., Data Collection and Analysis: The EGM is presented in the form of a matrix with two primary dimensions: interventions (rows) and outcomes (columns). Additional dimensions are country income groups, region, quality level for systematic reviews, type of study design used (e.g., case-control), type of road user studied (e.g., pedestrian, cyclists), age groups, and road type. The EGM is available online where the matrix of interventions and outcomes can be filtered by one or more dimensions. The webpage includes a bibliography of the selected studies and titles and abstracts available for preview. Quality appraisal for systematic reviews was conducted using a critical appraisal tool for systematic reviews, AMSTAR 2., Main Results: The EGM identified 1859 studies of which 322 were systematic reviews, 7 were protocol studies and 1530 were impact evaluations. Some studies included more than one intervention, outcome, study method, or study region. The studies were distributed among intervention categories as: human factors ( n  = 771), road design, infrastructure and traffic control ( n  = 661), legal and institutional framework ( n  = 424), post-crash pre-hospital care ( n  = 118) and vehicle factors and protective devices ( n  = 111). Fatal crashes as outcomes were reported in 1414 records and non-fatal injury crashes in 1252 records. Among the four intermediate outcomes, speed was most commonly reported ( n  = 298) followed by alcohol ( n  = 206), use of seatbelts ( n  = 167), and use of helmets ( n  = 66). Ninety-six percent of the studies were reported from high-income countries (HIC), 4.5% from upper-middle-income countries, and only 1.4% from lower-middle and low-income countries. There were 25 systematic reviews of high quality, 4 of moderate quality, and 293 of low quality., Authors' Conclusions: The EGM shows that the distribution of available road safety evidence is skewed across the world. A vast majority of the literature is from HICs. In contrast, only a small fraction of the literature reports on the many LMICs that are fast expanding their road infrastructure, experiencing rapid changes in traffic patterns, and witnessing growth in road injuries. This bias in literature explains why many interventions that are of high importance in the context of LMICs remain poorly studied. Besides, many interventions that have been tested only in HICs may not work equally effectively in LMICs. Another important finding was that a large majority of systematic reviews are of low quality. The scarcity of evidence on many important interventions and lack of good quality evidence-synthesis have significant implications for future road safety research and practice in LMICs. The EGM presented here will help identify priority areas for researchers, while directing practitioners and policy makers towards proven interventions., (© 2024 The Authors. Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides DDX41 mutation. Patients with myeloid malignancies and DDX41 variants responded well to therapy, with an overall response rate for patients with treatment naïve AML and MDS of 87% and 84%, respectively. The median overall survival (mOS) of patients with treatment-naïve AML or MDS was 49 and 71 months, respectively. Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively., (© 2023 Wiley Periodicals LLC.)

Aim: Most children under six with seizures experience febrile seizures (FS), which occur with a temperature of 38°C or higher and no apparent infectious or metabolic causes. FS has a multifaceted etiology, involving genetic and environmental factors. This study aimed to explore the connection between the cytokine system (part of the immune system related to inflammation) and FS to uncover potential relationships., Method: This research was carried out on 50 patients experiencing FS and 25 patients experiencing only fever served as cases and controls, respectively. The patient's blood was obtained under sterile circumstances from the antecubital/femoral vein as soon as feasible following the commencement of seizures. The complete hemogram analysis was done using the Mindray BC-5800 auto hematology analyzer (Mindray Medical International Limited, Shenzhen, China)., Result: The cases group had significantly higher interleukin-4 (IL-4) concentrations (292.85 pg/mL) than controls (81.04 pg/mL), indicating a statistically significant difference (p<0.05), respectively. In the current research, case participants had a significantly lower mean level of interleukin-6 (IL-6) than control participants. The average IL-6 concentration in cases was 28.00 pg/mL, whereas in controls was 93.09pg/mL. Patients with FS have an important function for the cytokine network to perform., Conclusion: The findings showed a significant difference in cytokine concentrations between patients with FS and control subjects, highlighting a potential link between the cytokine system and FS. Additionally, lower levels of IL-6 in case participants suggest a complex role of cytokines in FS, emphasizing the importance of the cytokine network in this condition., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Vishal et al.)

Introduction: The First UN Decade of Action for Road Safety (2011-2020) ended with most low/middle-income countries (LMICs) failing to reduce road traffic deaths. In contrast, Brazil reported a strong decline starting in 2012. However, comparisons with global health statistical estimates suggest that official statistics from Brazil under-report traffic deaths and overestimate declines. Therefore, we sought to assess the quality of official reporting in Brazil and explain discrepancies., Methods: We obtained national death registration data and classified deaths to road traffic deaths and partially specified causes that could include traffic deaths. We adjusted data for completeness and reattributed partially specified causes proportionately over specified causes. We compared our estimates with reported statistics and estimates from the Global Burden of Disease (GBD)-2019 study and other sources., Results: We estimate that road traffic deaths in 2019 exceeded the official figure by 31%, similar to traffic insurance claims (27.5%) but less than GBD-2019 estimates (46%). We estimate that traffic deaths have declined by 25% since 2012, close to the decline estimated by official statistics (27%) but much more than estimated by GBD-2019 (10%). We show that GBD-2019 underestimates the extent of recent improvements because GBD models do not track the trends evident in the underlying data., Conclusion: Brazil has made remarkable progress in reducing road traffic deaths in the last decade. A high-level evaluation of what has worked in Brazil could provide important guidance to other LMICs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Speeding behaviour of drivers is highly correlated to their tangible consequence. Therefore, this study aimed to evaluate the effectiveness of telematics-based feedback and financial incentives in reducing speeding behaviors through a randomized controlled field trial. This randomized controlled trial included four groups of (1) control, (2) information-only, (3) gain-of-reward, and (4) loss-of-reward. While drivers of the control group were unobtrusively monitored using telematics devices, drivers of the information-only group received real-time, weekly, and monthly feedback via text message. In both groups with financial incentives, in addition to receiving feedback, drivers could receive payments at the end of each month based on observed speeding. The primary outcome was the distance traveled at speeds more than 10% (S10 + ) above the posted speed limit as a proportion of the total traveled distance. A total of 397 male taxi drivers consented to participate in the study. After the stratified randomization, the mean age of the participant was 46.0 (95% Confidence Interval: 43.8 to 48.2), 47.0 (44.7 to 49.3), 46.1 (43.7 to 48.5), and 48.8 (46.5 to 51.1) years for the control, the information-only, the gain-of-reward, and the loss-of-reward groups, respectively. The mean S10 + rate per 100 km was 0.9 (0.5 to 1.2) for the control, 0.8 (0.4 to 1.1) for the information-only, 0.7 (0.3 to 1.1) for the gain-of-reward, and 1.3 (0.4 to 2.2) for the loss-of-reward group at the start of intervention. During the intervention phase, the loss-of-reward group with 0.6 (0.5 to 0.7) had the lowest mean of S10 + rate, followed by the gain-of-reward group with 0.8 (0.7 to 0.8). The loss-of-reward and gain-of-reward groups were the most influenced groups by the intervention, with 38.0% (13.2 to 55.7; p-value < 0.01) and 29.4% (2.0 to 49.2; p-value = 0.04) less S10 + rate than the control group, respectively. It was figured out that providing information regarding drivers' behavior without appropriating motives or penalties would have a minuscule impact.In addition, the group of drivers who were treated with instant punishment was the most influenced group by the intervention., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.

Strengthening crash surveillance is an urgent priority for road safety in low- and middle-income countries. We reviewed the online availability and completeness of First Information Reports (FIRs; police reports) of road traffic crashes in India. We developed a relational database to record information extracted from FIRs, and implemented it for one state (Chhattisgarh, 2017-2019). We found that FIRs can be downloaded in bulk from government websites of 15 states and union territories. Another 14 provide access online but restrict bulk downloading, and 7 do not provide online access. For Chhattisgarh, 87% of registered FIRs could be downloaded. Most FIRs reported the date, time, collision-type, and vehicle-types, but important crash characteristics (e.g. infrastructure attributes) were missing. India needs to invest in building the crash surveillance capacity for research and safety management. However, in the interim, maintaining a national database of a sample of FIRs can provide useful policy guidance.

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has a very poor prognosis. Determinants of clinical outcomes and optimal treatment remain uncertain. We retrospectively reviewed 108 cases of AML with inv(3)/t(3;3) and evaluated clinicopathological characteristics and clinical outcomes: 53 newly diagnosed (ND) AML and 55 relapsed/refractory (R/R) AML. Median age was 55 years. White blood cell (WBC) count ≥20x109/L and platelet count ≥140x109/L was observed in 25% and 32% of ND patients, respectively. Anomalies involving chromosome 7 were identified in 56% of patients. The most frequently mutated genes were SF3B1, PTPN11, NRAS, KRAS and ASXL1. In ND patients, the composite complete remission (CRc) rate was 46% overall; 46% with high-intensity treatments and 47% with lowintensity treatments. The 30-day mortality was 14% and 0%, with high- and low-intensity treatment, respectively. In R/R patients, the CRc rate was 14%. Venetoclax based-regimens were associated with a CRc rate of 33%. The 3-year overall survival (OS) was 8.8% and 7.1% in ND and R/R patients, respectively. The 3-year cumulative incidence of relapse was 81.7% overall. Older age, high WBC, high peripheral blast count, secondary AML and KRAS, ASXL1, DNMT3A mutations were associated with worse OS in univariable analyses. The 5-year OS rates were 44% and 6% with or without hematopoietic stem cell transplantation in CR1, respectively. AML with inv(3)/t(3;3) is associated with low CR rates, very high risk of relapse and dismal long-term survival. Intensive chemotherapy and hy pomethylating agents provide similar rates of remission and patients achieving CR benefit from hematopoietic stem cell transplantation in first CR.

Background: Asthma is a common childhood disease that leads to impairment of quality of life (QOL) of both the children affected by the disease and their caregivers. Management of asthma includes pharmacotherapy along with education about asthma and its self-management, which is most often given verbally. There is limited evidence regarding the benefits of using a written asthma action plan (WAAP) that has been improved using pictorial representation., Objective: The study aimed to assess the effectiveness of a WAAP in improving the QOL of children with bronchial asthma and also of their caregivers. It also educates the patients and families about various triggers and danger signs of an acute attack of asthma., Methods: This was an interventional study with the aim of improving the quality of asthma management. Children of age group 7-17 years in whom the diagnosis of asthma was made and those parents and children who could read and answer the questionnaire (mini-PAQLQ and PACQLQ) were included in the study. Subjects were randomized into Case and Control groups. The intervention was to give the randomly selected patients (Case group) an individualized WAAP along with standard asthma care to both groups. Both groups were followed up to assess and record variations in the quality of life., Results: The P value was highly significant in the following parameters post-intervention: missed doses of controller medication ( P value = 0.001), need for rescue medication (<0.001), ACT score (0.001), total PAQLQ (<0.001), and PACQLQ (<0.001) score. Though statistical significance was not established, improvement was also observed in the number of unscheduled OPD visits ( P value = 0.082) and hospitalization events ( P value = 0.554)., Conclusion: On being provided with the WAAP, the frequency of acute asthma events, treatment compliance, and QOL improved. There was a significant increase in the primary outcomes-PAQLQ and PACQLQ scores. Significant improvement in the secondary outcomes-number of missed school days, missed doses of controller medication, need for rescue medication, and ACT score was also observed., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Family Medicine and Primary Care.)

Background: There are large discrepancies between official statistics of traffic injuries in African countries and estimates from the Global Burden of Disease (GBD) study and WHO's Global Status Reports on Road Safety (GSRRS). We sought to assess the magnitude of the discrepancy in Ethiopia, its implications and how it can be addressed., Methods: We systematically searched for nationally representative epidemiological data sources for road traffic injuries and vehicle ownership in Ethiopia and compared estimates with those from GBD and GSRRS., Findings: GBD and GSRRS estimates vary substantially across revisions and across projects. GSRRS-2018 estimates of deaths (27 326 in 2016) are more than three times GBD-2019 estimates (8718), and these estimates have non-overlapping uncertainty ranges. GSRRS estimates align well with the 2016 Demographic and Health Survey (DHS-2016; 27 838 deaths, 95th CI: 15 938 to 39 738). Official statistics are much lower (5118 deaths in 2018) than all estimates. GBD-2019 estimates of serious non-fatal injuries are consistent with DHS-2016 estimates (106 050 injuries, 95th CI: 81 728 to 130 372) and older estimates from the 2003 World Health Survey. Data from five surveys confirm that vehicle ownership levels in Ethiopia are much lower than in other countries in the region., Interpretation: Inclusion of data from national health surveys in GBD and GSRRS can help reduce discrepancies in estimates of deaths and support their use in highlighting under-reporting in official statistics and advocating for better prioritisation of road safety in the national policy agenda. GBD methods for estimating serious non-fatal injuries should be strengthened to allow monitoring progress towards Sustainable Development Goal target 3.6., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Oral cancer is a major health concern in the Indian subcontinent, where it ranks among the top three types of cancer in the country. Tobacco and its products have been implicated as a major etiologic factor behind cancers. It is believed that tobacco is an epidemic in itself taking the death toll to 7 million globally. In India alone, mortality because of tobacco is more than 1.3 million. Dentists are the first to notice any change in the oral cavity or come across any suspicious looking oral lesion and therefore are instrumental in primary prevention and care., Methods: The present study data are of the patients enrolled in a Tobacco Cessation Center(TCC) at a Dental College in Meerut in Meerut from May 2012 (since its inception) to March 2020. The following methods of counseling were carried out: group counseling, interactive sessions, audio-visual aids, and individual counseling sessions. Self-training for oral cavity examination was also given after every group counseling session. Behavioral counseling and pharmacological intervention were given as per Fagerström Test for Nicotine Dependence (FTND) score. At the end of 1 year, patients who quit were graded into 0, 1, and 2, with 0 for those who failed to quit, 1 for those who did completely quit, and 2 for those who reduced their habit by more than 50%., Results: The quit rate achieved was 57.6% (complete responders -43.2% and partial responders 14.4%). The relapse reported was 1.8%., Conclusion: A Tobacco cessation Center set up in a Dental College could be of great help in the primary prevention of oral cancer and can bring a drastic increase in quit rates. Proper counseling skills once nurtured in young under-graduates can boost the tobacco-free India campaign., Competing Interests: None

Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: To evaluate road safety in member countries of the Association of Southeast Asian Nations and estimate the benefits that vehicle safety interventions would have in this group of countries., Methods: We used a counterfactual analysis to assess the reduction in traffic deaths and disability-adjusted life years (DALYs) lost if eight proven vehicle safety technologies and motorcycle helmets were entirely in use in countries of the Association of Southeast Asian Nations. We modelled each technology using country-level incidence estimations of traffic injuries, and the prevalence and effectiveness of the technology to calculate the reduction in deaths and DALYs if the technology was fitted in the entire vehicle fleet., Findings: The availability of electronic stability control, including the antilock braking systems, would provide the most benefits for all road users with estimates of 23.2% (sensitivity analysis range: 9.7-27.8) fewer deaths and 21.1% (9.5-28.1) fewer DALYs. Increased use of seatbelts was estimated to prevent 11.3% (8.11-4.9) of deaths and 10.3% (8.2-14.4) of DALYs. Appropriate and correct use of motorcycle helmets could result in 8.0% (3.3-12.9) fewer deaths and 8.9% (4.2-12.5) fewer DALYs., Conclusion: Our findings show the potential of improved vehicle safety design and personal protective devices (seatbelts and helmets) to reduce traffic deaths and disabilities in the Association of Southeast Asian Nations. These improvements can be achieved by vehicle design regulations and creating consumer demand for safer vehicles and motorcycle helmets through mechanisms such as new car assessment programmes and other initiatives., ((c) 2023 The authors; licensee World Health Organization.)

Background: With rapid urbanization, the urban environment, especially the neighborhood environment, has received increasing global attention. However, a comprehensive overview of the association between neighborhood risk factors and human health remains unclear due to the large number of neighborhood risk factor-human health outcome pairs., Method: On the basis of a whole year of panel discussions, we first obtained a list of 5 neighborhood domains, containing 33 uniformly defined neighborhood risk factors. We only focused on neighborhood infrastructure-related risk factors with the potential for spatial interventions through urban design tools. Subsequently, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic meta-review of 17 infrastructure-related risk factors of the 33 neighborhood risk factors (e.g., green and blue spaces, proximity to major roads, and proximity to landfills) was conducted using four databases, Web of Science, PubMed, OVID, and Cochrane Library, from January 2000 to May 2021, and corresponding evidence for non-communicable diseases (NCDs) was synthesized. The review quality was assessed according to the A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) standard., Results: Thirty-three moderate-and high-quality reviews were included in the analysis. Thirteen major NCD outcomes were found to be associated with neighborhood infrastructure-related risk factors. Green and blue spaces or walkability had protective effects on human health. In contrast, proximity to major roads, industry, and landfills posed serious threats to human health. Inconsistent results were obtained for four neighborhood risk factors: facilities for physical and leisure activities, accessibility to infrastructure providing unhealthy food, proximity to industry, and proximity to major roads., Conclusions: This meta-review presents a comprehensive overview of the effects of neighborhood infrastructure-related risk factors on NCDs. Findings on the risk factors with strong evidence can help improve healthy city guidelines and promote urban sustainability. In addition, the unknown or uncertain association between many neighborhood risk factors and certain types of NCDs requires further research., (© 2023. The Author(s).)

The treatment of cancer has remarkably improved because of increased knowledge of the abnormalities at the molecular level, which results in human cancer growth. This has initiated the development of ever more successful as well as effective targeted cancer therapies. Detection of cancer is diagnosed basically by performing routine biopsy/cytology, which has many drawbacks. Therefore, the concept of liquid biopsy has been introduced to oncology, which has the potential to revolutionise the management of cancer patients, eliminating the invasive procedures needed to obtain tissue samples and provide information. Liquid biopsy is the analysis of tumour cells or tumour cell products obtained from blood or other body fluids, providing a broad range of opportunities in the field of pathology. Here, we focus on the most prominent liquid biopsy markers, circulating tumour cells and circulating tumour-derived deoxyribonucleic acid (DNA), in the blood of patients. In this review, we discuss recent clinical studies on these biomarkers for early detection and prognostication of cancer, which helps in successful management. Hence, liquid biopsy is introduced with great promise for personalised medicine because of its ability to provide multiple non-invasive snapshots of the primary and metastatic tumours., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Oral and Maxillofacial Pathology.)

RUNX1-mutated (mRUNX1) acute myeloid leukemia (AML) has historically been associated with poor outcomes in the setting of conventional chemotherapy. The prognostic impact of mRUNX1 AML is not well-established in the current era of lower-intensity treatment regimens incorporating venetoclax. We retrospectively analyzed 907 patients with newly diagnosed AML, including 137 patients with mRUNX1 AML, who underwent first-line therapy with intensive chemotherapy (IC), low-intensity therapy without venetoclax (LIT without VEN), or LIT with VEN. When stratified by RUNX1 status, there was no statistically significant difference in outcomes between mRUNX1 and wild-type (wtRUNX1) AML, regardless of therapy received. However, among patients who received LIT with VEN, there was a trend towards superior overall survival (OS) in those with mRUNX1 AML (median OS for mRUNX1 vs. wtRUNX1: 25.1 vs. 11.3 months; 2-year OS 54% vs. 33%; p = 0.12). In patients without another adverse-risk cyto-molecular feature, the presence of mRUNX1 conferred inferior OS in patients who received IC (p = 0.02) or LIT without VEN (p = 0.003) but not in those who received LIT with VEN (mRUNX1 vs. wtRUNX1: 25.1 vs. 30.0 months; 2-year OS 59% vs. 54%; p = 0.86). A multivariate analysis showed possible interaction between RUNX1 mutation status and treatment, suggesting a differential prognostic impact of RUNX1 mutations when patients received IC versus LIT with VEN. In summary, the prognostic impact of mRUNX1 AML may be treatment-dependent, and the presence of RUNX1 mutations may not impact clinical outcomes when venetoclax-based regimens are used., (© 2022 Wiley Periodicals LLC.)

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p < .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p < .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p < .001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS., (© 2022 Wiley Periodicals LLC.)

Competing Interests: There are no conflicts of interest.