Substantial Heterogeneity Research Articles

Analysis of the senescence-associated cell surfaceome reveals potential senotherapeutic targets.

The accumulation of senescent cells is thought to play a crucial role in aging-associated physiological decline and the pathogenesis of various age-related pathologies. Targeting senescence-associated cell surface molecules through immunotherapy emerges as a promising avenue for the selective removal of these cells. Despite its potential, a thorough characterization of senescence-specific surface proteins remains to be achieved. Our study addresses this gap by conducting an extensive analysis of the cell surface proteome, or "surfaceome", in senescent cells, spanning various senescence induction regimes and encompassing both murine and human cell types. Utilizing quantitative mass spectrometry, we investigated enriched cell surface proteins across eight distinct models of senescence. Our results uncover significant changes in surfaceome expression profiles during senescence, highlighting extensive modifications in cell mechanics and extracellular matrix remodeling. Our research also reveals substantive heterogeneity of senescence, predominantly influenced by cell type and senescence inducer. A key discovery of our study is the identification of four unique cell surface proteins with extracellular epitopes. These proteins are expressed in senescent cells, absent or present at low levels in their proliferating counterparts, and notably upregulated in tissues from aged mice and an Alzheimer's disease mouse model. These proteins stand out as promising candidates for senotherapeutic targeting, offering potential pathways for the detection and strategic targeting of senescent cell populations in aging and age-related diseases.

MOIRE: A software package for the estimation of allele frequencies and effective multiplicity of infection from polyallelic data.

Malaria parasite genetic data can provide insight into parasite phenotypes, evolution, and transmission. However, estimating key parameters such as allele frequencies, multiplicity of infection (MOI), and within-host relatedness from genetic data has been challenging, particularly in the presence of multiple related coinfecting strains. Existing methods often rely on single nucleotide polymorphism (SNP) data and do not account for within-host relatedness. In this study, we introduce a Bayesian approach called MOIRE (Multiplicity Of Infection and allele frequency REcovery), designed to estimate allele frequencies, MOI, and within-host relatedness from genetic data subject to experimental error. Importantly, MOIRE is flexible in accommodating both polyallelic and SNP data, making it adaptable to diverse genotyping panels. We also introduce a novel metric, the effective MOI (eMOI), which integrates MOI and within-host relatedness, providing a robust and interpretable measure of genetic diversity. Using extensive simulations and real-world data from a malaria study in Namibia, we demonstrate the superior performance of MOIRE over naive estimation methods, accurately estimating MOI up to 7 with moderate sized panels of diverse loci (e.g. microhaplotypes). MOIRE also revealed substantial heterogeneity in population mean MOI and mean relatedness across health districts in Namibia, suggesting detectable differences in transmission dynamics. Notably, eMOI emerges as a portable metric of within-host diversity, facilitating meaningful comparisons across settings, even when allele frequencies or genotyping panels are different. MOIRE represents an important addition to the analysis toolkit for malaria population dynamics. Compared to existing software, MOIRE enhances the accuracy of parameter estimation and enables more comprehensive insights into within-host diversity and population structure. Additionally, MOIRE's adaptability to diverse data sources and potential for future improvements make it a valuable asset for research on malaria and other organisms, such as other eukaryotic pathogens. MOIRE is available as an R package at https://eppicenter.github.io/moire/.

Dynamic processes in behavioral activation therapy for anhedonic adolescents: Modeling common and patient-specific relations.

Behavioral activation (BA) is a brief intervention for depression encouraging gradual and systematic re-engagement with rewarding activities and behaviors. Given this treatment focus, BA may be particularly beneficial for adolescents with prominent anhedonia, a predictor of poor treatment response and common residual symptom. We applied group iterative multiple model estimation (GIMME) to ecological momentary assessment (EMA) treatment data to investigate common and person-specific processes during BA for anhedonic adolescents. Thirty-nine adolescents (Mage = 15.7 years old, 67% female, 81% White) with elevated anhedonia (Snaith-Hamilton Pleasure Scale) were enrolled in a 12-week BA trial, with weekly anhedonia assessments. EMA surveys were triggered every other week (2-3 surveys per day) throughout treatment assessing current positive affect (PA) and negative affect (NA), engagement in pleasurable activities and social interactions, anticipatory pleasure, rumination, and recent pleasurable and stressful experiences. A multilevel model revealed significant decreases in anhedonia, t(25.5) = -4.76, p < .001, over the 12-week trial. GIMME results indicated substantial heterogeneity in variable networks across patients. PA was the variable with the greatest number (22% of all paths vs. 11% for NA) of predictive paths to other symptoms (i.e., highest out-degree). Higher PA (but not NA) out-degree was associated with greater anhedonia improvement, t(25.8) = -2.22, p = .035. Results revealed substantial heterogeneity in variable relations across patients, which may obscure the search for common processes of change in BA. PA may be a particularly important treatment target for anhedonic adolescents in BA. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Socio-spatial trajectories and health disparities among older adults in Chile

In this study, we examine residential trajectories since birth among older adults in the Santiago Metropolitan Area, Chile, and their association with health outcomes. We linked retrospective residential information for a sample of 802 individuals aged 65–75 in 2019 to context-based information from decennial censuses. Our analysis reveals substantive heterogeneity in individuals' residential trajectories, thus mirroring social and urban changes in Chile's largest city. We found significant associations between residential histories and health outcomes at the time of the interview. Consistent residence in advantaged areas was linked to better health, whereas relocating to the metropolitan area from elsewhere was generally linked to poorer health, except for those moving to emerging middle-class areas. These findings underscore the importance of longitudinal and life course approaches in understanding the complex relationship between place and health.

Examining the relationship of country-level digital ad spend and cross-border e-commerce buyers under cultural and political globalization

PurposeCross-border e-commerce continues to garner much attention within the international marketing literature as the world becomes hyperconnected through digital channels. Although there is an abundance of international marketing research on cross-border e-commerce, there is a lack of information regarding the influences of meta-institutional factors, such as a country’s level of globalization, on the relationship between digital advertising and cross-border e-commerce buyers. The objective of this research is to examine the effects of digital media ad spend at the country level on cross-border e-commerce buyers across countries under differing degrees of formal (i.e. political) and informal (i.e. cultural) institutional globalization.Design/methodology/approachThis work examines the influence of digital ad spend at the country level and the degree of the country’s formal and informal institutional globalization on the share of cross-border e-commerce buyers. We examine this issue within a 21-country, 8-year, unbalanced panel dataset.FindingsWe find that there is substantive heterogeneity in degrees of formal (i.e. political) and informal (i.e. cultural) institutional globalization and cross-border e-commerce across countries. Digital ad spend at the country level is positively associated with cross-border e-commerce buyers within a country. A country’s level of political globalization enhances, but cultural globalization was found to dampen the positive association. The results indicate that political and cultural globalization of a country both contribute to increased interconnectedness with the global market, yet the nature of the interconnection differs.Originality/valueThe findings are informative to international marketing managers navigating the digital landscape and highlight the importance of institutions in international marketing activities. The study specifically demonstrates the varying effects of the meta-institutional factors of a country’s level of political and cultural globalization on the association between digital ad spend and cross-border e-commerce buyers at the country level, across a wide variety of countries, thus also contributing to the effort to improve generalizations from multi-country comparisons in international marketing research.

Clinical Applicability of Autologous Chondrocyte Implantation for the Treatment of Osteochondral Defects: A Meta-analysis.

Osteoarthritis and other joint disorders are the leading cause of disability in the elderly and the treatment of joint lesions is challenging. Autologous chondrocyte implantation (ACI) has been reported with variable effects for the treatment of osteochondral and other joint lesions. In this study, we performed a meta-analysis of the recent literature to determine the clinical applicability of ACI for osteochondral defects. A meta-analysis was performed on the recent literature showing the effects of ACI on osteochondral defects. The PUBMED, ScienceDirect and Google Scholar databases were used to identify eligible studies from Jan 2010 to Sep 2022. Both fixed and random models of meta-analysis were applied with all reported scoring systems to quantify the effectiveness of ACI on osteochondral defects. The pool data of 965 patients as a case series after ACI from a fixed model showed a significant improvement in the osteochondral defects (odds ratio = 8.75, 95%CI = 7.127 to 10.743, p = 0.000). These results were further verified by a random model of meta-analysis. The data also showed a substantial heterogeneity among the studies used in the meta-analysis (Q-value = 160.41, I-squared = 87.53, p = 0.000). Furthermore, this meta-analysis also compared different ACI procedures with different scoring systems but the overall outcome remains the same as ACI was found to be useful for the healing of the osteochondral defects. This meta-analysis of 965 case series revealed that the ACI markedly improved the damage osteochondral defects scores but the optimal treatment is still controversial, therefore further studies are needed to validate these findings in a clinical setting.

Longitudinal patterns of posttraumatic stress disorder symptoms among sexual assault survivors: A latent transition analysis.

The aim of this study was to identify latent classes of posttraumatic stress disorder (PTSD) symptoms in a community sample of sexual assault survivors whose assaults occurred varying lengths of time in the past and to explore patterns of transition between those latent classes over time. Latent class analysis was used to identify naturally occurring subgroups of PTSD symptoms in a sample of sexual assault survivors who completed two mailed surveys 1 year apart (N = 1,271). Latent transition analysis was then used to examine individuals' probabilities of transitioning into each latent class at Time 2 based on their latent class membership at Time 1. A four-class model emerged as the best fitting model at both Time 1 and Time 2. Classes demonstrated overall severity and symptom cluster severity differences. Transition into a lower severity class was more common than transition into a higher severity class, though escalation was demonstrated by 6-20% of participants in each latent class. The substantial heterogeneity in sexual assault survivors' PTSD symptoms highlights the variety of ways that posttraumatic stress may be experienced years after a sexual assault. Future research should explore factors that affect long-term symptoms, including cumulative lifetime trauma and social support. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Machine learning models reveal distinct disease subgroups and improve diagnostic and prognostic accuracy for individuals with pathogenic SCN8A gain-of-function variants.

Distinguishing clinical subgroups for patients suffering with diseases characterized by a wide phenotypic spectrum is essential for developing precision therapies. Patients with gain-of-function (GOF) variants in the SCN8A gene exhibit substantial clinical heterogeneity, viewed historically as a linear spectrum ranging from mild to severe. To test for hidden clinical subgroups, we applied two machine-learning algorithms to analyze a dataset of patient features collected by the International SCN8A Patient Registry. We used two research methodologies: a supervised approach that incorporated feature severity cutoffs based on clinical conventions, and an unsupervised approach employing an entirely data-driven strategy. Both approaches found statistical support for three distinct subgroups and were validated by correlation analyses using external variables. However, distinguishing features of the three subgroups within each approach were not concordant, suggesting a more complex phenotypic landscape. The unsupervised approach yielded strong support for a model involving three partially ordered subgroups rather than a linear spectrum. Application of these machine-learning approaches may lead to improved prognosis and clinical management of individuals with SCN8A GOF variants and provide insights into the underlying mechanisms of the disease.

Shared Decision-Making in Cardiovascular Risk Factor Management

The effect of shared decision-making (SDM) and the extent of its use in interventions to improve cardiovascular risk remain unclear. To assess the extent to which SDM is used in interventions aimed to enhance the management of cardiovascular risk factors and to explore the association of SDM with decisional outcomes, cardiovascular risk factors, and health behaviors. For this systematic review and meta-analysis, a literature search was conducted in the Medline, CINAHL, Embase, Cochrane, Web of Science, Scopus, and ClinicalTrials.gov databases for articles published from inception to June 24, 2022, without language restrictions. Randomized clinical trials (RCTs) comparing SDM-based interventions with standard of care for cardiovascular risk factor management were included. The systematic search resulted in 9365 references. Duplicates were removed, and 2 independent reviewers screened the trials (title, abstract, and full text) and extracted data. Data were pooled using a random-effects model. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Decisional outcomes, cardiovascular risk factor outcomes, and health behavioral outcomes. This review included 57 RCTs with 88 578 patients and 1341 clinicians. A total of 59 articles were included, as 2 RCTs were reported twice. Nearly half of the studies (29 [49.2%]) tested interventions that targeted both patients and clinicians, and an equal number (29 [49.2%]) exclusively focused on patients. More than half (32 [54.2%]) focused on diabetes management, and one-quarter focused on multiple cardiovascular risk factors (14 [23.7%]). Most studies (35 [59.3%]) assessed cardiovascular risk factors and health behaviors as well as decisional outcomes. The quality of studies reviewed was low to fair. The SDM intervention was associated with a decrease of 4.21 points (95% CI, -8.21 to -0.21) in Decisional Conflict Scale scores (9 trials; I2 = 85.6%) and a decrease of 0.20% (95% CI, -0.39% to -0.01%) in hemoglobin A1c (HbA1c) levels (18 trials; I2 = 84.2%). In this systematic review and meta-analysis of the current state of research on SDM interventions for cardiovascular risk management, there was a slight reduction in decisional conflict and an improvement in HbA1c levels with substantial heterogeneity. High-quality studies are needed to inform the use of SDM to improve cardiovascular risk management.

Abstract 1610: Elucidating tumor evolution and heterogeneity in metastatic bladder cancer from rapid autopsies

Abstract Background: Bladder Cancer is a highly prevalent cancer with staggering mortality of about 20%. Metastatic BLCA (mBLCA) with variant histologies are aggressive and have a poor prognosis. The extent and impact of tumor heterogeneity in these variant subtypes are not fully understood. This work explores the intricate characterization of intra-patient and inter-patient tumor heterogeneity through genomic and transcriptomic analyses, drawing insights from a unique rapid autopsy cohort comprising 20 patients. The resulting revelations provide critical perspectives on heterogeneity and clonal evolution in mBLCA, underscoring the essential role of understanding these dynamics for the development of personalized treatment strategies. Approach: Our research focuses on the genetic and molecular characteristics of these tumors, including the vast landscape of tumor heterogeneity, clonal evolution, genomic alterations, mutational signatures, and structural variants. Within the tumor microenvironment, we identified diverse cell populations with distinct genetic profiles. A detailed examination of mutational signatures sheds light on the specific processes underlying genetic alterations, while the investigation of structural variants elucidates their consequential role in cancer development and progression. Advanced bioinformatics tools are deployed to process and interpret the vast genomic and transcriptomic datasets, facilitating the identification of clonal populations, their genetic features, and the trajectory of clonal evolution. Furthermore, statistical models are employed to discern correlations between mutational signatures, treatment responses, and clinical outcomes. Summary: The study unveils substantial inter-patient heterogeneity and discernible differences in mutational signatures, revealing intriguing correlations with treatment responses. These variations are intricately connected to underlying genomic alterations, copy number alterations, and gene expression patterns, offer a detailed perspective on the molecular landscape of mBLCA. Conclusion: This multi-omics exploration stands as the most extensive study of its kind, leveraging rapid autopsy samples of metastatic variant histology BLCA. The research provides unprecedented resolution of genomic alterations and intra- and inter-patient tumor heterogeneity. The exploration of clonal evolution enhances our appreciation of the temporal dynamics of tumor progression, establishing a robust foundation for future therapeutic interventions precisely targeting evolving tumor clones. As we advance into an era of personalized medicine, these findings pave the way for tailored therapeutic strategies in the challenging landscape of metastatic variant histology Bladder Cancer. Citation Format: Pushpa Itagi, Sonali Arora, Thomas Persse, Michael Yang, Patricia Galipeau, Yixin Lin, Funda Vakar-Lopez, John K. Lee, Petros Grivas, Robert B. Montgomery, Jonathan L. Wright, Hung-Ming Lam, Andrew Hsieh, Gavin Ha. Elucidating tumor evolution and heterogeneity in metastatic bladder cancer from rapid autopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1610.

Temporal trends in prevalence and disability of chronic kidney disease caused by specific etiologies: an analysis of the Global Burden of Disease Study 2019.

The prevalence of disability in CKD is high. In this context the aim of the present study wasto assess the temporal trends of prevalence and disability progression for chronic kidney disease (CKD) caused by specific etiologies. Using data from the Global Burden of Diseases Study (GBD) 2019, we examined the age-standardized rates of CKD prevalence and disability-adjusted life-years for different etiologies, including Type 1/2 diabetes mellitus (T1DM/T2DM), glomerulonephritis, and hypertension. We also calculated the average annual percentage changes to assess trends. Additionally, we utilized the joinpoint regression model to identify significant shifts over time. From 1990 to 2019, the global prevalence of CKD due to various etiologies exhibited an overall increasing trend, albeit with fluctuations. Notably, CKD due to T1DM, glomerulonephritis, and hypertension consistently demonstrated a significant upward trend across all continents, while the prevalence of CKD due to T2DM varied across continents. In terms of disability-adjusted life-years, CKD due to T2DM and hypertension exhibited a significant rising trend over the past 30 years. However, changes in age standardized disability-adjusted life-years for CKD due to different etiologies were not consistent across continents, with an upward trend observed in The Americasand a contrasting trend in Asia. Furthermore, both age-standardized prevalence rate and age standardized disability-adjusted life-year trends for CKD varied significantly across 204 countries and territories. Additionally, a negative association was observed between the Socio-demographic Index and the disability progression of CKD. The prevalence and disability burden of CKD caused by specific etiologies show substantial heterogeneity worldwide, highlighting significant disparities in the distribution of CKD. It is crucial to implement geographic and personalized strategies in different regions to alleviate the burden of CKD effectively.

Nonlinear relationships between human development and international student mobility: The prominent role of employment prospects and cultural and linguistic ties

AbstractHigher education is a key global market and considerable literature has focused on investigating the determinants of international student mobility (ISM). However, less is known about the extent to which the relative influence of these factors is moderated by local conditions and vary across origin countries. Drawing on a unique data set of undergraduate applications from the UK Colleges and Admissions Service, we analyse variations in the contextual determinants of ISM flows to the United Kingdom across countries of origin over a 10‐year period (2009–2019). We run a suite of negative binomial gravity models to understand the key influences of ISM and uncover the spatial heterogeneity of these influences. Our findings reveal a nonlinear relationship between the level of development of origin countries and ISM flows. Although countries from higher development levels are more likely to send students to the United Kingdom, there appears to be a dip in applications at the mid‐levels of development. Given the nonlinearity of this relationship, we seek to understand how countries across different levels of development respond to the typical factors that are seen to influence flows of international students. We also see substantial heterogeneity of the influence of different factors for origin countries, with some countries being influenced by employment opportunities and others by cultural and linguistic ties. However, this variation is not necessarily determined by the countries’ level of development. Our findings have implications for policy makers, educators and researchers seeking to navigate and influence global student mobility trends. Our study highlights the need for tailored strategies to attract and retain international students from specific origin countries, recognising the multifaceted nature of ISM determinants.

Retinol-binding protein 4 (RBP4) circulating levels and gestational diabetes mellitus: a systematic review and meta-analysis.

Gestational diabetes mellitus (GDM) is a prevalent condition where diabetes is diagnosed during pregnancy, affecting both maternal and fetal outcomes. Retinol-binding protein 4 (RBP4) is a circulating adipokine which belongs to the lipocalin family and acts as a specific carrier protein that delivers retinol (vitamin A) from the liver to the peripheral tissues. Growing data indicate that circulating RBP4 levels may positively correlate with GDM. Thus, this systematic review and meta-analysis aimed to investigate the potential relationship between circulating RBP4 levels and GDM when measured at various stages of pregnancy. MEDLINE, CINAHL, EMCARE, EMBASE, Scopus, and Web of Science databases were searched to identify studies comparing pregnant women with and without GDM, whose circulating RBP4 levels were measured in at least one pregnancy trimester. Findings were reported using standardized mean difference (SMD) and random-effects models were used to account for variability among studies. Furthermore, the risk of bias was assessed using the RoBANS tool. Out of the 34 studies identified, 32 were included in the meta-analysis (seven with circulating RBP4 levels measured in the first trimester, 19 at 24-28 weeks, and 14 at >28 weeks of pregnancy). RBP4 levels were statistically higher in the GDM group than in controls when measured during all these pregnancy stages, with the noted RBP4 SMD being 0.322 in the first trimester (95% CI: 0.126-0.517; p < 0.001; 946 GDM cases vs. 1701 non-GDM controls); 0.628 at 24-28 weeks of gestation (95% CI: 0.290-0.966; p < 0.001; 1776 GDM cases vs. 1942 controls); and 0.875 at >28 weeks of gestation (95% CI: 0.252-1.498; p = 0.006; 870 GDM cases vs. 1942 non-GDM controls). Significant study heterogeneity was noted for all three pregnancy timepoints. The present findings indicate consistently higher circulating RBP4 levels in GDM cases compared to non-GDM controls, suggesting the potential relevance of RBP4 as a biomarker for GDM. However, the documented substantial study heterogeneity, alongside imprecision in effect estimates, underscores the need for further research and standardization of measurement methods to elucidate whether RBP4 can be utilized in clinical practice as a potential GDM biomarker. PROSPERO (CRD42022340097: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022340097).

Diagnostic tests for human Schistosoma mansoni and Schistosoma haematobium infection: a systematic review and meta-analysis

Accurate diagnosis is pivotal for implementing strategies for surveillance, control, and elimination of schistosomiasis. Despite their low sensitivity in low-endemicity areas, microscopy-based urine filtration and the Kato-Katz technique are considered as reference diagnostic tests for Schistosoma haematobium and Schistosoma mansoni infections, respectively. We aimed to collate all available evidence on the accuracy of other proposed diagnostic techniques. In this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane Library, and LILACS for studies published from database inception to Dec 31, 2022, investigating the sensitivity and specificity of diagnostic tests for S haematobium and S mansoni infections against Kato-Katz thick smears or urine microscopy (reference tests) involving adults (aged ≥18 years), school-aged children (aged 7 to 18 years), or preschool-aged children (aged 1 month to 7 years). We extracted raw data on true positives, true negatives, false positives, and false negatives for the diagnostic tests and data on the number of participants, study authors, publication year, journal, study design, participants' age and sex, prevalence of Schistosoma infection, and treatment status. To account for imperfect reference tests, we used a hierarchical Bayesian latent class meta-analysis to model test accuracy. Overall, we included 121 studies, assessing 28 different diagnostic techniques. Most studies (103 [85%] of 121) were done in Africa, 14 (12%) in South America, one (1%) in Asia, and one (1%) in an unknown country. Compared with the reference test, Kato-Katz thick smears, circulating cathodic antigen urine cassette assay version 1 (CCA1, 36 test comparisons) had excellent sensitivity (95% [95% credible interval 88-99]) and reasonable specificity (74% [63-83]) for S mansoni. ELISA-based tests had a performance comparable to circulating cathodic antigen, but there were few available test comparisons. For S haematobium, proteinuria (42 test comparisons, sensitivity 73% [62-82]; specificity 94% [89-98]) and haematuria (75 test comparisons, sensitivity 85% [80-90]; specificity 96% [92-99]) reagent strips showed high specificity, with haematuria reagent strips having better sensitivity. Despite limited data, nucleic acid amplification tests (NAATs; eg, PCR or loop-mediated isothermal amplification [LAMP]) showed promising results with sensitivity estimates above 90%. We found an unclear risk of bias of about 70% in the use of the reference or index tests and of 50% in patient selection. All analyses showed substantial heterogeneity (I2>80%). Although NAATs and immunological diagnostics show promise, the limited information available precludes drawing definitive conclusions. Additional research on diagnostic accuracy and cost-effectiveness is needed before the replacement of conventional tests can be considered. WHO and Luxembourg Institute of Health.

The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.

Clinically Relevant Laboratory Monitoring of Gender-Affirming Hormone Therapy in Transgender People-Experiences from a Teaching Hospital in the Netherlands.

Transgender care is shifting from academic to nonacademic settings leading to use of common (immunoassay) compared to sophisticated (mass spectrometry) methods to monitor estradiol and testosterone during gender-affirming hormone therapy (GAHT). The type of assay can influence results and have significant implications for clinical decision making. An evidence gap is present in recommendations regarding the assay needed to monitor GAHT. The present study aimed to summarize current evidence and evaluate immunoassay estradiol and testosterone concentrations in transgender people visiting a nonacademic hospital for GAHT. Clinical practice guidelines on GAHT and scientific literature on assay methodologies were screened and summarized. Laboratory and medical data from 252 patients who visited the transgender outpatient clinic of the Maasstad Hospital for GAHT between 2020 and 2022 were retrospectively analyzed. Our research showed that the most used clinical practice guidelines for GAHT provide hormonal target values without recommending a preferred method. A comprehensive literature search on agreement between immunoassay and mass spectrometry showed substantial heterogeneity in results. Retrospective analysis of our immunoassay measured data in transgender people showed hormonal changes during GAHT that are to be expected from the medication used. We demonstrate that laboratory monitoring of GAHT in a nonacademic hospital can be done safely by immunoassay in most cases. Only in cases where clinical observation is discordant with the hormonal results do more sophisticated methods need to be deployed. A best practice model was proposed for transgender care in nonacademic hospitals.

A systematic review of second-hand smoking mass media campaigns (2002–2022)

BackgroundSecond-hand smoking (SHS) increases the risk of chronic disease in adults and poses a serious health threat to children. Mass media campaigns are instrumental in raising awareness and reducing SHS exposure. There is a need to identify recent SHS mass media campaigns and assess their sustainability in terms of knowledge, attitudes, and behavioural changes. This systematic review summarises the characteristics and outcomes of mass media campaigns on SHS prevention.MethodsPubMed, Embase, Web of Science, and grey literature were searched in November 2022 for SHS campaigns implemented between 2016 and 2022. The eligibility criteria included campaigns on the dangers or effects of SHS with any target group, dissemination medium, study design, or language. The database search identified 1,413 peer-reviewed titles, of which 82 full-texts were screened, with 14 meeting the eligibility criteria. The grey literature search identified 9,807 sources, of which 61 were included. We extracted data on the campaign characteristics, metrics, and smoking-related outcomes. The JBI critical appraisal tool was used to assess the risk of bias of the included studies.ResultsWe found 73 SHS campaigns conducted between 2002 and 2022, across 50 countries. The campaigns reached 378 million people. The reported recall rates range from 8 to 76%. Of the 11 studies that reported smoking-related outcomes, 10 reported increased knowledge in understanding SHS risks (73-85%), five reported an increased prevalence of smoke-free homes, and two reported an increase in number of participants persuading others to quit smoking. Two studies reported a decrease in overall smoking, whereas three studies observed a reduction in smoking in the presence of children.ConclusionThe available data provide some support for the effectiveness of SHS campaigns in reducing smoking behaviours in homes and around children. However, the certainty of evidence was low due to the lack of a control group and the substantial heterogeneity in the outcomes assessed. Future campaigns need comprehensive evaluation and reporting to reduce publication bias.

Burden of female breast cancer in India: estimates of YLDs, YLLs, and DALYs at national and subnational levels based on the national cancer registry programme.

Female breast cancer (BC) is the leading cause of cancer incidence and mortality in India, andaccounted for 13.5% of new cancer cases and 10% of cancer-related deaths in 2020. This study aims to estimate and report the female BC burden in India at state level from 2012 to 2016 in terms of years of life lost, years lived with disability, and disability-adjusted life years (DALYs), and to project the burden for the year 2025. The cancer incidence and mortality data from 28 population-based cancer registrieswere analysed. The mean mortality to incidence ratio was estimated, and mortality figures were adjusted for underreporting. The burden of female BC was estimated at national and subnational levels using Census data, World Health Organisation's lifetables, disability weights, and the DisMod-II tool. A negative binomial regression is employed to project burden for 2025. The burden of BC among Indian women in 2016 was estimated to be 515.4 DALYs per 100,000 women after age standardization. The burden metrics at state level exhibited substantial heterogeneity. Notably, Tamil Nadu, Telangana, Karnataka, and Delhi had a higher burden of BC than states in the eastern and north-eastern regions. The projection for 2025 indicates to a substantial increase, reaching 5.6 million DALYs. The female BC burden in India was significantly high in 2016 and is expected to substantially increase. Undertaking a multidisciplinary, context-specific approach for its prevention and controlcan address this rising burden.

Incidence, contributing factors and outcomes of birth injury among newborns in Africa: a systematic review of quantitative evidence protocol

IntroductionBirth injury is a significant public health problem in Africa, with a high incidence and associated mortality and morbidity. Systematic reviews that indicate the incidence, contributing factors and outcomes of...

Effectiveness of shared medical appointments delivered in primary care for improving health outcomes in patients with long-term conditions: a systematic review of randomised controlled trials

ObjectivesTo examine the effectiveness of shared medical appointments (SMAs) compared with one-to-one appointments in primary care for improving health outcomes and reducing demand on healthcare services by people with one...