Metformin in pregnancy and childhood neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to examine the impact of maternal metformin use during pregnancy on offspring neurodevelopmental outcomes. DATA SOURCES: MEDLINE, Embase, and Web of Science (Core Collection) were searched from inception until July 1, 2023. STUDY ELIGIBILITY CRITERIA: Studies of women who received treatment with metformin at any stage of pregnancy for any indication with neurodevelopmental data available for their offspring were included. Studies without a control group were excluded. Randomized controlled trials, case-control, cohort, and cross-sectional studies were included in the review. METHODS: Studies were screened for inclusion and data were extracted independently by 2 reviewers. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale for nonrandomized studies, and the Risk of Bias 2 tool for randomized trials. RESULTS: A total of 7 studies met the inclusion criteria, including a combined cohort of 14,042 children with 7641 children who were exposed and followed for up to 14 years of age. Metformin use during pregnancy was not associated with neurodevelopmental delay in infancy (relative risk, 1.09; 95% confidence interval, 0.54-2.17; 3 studies; 9668 children) or at ages 3 to 5 years (relative risk, 0.90; 95% confidence interval, 0.56-1.45; 2 studies; 6118 children). When compared with unexposed peers, metformin use during pregnancy was not associated with altered motor scores (mean difference, 0.30; 95% confidence interval, -1.15 to 1.74; 3 studies; 714 children) or cognitive scores (mean difference, -0.45; 95% confidence interval, -1.45 to 0.55; 4 studies; 734 children). Studies that were included were of high quality and deemed to be at low risk of bias. CONCLUSION: In utero exposure to metformin does not seem to be associated with adverse neurodevelopmental outcomes in children up to the age of 14 years. These findings provide reassurance to clinicians and pregnant women considering metformin use during pregnancy.

Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer.

Viral mimicry describes the immune response induced by endogenous stimuli such as double-stranded RNA (dsRNA) from endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune responses. Here, we systematically identify mechanisms of viral mimicry adaptation associated with cancer cell dependencies. Among the top hits is the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1 dependency is mediated by mitochondrial antiviral signaling protein and protein kinase R activation and is associated with higher levels of cytosolic dsRNA, higher levels of a subset of Alus capable of forming dsRNA, and higher interferon-stimulated gene expression, indicating that cells die due to induction of viral mimicry. Furthermore, dsRNA-inducing drugs such as 5-aza-2'-deoxycytidine and palbociclib can generate a synthetic dependency on XRN1 in cells initially resistant to XRN1 knockout. These results indicate that XRN1 is a promising target for future cancer therapeutics.

Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia.

Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling.

The levels and trends of metabolic risk factors in the elderly population at the national and sub-national scale in Iran from 1990 to 2016.

Purpose: Describing the trends of metabolic risk factors (MRFs) in the elderly population. Methods: We used modeled data from previous comprehensive systematic reviews for MRFs among adults aged ≥ 60 years. Two stages of age-specific Spatio-temporal modeling and Gaussian process regression were used to estimate the mean of MRFs. We used crosswalk modeling to estimate the prevalence of elevated and raised Total cholesterol (TC), overweight/obesity and obesity, hypertension, and diabetes. Estimates were analyzed based on combinations of sex, age, year, and province from 1990 to 2016. Results: Comparing prevalence estimates from 2016 with those of 1990, in the elderly population, the age-standardized prevalence of overweight/obesity, obesity, diabetes, and hypertension increased, conversely, the prevalence of hypercholesteremia decreased. The prevalence of hypertension increased about 141.5% and 129.9% in men and women respectively. The age-standardized prevalence of diabetes increased about 109.5% in females, and 116.0% in males. Prevalence of elevated TC at the national level decreased to 67.4% (64.1-70.4) in women and to 51.1% (47.5-54.8) in men. These findings were almost shown across provinces. In general, the northern and western provinces had the highest prevalence of overweight/obesity in women in 2016. Conclusion: The rising prevalence of most MRFs, as well as the greater prevalence and mean of all MRFs in women, necessitate effective public health policies to reduce the burden of non-communicable diseases and run preventive programs. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01297-z.

Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence. METHODS: Efficacy studies of patients with uncomplicated P. vivax malaria, including a treatment arm with daily primaquine, published between January 1999 and March 2020 were identified. Individual patient data from eligible studies were pooled using standardized methodology. Adherence to primaquine was inferred from i) the percentage of supervised doses and ii) the total mg/kg dose received compared to the target total mg/kg dose per protocol. The effect of adherence to primaquine on the incidence of P. vivax recurrence between days 7 and 90 was investigated by Cox regression analysis. RESULTS: Of 82 eligible studies, 32 were available including 6917 patients from 18 countries. For adherence assessed by percentage of supervised primaquine, 2790 patients (40.3%) had poor adherence (≤ 50%) and 4127 (59.7%) had complete adherence. The risk of recurrence by day 90 was 14.0% [95% confidence interval: 12.1-16.1] in patients with poor adherence compared to 5.8% [5.0-6.7] following full adherence; p = 0.014. After controlling for age, sex, baseline parasitaemia, and total primaquine dose per protocol, the rate of the first recurrence was higher following poor adherence compared to patients with full adherence (adjusted hazard ratio (AHR) = 2.3 [1.8-2.9]). When adherence was quantified by total mg/kg dose received among 3706 patients, 347 (9.4%) had poor adherence, 88 (2.4%) had moderate adherence, and 3271 (88.2%) had complete adherence to treatment. The risks of recurrence by day 90 were 8.2% [4.3-15.2] in patients with poor adherence and 4.9% [4.1-5.8] in patients with full adherence; p < 0.001. CONCLUSION: Reduced adherence, including less supervision, increases the risk of vivax recurrence.

Risk of incident cardiovascular diseases at national and subnational levels in Iran from 2000 to 2016 and projection through 2030: Insights from Iran STEPS surveys.

BACKGROUND: Cardiovascular Disease (CVD) is the leading cause of death in developing countries. CVD risk stratification guides the health policy to make evidence-based decisions. AIM: To provide current picture and future trend of CVD risk in the adult Iranian population. METHODS: Nationally representative datasets of 2005, 2006, 2007, 2008, 2009, 2011, and 2016 STEPwise approach to non-communicable diseases risk factor surveillance (STEPS) studies were used to generate the 10-year and 30-year risks of CVD based on Framingham, Globorisk, and World Health Organization (WHO) risk estimation models. Trend of CVD risk was calculated from 2000 until 2016 and projected to 2030. RESULTS: In 2016, based on Framingham model, 14.0% of the Iranian, aged 30 to 74, were at great risk (≥20%) of CVD in the next 10 years (8.0% among females, 20.7% among males). Among those aged 25 to 59, 12.7% had ≥45% risk of CVD in the coming 30 years (9.2% among females, 16.6 among males). In 2016, CVD risk was higher among urban area inhabitants. Age-standardized Framingham 10-year CVD risk will increase 32.2% and 19%, from 2000 to 2030, in females and males, respectively. Eastern provinces had the lowest and northern provinces had the greatest risk. CONCLUSIONS: This study projected that CVD risk has increased from 2000 to 2016 in Iran. Without further risk factor modification, this trend will continue until 2030. We have identified populations at higher risks of CVD to guide future intervention.

The levels and trends of diabetes prevalence at national and sub-national levels in Iran (1990 - 2016).

Background: The increasing trends in Diabetes prevalence and its attributed burden emphasized as an important issue that needs serious and urgent attention, all over the word. We estimated the mean Fasting Plasma Glucose (FPG) and the prevalence of Diabetes in aged 25 years or older Iranian adults, by sex, age, province, and year through the time period of 1990 to 2016. Methods: In order to access the most comprehensive relevant data at the same time the systematic data searched added to the data of 5 national surveys and 7 sub-national population based investigations. Two round of modeling, including the Age-Spatio-Temporal and Gaussian Process Regression were used for estimation of mean FPG trend and uncertainties. To estimate Diabetes estimations in target groups, a crosswalk model was applies to the FPG estimates. The model reiterated separately for women and men. All of estimations standardized based on the Iran national census population of 2016 by year, age groups and sexes at national and sub-national levels. Results: In 2016, the number of the diabetic population was 4.43 (3.93-4.99) million (2.38 million women). Between 1990 and 2016, the age-standardized mean of FPG increased from 84.69 mg/dl (79.8-89.8) to 100.5 mg/dl (97.9-103.3) in women and from 82.7 mg/dl (78.3-87.5) to 98.8 mg/dl (96.2-101.4) in men. Simultaneously, with considerable difference, the Diabetes prevalence, has increased from 6.1% (4.7-7.8) to 9.8% (8.7-11.1) in women and from 5.0% 18 (3.8-6.3) to 8.1% (7.2-9.2) in men (75% attributed to population growth). Considering the geographical patterns, the greatest increment in the prevalence of Diabetes detected in the northwestern and the central provinces. Conclusion: Significant increasing trends of Diabetes led to alarming threat, which can make the strategies and goals of our prevention programs out of control. We should plan for more effective communicative interventions for prevention and management of Diabetes, to be designed, implemented and monitored based on the updated scientific evidence. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01197-2.

macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma.

Self-renewal is a crucial property of glioblastoma cells that is enabled by the choreographed functions of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover an epigenetic axis of self-renewal mediated by the histone variant macroH2A2. With omics and functional assays deploying patient-derived in vitro and in vivo models, we show that macroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. macroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. Consistent with these results, our analyses of clinical cohorts indicate that high transcriptional levels of this histone variant are associated with better prognosis of high-grade glioma patients. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest additional treatment approaches for glioblastoma patients.

Predicting Iran's achievement to Sustainable Development Goal 3.2: A systematic analysis of neonatal mortality with scenario-based projections to 2030.

BACKGROUND: Sustainable Development Goal 3.2 (SDG 3.2) is to reduce Under-5 and neonatal mortality rates (U5MR and NMR), two major health systems' performance indicators, globally by 2030. We aimed to report Iran's U5MR and NMR status during 2010-2017 and its achievement of SDG 3.2 by 2030, using scenario-based projection. STUDY DESIGN: To estimate the national and subnational levels of U5MR and NMR, we applied an Ensemble Bayesian Model Averaging (EBMA) with Gaussian Process Regression (GPR) and Spatio_temporal models. We used all available data sources including: 12-year data from the Death Registration System (DRS), two censuses, and a demographic and health surveys (DHS). This study employed two approaches, Maternal Age Cohort (MAC) and Maternal Age Period (MAP), to analyze summary birth history data obtained from censuses and DHS. In addition, we calculated the child mortality rate directly from DHS using the complete birth history method. National and subnational NMR was projected up to 2030 with a scenario-based method using average Annual Rate of Reduction (ARR) introduced by UN-IGME. RESULTS: In 2017, national U5MR and NMR were 15·2 (12·4-18·0) and 11·8 (10·4-13·2), with an average ARR of 5·1% (2·1-8·9) and 3·1% (0·9-5·8) during 2010-2017, respectively. According to our projection scenarios, 17 provinces have not fulfilled SDG 3.2 for NMR yet, and the current trend (the current trend of NMR improvement in Iran) will not result in reaching SDG for some provinces by 2030; However, if each province has the same neonatal mortality annual reduction rate as the best-performing province in the same region, besides achieving SDG, the national NMR will be reduced to 5·2, and almost 92,000 newborn lives will be saved. CONCLUSIONS: Iran has achieved SDG3.2 regarding U5MR and NMR; however, there are provincial inequalities. For all provinces to reach SDG3.2, health policies should focus on reducing provincial inequalities by precise planning for neonatal health care.

Level and trend of total plasma cholesterol in national and subnational of Iran: a systematic review and age-spatio-temporal analysis from 1990 to 2016.

Purpose: We aimed to estimate the level and trend of plasma cholesterol and raised total cholesterol (TC > 200 mg/dl) prevalence at national and subnational level of Iran. Methods: Nine national surveys and 27 studies, encompassing 3,505 unique points on over 500,000 adults, aged > 25 years with a report of laboratory measurement of TC were found. Age-spatio-temporal model and Gaussian Process Regression were used to estimate mean TC for each sex, 5-year age groups, and 31 provinces from 1990 to 2016. Results: At national level, age-standardized prevalence of TC > 200 mg/dL has decreased from 57·2%(53·3-61·1) to 22·4%(20·5-24·3) in women and 53·2%(49·1-57·3) to 18·0%(16·4-19·6) in men. TC distribution presented a condensation between 170-200 mg/dL. At subnational level, decreasing and converging patterns of raised TC prevalence were detected. Conclusion: The decrease in raised TC is likely the result of statin widespread use, food industry improvements, and the expanded primary health care. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-01052-w.

Mortality and Years of Life Lost due to Burn Injury Among Older Iranian People; a Cross-Sectional study.

Introduction: The mortality of burn injury is a serious health problem among older people. The present study aimed to determine the epidemiological characteristics of burn mortality and Years of Life Lost (YLLs) among people aged ≥ 60. Methods: The National and Subnational Burden of Disease (NASBOD) study includes population-based cross-sectional data from the death registration system of Iran and those recorded by the cemeteries of Tehran and Esfahan were used in this study. Spatio-temporal and Gaussian process regression models were applied to estimate rates and trends of mortality and cause-specific mortality fractions. YLLs were calculated using Iranian life expectancy and the number of deaths. Results: The mortality rate for 1990 and 2015 was 17.4 and 4.5 per 100,000, respectively. From 1990 through 2015, the annual percentage of change in burn mortality rate was -6.1% in females and -4.4% in males. During 2015, there were 326 deaths following burns in people aged 60+ with 4586 person YLLs, and in 1990 there were 523 deaths with 4862 person-YLLs. The male-female ratio for 1990 and 2015 were 0.80 and 0.88, respectively. The age-standardized mortality rate was higher than 8.5 per 100,000 in border provinces in 2015. The provinces with better socioeconomic situations, such as Tehran, had a lower mortality rate than poor provinces, such as Sistan va Baluchistan. Conclusion: Although burn mortality in old people decreased in those 26 years, it is still high compared to high-income countries. Continued efforts to increase preventive measures and adequate access to quality care, especially in border provinces, is suggested.

PRMT inhibition induces a viral mimicry response in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.

Trends of Diabetes Mortality in Iran at National and Sub-National Levels from 1990 to 2015 and Its Association with Socioeconomic Factors.

Background: Following global commitments to prevent and control non-communicable diseases, we sought to estimate national and sub-national trends in diabetes mortality in Iran and assess its association with socioeconomic factors. Methods: In a systematic analytical study, to assess the correlation between diabetes mortality and socioeconomic factors, we used data obtained from the Death Registration System (DRS), the Spatio-temporal model and Gaussian Process Regression (GPR) levels and the diabetes mortality trends, which were estimated by sex, age and year at national and sub-national levels from 1990 to 2015. Results: Between the years 1990 and 2015, the age-standardized diabetes mortality rate (per 100,000) increased from 3.40 (95% UI: 2.33 to 4.99) to 7.72 (95% UI: 5.51 to 10.78) in males and from 4.66 (95% UI: 3.23 to 6.76) to 10.38 (95% UI: 7.54 to 14.23) in females. In 1990, the difference between the highest age-standardized diabetes mortality rate among males was 3.88 times greater than the lowest (5.97 vs. 1.54), and in 2015 this difference was 3.96 times greater (14.65 vs. 3.70). This provincial difference was higher among females and was 5.13 times greater in 1990 (8.41 vs. 1.64) and 5.04 times greater in 2015 (19.87 vs. 3.94). The rate of diabetes mortality rose with urbanization yet declined with an increase in wealth and years of schooling as the main socio-economic factors. Conclusion: The rising trend of diabetes mortality rate at the national level and the sub-national disparities associated with socioeconomic status in Iran warrant the implementation of specific interventions recommended by the '25 by 25' goal.

Levels and Trends of Hypertension at National and Subnational Scale in Iran from 1990 to 2016: A Systematic Review and Pooled Analysis.

BACKGROUND: Raised blood pressure is a serious risk factor for several non-communicable diseases (NCDs) in Iran. In this study, we aimed to estimate the mean of systolic blood pressure (SBP) and diastolic blood pressure (DBP) and subsequently, the prevalence of hypertension by sex, age, province, and year in Iran. METHODS: We conducted a systematic review using PubMed, Web of Science, and Scopus databases through December 2017. We also used individual level data from eight national surveys, aggregated data from seven subnational population-based studies, and extracted data reported in 52 published studies. We used a two-stage model including Age-Spatio-Temporal and Gaussian process regression (GPR) to estimate mean systolic and diastolic blood pressure and used a crosswalk model to estimate the prevalence of hypertension by sex, age, province, and year. RESULTS: The number of hypertensive adults increased in Iran from 1.8 million (882 thousand in women) in 1990 to 13.6 million (7.2 million in women) in 2016. The national age-standardized prevalence of hypertension increased from 8.7% (7.8-9.7) to 28.8% (27.7-30.0) in women and from 8.0% (7.2-8.9) to 24.2% (23.1-25.3) in men from 1990 to 2016. Mean systolic and diastolic blood pressures show a similar increasing trend. CONCLUSION: During the past 27 years, we observed an increase in the age-standardized prevalence and mean levels of blood pressure. If the current trend in levels of blood pressure and prevalence of hypertension continue in the coming years, Iran will not achieve the sixth target of the Global Action Plan by 2020 and the Sustainable Development Goals (SDGs) by 2030.

Levels and Trends of BMI, Obesity, and Overweight at National and Sub-national Levels in Iran from 1990 to 2016; A Comprehensive Pooled Analysis of Half a Million Individuals.

BACKGROUND: In developing countries like Iran, the burden of obesity increases through comorbid diseases. We estimated the mean body mass index (BMI) and prevalence of overweight/obesity by components of sex, age, province, and year in Iran from 1990 to 2016. METHODS: Through a comprehensive systematic review, all relevant data sources pooled results with individual level national and sub-national population-based studies. Two stages of age-spatio-temporal modeling and Gaussian process regression were used to estimate mean BMI, followed by estimation of obesity and overweight prevalence through the crosswalk modeling. RESULTS: In 2016, the age-standardized mean BMI was 27.9 (27.2-28.7) kg/m² in women and 25.9 (25.2-26.5) kg/m² in men. At the same time, the prevalence rates of overweight and obesity were 71.7% (67.9-75.8), and 36.8% (34.1-39.7) in females, and 57.1% (53.7-60.6), and 18.4% (16.9-20) in men. This shows a considerable increase from 1990 when the figures were respectively 24.4 (23.3-25.5) , 36.6% (32.2-41.5), and 8.2% (95% UI: 6.9-9.7) in women, and 23.5 (22.5-24.5), 30% (26.4-34), and 4.7% (4.0-5.5) in men, with 66% attributed to population growth. CONCLUSION: Considering the increasing trends of BMI, Sustainable Development Goals (SDGs) seem far out of reach. We need to call for action, aiming for both weight loss strategies and controlling the comorbidities that mediate high BMI risk.

Introducing an efficient sampling method for national surveys with limited sample sizes: application to a national study to determine quality and cost of healthcare.

BACKGROUND: Sampling a small number of participants from an entire country is not straightforward. In this case, researchers reluctantly sample from a single setting or few settings, which limits the generalizability of findings. Therefore, there is a need to design efficient sampling method for small sample size surveys that can produce generalizable results at the country level. METHODS: Data comprised of twenty proxy variables to measure health services demands, structures, and outcomes of 413 districts of Iran. We used two data mining methods (hierarchical clustering method (HCM) and model-based clustering method (MCM)) to create homogenous groups of districts, i.e., strata based on these variables. We compared the internal and stability validity of the methods by statistical indices. An expert group checked the face validity of the methods, particularly regarding the total number of strata and the combination of districts in each stratum. The efficiency of selected method, which is measured by the inverse of variance, was compared with a simple random sampling (SRS) through simulation. The sampling design was tested in a national study in Iran, which aimed to evaluate the quality and costs of medical care for eight selected diseases by only recruiting 300 participants per disease at the country level. RESULTS: MCM and HCM divided the districts into eight and two clusters, respectively. The measures of internal and stability validity showed that clusters created by MCM were more separated, compact, and stable, thus forming our optimum strata. The probability of death from stroke, chronic obstructive pulmonary disease, and in-hospital mortality rate were the most important indicators that distinguished the eight strata. Based on the simulation results, MCM increased the efficiency of the sampling design up to 1.7 times compared to SRS. CONCLUSIONS: The use of data mining improved the efficiency of sampling up to 1.7 times greater than SRS and markedly reduced the number of strata to eight in the entire country. The proposed sampling design also identified key variables that could be used to classify districts in Iran for sampling from these target populations in the future studies.

DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells.

We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8+ T cells. In vivo HMA treatment promotes CD8+ T cell tumor infiltration and suppresses tumor growth via CD8+ T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8+ T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T cell activation-related transcriptional networks, culminating with over-activation of NFATc1 short isoforms. Mechanistically, demethylation of an intragenic CpG island immediately downstream to the 3' UTR of the short isoform was associated with antisense transcription and alternative polyadenylation of NFATc1 short isoforms. High-dimensional single-cell mass cytometry analyses reveal a selective effect of HMAs on a subset of human CD8+ T cell subpopulations, increasing both the number and abundance of a granzyme Bhigh, perforinhigh effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response.

Evaluating equality in prescribing Novel Oral Anticoagulants (NOACs) in England: The protocol of a Bayesian small area analysis.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting about 1.6% of the population in England. Novel oral anticoagulants (NOACs) are approved AF treatments that reduce stroke risk. In this study, we estimate the equality in individual NOAC prescriptions with high spatial resolution in Clinical Commissioning Groups (CCGs) across England from 2014 to 2019. METHODS: A Bayesian spatio-temporal model will be used to estimate and predict the individual NOAC prescription trend on 'prescription data' as an indicator of health services utilisation, using a small area analysis methodology. The main dataset in this study is the "Practice Level Prescribing in England," which contains four individual NOACs prescribed by all registered GP practices in England. We will use the defined daily dose (DDD) equivalent methodology, as recommended by the World Health Organization (WHO), to compare across space and time. Four licensed NOACs datasets will be summed per 1,000 patients at the CCG-level over time. We will also adjust for CCG-level covariates, such as demographic data, Multiple Deprivation Index, and rural-urban classification. We aim to employ the extended BYM2 model (space-time model) using the RStan package. DISCUSSION: This study suggests a new statistical modelling approach to link prescription and socioeconomic data to model pharmacoepidemiologic data. Quantifying space and time differences will allow for the evaluation of inequalities in the prescription of NOACs. The methodology will help develop geographically targeted public health interventions, campaigns, audits, or guidelines to improve areas of low prescription. This approach can be used for other medications, especially those used for chronic diseases that must be monitored over time.