Improvement in trauma care for road traffic injuries: an assessment of the effect on mortality in low-income and middle-income countries.

Over 90% of the annual 1·35 million worldwide deaths due to road traffic injuries (RTIs) occur in low-income and middle-income countries (LMICs). For this Series paper, our aim was two-fold. Firstly, to review evidence on effective interventions for victims of RTIs; and secondly, to estimate the potential number of lives saved by effective trauma care systems and clinical interventions in LMICs. We reviewed all the literature on trauma-related health systems and clinical interventions published during the past 20 years using MEDLINE, Embase, and Web of Science. We included studies in which mortality was the primary outcome and excluded studies in which trauma other than RTIs was the predominant injury. We used data from the Global Status Report on Road Safety 2018 and a Monte Carlo simulation technique to estimate the potential annual attributable number of lives saved in LMICs. Of the 1921 studies identified for our review of the literature, 62 (3·2%) met the inclusion criteria. Only 28 (1·5%) had data to calculate relative risk. We found that more than 200 000 lives per year can be saved globally with the implementation of a complete trauma system with 100% coverage in LMICs. Partial system improvements such as establishing trauma centres (>145 000 lives saved) and instituting and improving trauma teams (>115 000) were also effective. Emergency medical services had a wide range of effects on mortality, from increasing mortality to saving lives (>200 000 excess deaths to >200 000 lives saved per year). For clinical interventions, damage control resuscitation (>60 000 lives saved per year) and institution of interventional radiology (>50 000 lives saved per year) were the most effective interventions. On the basis of the scarce evidence available, a few key interventions have been identified to provide guidance to policy makers and clinicians on evidence-based interventions that can reduce deaths due to RTIs in LMICs. We also highlight important gaps in knowledge on the effects of other interventions.

Socioeconomic Condition and Prevalence of Malaria Fever in Pakistani Children: Findings from a Community Health Survey.

OBJECTIVE: We assessed the prevalence of malarial fever and its association with demographic and socioeconomic factors in children <5 years of age. METHODS: Using the data of Pakistan Demographic and Health Survey (PDHS), the socioeconomic condition (SEC) was assessed by using a household wealth index as a proxy indicator, generated through principal component analysis. Two-stage sampling was used for selection of households, and multilevel logistic regression analysis was performed. RESULTS: The PDHS contains 10 935 children <5 years of age with valid information about malaria fever. In total, 36% (3930) children have malaria 2 weeks before the survey. A decreasing trend in prevalence of malaria fever was found with increasing SEC. Compared with SEC Quintile V, children of SEC Quintile I were more likely to get fever [adjusted odds ratio (AOR)=1.40 (1.15-1.69)] and of SEC Quintile II [AOR = 1.23 (1.03-1.45)]. CONCLUSION: SEC has a significant impact on the prevalence of malaria fever in the context of different regions in Pakistan.

Economic Evaluation of a New Polygenic Risk Score to Predict Nephropathy in Adult Patients With Type 2 Diabetes.

OBJECTIVES: The current screening method for diabetic nephropathy (DN) is based on detection of albumin in the urine and decline of glomerular filtration rate. The latter usually occurs relatively late in the course of the disease. A polygenic risk score (PRS) was recently developed for early prediction of the risk for patients with type 2 diabetes (T2D) to develop DN. The aim of this study was to assess the economic impact of the implementation of the PRS for early prediction of DN in patients with T2D compared with usual screening methods in Canada. METHODS: A cost-utility analysis was developed using a Markov model. Health states include pre-end-stage renal disease (ESRD), ESRD and death. Model efficacy parameters were based on prediction of outcome data by polygenic risk testing of the genotyped participants in the Action in Diabetes and Vascular Disease PreterAx and DiamicronN Controlled Evaluation trial. Analyses were conducted from Canadian health-care and societal perspectives. Deterministic and probabilistic sensitivity analyses were conducted to assess results robustness. RESULTS: Over a lifetime horizon, the PRS was a dominant strategy, from both a health-care system and societal perspective. The PRS was less expensive and more efficacious in terms of quality-adjusted life-years compared with usual screening technics. Deterministic and probabilistic sensitivity analyses showed that results remained dominant in most simulations. CONCLUSIONS: This economic evaluation demonstrates that the PRS is a dominant option compared with usual screening methods for the prevention of DN in patients with T2D. Adoption of the PRS would reduce costs saving but would also help prevent ESRD and improve patients' quality of life.

Shift work and risk of skin cancer: A systematic review and meta-analysis.

Shift work with circadian disruption has been considered as a carcinogenic risk factor for skin cancer. The few prior studies that investigated the association between shift work and skin cancer have inconclusive results. Our main objective was to evaluate the associations between shift work and the risks of different types of skin cancer. We systematically searched PubMed, Web of Science, Cochrane Library, EMBASE and Science Direct until October 2018 for studies that included a relationship between shift work and skin cancer. Our search yielded 193 articles and 9 studies met the criteria for our review. The included studies involved 3,579,147 participants and 17,308 skin cancer cases. Overall, ever shift work, was associated with increased risk of melanoma (RR = 1.10, 95% CI = 1.05-1.16) and a significant decrease in the risk of BCC (RR = 0.90, 95% CI = 0.88-0.93). No association between shift work and the risk of SCC was detected. Interestingly, our dose response analysis demonstrated that the risk of melanoma cumulatively increases by 2% for every year of shift work (RR = 1.02; 95% CI = 1.00-1.03). In conclusion, shift work is associated with increased risk of melanoma and deceased risk of BCC. Further studies are needed to confirm our findings and to elucidate the related potential biological mechanisms.

Initial estimates of COVID-19 infections in hospital workers in the United States during the first wave of pandemic.

OBJECTIVE: We estimated the number of hospital workers in the United States (US) that might be infected or die during the COVID-19 pandemic based on the data in the early phases of the pandemic. METHODS: We calculated infection and death rates amongst US hospital workers per 100 COVID-19-related deaths in the general population based on observed numbers in Hubei, China, and Italy. We used Monte Carlo simulations to compute point estimates with 95% confidence intervals for hospital worker (HW) infections in the US based on each of these two scenarios. We also assessed the impact of restricting hospital workers aged ≥ 60 years from performing patient care activities on these estimates. RESULTS: We estimated that about 53,000 hospital workers in the US could get infected, and 1579 could die due to COVID19. The availability of PPE for high-risk workers alone could reduce this number to about 28,000 infections and 850 deaths. Restricting high-risk hospital workers such as those aged ≥ 60 years from direct patient care could reduce counts to 2,000 healthcare worker infections and 60 deaths. CONCLUSION: We estimate that US hospital workers will bear a significant burden of illness due to COVID-19. Making PPE available to all hospital workers and reducing the exposure of hospital workers above the age of 60 could mitigate these risks.

MCM2, MCM4, and MCM6 in Breast Cancer: Clinical Utility in Diagnosis and Prognosis.

Breast cancer is a heterogeneous disease comprising the estrogen receptor (ER)-positive luminal subtype which is subdivided into luminal A and luminal B and ER-negative breast cancer which includes the triple-negative subtype. This study has four aims: 1) to examine whether Minichromosome Maintenance (MCM)2, MCM4, and MCM6 can be used as markers to differentiate between luminal A and luminal B subtypes; 2) to study whether MCM2, MCM4, and MCM6 are highly expressed in triple-negative breast cancer, as there is an urgent need to search for surrogate markers in this aggressive subtype, for drug development purposes; 3) to compare the prognostic values of these markers in predicting relapse-free survival; and 4) to compare the three approaches used for scoring the protein expression of these markers by immunohistochemistry (IHC). MCM2, MCM4, MCM6, and MKI67 mRNA expression was first studied using in silico analysis of available breast cancer datasets. We next used IHC to evaluate their protein expression on tissue microarrays using three scoring methods. MCM2, MCM4, and MCM6 can help in distinction between luminal A and luminal B whose therapeutic management and clinical outcomes are different. MCM2, MCM4, MCM6, and Ki-67 are highly expressed in breast cancer of high histological grades that comprise clinically aggressive tumors such as luminal B, HER2-positive, and triple-negative subtypes. Low transcript expression of these markers is associated with increased probability of relapse-free survival. A positive relationship exists among the three scoring methods of each of the four markers. An independent validation cohort is needed to confirm their clinical utility.

Role of Maternal Education and Vaccination Coverage: Evidence From Pakistan Demographic and Health Survey.

The aim of this study was to examine the impact of maternal education on child immunization uptake in Pakistan, both at individual and community levels. Pakistan Demographic and Health Survey data were used for analysis. Multilevel logistic regression was used to access the individual- and community-level factors associated with childhood immunization coverage. Out of 6765 children 2659 (39.3%) were fully immunized. Parents education, access to media, and wealth status have positive while ethnicity and working status of mother have a negative impact on the immunization uptake. In the community with a high percentage of educated mothers, the odds of immunized children were high (odds ratio = 1.43, 95% confidence interval = 1.14-1.80) as compared with communities with lower percentage of educated mothers. Moreover, significant variation was found in the likelihood of full immunization across communities. Both community- and individual-level factors have substantial impact on children immunization status. There is a need of improvement in maternal education, poverty alleviation, and removal of rural-urban disparities.

The Impact of Waiting List BMI Changes on the Short-term Outcomes of Lung Transplantation.

BACKGROUND: Obesity and underweight are associated with a higher postlung transplantation (LTx) mortality. This study aims to assess the impact of the changes in body mass index (BMI) during the waiting period for LTx on early postoperative outcomes. METHODS: Medical records of 502 consecutive cases of LTx performed at our institution between 1999 and 2015 were reviewed. Patients were stratified per change in BMI category between pre-LTx assessment (candidate BMI) and transplant BMI as follows: A-candidate BMI, less than 18.5 or 18.5 to 29.9 and transplant BMI, less than 18.5; B-candidate BMI, less than 18.5 and transplant BMI, 18.5 to 29.9; C-candidate BMI, 18.5 to 29.9 and transplant BMI, 18.5 to 29.9; D-candidate BMI, 30 or greater and transplant BMI, 18.5 to 29.9; and E-candidate BMI, 30 or greater or 18.5 to 29.9 and transplant BMI, 30 or greater. Our primary outcome was in-hospital mortality and secondary outcomes were length of mechanical ventilation, intensive care unit length of stay (LOS), hospital LOS and postoperative complications. RESULTS: BMI variation during the waiting time was common, as 1/3 of patients experienced a change in BMI category. Length of mechanical ventilation (21 days vs 9 days; P = 0.018), intensive care unit LOS (26 days vs 15 days; P = 0.035), and rates of surgical complications (76% vs 44%; P = 0.018) were significantly worse in patients of group E versus group D. Obese candidates who failed to decrease BMI less than 30 by transplant exhibited an increased risk of postoperative mortality (odds ratio, 2.62; 95% confidence interval, 1.01-6.48) compared with patients in group C. Pre-LTx BMI evolution had no impact on postoperative morbidity and mortality in underweight patients. CONCLUSIONS: Our results suggest that obese candidates with an unfavorable pretransplant BMI evolution are at greater risk of worse post-LTx outcomes.

Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension risks in males with hypogonadism.

Several members of the EPH kinase family and their ligands are involved in blood pressure regulation, and such regulation is often sex- or sex hormone-dependent, based on animal and human genetic studies. EPHB6 gene knockout (KO) in mice leads to hypertension in castrated males but not in un-manipulated KO males or females. To assess whether this finding in mice is relevant to human hypertension, we conducted a human genetic study for the association of EPHB6 and its two ligands, EFNB1 and EFNB3, with hypertension in hypogonadic patients. Seven hundred and fifty hypertensive and 750 normotensive Han Chinese patients, all of whom were hypogonadic, were genotyped for single nucleotide polymorphisms (SNPs) within the regions of the genes, plus an additional 50 kb 5' of the genes for EPHB6, EFNB1 and EFNB3. An imputed insertion/deletion polymorphism, rs35530071, was found to be associated with hypertension at p-values below the Bonferroni-corrected significance level of 0.0024. This marker is located 5' upstream of the EFNB3 gene start site. Previous animal studies showed that while male EFNB3 gene knockout mice were normotensive, castration of these mice resulted in hypertension, corroborating the results of the human genetic study. Considering the significant associations of EFNB3 SNPs with hypertension in hypogonadic males and supporting evidence from castrated EFNB3 KO mice, we conclude that loss-of-function variants of molecules in the EPHB6 signaling pathway in the presence of testosterone are protective against hypertension in humans.

PROX1 gene CC genotype as a major determinant of early onset of type 2 diabetes in slavic study participants from Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation study.

BACKGROUND: The prevalence of diabetic nephropathy varies according to ethnicity. Environmental as well as genetic factors contribute to the heterogeneity in the presentation of diabetic nephropathy. Our objective was to evaluate this heterogeneity within the Caucasian population. METHODS: The geo-ethnic origin of the 3409 genotyped Caucasian type 2 diabetes (T2D) patients of Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation was determined using principal component analysis. Genome-wide association studies analyses of age of onset of T2D were performed for geo-ethnic groups separately and combined. RESULTS: The first principal component separated the Caucasian study participants into Slavic and Celtic ethnic origins. Age of onset of diabetes was significantly lower in Slavic patients (P = 7.3 × 10), whereas the prevalence of hypertension (P = 4.9 × 10) and albuminuria (5.1 × 10) were significantly higher. Age of onset of T2D and albuminuria appear to have an important genetic component as the values of these traits were also different between Slavic and Celtic individuals living in the same countries. Common and geo-ethnic-specific loci were found to be associated to age of onset of diabetes. Among the latter, the PROX1/PROX1-AS1 genes (rs340841) had the highest impact. Single-nucleotide polymorphism rs340841 CC genotype was associated with a 4.4 year earlier onset of T2D in Slavic patients living or not in countries with predominant Slavic populations. CONCLUSION: These results reveal the presence of distinct genetic architectures between Caucasian ethnic groups that likely have clinical relevance, among them PROX1 gene is a strong candidate of early onset of diabetes with variations depending on ethnicity.

Pulmonary arteriovenous malformation (PAVM) reperfusion after percutaneous embolization: Sensitivity and specificity of non-enhanced CT.

PURPOSE: To evaluate the sensitivity and specificity of non-enhanced chest CT to detect reperfusion after pulmonary arteriovenous malformation (PAVM) embolization. MATERIALS AND METHODS: The Institutional Review Board approved this retrospective HIPAA-compliant study and waived the need for patient consent. All consecutive patients who underwent PAVM embolization between January 2000 and April 2011 were included. Complex PAVMs and patients without available pre- and/or post-embolization CT were excluded. PAVM artery, aneurysm and vein diameters were measured on non-enhanced chest CT before and after PAVM embolization. Pulmonary angiography (PA) was the reference standard to assess PAVM reperfusion. Reperfusion detection was analyzed with receiver operating characteristic (ROC) curves according to percentage of diameter reduction cut-off. Inter-observer concordance was ascertained with intra-class correlation coefficients (ICCs). RESULTS: Out of 68 patients with PAVM embolizations, 42 (62%) had 108 PAVMs that met inclusion/exclusion criteria. Areas under the ROC curves for PAVM reperfusion detection were 0.84, 0.87, and 0.78, respectively, for PAVM artery, aneurysm and vein (p>0.05). Sensitivity varied between 51% and 56%, and specificity between 86% and 98% for the <30% diameter reduction cut-off. Sensitivity was between 98% and 100%, and specificity, between 20% and 47% for the <70% diameter reduction cut-off. ICCs for inter-observer concordance were 0.58, 0.88 and 0.68 for percentage reduction of PAVM artery, aneurysm and vein, respectively. CONCLUSION: PAVM diameter reduction cut-offs of <30% and <70%, to detect PAVM reperfusion on non-enhanced CT reported in the literature, would respectively result in low sensitivity and specificity.

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk.

Ephrin B2 (EFNB2) is a ligand for erythropoietin-producing hepatocellular kinases (EPH), the largest family of receptor tyrosine kinases. It has critical functions in many biological systems, but is not known to regulate blood pressure. We generated mice with a smooth muscle cell (SMC)-specific deletion of EFNB2 and investigated its roles in blood pressure regulation and vascular SMC (VSMC) contractility. Male Efnb2 knockout (KO) mice presented reduced blood pressure, whereas female KO mice had no such reduction. Both forward signaling from EFNB2 to EPHs and reverse signaling from EPHs to EFNB2 were involved in regulating VSMC contractility, with EPHB4 serving as a critical molecule for forward signaling, based on crosslinking studies. We also found that a region from aa 313 to aa 331 in the intracellular tail of EFNB2 was essential for reverse signaling regulating VSMC contractility, based on deletion mutation studies. In a human genetic study, we identified five SNPs in the 3' region of the EFNB2 gene, which were in linkage disequilibrium and were significantly associated with hypertension for male but not female subjects, consistent with our findings in mice. The coding (minor) alleles of these five SNPs were protective in males. We have thus discovered a previously unknown blood pressure-lowering mechanism mediated by EFNB2 and identified EFNB2 as a gene associated with hypertension risk in humans.