Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins

Objective- To evaluate the efficacy of intensive lipid lowering with higher-dose statins. Methods- Meta-analysis of seven randomized controlled trials comprising 50,972 participants. Results- Mean follow-up was 3.1years with mean age 63years. Final LDL-C levels in intensive lipid-lowering group were 1.42-2.07mmol/l compared to 2.1-3.5mmol/l in the less intensive or control group. The intensive arm had significantly lower risks for stroke OR 0.80 (95% CI 0.71-0.89); major coronary events OR 0.74 (95% CI 0.65-0.83); cardiovascular disease (CVD) or coronary heart disease (CHD) deaths OR 0.84 (95% CI 0.74-0.95). Significantly higher liver enzyme abnormalities occurred in intensive group * (OR 3.96; 95% CI 2.08-7.53), but it was not associated with drug discontinuations (OR 1.20; 95% CI 0.88-1.64). Conclusion- In those at high risk of cardiovascular events, intensive lipid lowering with statins to LDL-C level <2.1mmol/l significantly reduces risk of stroke, major coronary events and CVD or CHD deaths compared to LDL-C level ≥2.1mmol/l. [ *Correction added on 11 January 2011 after first online publication on 27 October 2010. The phrase, "Significantly higher liver enzyme abnormalities occurred in less intensive group", was amended to "Significantly higher liver enzyme abnormalities occurred in intensive group".] © 2010 John Wiley & Sons A/S

Vitamin D concentrations during pregnancy and in cord blood: a systematic review and meta-analysis

Context: Effect size estimates for the association between vitamin D concentrations in maternal blood during pregnancy and in cord blood vary widely across studies, but no meta-analysis has been conducted to ascertain this association. Objective: The aim of this systematic review was to estimate the pooled effect size for the association between circulating 25-hydroxyvitamin D (25[OH]D) concentrations, a marker of vitamin D status, in maternal blood during pregnancy and in cord blood. Data Sources: The PubMed, Embase, and Web of Science databases were searched from their inception to February 2021. Data Extraction: Following the application of prespecified inclusion and exclusion criteria, 94 articles were eligible for full-text review, which was conducted by 2 authors independently. A third author was consulted when necessary and consensus reached. In total, 26 articles, which comprised 30 studies and 6212 mother-infant dyads, were included. Methodological quality was assessed using a modified version of the Joanna Briggs Institute’s Critical Appraisal Checklist for Studies Reporting Prevalence Data. Correlation coefficient (r) values for the association between maternal serum 25(OH)D concentrations during pregnancy and in cord blood were extracted. Data Analysis: The r values were pooled using random-effects meta-analyses. Sensitivity and subgroup analyses were performed to investigate sources of heterogeneity. The pooled r for all studies was 0.72 (95%CI, 0.64–0.79), indicating high heterogeneity (I2 = 95%, P < 0.01). After influential and outlier studies were removed, the pooled r for 9 studies was 0.70 (95%CI, 0.66–0.74), which resulted in a substantial reduction in heterogeneity (I2 = 41%, P=0.10). Conclusion: The findings support a positive and large correlation between maternal vitamin D concentrations during pregnancy and vitamin D concentrations in cord blood. Systematic Review Registration: PROSPERO registration number CRD42021273348

P5-06-03: Gene Expression Associated with Breast Cancer Primary and Secondary Resistance to Neoadjuvant Chemotherapy.

Abstract In breast cancer, neoadjuvant chemotherapy may provide valuable information on tumor resistance mechanisms, as variable degrees of tumor response, from pathological complete response until progressive disease, may be observed. To have a better insight of the resistance process to chemotherapy, we have compared resistant pre chemotherapy samples (representing primary or intrinsic resistance) and residual post chemotherapy from partially responsive tumors (secondary or acquired resistance), by means of their transcriptional profile.Tumors from 36 patients submitted to neoadjuvant chemotherapy (4 cycles doxorrubicin and cyclophosphamide) were collected (12 pre-chemotherapy from primary resistant samples and 24 post chemotherapy from residual samples) and analyzed by cDNA microarray (training set, n=25, 9 resistant; 16 residual) and/or by qRT-PCR (technical validation set, n=11, and biological validation set, n=11; 8 resistant; 14 residual). In samples from the training set analysed using a cDNA microarray platform with 4608 genes (Student's t test; p &amp;lt;0,01; FDR &amp;lt;10), 138 genes were differentially expressed between resistant and residual samples, which correctly classified tumors in unsupervised hierarchical clustering analysis, with high confidence. Genes were mainly involved in regulation of cell cycle, regulation of cell growth, cell division, protein modification and DNA dependent DNA replication. Among genes involved in cell growth and cell division, 12 were selected to be further evaluated, using qRT-PCR: MORF4L2, NOTCH2, HTRA1, DLC1, CYR61, MLH1, CHFR, CDC16, CDKL1, NOTCH2, HRAS, CDK2, in technical and biological validation sets of samples. In the technical validation group, a significant positive correlation was observed for the expression of five genes (as evaluated by microarray and qRT-PCR, Spearman correlation, p&amp;lt;0.05), which were then tested in discriminant analysis to detect the best combination to classify resistant and residual tumors. The best combinations included all the five selected genes, CYR61/DLC1/CDKL1/NOTCH2/HTRA1, as well as three of them, CYR61/DLC1/HTRA1, which correctly classified 100% and 91% of tumors from the technical and biological validation groups (100% and 73% in leave one out cross validation, respectively). CYR61 was more expressed in residual samples, however no other main individual gene expression differences were detected. Our data indicate that primary and secondary chemoresistance may present some differences, involving mainly cell growth and cell proliferation processes. CYR61, a CCN growth factor family member, may be synthesized by tumor cells as well as by adjacent fibroblasts, exhibiting autocrine and paracrine actions, stimulating proliferation, migration and chemoresistance. CYR61 enhanced expression in post chemotherapy samples suggests that epithelial stromal interactions may be active players in the chemoresistance process, deserving more detailed analysis for targeted therapies. Supported by FAPESP. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-03.</jats:p

Exercise to Reduce Mobility Disability and Prevent Falls After Fall-Related Leg or Pelvic Fracture: RESTORE Randomized Controlled Trial

Background: Disability and falls are common following fall-related lower limb and pelvic fractures. Objective: To evaluate the impact of an exercise self-management intervention on mobility-related disability and falls after lower limb or pelvic fracture. Design: Randomized controlled trial. Participants: Three hundred thirty-six community dwellers aged 60+ years within 2 years of lower limb or pelvic fracture recruited from hospitals and community advertising. Interventions: RESTORE (Recovery Exercises and STepping On afteR fracturE) intervention (individualized, physiotherapist-prescribed home program of weight-bearing balance and strength exercises, fall prevention advice) versus usual care. Main Measures: Primary outcomes were mobility-related disability and rate of falls. Key Results: Primary outcomes were available for 80% of randomized participants. There were no significant between-group differences in mobility-related disability at 12 months measured by (a) Short Physical Performance Battery (continuous version, baseline-adjusted between-group difference 0.08, 95% CI − 0.01 to 0.17, p = 0.08, n = 273); (b) Activity Measure Post Acute Care score (0.18, 95% CI − 2.89 to 3.26, p = 0.91, n = 270); (c) Late Life Disability Instrument (1.37, 95% CI − 2.56 to 5.32, p = 0.49, n = 273); or in rate of falls over the 12-month study period (incidence rate ratio 0.96, 95% CI 0.69 to 1.34, n = 336, p = 0.83). Between-group differences favoring the intervention group were evident in some secondary outcomes: balance and mobility, fall risk (Physiological Profile Assessment tool), physical activity, mood, health and community outings, but these should be interpreted with caution due to risk of chance findings from multiple analyses. Conclusions: No statistically significant intervention impacts on mobility-related disability and falls were detected, but benefits were seen for secondary measures of balance and mobility, fall risk, physical activity, mood, health, and community outings. Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12610000805077

Long-term outcomes of 231 patients with essential thrombocythemia: prognostic factors to bleeding, thrombosis, myelofibrosis and leukaemia

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