Genome-wide structural variant analysis identifies risk loci for non-Alzheimer's dementias

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered

Maternal and child health interventions in Nigeria: a systematic review of published studies from 1990 to 2014

BACKGROUND: Poor maternal and child health indicators have been reported in Nigeria since the 1990s. Many interventions have been instituted to reverse the trend and ensure that Nigeria is on track to achieve the Millennium Development Goals. This systematic review aims at describing and indirectly measuring the effect of the Maternal, Newborn, and Child Health (MNCH) interventions implemented in Nigeria from 1990 to 2014. METHODS: PubMed and ISI Web of Knowledge were searched from 1990 to April 2014 whereas POPLINE® was searched until 16 February 2015 to identify reports of interventions targeting Maternal, Newborn, and Child Health in Nigeria. Narrative and graphical synthesis was done by integrating the results of extracted studies with trends of maternal mortality ratio (MMR) and under five mortality (U5MR) derived from a joint point regression analysis using Nigeria Demographic and Health Survey data (1990-2013). This was supplemented by document analysis of policies, guidelines and strategies of the Federal Ministry of Health developed for Nigeria during the same period. RESULTS: We identified 66 eligible studies from 2,662 studies. Three interventions were deployed nationwide and the remainder at the regional level. Multiple study designs were employed in the enrolled studies: pre- and post-intervention or quasi-experimental (n = 40; 61%); clinical trials (n = 6;9%); cohort study or longitudinal evaluation (n = 3;5%); process/output/outcome evaluation (n = 17;26%). The national MMR shows a consistent reduction (Annual Percentage Change (APC) = -3.10%, 95% CI: -5.20 to -1.00 %) with marked decrease in the slope observed in the period with a cluster of published studies (2004-2014). Fifteen intervention studies specifically targeting under-five children were published during the 24 years of observation. A statistically insignificant downward trend in the U5MR was observed (APC = -1.25%, 95% CI: -4.70 to 2.40%) coinciding with publication of most of the studies and development of MNCH policies. CONCLUSIONS: The development of MNCH policies, implementation and publication of interventions corresponds with the downward trend of maternal and child mortality in Nigeria. This systematic review has also shown that more MNCH intervention research and publications of findings is required to generate local and relevant evidence

Men’s experiences of surviving testicular cancer: An integrated literature review

Purpose: To synthesise literature in order to elucidate the experiences of men who have survived testicular cancer and determine their quality of life following treatment. Methods: An integrated review sought appropriate literature by utilising a keyword search across seven databases. Retrieved studies were appraised for quality, with 2 qualitative, 12 quantitative and 2 mixed method studies deemed appropriate for this review. The data were extracted and aggregated into categories by way of a thematic analysis. The themes were personal challenges and impact on health, psychological and emotive challenges, perception of reproduction and sexual changes and outlook and support. Results: Men experienced physical, emotional and sexual difficulties. Some men believed they were infertile, despite evidence that fertility is not compromised in the long term. Psychological conditions can be exacerbated by cultural pressures to conceive and cultural expressions about male identity. Men who had undergone orchidectomy reported minimal impact on their mental health than the men who had chemotherapy or radiotherapy as part of their treatment modality. Sexual dysfunction caused by chemotherapy-associated side effects was detrimental to men’s quality of life. In addition, men who had a partner, who were employed, and who had children were able to adjust better after treatment than those who did not. Provision of clear and honest information post-treatment helped testicular cancer survivors return to their normal lives. Conclusions: The evidence from the review suggests that the burden of disease for testicular cancer survivors is overall low. Men who had surgical intervention and were treated for testicular cancer experienced minimal impact on their mental health status than the men who had chemotherapy or radiotherapy as part of their treatment modality. Implications for Cancer Survivors: There is a need to provide appropriate referrals to the relevant services, including psychosocial support, and the development of more adequate communication resources for men following treatment for testicular cancer

Study protocol for a Developmental Epidemiological Study of Children born through Reproductive Technologies (DESCRT).

Study questionsThe primary objective of this study is to determine what parental factors or specific ART may influence the risk for adverse cardiometabolic outcomes among children so conceived and their parents. The secondary objective of this study is to prospectively examine the effects of infertility or ART on the intrauterine environment, obstetric and neonatal outcomes.What is known alreadyPregnancies conceived with ART are at an increased risk of being affected by adverse obstetric and neonatal outcomes when compared to spontaneously conceived (SC) pregnancies among fertile women. Small cohort studies have suggested ART-conceived children may have a higher risk of long-term cardiometabolic disturbances as well. Currently, few studies have compared long-term cardiometabolic outcomes among ART-conceived children and non-IVF treated (NIFT) children, to children conceived spontaneously to parents with infertility (subfertile parents).Study design size durationThe Developmental Epidemiological Study of Children born through Reproductive Technologies (DESCRT) is a prospective cohort study that aims to: establish a biobank and epidemiological cohort of children born to subfertile or infertile parents who either conceived spontaneously (without assistance) or used reproductive technologies to conceive (all offspring were from couples assessed and/or treated in the same institute); prospectively examine the effects of infertility or ART on the intrauterine environment, obstetric and neonatal outcomes; and determine what parental factors or ART may influence the cardiometabolic risk of children so conceived. Pregnancies and resultant children will be compared by mode of conception, namely offspring that were conceived without medical assistance or SC or following NIFT, IVF with fresh embryo transfer or frozen embryo transfer (FET), and by fertilization method (conventional versus ICSI). DESCRT has a Child group evaluating long-term outcomes of children as well as a Pregnancy group that will compare obstetric and neonatal outcomes of children conceived since the commencement of the study. Recruitment started in May of 2017 and is ongoing. When the study began, we estimated that ∼4000 children would be eligible for enrollment.Participants/materials setting methodsEligible participants are first-trimester pregnancies (Pregnancy group) or children (Child group) born to parents who were evaluated at an infertility center in the University of California, San Francisco, CA, USA who were SC or conceived after reproductive treatments (NIFT, IVF ± ICSI, FET). Children in the Child group were conceived at UCSF and born from 2001 onwards. In the Pregnancy group, enrollment began in November of 2017.The primary outcome is the cardiometabolic health of offspring in the Child group, as measured by blood pressure and laboratory data (homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose disposition). There are several secondary outcome measures, including: outcomes from parental survey response (assessing parent/child medical history since delivery-incidence of cardiometabolic adverse events), anthropomorphic measurements (BMI, waist circumference, skinfold thickness), and laboratory data (liver enzymes, lipid panel, metabolomic profiles). In the Pregnancy group, outcomes include laboratory assessments (bhCG, maternal serum analytes, soluble fms-like tyrosine kinase-1 (sFLT-1), and placental growth factor (PlGF)) and placental assessments (placental volume in the second and third trimester and placental weight at delivery). Importantly, aliquots of blood and urine are stored from parents and offspring as part of a biobank. The DESCRT cohort is unique in two ways. First, there is an extensive amount of clinical and laboratory treatment data: parental medical history and physical examination at the time of treatment, along with ovarian reserve and infertility diagnosis; and treatment specifics: for example, fertilization method, culture O2 status, embryo quality linked to each participant. These reproductive data will aid in identifying explanatory variables that may influence the primary cardiometabolic outcomes of the offspring-and their parents. Second, the DESCRT control group includes pregnancies and children SC from parents with subfertility, which may help to assess when infertility, as opposed to reproductive treatments, may be affecting offspring cardiometabolic health.Study funding/competing interestsThis study is funded by the National Institutes of Health NICHD (1R01HD084380-01A1). A.J.A. is a shareholder in Carrot and consultant for Flo Health. The other authors have no conflicts of interest.Trial registration numberNCT03799107.Trial registration date10 January 2019.Date of first patient’s enrollment10 May 2017