Testing for lynch syndrome in people with endometrial cancer using immunohistochemistry and microsatellite instability-based testing strategies – a systematic review of test accuracy

Background Lynch syndrome is an inherited genetic condition that is associated with an increased risk of cancer, including endometrial and colorectal cancer. We assessed the test accuracy of immunohistochemistry and microsatellite instability-based testing (with or without MLH1 promoter methylation testing) for Lynch syndrome in women with endometrial cancer. Methods We conducted a systematic review of literature published up to August 2019. We searched bibliographic databases, contacted experts and checked reference lists of relevant studies. Two reviewers conducted each stage of the review. Results Thirteen studies were identified that included approximately 3500 participants. None of the studies was at low risk of bias in all domains. Data could not be pooled due to the small number of heterogeneous studies. Sensitivity ranged from 60.7–100% for immunohistochemistry, 41.7–100% for microsatellite instability-based testing, and 90.5–100% for studies combining immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation testing. Specificity ranged from 60.9–83.3% (excluding 1 study with highly selective inclusion criteria) for immunohistochemistry, 69.2–89.9% for microsatellite instability-based testing, and 72.4–92.3% (excluding 1 study with highly selective inclusion criteria) for testing strategies that included immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation. We found no statistically significant differences in test accuracy estimates (sensitivity, specificity) in head-to-head studies of immunohistochemistry versus microsatellite instability-based testing. Reported test failures were rare. Conclusions Sensitivity of the index tests were generally high, though most studies had much lower specificity. We found no evidence that test accuracy differed between IHC and MSI based strategies. The evidence base is currently small and at high risk of bias

SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts

Acknowledgements We sincerely thank the patients and family members who participated in this study. We would also like to thank Stefan Esher, Umeå University, for help with genealogy, and Anna Westerlund for excellent technical assistance. This work was supported by grants from the FOU, at the Umeå university hospital, and the Medical Faculty at Umeå University. The work at University of Gothenburg was supported by grants from The Swedish Research Council, the Swedish Rheumatism Association, the Royal 80-Year Fund of King Gustav V, ALF/LUA research grant from Sahlgrenska University Hospital in Gothenburg and the Lundberg Foundation. The work at the University of Gothenburg and the University of Aberdeen was supported by Euroclast, a Marie Curie FP7-People-2013-ITN: # 607446.Peer reviewedPublisher PD

A gene-rich linkage map in the dioecious species Actinidia chinensis (kiwifruit) reveals putative X/Y sex-determining chromosomes

<p>Abstract</p> <p>Background</p> <p>The genus <it>Actinidia </it>(kiwifruit) consists of woody, scrambling vines, native to China, and only recently propagated as a commercial crop. All species described are dioecious, but the genetic mechanism for sex-determination is unknown, as is the genetic basis for many of the cluster of characteristics making up the unique fruit. It is, however, an important crop in the New Zealand economy, and a classical breeding program would benefit greatly by knowledge of the trait alleles carried by both female and male parents. The application of marker assisted selection (MAS) in seedling populations would also aid the accurate and efficient development of novel fruit types for the market.</p> <p>Results</p> <p>Gene-rich female, male and consensus linkage maps of the diploid species <it>A. chinensis </it>have been constructed with 644 microsatellite markers. The maps consist of twenty-nine linkage groups corresponding to the haploid number n = 29. We found that sex-linked sequence characterized amplified region (SCAR) markers and the 'Flower-sex' phenotype consistently mapped to a single linkage group, in a subtelomeric region, in a section of inconsistent marker order. The region also contained markers of expressed genes, some of unknown function. Recombination, assessed by allelic distribution and marker order stability, was, in the remainder of the linkage group, in accordance with other linkage groups. Fully informative markers to other genes in this linkage group identified the comparative linkage group in the female map, where recombination ratios determining marker order were similar to the autosomes.</p> <p>Conclusion</p> <p>We have created genetic linkage maps that define the 29 linkage groups of the haploid genome, and have revealed the position and extent of the sex-determining locus in <it>A. chinensis</it>. As all <it>Actinidia </it>species are dioecious, we suggest that the sex-determining loci of other <it>Actinidia </it>species will be similar to that region defined in our maps. As the extent of the non-recombining region is limited, our result supports the suggestion that the subtelomeric region of an autosome is in the early stages of developing the characteristics of a sex chromosome. The maps provide a reference of genetic information in <it>Actinidia </it>for use in genetic analysis and breeding programs.</p

An R2R3 MYB transcription factor determines red petal colour in an Actinidia (kiwifruit) hybrid population

Background Red colour in kiwifruit results from the presence of anthocyanin pigments. Their expression, however, is complex, and varies among genotypes, species, tissues and environments. An understanding of the biosynthesis, physiology and genetics of the anthocyanins involved, and the control of their expression in different tissues, is required. A complex, the MBW complex, consisting of R2R3-MYB and bHLH transcription factors together with a WD-repeat protein, activates anthocyanin 3-O-galactosyltransferase (F3GT1) to produce anthocyanins. We examined the expression and genetic control of anthocyanins in flowers of Actinidia hybrid families segregating for red and white petal colour. Results Four inter-related backcross families between Actinidia chinensis Planch. var. chinensis and Actinidia eriantha Benth. were identified that segregated 1:1 for red or white petal colour. Flower pigments consisted of five known anthocyanins (two delphinidin-based and three cyanidin-based) and three unknowns. Intensity and hue differed in red petals from pale pink to deep magenta, and while intensity of colour increased with total concentration of anthocyanin, no association was found between any particular anthocyanin data and hue. Real time qPCR demonstrated that an R2R3 MYB, MYB110a, was expressed at significant levels in red-petalled progeny, but not in individuals with white petals. A microsatellite marker was developed that identified alleles that segregated with red petal colour, but not with ovary, stamen filament, or fruit flesh colour in these families. The marker mapped to chromosome 10 in Actinidia. The white petal phenotype was complemented by syringing Agrobacterium tumefaciens carrying Actinidia 35S::MYB110a into the petal tissue. Red pigments developed in white petals both with, and without, co-transformation with Actinidia bHLH partners. MYB110a was shown to directly activate Actinidia F3GT1 in transient assays. Conclusions The transcription factor, MYB110a, regulates anthocyanin production in petals in this hybrid population, but not in other flower tissues or mature fruit. The identification of delphinidin-based anthocyanins in these flowers provides candidates for colour enhancement in novel fruits

The effect of mode of delivery on health-related quality-of-life in mothers: a systematic review and meta-analysis

Background: Previous research is inconclusive on the effects of mode of delivery on maternal health-related quality-of-life (HRQoL). We conducted a systematic review and meta-analysis to assess the current evidence for associations between mode of delivery and postpartum health-related quality-of-life. Methods: Electronic databases MEDLINE ALL (OVID), Web of Science, The Cochrane Library, CINAHL and EMBASE (OVID) were searched for English written articles investigating the relationship between mode of delivery and quality-of-life published form inception to 15th October 2020. Two reviewers independently screened titles and abstracts, assessed full texts, and extracted data. Meta-analysis was conducted where possible. Results: Twenty-one studies, including 19,879 women, met the inclusion criteria. A meta-analysis of 18 studies found HRQoL scores were significantly higher for women after vaginal delivery in comparison to caesarean (emergency and elective combined) (Effect Size (ES) 0.17, 95% CI 0.01–0.25, n = 7665) with highest scores after assisted vaginal delivery (ES 0.21, 95% CI 0.13–0.30, n = 2547). Physical functioning (ES 11.18, 95% CI = 2.29–20.06, n = 1746), physical role (ES 13.10, 95% CI = 1.16–25.05, n = 1471), vitality (ES 6.31, 95% CI = 1.14–10.29, n = 1746) and social functioning (ES 5.69, 95% CI = 1.26–10.11, n = 1746) were significantly higher after vaginal delivery compared to caesarean. Conclusions: Health-related quality-of-life scores were higher for women after vaginal delivery in comparison to caesarean section. Consequently, women should be encouraged to deliver vaginally where possible. The findings of this research should be available to the relevant population to help support informed choice

Diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years

Adolescent overweight and obesity has increased globally, and can be associated with short- and long-term health consequences. Modifying known dietary and behavioural risk factors through behaviour changing interventions (BCI) may help to reduce childhood overweight and obesity. This is an update of a review published in 2009. To assess the effects of diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years. We performed a systematic literature search in: CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and the trial registers ClinicalTrials.gov and ICTRP Search Portal. We checked references of identified studies and systematic reviews. There were no language restrictions. The date of the last search was July 2016 for all databases. We selected randomised controlled trials (RCTs) of diet, physical activity and behavioural interventions for treating overweight or obesity in adolescents aged 12 to 17 years. Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using the GRADE instrument and extracted data following the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. We included 44 completed RCTs (4781 participants) and 50 ongoing studies. The number of participants in each trial varied (10 to 521) as did the length of follow-up (6 to 24 months). Participants ages ranged from 12 to 17.5 years in all trials that reported mean age at baseline. Most of the trials used a multidisciplinary intervention with a combination of diet, physical activity and behavioural components. The content and duration of the intervention, its delivery and the comparators varied across trials. The studies contributing most information to outcomes of weight and body mass index (BMI) were from studies at a low risk of bias, but studies with a high risk of bias provided data on adverse events and quality of life.The mean difference (MD) of the change in BMI at the longest follow-up period in favour of BCI was -1.18 kg/m(2) (95% confidence interval (CI) -1.67 to -0.69); 2774 participants; 28 trials; low quality evidence. BCI lowered the change in BMI z score by -0.13 units (95% CI -0.21 to -0.05); 2399 participants; 20 trials; low quality evidence. BCI lowered body weight by -3.67 kg (95% CI -5.21 to -2.13); 1993 participants; 20 trials; moderate quality evidence. The effect on weight measures persisted in trials with 18 to 24 months' follow-up for both BMI (MD -1.49 kg/m(2) (95% CI -2.56 to -0.41); 760 participants; 6 trials and BMI z score MD -0.34 (95% CI -0.66 to -0.02); 602 participants; 5 trials).There were subgroup differences showing larger effects for both BMI and BMI z score in studies comparing interventions with no intervention/wait list control or usual care, compared with those testing concomitant interventions delivered to both the intervention and control group. There were no subgroup differences between interventions with and without parental involvement or by intervention type or setting (health care, community, school) or mode of delivery (individual versus group).The rate of adverse events in intervention and control groups was unclear with only five trials reporting harms, and of these, details were provided in only one (low quality evidence). None of the included studies reported on all-cause mortality, morbidity or socioeconomic effects.BCIs at the longest follow-up moderately improved adolescent's health-related quality of life (standardised mean difference 0.44 ((95% CI 0.09 to 0.79); P = 0.01; 972 participants; 7 trials; 8 comparisons; low quality of evidence) but not self-esteem.Trials were inconsistent in how they measured dietary intake, dietary behaviours, physical activity and behaviour. We found low quality evidence that multidisciplinary interventions involving a combination of diet, physical activity and behavioural components reduce measures of BMI and moderate quality evidence that they reduce weight in overweight or obese adolescents, mainly when compared with no treatment or waiting list controls. Inconsistent results, risk of bias or indirectness of outcome measures used mean that the evidence should be interpreted with caution. We have identified a large number of ongoing trials (50) which we will include in future updates of this review

Repeated plague infections across six generations of Neolithic Farmers

In the period between 5,300 and 4,900 calibrated years before present (cal. bp), populations across large parts of Europe underwent a period of demographic decline1, 2. However, the cause of this so-called Neolithic decline is still debated. Some argue for an agricultural crisis resulting in the decline3, others for the spread of an early form of plague4. Here we use population-scale ancient genomics to infer ancestry, social structure and pathogen infection in 108 Scandinavian Neolithic individuals from eight megalithic graves and a stone cist. We find that the Neolithic plague was widespread, detected in at least 17% of the sampled population and across large geographical distances. We demonstrate that the disease spread within the Neolithic community in three distinct infection events within a period of around 120 years. Variant graph-based pan-genomics shows that the Neolithic plague genomes retained ancestral genomic variation present in Yersinia pseudotuberculosis, including virulence factors associated with disease outcomes. In addition, we reconstruct four multigeneration pedigrees, the largest of which consists of 38 individuals spanning six generations, showing a patrilineal social organization. Lastly, we document direct genomic evidence for Neolithic female exogamy in a woman buried in a different megalithic tomb than her brothers. Taken together, our findings provide a detailed reconstruction of plague spread within a large patrilineal kinship group and identify multiple plague infections in a population dated to the beginning of the Neolithic decline

Preeclampsia and Blood Pressure Trajectory during Pregnancy in Relation to Vitamin D Status

Every tenth pregnancy is affected by hypertension, one of the most common complications and leading causes of maternal death worldwide. Hypertensive disorders in pregnancy include pregnancy-induced hypertension and preeclampsia. The pathophysiology of the development of hypertension in pregnancy is unknown, but studies suggest an association with vitamin D status, measured as 25-hydroxyvitamin D (25(OH)D). The aim of this study was to investigate the association between gestational 25(OH)D concentration and preeclampsia, pregnancy-induced hypertension and blood pressure trajectory. This cohort study included 2000 women. Blood was collected at the first (T1) and third (T3) trimester (mean gestational weeks 10.8 and 33.4). Blood pressure at gestational weeks 10, 25, 32 and 37 as well as symptoms of preeclampsia and pregnancy-induced hypertension were retrieved from medical records. Serum 25(OH)D concentrations (LC-MS/MS) in T1 was not significantly associated with preeclampsia. However, both 25(OH)D in T3 and change in 25(OH)D from T1 to T3 were significantly and negatively associated with preeclampsia. Women with a change in 25(OH)D concentration of ≥30 nmol/L had an odds ratio of 0.22 (p = 0.002) for preeclampsia. T1 25(OH)D was positively related to T1 systolic (β = 0.03, p = 0.022) and T1 diastolic blood pressure (β = 0.02, p = 0.016), and to systolic (β = 0.02, p = 0.02) blood pressure trajectory during pregnancy, in adjusted analyses. There was no association between 25(OH)D and pregnancy-induced hypertension in adjusted analysis. In conclusion, an increase in 25(OH)D concentration during pregnancy of at least 30 nmol/L, regardless of vitamin D status in T1, was associated with a lower odds ratio for preeclampsia. Vitamin D status was significantly and positively associated with T1 blood pressure and gestational systolic blood pressure trajectory but not with pregnancy-induced hypertension

Factors associated with attendance at screening for breast cancer : a systematic review and meta-analysis

Objective: Attendance at population-based breast cancer (mammographic) screening varies. This comprehensive systematic review and meta-analysis assesses all identified patient-level factors associated with routine population breast screening attendance. Design: CINAHL, Cochrane Library, Embase, Medline, OVID, PsycINFO and Web of Science were searched for studies of any design, published January 1987–June 2019, and reporting attendance in relation to at least one patient-level factor. Data synthesis: Independent reviewers performed screening, data extraction and quality appraisal. OR and 95% CIs were calculated for attendance for each factor and random-effects meta-analysis was undertaken where possible. Results: Of 19 776 studies, 335 were assessed at full text and 66 studies (n=22 150 922) were included. Risk of bias was generally low. In meta-analysis, increased attendance was associated with higher socioeconomic status (SES) (n=11 studies; OR 1.45, 95% CI: 1.20 to 1.75); higher income (n=5 studies; OR 1.96, 95% CI: 1.68 to 2.29); home ownership (n=3 studies; OR 2.16, 95% CI: 2.08 to 2.23); being non-immigrant (n=7 studies; OR 2.23, 95% CI: 2.00 to 2.48); being married/cohabiting (n=7 studies; OR 1.86, 95% CI: 1.58 to 2.19) and medium (vs low) level of education (n=6 studies; OR 1.24, 95% CI: 1.09 to 1.41). Women with previous false-positive results were less likely to reattend (n=6 studies; OR 0.77, 95% CI: 0.68 to 0.88). There were no differences by age group or by rural versus urban residence. Conclusions: Attendance was lower in women with lower SES, those who were immigrants, non-homeowners and those with previous false-positive results. Variations in service delivery, screening programmes and study populations may influence findings. Our findings are of univariable associations. Underlying causes of lower uptake such as practical, physical, psychological or financial barriers should be investigated. Trial registration number: CRD42016051597