The Mayer-Rokitansky-Küster-Hauser syndrome (congenital absence of uterus and vagina) – phenotypic manifestations and genetic approaches

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome affects at least 1 out of 4500 women and has for a long time been considered as a sporadic anomaly. Congenital absence of upper vagina and uterus is the prime feature of the disease which, in addition, is often found associated with unilateral renal agenesis or adysplasia as well as skeletal malformations (MURCS association). The phenotypic manifestations of MRKH overlap various other syndromes or associations and thus require accurate delineation. Since MRKH manifests itself in males, the term GRES syndrome (Genital, Renal, Ear, Skeletal) might be more appropriate when applied to both sexes. The MRKH syndrome, when described in familial aggregates, seems to be transmitted as an autosomal dominant trait with an incomplete degree of penetrance and variable expressivity. This suggests the involvement of either mutations in a major developmental gene or a limited chromosomal deletion. Until recently progress in understanding the genetics of MRKH syndrome has been slow, however, now HOX genes have been shown to play key roles in body patterning and organogenesis, and in particular during genital tract development. Expression and/or function defects of one or several HOX genes may account for this syndrome

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Lessons from non-canonical splicing

Recent improvements in experimental and computational techniques that are used to study the transcriptome have enabled an unprecedented view of RNA processing, revealing many previously unknown non-canonical splicing events. This includes cryptic events located far from the currently annotated exons and unconventional splicing mechanisms that have important roles in regulating gene expression. These non-canonical splicing events are a major source of newly emerging transcripts during evolution, especially when they involve sequences derived from transposable elements. They are therefore under precise regulation and quality control, which minimizes their potential to disrupt gene expression. We explain how non-canonical splicing can lead to aberrant transcripts that cause many diseases, and also how it can be exploited for new therapeutic strategies

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Growth and physiological responses of Eucalyptus Globulus Labilladiere following defoliation

Many defoliating herbivores cause damages to Eucalyptus globulus Labill. plantations, reducing the quality and value of the wood products they source. This damage ranges from mild to severe removal of leaf surface, and can result in significant reductions in yield. Our knowledge of physiological responses to defoliation in this species is incomplete, with previous studies focusing on very young trees and ignoring the potential interaction of abiotic stress with defoliation. Projections of future climates in many of the eucalypt-growing parts of the world suggest that abiotic stress, particularly degree of water stress will increase. In addition, there is strong evidence that changing climate, and particularly increasing temperature, is likely to favour many of the defoliating pests commonly associated with E. globulus. The objectives of work described in this thesis were to investigate the physiological strategies adopted by E. globulus in response to a defoliation event, determine their effects on growth and water relations, and examine the interaction with limited water supply, with the aim of improving our capacity to predict the impact of defoliation on tree productivity and water use. The main studies investigating tree responses to defoliation have utilised artificial defoliation treatments rather than natural defoliation because of logistical constraints. Although artificial manipulations are assumed to have significant advantages, the adequacy of the artificial method has been questioned in term of accuracy and differences in the plant responses. I tested that E. globulus respond differently to both artificial and natural defoliations. The results showed that the directions of response to artificial and insect defoliation were very similar. However, the influence of differential magnitude of the responses was more difficult to ascertain. I conclude that artificial defoliation may not accurately reflect the full strength of effects from insect defoliation, and caution must be exercised in extrapolating results of simulated herbivory experiments. Most previous studies of E. globulus responses to defoliation have focused on young, pre-canopy closure trees, and none have examined physiological responses of older trees to defoliation. Substantial defoliation can occur post-canopy closure. The effects of a single defoliation event on 4-year-old E. globulus were investigated on growth, photosynthetic and water relation responses in non-limited water supply conditions. The trees responded to removal of 45% of leaf area by a transient change in stem growth, change in crown architecture, the up-regulation of photosynthesis likely via the improvement of tree water status. It was concluded that 4-year-old E. globulus were able to compensate for the loss of foliage. Plantations of E. globulus are being established increasingly on lower rainfall sites, and in addition drought conditions are projected to increase in many areas of Australia over the next century. There is little understanding of the interactions of water stress and defoliation, although some results suggest that defoliation may be beneficial to trees growing under water limitation. I tested the hypothesis that partial defoliation would alleviate the effects of water stress. The effect leaf removal on 75% of crown length of 1-year-old E. globulus on growth, gas exchange and water use was examined in irrigated and rain-fed plots. Over a short-term period, trees responded to the interaction of limited water supply and defoliation by maintaining tree growth, increasing tree transpiration rate per unit leaf area, canopy conductance and hydraulic conductance, while maintaining the gradient of leaf water potential constant. It was concluded that defoliated trees were able to ease the effect of water stress by improving plant water status. Also, the findings were meeting the requirements of the theoretical hydraulic model