Höhergradige Mehrlingsschwangerschaften: Untersuchung zum Outcome nach Mehrlingsreduktion unter besonderer Berücksichtigung der Chorionizität

Einleitung: Durch den Einsatz von reproduktionsmedizinischen Verfahren ist die Inzidenz von Mehrlingsschwangerschaften in den letzten Jahrzehnten stetig angestiegen. Mehrlingsschwangerschaften gelten generell als Risikoschwangerschaften und gehen mit einer erhöhten maternalen sowie fetalen Mortaliät und Morbidität einher. Ziel dieser Arbeit ist es, das Outcome höhergradiger Mehrlingschwangerschaften unter Berücksichtigung von möglicher Mehrlingsreduktion (MFPR) sowie dem Einfluss der Chorionizität zu untersuchen. Methode: Es handelt sich um eine retrospektive Analyse prospektiv erhobener Daten zu 157 Drillings- sowie 59 höhergradigen Mehrlingsschwangerschaften (Vier- bis Neunlinge), die zwischen der 10. und 14. SSW rekrutiert wurden und im Zeitraum vom 1.1.1999 und dem 6.2.2013 am Zentrum für Frauenheilkunde und Geburtshilfe im Bereich Pränatale Medizin der Universität Bonn vorstellig waren. Alle Patientinnen erhielten eine detaillierte Ersttrimesterdiagnostik und wurden interdisziplinär zur Frage höhergradiger Mehrlinge und dem Frühgeburtsrisiko unter Heranziehung von Neonatologen und Psychologen beraten. Ergebnisse: Wir fanden bei Drillingsschwangerschaften zwischen der MFPR- und der expektativen Gruppe keinen signifikanten Unterschied in Hinblick auf die Abortrate. Ein signifikant besseres Outcome erzielten die reduzierten Schwangerschaften in Hinblick auf die Verringerung der Frühgeburtlichkeit und die Zunahme der Geburtsgewichte. Unsere Ergebnisse bestätigen die besondere Gefährdung von Drillingsschwangerschaften mit monochorialer Komponente. Schlussfolgerung: Gestationsalter und Geburtsgewicht haben maßgeblichen Einfluss auf die perinatale Mortalität und Morbidität, daher trägt die Mehrlingsreduktion folglich zu einer deutlich verbesserten neonatalen Prognose der verbliebenen Kinder bei. Vorrangiges Ziel sollte es jedoch sein, das Auftreten von Mehrlingsschwangerschaften durch Restriktionen in der Reproduktionsmedizin zu vermeiden. Es liegt in den Händen der Ärzte, einen verantwortungsvollen Umgang mit den reproduktionsmedizinischen Maßnahmen sowie den pränatalmedizinischen Möglichkeiten umzusetzen

Transient Astrophysics Probe: White Paper

The Transient Astrophysics Probe (TAP) is a wide-field multi-wavelength transient mission proposed for flight starting in the late 2020s. The mission instruments include unique ``Lobster-eye'' imaging soft X-ray optics that allow an approximately 1600-degrees-squared Field of View (FoV); a high sensitivity, 1-degree-squared FoV soft X-ray telescope; a 1-degree-squared FoV Infrared telescope with bandpass 0.6 to 3 microns; and a set of 8 NaI gamma-ray detectors. TAP's most exciting capability will be the observation of tens per year of X-ray and Infrared counterparts of gravitational waves (GWs) involving stellar-mass black holes and neutron stars detected by LIGO (Laser Interferometer Gravitational-Wave Observatory ) / Virgo / KAGRA (Kamioka (Japan) Gravitational Wave Detector) / LIGO-India, and possibly several per year X-ray counterparts of GWs from supermassive black holes, detected by LISA (Laser Interferometer Space Antenna) and Pulsar Timing Arrays. TAP will also discover hundreds of X-ray transients related to compact objects, including tidal disruption events, supernova shock breakouts, and Gamma-Ray Bursts from the epoch of reionization

All-sky Medium Energy Gamma-ray Observatory: Exploring the Extreme Multimessenger Universe

The All-sky Medium Energy Gamma-ray Observatory (AMEGO) is a probe class mission concept that will provide essential contributions to multimessenger astrophysics in the late 2020s and beyond. AMEGO combines high sensitivity in the 200 keV to 10 GeV energy range with a wide field of view, good spectral resolution, and polarization sensitivity. Therefore, AMEGO is key in the study of multimessenger astrophysical objects that have unique signatures in the gamma-ray regime, such as neutron star mergers, supernovae, and flaring active galactic nuclei. The order-of-magnitude improvement compared to previous MeV missions also enables discoveries of a wide range of phenomena whose energy output peaks in the relatively unexplored medium-energy gamma-ray band

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Gender injustice in compensating injury to autonomy in English and Singaporean negligence law

The extent to which English law remedies injury to autonomy (ITA) as a stand-alone actionable damage in negligence is disputed. In this article I argue that the remedy available is not only partial and inconsistent (Keren-Paz in Med Law Rev, 2018) but also gendered and discriminatory against women. I first situate the argument within the broader feminist critique of tort law as failing to appropriately remedy gendered harms, and of law more broadly as undervaluing women’s interest in reproductive autonomy. I then show by reference to English remedies law’s first principles how imposed motherhood cases—Rees v Darlington and its predecessor McFarlane v Tayside Health Board—result in gender injustice when compared with other autonomy cases such as Chester v Afshar and Yearworth v North Bristol NHS Trust: A minor gender-neutral ITA is better remedied than the significant gendered harm of imposing motherhood on the claimant; men’s reproductive autonomy is protected to a greater extent than women’s; women’s reproductive autonomy is protected by an exceptional, derisory award. Worst of all, courts refuse to recognise imposed motherhood as detriment; and the deemed, mansplained, nonpecuniary joys of motherhood are used to offset pecuniary upkeep costs, forcing the claimant into a position she sought to avoid and thus further undermining her autonomy. The recent Singaporean case ACB v Thomson Medical Pte Ltd, awarding compensation for undermining the claimant’s genetic affinity in an IVF wrong-sperm-mix-up demonstrates some improvement in comparison to English law, and some shared gender injustices in the context of reproductive autonomy. ACB’s analysis is oblivious to the nature of reproductive autonomy harm as gendered; and prioritises the father’s interest in having genetic affinity with the baby over a woman’s interest in not having motherhood imposed upon her

A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish populationregister data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Expectant management versus multifetal pregnancy reduction in higher order multiple pregnancies containing a monochorionic pair and a review of the literature

To compare the perinatal outcome in multifetal pregnancies containing a monochorionic twin pair, managed either expectantly or by fetal reduction (MFPR). This was a retrospective analysis of prospectively collected data on 47 triplet and 10 quadruplet pregnancies recruited between 10 and 14 weeks. Main outcome measures were miscarriage < 24 weeks, preterm birth, fetal growth restriction, birth weight and survival rates. For triplets the miscarriage rates < 24 weeks were 6.3 % after reduction and 20.0 % for expectant management and MFPR, respectively. While we recorded no case of severe preterm delivery < 30 weeks in the reduction group, it was 25 % in those with expectant management. Mean gestational age and birth weight were significantly higher after fetal reduction than for the conservative approach (37.7 +/- 1.6 weeks vs. 30.9 +/- 3.2 weeks, p < 0.01 and 2676 +/- 705 g vs. 1429 +/- 542 g, p < 0.01). Expectantly managed triplets were complicated by twin-twin transfusion syndrome in 18.8 % and intrauterine fetal death in 8.3 %. Survival rates were 85.4 % for those managed expectantly and 80.0 % after fetal reduction. Mean gestational age of ongoing quadruplets was 26.9 +/- 2.0 weeks vs. 34.5 +/- 4.3 weeks for those with reduction of the monochorionic pair (p < 0.05). Survival rates were 100 % in the reduction group and 58.3 % in the expectant management group (p < 0.05). There was an inverse correlation between the final number of fetuses and the birth weight. Fetal reduction in triplets and quadruplets including a monochorionic pair is associated with decreased early prematurity. While in quadruplets the overall survival is higher after reduction, there was no difference for dichorionic triplets with reduction or conservative management. Complications owing to monochorionicity are frequently observed