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The decline in available oestrogen after menopause is a possible etiological factor in pelvic floor disorders like vaginal atrophy (VA), urinary incontinence (UI), overactive bladder (OAB) and pelvic organ prolapse (POP). This systematic review will examine the evidence for local oestrogen therapy in the treatment of these pelvic floor disorders.We performed a systematic search in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the non-MEDLINE subset of PubMed from inception to May 2014. We searched for local oestrogens and VA (I), UI/OAB (II) and POP (III). Part I was combined with broad methodological filters for randomized controlled trials (RCTs) and secondary evidence. For part I and II two reviewers independently selected RCTs evaluating the effect of topical oestrogens on symptoms and signs of VA and UI/OAB. In part III all studies of topical oestrogen therapy in the treatment of POP were selected. Data extraction and the assessment of risk of bias using the Cochrane Risk of Bias Tool was undertaken independently by two reviewers.The included studies varied in ways of topical application, types of oestrogen, dosage and treatment durations. Objective and subjective outcomes were assessed by a variety of measures. Overall, subjective and urodynamic outcomes, vaginal maturation and vaginal pH changed in favor of vaginal oestrogens compared to placebo. No obvious differences between different application methods were revealed. Low doses already seemed to have a beneficial effect. Studies evaluating the effect of topical oestrogen in women with POP are scarce and mainly assessed symptoms and signs associated with VA instead of POP symptoms.Topical oestrogen administration is effective for the treatment of VA and seems to decrease complaints of OAB and UI. The potential for local oestrogens in the prevention as well as treatment of POP needs further research.

Rain-fed peatlands are dominated by peat mosses (Sphagnum sp.), which for their growth depend on nutrients, water and CO2 uptake from the atmosphere. As the isotopic composition of carbon (12,13C) and oxygen (16,18O) of these Sphagnum mosses are affected by environmental conditions, Sphagnum tissue accumulated in peat constitutes a potential long-term archive that can be used for climate reconstruction. However, there is inadequate understanding of how isotope values are influenced by environmental conditions, which restricts their current use as environmental and palaeoenvironmental indicators. Here we tested (i) to what extent C and O isotopic variation in living tissue of Sphagnum is species-specific and associated with local hydrological gradients, climatic gradients (evapotranspiration, temperature, precipitation) and elevation; (ii) whether the C isotopic signature can be a proxy for net primary productivity (NPP) of Sphagnum; and (iii) to what extent Sphagnum tissue δ18O tracks the δ18O isotope signature of precipitation. In total, we analysed 337 samples from 93 sites across North America and Eurasia using two important peat-forming Sphagnum species (S. magellanicum, S. fuscum) common to the Holarctic realm. There were differences in δ13C values between species. For S. magellanicum δ13C decreased with increasing height above the water table (HWT, R2 = 17 %) and was positively correlated to productivity (R2 = 7 %). Together these two variables explained 46 % of the between-site variation in δ13C values. For S. fuscum, productivity was the only significant predictor of δ13C but had low explanatory power (total R2 = 6 %). For δ18O values, approximately 90 % of the variation was found between sites. Globally modelled annual δ18O values in precipitation explained 69 % of the between-site variation in tissue δ18O. S. magellanicum showed lower δ18O enrichment than S. fuscum (−0.83 ‰ lower). Elevation and climatic variables were weak predictors of tissue δ18O values after controlling for δ18O values of the precipitation. To summarize, our study provides evidence for (a) good predictability of tissue δ18O values from modelled annual δ18O values in precipitation, and (b) the possibility of relating tissue δ13C values to HWT and NPP, but this appears to be species-dependent. These results suggest that isotope composition can be used on a large scale for climatic reconstructions but that such models should be species-specific.

Peatlands, storing significant amounts of carbon, are extremely vulnerable to climate change. The effects of climate change are projected to lead to a vegetation shift from Sphagnum mosses to sedges and shrubs. Impacts on the present moss-dominated peat remain largely unknown. In this study, we used a multiproxy approach to investigate the influence of contrasting vascular plant types (sedges, shrubs) on peat chemistry and decomposition. Peat cores of 20 cm depth and plant material (Sphagnum spp., Calluna vulgaris and Eriophorum vaginatum) from two ombrotrophic peatlands in the Italian Alps with a mean annual temperature difference of 1.4 ∘C were analyzed. Peat cores were taken under adjacent shrub and sedge plants growing at the same height above the water table. We used carbon, nitrogen and their stable isotopes to assess general patterns in the degree of decomposition across sampling locations and depths. In addition, analytical pyrolysis was applied to disentangle effects of vascular plants (sedge, shrub) on chemical properties and decomposition of the moss-dominated peat. Pyrolysis data confirmed that Sphagnum moss dominated the present peat irrespective of depth. Nevertheless, vascular plants contributed to peat properties as revealed by, e.g., pyrolysis products of lignin. The degree of peat decomposition increased with depth as shown by, e.g., decreasing amounts of the pyrolysis product of sphagnum acid and increasing δ13C with depth. Multiple parameters also revealed a higher degree of decomposition of Sphagnum-dominated peat collected under sedges than under shrubs, particularly at the high temperature site. Surprisingly, temperature effects on peat decomposition were less pronounced than those of sedges. Our results imply that vascular plants affect the decomposition of the existing peat formed by Sphagnum, particularly at elevated temperature. These results suggest that changes in plant functional types may have a stronger impact on the soil carbon feedback in a warmer world than hitherto assumed.

Dune development along highly dynamic land–sea boundaries is the result of interaction between vegetation and dune size with sedimentation and erosion processes. Disentangling the contribution of vegetation characteristics from that of dune size would improve predictions of nebkha dune development under a changing climate, but has proven difficult due to the scarcity of spatially continuous monitoring data. This study explored the contributions of vegetation and dune size to dune development for locations differing in shelter from the sea. We monitored a natural nebkha dune field of 8 ha, along the coast of the island Texel, the Netherlands, for 1 year using an unmanned aerial vehicle (UAV) with camera. After constructing a digital surface model and orthomosaic we derived for each dune (1) vegetation characteristics (species composition, vegetation density, and maximum vegetation height), (2) dune size (dune volume, area, and maximum height), (3) degree of shelter (proximity to other nebkha dunes and the sheltering by the foredune). Changes in dune volume over summer and winter were related to vegetation, dune size and degree of shelter. We found that a positive change in dune volume (dune growth) was linearly related to initial dune volume over summer but not over winter. Big dunes accumulated more sand than small dunes due to their larger surface area. Exposed dunes increased more in volume (0.81 % per dune per week) than sheltered dunes (0.2 % per dune per week) over summer, while the opposite occurred over winter. Vegetation characteristics did not significantly affect dune growth in summer, but did significantly affect dune growth in winter. Over winter, dunes dominated by Ammophila arenaria, a grass species with high vegetation density throughout the year, increased more in volume than dunes dominated by Elytrigia juncea, a grass species with lower vegetation density (0.43 vs. 0.42 (m3 m−3) week−1). The effect of species was irrespective of dune size or distance to the sea. Our results show that dune growth in summer is mainly determined by dune size, whereas in winter dune growth was determined by vegetation type. In our study area the growth of exposed dunes was likely restricted by storm erosion, whereas growth of sheltered dunes was restricted by sand supply. Our results can be used to improve models predicting coastal dune development.

Peatlands accumulated large carbon (C) stocks as peat in historical times. Currently however, many peatlands are on the verge of becoming sources with their C sequestration function becoming sensitive to environmental changes such as increases in temperature, decreasing water table and enhanced nitrogen deposition. Long term changes in vegetation composition are both, a consequence and indicator of future changes in C sequestration. Spatial continuous accurate assessment of the vegetation composition is a current challenge in keeping a close watch on peatland vegetation changes. In this study we quantified the fractional cover of three major plant functional types (PFTs; Sphagnum mosses, graminoids, and ericoid shrubs) in peatlands, using field spectroscopy reflectance measurements (400–2400 nm) on 25 plots differing in PFT cover. The data was validated using point intercept methodology on the same plots. Our results showed that the detection of open Sphagnum versus Sphagnumcovered by vascular plants (shrubs and graminoids) is feasible with an R2 of 0.81. On the other hand, the partitioning of the vascular plant fraction into shrubs and graminoids revealed lower correlations of R2 of 0.54 and 0.57, respectively. This study was based on a dataset where the reflectance of all main PFTs and their pure components within the peatland was measured at local spatial scales. Spectrally measured species or plant community abundances can further be used to bridge scaling gaps up to canopy scale, ultimately allowing upscaling of the C balance of peatlands to the ecosystem level.

Peatlands cover only 3% of the Earth's land surface but boreal and subarctic peatlands store about 15–30% of the world's soil carbon (C) as peat. Despite their potential for large positive feedbacks to the climate system through sequestration and emission of greenhouse gases, peatlands are not explicitly included in global climate models and therefore in predictions of future climate change. In April 2007 a symposium was held in Wageningen, the Netherlands, to advance our understanding of peatland C cycling. This paper synthesizes the main findings of the symposium, focusing on (i) small-scale processes, (ii) C fluxes at the landscape scale, and (iii) peatlands in the context of climate change. The main drivers controlling C fluxes are largely scale dependent and most are related to some aspects of hydrology. Despite high spatial and annual variability in Net Ecosystem Exchange (NEE), the differences in cumulative annual NEE are more a function of broad scale geographic location and physical setting than internal factors, suggesting the existence of strong feedbacks. In contrast, trace gas emissions seem mainly controlled by local factors. Key uncertainties remain concerning the existence of perturbation thresholds, the relative strengths of the CO2 and CH4 feedback, the links among peatland surface climate, hydrology, ecosystem structure and function, and trace gas biogeochemistry as well as the similarity of process rates across peatland types and climatic zones. Progress on these research areas can only be realized by stronger co-operation between disciplines that address different spatial and temporal scales.

Background & Aims: Obesity is associated with vitamin D (VitD) deficiency. However, previous studies showed mixed effects of VitD (25-hydroxyVitD/calcidiol) supplementation on body weight. The biological actions of VitD require the hydroxylation of inactive VitD into active VitD (1.25-dihydroxyVitD/calcitriol). This step is highly regulated; therefore, supplementing with inactive VitD might not be sufficient to overcome the potential adverse health effects of VitD deficiency. The objective of this study was to conduct a systematic review and individual participant data (IPD) meta-analysis of data acquired from randomised placebo-controlled calcitriol trials (RCTs) to determine the effects of calcitriol on body weight and weight-related parameters., Methods: Studies were identified from MEDLINE, EMBASE, and CENTRAL databases up to January 27, 2024, and excluded those involving dialysis or cancer patients. We obtained IPD from eligible trials and assessed bias using the Cochrane Collaboration risk-of-bias tool and methodological quality using the Heyland Methodological Quality Score. The study was prospectively registered with PROSPERO (CRD42017076202)., Results: Although none of the studies reported information regarding our primary objective, we obtained IPD for 411 patients, with 206 randomised to receive calcitriol and 205 to placebo. This dataset enabled us to conduct an IPD meta-analysis with 17,084 person-months of follow-up (median: 11 months). Meta-analysis showed that calcitriol does not alter body weight, BMI, waist circumference, fat mass or lean body mass compared to placebo. Adjusting for age and sex did not alter the outcomes., Conclusions: In conclusion, this systematic review and IPD meta-analysis indicate that calcitriol does not affect body weight in normal-weight postmenopausal women and lean patients with type 1 diabetes nor in people suffering from obesity, type 2 diabetes and chronic kidney disease. Whether calcitriol lowers body weight in VitD-sufficient people with obesity remains to be elucidated., Competing Interests: Conflict of interest We declare that there are no conflicts of interest regarding this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Together with warming air temperatures, Arctic ecosystems are expected to experience increases in heavy rainfall events. Recent studies report accelerated degradation of permafrost under heavy rainfall, which could put significant amounts of soil carbon and infrastructure at risk. However, controlled experimental evidence of rainfall effects on permafrost thaw is scarce. We experimentally tested the impact and legacy effect of heavy rainfall events in early and late summer for five sites varying in topography and soil type on the High Arctic archipelago of Svalbard. We found that effects of heavy rainfall on soil thermal regimes are small and limited to one season. Thaw rates increased under heavy rainfall in a loess terrace site, but not in polygonal tundra soils with higher organic matter content and water tables. End-of-season active layer thickness was not affected. Rainfall application did not affect soil temperature trends, which appeared driven by timing of snowmelt and organic layer thickness, particularly during early summer. Late summer rainfall was associated with slower freeze-up and colder soil temperatures the following winter. This implies that rainfall impacts on Svalbard permafrost are limited, locally variable and of short duration. Our findings diverge from earlier reports of sustained increases in permafrost thaw following extreme rainfall, but are consistent with observations that maritime permafrost regions such as Svalbard show lower rainfall sensitivity than continental regions. Based on our experiment, no substantial in-situ effects of heavy rainfall are anticipated for thawing of permafrost on Svalbard under future warming. However, further work is needed to quantify permafrost response to local redistribution of active layer flow under natural rainfall extremes. In addition, replication of experiments across variable Arctic regions as well as long-term monitoring of active layers, soil moisture and local climate will be essential to develop a panarctic perspective on rainfall sensitivity of permafrost., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Prenatal ultrasound is widely used to screen for structural anomalies before birth. While this is traditionally done in the second trimester, there is an increasing use of first-trimester ultrasound for early detection of lethal and certain severe structural anomalies., Objectives: To evaluate the diagnostic accuracy of ultrasound in detecting fetal structural anomalies before 14 and 24 weeks' gestation in low-risk and unselected pregnant women and to compare the current two main prenatal screening approaches: a single second-trimester scan (single-stage screening) and a first- and second-trimester scan combined (two-stage screening) in terms of anomaly detection before 24 weeks' gestation., Search Methods: We searched MEDLINE, EMBASE, Science Citation Index Expanded (Web of Science), Social Sciences Citation Index (Web of Science), Arts & Humanities Citation Index and Emerging Sources Citation Index (Web of Science) from 1 January 1997 to 22 July 2022. We limited our search to studies published after 1997 and excluded animal studies, reviews and case reports. No further restrictions were applied. We also screened reference lists and citing articles of each of the included studies., Selection Criteria: Studies were eligible if they included low-risk or unselected pregnant women undergoing a first- and/or second-trimester fetal anomaly scan, conducted at 11 to 14 or 18 to 24 weeks' gestation, respectively. The reference standard was detection of anomalies at birth or postmortem., Data Collection and Analysis: Two review authors independently undertook study selection, quality assessment (QUADAS-2), data extraction and evaluation of the certainty of evidence (GRADE approach). We used univariate random-effects logistic regression models for the meta-analysis of sensitivity and specificity., Main Results: Eighty-seven studies covering 7,057,859 fetuses (including 25,202 with structural anomalies) were included. No study was deemed low risk across all QUADAS-2 domains. Main methodological concerns included risk of bias in the reference standard domain and risk of partial verification. Applicability concerns were common in studies evaluating first-trimester scans and two-stage screening in terms of patient selection due to frequent recruitment from single tertiary centres without exclusion of referrals. We reported ultrasound accuracy for fetal structural anomalies overall, by severity, affected organ system and for 46 specific anomalies. Detection rates varied widely across categories, with the highest estimates of sensitivity for thoracic and abdominal wall anomalies and the lowest for gastrointestinal anomalies across all tests. The summary sensitivity of a first-trimester scan was 37.5% for detection of structural anomalies overall (95% confidence interval (CI) 31.1 to 44.3; low-certainty evidence) and 91.3% for lethal anomalies (95% CI 83.9 to 95.5; moderate-certainty evidence), with an overall specificity of 99.9% (95% CI 99.9 to 100; low-certainty evidence). Two-stage screening had a combined sensitivity of 83.8% (95% CI 74.7 to 90.1; low-certainty evidence), while single-stage screening had a sensitivity of 50.5% (95% CI 38.5 to 62.4; very low-certainty evidence). The specificity of two-stage screening was 99.9% (95% CI 99.7 to 100; low-certainty evidence) and for single-stage screening, it was 99.8% (95% CI 99.2 to 100; moderate-certainty evidence). Indirect comparisons suggested superiority of two-stage screening across all analyses regarding sensitivity, with no significant difference in specificity. However, the certainty of the evidence is very low due to the absence of direct comparisons., Authors' Conclusions: A first-trimester scan has the potential to detect lethal and certain severe anomalies with high accuracy before 14 weeks' gestation, despite its limited overall sensitivity. Conversely, two-stage screening shows high accuracy in detecting most fetal structural anomalies before 24 weeks' gestation with high sensitivity and specificity. In a hypothetical cohort of 100,000 fetuses, the first-trimester scan is expected to correctly identify 113 out of 124 fetuses with lethal anomalies (91.3%) and 665 out of 1776 fetuses with any anomaly (37.5%). However, 79 false-positive diagnoses are anticipated among 98,224 fetuses (0.08%). Two-stage screening is expected to correctly identify 1448 out of 1776 cases of structural anomalies overall (83.8%), with 118 false positives (0.1%). In contrast, single-stage screening is expected to correctly identify 896 out of 1776 cases before 24 weeks' gestation (50.5%), with 205 false-positive diagnoses (0.2%). This represents a difference of 592 fewer correct identifications and 88 more false positives compared to two-stage screening. However, it is crucial to acknowledge the uncertainty surrounding the additional benefits of two-stage versus single-stage screening, as there are no studies directly comparing them. Moreover, the evidence supporting the accuracy of first-trimester ultrasound and two-stage screening approaches primarily originates from studies conducted in single tertiary care facilities, which restricts the generalisability of the results of this meta-analysis to the broader population., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Obesity increases the risk of atrial fibrillation (AF), potentially through proteins secreted by adipose tissue (AT) that affect atrial electrical and structural remodeling. We aim to give a comprehensive overview of circulating AT proteins involved in inflammation and fibrosis, that are associated with prevalent AF (paroxysmal or persistent) and the risk on developing new-onset AF. These include adipokines, defined as proteins enriched in AT as adiponectin, but also proteins less specific to AT. We systematically performed an explorative search for studies reporting associations between proteins secreted from cells residing in the AT and AF, and additionally assessed the effect of obesity on these proteins by a secondary search. The AT proteins involved in inflammation were mostly increased in patients with prevalent and new-onset AF, and with obesity, while the AT enriched adipokines were mostly not associated with AF. This review provides insight into circulating adipose tissue proteins involved in AF substrate formation., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Background: Hyperemesis gravidarum is the severe form of nausea and vomiting during pregnancy and can lead to undernutrition and low maternal weight gain. Previous epidemiologic and animal studies have shown that undernutrition and low maternal weight gain in pregnancy can increase the risk of unfavorable perinatal outcomes, like shorter gestational age, small for gestational age and lower weight at birth., Objective: To evaluate the effect of hyperemesis gravidarum on perinatal outcomes., Search Strategy: OVID Medline and Embase were searched from inception to February 9th, 2022., Study Eligibility: Studies reporting on perinatal outcomes of infants born to mothers with hyperemesis gravidarum or severe nausea and vomiting in pregnancy were included. Case reports, case series, animal studies, reviews, editorials and conference abstracts were excluded., Data Collection and Analysis: Two reviewers independently selected and extracted data. Risk of bias was assessed by the Newcastle-Ottawa Quality Assessment Scale. We conducted meta-analyses where possible., Results: Our search yielded 1387 unique papers, of which 61 studies (n = 20,532,671 participants) were included in our systematic review. Meta-analyses showed that hyperemesis gravidarum was associated with preterm birth < 34 weeks (2 studies n = 2,882: OR 2.81, 95 %CI: 1.69-4.67), birth weight < 1500 g (2 studies, n = 489,141: OR 1.43, 95 %CI: 1.02-1.99), neonatal resuscitation (2 studies, n = 4,289,344: OR 1.07, 95 %CI: 1.05-1.10), neonatal intensive care unit admission (7 studies, n = 6,509,702: OR 1.20, 95 %CI: 1.14-1.26) and placental abruption (6 studies, n = 9,368,360: OR 1.15, 95 %CI: 1.05-1.25). Hyperemesis gravidarum was associated with reductions in birthweight > 4000 g (2 studies, n = 5,503,120: OR 0.74, 95 %CI: 0.72-0.76) and stillbirth (9 studies, n = 3,973,154: OR 0.92, 95 %CI: 0.85-0.99). Meta-analyses revealed no association between hyperemesis gravidarum and Apgar scores < 7 at 1 and 5 min; fetal loss, perinatal deaths and neonatal deaths., Conclusion: Hyperemesis gravidarum is associated with several adverse perinatal outcomes including low birth weight and preterm birth. We also found that pregnancies complicated by hyperemesis gravidarum less frequently were complicated by macrosomia and stillbirth. We were unable to investigate underlying mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Prenatal factors such as maternal stress, infection and nutrition affect fetal brain development and may also influence later risk for dementia. The purpose of this systematic review was to provide an overview of all studies which investigated the association between prenatal factors and later risk for dementia., Methods: We systematically searched MEDLINE and Embase for original human studies reporting on associations between prenatal factors and dementia from inception to 23 November 2022. Prenatal factors could be any factor assessed during pregnancy, at birth or postnatally, provided they were indicative of a prenatal exposure. Risk of bias was assessed using the Newcastle Ottawa Scale. We followed PRISMA guidelines for reporting., Results: A total of 68 studies met eligibility criteria (including millions of individuals), assessing maternal age (N = 30), paternal age (N = 22), birth order (N = 15), season of birth (N = 16), place of birth (N = 13), prenatal influenza pandemic (N = 1) or Chinese famine exposure (N = 1), birth characteristics (N = 3) and prenatal hormone exposure (N = 4). We observed consistent results for birth in a generally less optimal environment (e.g. high infant mortality area) being associated with higher dementia risk. Lower and higher birth weight and prenatal famine exposure were associated with higher dementia risk. The studies on season of birth, digit ratio, prenatal influenza pandemic exposure, parental age and birth order showed inconsistent results and were hampered by relatively high risk of bias., Conclusion: Our findings suggest that some prenatal factors, especially those related to a suboptimal prenatal environment, are associated with an increased dementia risk. As these associations may be confounded by factors such as parental socioeconomic status, more research is needed to examine the potential causal role of the prenatal environment in dementia., (© 2023. The Author(s).)

Environmental exposures including toxins and nutrition may hamper the developing brain in utero, limiting the brain's reserve capacity and increasing the risk for Alzheimer's disease (AD). The purpose of this systematic review is to summarize all currently available evidence for the association between prenatal exposures and AD-related volumetric brain biomarkers. We systematically searched MEDLINE and Embase for studies in humans reporting on associations between prenatal exposure(s) and AD-related volumetric brain biomarkers, including whole brain volume (WBV), hippocampal volume (HV) and/or temporal lobe volume (TLV) measured with structural magnetic resonance imaging (PROSPERO; CRD42020169317). Risk of bias was assessed using the Newcastle Ottawa Scale. We identified 79 eligible studies (search date: August 30th, 2020; Ntotal=24,784; median age 10.7 years) reporting on WBV (N = 38), HV (N = 63) and/or TLV (N = 5) in exposure categories alcohol (N = 30), smoking (N = 7), illicit drugs (N = 14), mental health problems (N = 7), diet (N = 8), disease, treatment and physiology (N = 10), infections (N = 6) and environmental exposures (N = 3). Overall risk of bias was low. Prenatal exposure to alcohol, opioids, cocaine, nutrient shortage, placental dysfunction and maternal anemia was associated with smaller brain volumes. We conclude that the prenatal environment is important in shaping the risk for late-life neurodegenerative disease., Competing Interests: Declaration of Competing Interest none., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Fetal heart-rate irregularities occur in 1-2% of pregnancies and are usually caused by premature atrial contractions (PAC). Although PAC are considered benign, they may be associated with cardiac defects and tachyarrhythmia. We aimed to determine the incidence of congenital heart defects (CHDs) and complications in fetuses with PAC., Methods: This was a systematic review and meta-analysis conducted in accordance with the PRISMA statement for reporting items for systematic reviews and meta-analyses. MEDLINE and EMBASE were searched from 1990 to June 2021 to identify studies on fetuses with PAC. The primary outcome was CHD; secondary outcomes were complications using the endpoints supraventricular tachyarrhythmia (SVT), cardiac failure and intrauterine fetal demise. Meta-analysis of proportions was performed, subdivided into high-risk and low-risk populations based on reason for referral. Pooled incidences with 95% CIs were calculated., Results: Of 2443 unique articles identified, 19 cohort studies including 2260 fetuses were included. The pooled incidence of CHD in fetuses with PAC was 2.8% (95% CI, 1.5-4.1%), when 0.6% is the incidence expected in the general population. The pooled incidence of CHD was 7.2% (95% CI, 3.5-10.9%) in the high-risk population and 0.9% (95% CI, 0.0-2.0%) in the low-risk population. SVT occurred in 1.4% (95% CI, 0.6-3.4%) of fetuses diagnosed with PAC. Cardiac failure was described in 16 fetuses (1.4% (95% CI, 0.5-3.5%)), of which eight were CHD-related. Intrauterine fetal demise occurred in four fetuses (0.9% (95% CI, 0.5-1.7%)) and was related to CHD in two cases., Conclusions: Our findings suggest that the risk of CHD in fetuses with PAC is 4-5 times higher than that in the general population. CHD was present more frequently in the high-risk population. Consequently, an advanced ultrasound examination to diagnose PAC correctly and exclude CHD is recommended. Complications of PAC are rare but can result in fetal demise, thus weekly fetal heart-rate monitoring remains advisable to enable early detection of SVT and to prevent cardiac failure. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

The prevalence of obesity is increasing worldwide. Experimental animal studies demonstrate that maternal obesity during pregnancy directly affects cardiac structure and function in their offspring, which could contribute to their increased cardiovascular disease (CVD) risk. Currently, a systematic overview of the available evidence regarding maternal obesity and alterations in cardiac structure and function in human offspring is lacking. We systematically searched the electronic databases Embase, MEDLINE and NARCIS from inception to June 29, 2022 including human studies comparing cardiac structure and function from fetal life onwards in offspring of women with and without obesity. The review protocol was registered with PROSPERO International Prospective Register of Systematic Reviews (identifier: CRD42019125071). Risk of bias was assessed using a modified Newcastle-Ottawa scale. Results were expressed using standardized mean differences (SMD). The search yielded 1589 unique publications, of which thirteen articles were included. Compared to offspring of women without obesity, fetuses of women with obesity had lower left ventricular strain, indicative of reduced systolic function, that persisted in infancy (SMD -2.4, 95% confidence interval (CI) -4.4 standard deviation (SD) to -0.4 SD during fetal life and SMD -1.0, 95% CI -1.6 SD to -0.3 SD in infancy). Furthermore, infants born to women with obesity had a thicker interventricular septum (SMD 0.6 SD, 95% CI 0.0 to 1.2 SD) than children born to women without obesity. In conclusion, cardiac structure and function differs between fetuses and children of women with and without obesity. Some of these differences were present in fetal life, persisted in childhood and are consistent with increased CVD risk. Long-term follow-up research is warranted, as studies in offspring of older age are lacking., Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (Copyright: © 2022 den Harink et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: A significant number of older patients planned for transcatheter aortic valve implantation (TAVI) experience a decline in physical functioning and death, despite a successful procedure., Objective: To systematically review the literature on the association of preprocedural muscle strength and physical performance with functional decline or long-term mortality after TAVI., Methods: We followed the PRISMA guidelines and pre-registered this review at PROSPERO (CRD42020208032). A systematic search was conducted in MEDLINE and EMBASE from inception to 10 December 2021. Studies reporting on the association of preprocedural muscle strength or physical performance with functional decline or long-term (>6 months) mortality after the TAVI procedure were included. For outcomes reported by three or more studies, a meta-analysis was performed., Results: In total, two studies reporting on functional decline and 29 studies reporting on mortality were included. The association with functional decline was inconclusive. For mortality, meta-analysis showed that low handgrip strength (hazard ratio (HR) 1.80 [95% confidence interval (CI): 1.22-2.63]), lower distance on the 6-minute walk test (HR 1.15 [95% CI: 1.09-1.21] per 50 m decrease), low performance on the timed up and go test (>20 s) (HR 2.77 [95% CI: 1.79-4.30]) and slow gait speed (<0.83 m/s) (HR 2.24 [95% CI: 1.32-3.81]) were associated with higher long-term mortality., Conclusions: Low muscle strength and physical performance are associated with higher mortality after TAVI, while the association with functional decline stays inconclusive. Future research should focus on interventions to increase muscle strength and physical performance in older cardiac patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Hyperemesis gravidarum is characterized by severe nausea and vomiting in pregnancy, frequently resulting in severe maternal nutritional deficiency. Maternal undernutrition is associated with adverse offspring health outcomes. Whether hyperemesis gravidarum permanently affects offspring health remains unclear. This review aimed to evaluate the effects of maternal hyperemesis gravidarum on offspring health., Data Sources: MEDLINE and Embase were searched from inception to September 6, 2021., Study Eligibility Criteria: Studies reporting on health at any age beyond the perinatal period of children born to mothers with hyperemesis gravidarum were included., Methods: Two reviewers independently selected studies and extracted data. The Newcastle-Ottawa Quality Assessment Scale was used to assess risk of bias. We conducted a narrative synthesis and meta-analysis where possible. In meta-analyses with high heterogeneity (I 2 >75%), we did not provide a pooled odds ratio., Results: Nineteen studies were included in this systematic review (n=1,814,785 offspring). Meta-analysis (n=619, 2 studies: 1 among adolescents and 1 among adults) showed that hyperemesis gravidarum was associated with anxiety disorder (odds ratio, 1.74; 95% confidence interval, 1.04-2.91; I 2 , 0%) and sleep problems in offspring (odds ratio, 2.94; 95% confidence interval, 1.25-6.93; I 2 , 0%). Hyperemesis gravidarum was associated with testicular cancer in male offspring aged up to 40 years on meta-analysis (5 studies, n=20,930 offspring), although heterogeneity was observed on the basis of a wide 95% prediction interval (odds ratio, 1.60; 95% confidence interval, 1.07-2.39; I 2 , 0%; 95% prediction interval, 0.83-3.08). All 6 studies reporting on attention deficit (hyperactivity) disorder and autism spectrum disorder reported an increase among children of mothers with hyperemesis gravidarum in comparison with children of unaffected mothers. Meta-analysis showed high heterogeneity, precluding us from reporting a pooled odds ratio. Most studies reporting on cognitive and motor problems found an increase among hyperemesis gravidarum-exposed children. One study investigated brain structure and found smaller cortical volumes and areas among children from hyperemesis gravidarum-affected pregnancies than among those from unaffected pregnancies. Studies evaluating anthropometry and cardiometabolic disease risk of hyperemesis gravidarum-exposed children had inconsistent findings., Conclusion: Our systematic review showed that maternal hyperemesis gravidarum is associated with small increases in adverse health outcomes among children, including neurodevelopmental disorders, mental health disorders, and possibly testicular cancer, although evidence is based on few studies of low quality., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary hypertension (PH), right ventricular (RV) dysfunction, and tricuspid regurgitation (TR) are commonly present in patients with mitral regurgitation (MR) and known to impair prognosis. This systematic review and meta-analysis aimed to determine the prognostic value of PH, RV function, and TR on mortality after transcatheter mitral valve repair (TMVR)., Methods: A systematic search was performed to identify studies investigating PH, RV function, or TR in patients who underwent TMVR. Studies were included for pooled analysis if hazard ratios (HR) for all-cause mortality were given., Results: A total of 8,672 patients from 21 selected studies were included (PH, 11 studies; RV function, nine studies; TR, 10 studies). Mean follow-up was 2.7±1.6 years. The HRs and 95% CIs for all-cause mortality of PH (dichotomised: HR 1.70, 95% CI 1.00-2.87; per 10 mmHg increase in systolic PAP: HR 1.17, 95% CI 1.07-1.29), RV function (dichotomised: HR 1.86, 95% CI 1.45-2.38; per 5 mm decrease in TAPSE: HR 1.18, 95% CI 0.97-1.43) and TR (HR 1.51, 95% CI 1.28-1.79) indicated a significant association., Conclusion: Prognosis after TMVR is worse in patients with significant MR when concomitant PH, RV dysfunction, or TR are present. Careful assessment of these parameters should therefore precede clinical decision-making for TMVR. The current results encourage investigation into whether (1) intervention at an earlier stage of MR reduces incidence of PH, RV dysfunction, and TR; and (2) transcatheter treatment of concomitant TR can improve clinical outcome and prognosis for these patients., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02)., Conclusion: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a "rebound" vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action., What Is Known: • In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo., What Is New: • The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension. • The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed., (© 2022. The Author(s).)

Background: When treating Merkel cell carcinoma (MCC), the relation between wide local excision (WLE) margin and recurrence or survival is unclear. Mohs micrographic surgery (MMS) is an alternative surgical option for MCC, but it is unknown whether the local recurrence rate differs between MMS and WLE., Objective: To systematically assess the available literature to determine the recurrence and survival rates when treating MCC with MMS and different clinical excision margins., Materials and Methods: The MEDLINE, EMBASE, and CENTRAL databases were searched. Two independent reviewers selected studies that defined clear excision margins and either recurrence or survival. When possible, individual cases were extracted from case series and included in the analyses. Other studies were reviewed narratively., Results: Overall, 1108 studies were identified; of which, 19 case series (168 cases) and 12 cohort studies were eligible. None of the cohort studies showed significant differences in recurrence or survival for either excision margins or MMS. Equally, logistic and Cox regression analyses of the case series revealed no significant differences in recurrence or survival between different excision margins and MMS., Conclusion: Synthesis of the available data does not indicate differences in recurrence and/or survival rates for MCC between different clinical excision margins and MMS., (Copyright © 2022 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Permafrost thaw can accelerate climate warming by releasing carbon from previously frozen soil in the form of greenhouse gases. Rainfall extremes have been proposed to increase permafrost thaw, but the magnitude and duration of this effect are poorly understood. Here we present empirical evidence showing that one extremely wet summer (+100 mm; 120% increase relative to average June-August rainfall) enhanced thaw depth by up to 35% in a controlled irrigation experiment in an ice-rich Siberian tundra site. The effect persisted over two subsequent summers, demonstrating a carry-over effect of extremely wet summers. Using soil thermal hydrological modelling, we show that rainfall extremes delayed autumn freeze-up and rainfall-induced increases in thaw were most pronounced for warm summers with mid-summer precipitation rainfall extremes. Our results suggest that, with rainfall and temperature both increasing in the Arctic, permafrost will likely degrade and disappear faster than is currently anticipated based on rising air temperatures alone., (© 2022. The Author(s).)

Aims: To determine the effects of oestrogen or oestrogen deprivation on vaginal wound healing. Impaired wound healing following prolapse surgery may increase the risk of recurrent prolapse in the future. Vaginal oestrogen therapy may improve wound healing, hereby possibly improving surgical outcomes., Methods: A systematic search of OVID MEDLINE, OVID Embase, and Web of Science was conducted up to January 28, 2020. We included original studies comparing wound healing-related outcomes of oestrogen exposed subjects (female animals and women) to hypo-oestrogenic subjects after vaginal surgery. Data on wound healing-related outcome measures were extracted. For each individual comparison, the standardised mean difference (Hedges' g; SMD) and 95% confidence interval (CI) were calculated., Results: Of the 1474 studies reviewed, 14 studies were included for review, and 11 provided data for meta-analysis. Oestrogen improves neovascularisation (SMD: 1.13, 95% CI: 0.67-1.60), microscopic wound closure (SMD: 0.98, 95% CI: 0.66-1.29), collagen synthesis (SMD: 1.08, 95% CI: 0.42-1.74), and tissue strength (SMD: 1.26, 95% CI: 0.53-1.99) in animals. Oestrogen increases granulation (SMD: 1.67, 95% CI: 0.54-2.79) and accelerates macroscopic wound closure (SMD: 1.82, 95% CI: 1.22-2.42) in women and animals. Oestrogen decreases the inflammatory response (SMD: -0.58, 95% CI: -1.14 to -0.02) in women and animals and reduces levels of transforming growth factor (TGF)-β1 (SMD: -1.68, 95% CI: -2.52 to -0.83) in animals. All results were statistically significant., Conclusions: Oestrogen therapy has a positive effect on vaginal wound healing. Future studies should determine whether oestrogen therapy has the potential to improve surgical outcomes., (© 2021 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Natural peatlands contribute significantly to global carbon sequestration and storage of biomass, most of which derives from Sphagnum peat mosses. Atmospheric CO 2 levels have increased dramatically during the twentieth century, from 280 to > 400 ppm, which has affected plant carbon dynamics. Net carbon assimilation is strongly reduced by photorespiration, a process that depends on the CO 2 to O 2 ratio. Here we investigate the response of the photorespiration to photosynthesis ratio in Sphagnum mosses to recent CO 2 increases by comparing deuterium isotopomers of historical and contemporary Sphagnum tissues collected from 36 peat cores from five continents. Rising CO 2 levels generally suppressed photorespiration relative to photosynthesis but the magnitude of suppression depended on the current water table depth. By estimating the changes in water table depth, temperature, and precipitation during the twentieth century, we excluded potential effects of these climate parameters on the observed isotopomer responses. Further, we showed that the photorespiration to photosynthesis ratio varied between Sphagnum subgenera, indicating differences in their photosynthetic capacity. The global suppression of photorespiration in Sphagnum suggests an increased net primary production potential in response to the ongoing rise in atmospheric CO 2 , in particular for mire structures with intermediate water table depths., (© 2021. The Author(s).)

Background: Early onset fetal growth restriction secondary to placental insufficiency can lead to severe maternal and neonatal morbidity and mortality. Pre-clinical studies and a few small randomised clinical trials have suggested that phosphodiesterase type 5 (PDE-5) inhibitors may have protective effects against placental insufficiency in this context; however, robust evidence is lacking. The STRIDER Consortium conducted four randomised trials to investigate the use of a PDE-5 inhibitor, sildenafil, for the treatment of early onset fetal growth restriction. We present a protocol for the pre-planned systematic review with individual participant data meta-analysis, aggregate meta-analysis, and trial sequential analysis of these and other eligible trials. The main objective of this study will be to evaluate the effects of PDE-5 inhibitors on neonatal morbidity compared with placebo or no intervention among pregnancies with fetal growth restriction., Methods: We will search the following electronic databases with no language or date restrictions: OVID MEDLINE, OVID EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and the clinical trial registers Clinicaltrials.gov and World Health Organisation International Clinical Trials Registry Platform (ICTRP). We will identify randomised trials of PDE-5 inhibitors in singleton pregnancies with growth restriction. Two reviewers will independently screen all citations, full-text articles, and abstract data. Our primary outcome will be infant survival without evidence of serious adverse neonatal outcome. Secondary outcomes will include gestational age at birth and birth weight z-scores. We will assess bias using the Cochrane Risk of Bias 2 tool. We will conduct aggregate meta-analysis using fixed and random effects models, Trial Sequential Analysis, and individual participant data meta-analysis using one- and two-stage approaches. The certainty of evidence will be assessed with GRADE., Discussion: This pre-defined protocol will minimise bias during analysis and interpretation of results, toward the goal of providing robust evidence regarding the use of PDE-5 inhibitors for the treatment of early onset fetal growth restriction., Systematic Review Registration: PROSPERO (CRD42017069688)., (© 2021. The Author(s).)