Is the microRNA (miRNA) expression pattern of cumulus oophorus cells (COCs) in women undergoing medically assisted reproduction (MAR) procedures differentially modulated according to patient age and gonadotropin treatment strategy? Maternal age is an independent factor impacting miRNA expression in COCs while gonadotropin treatment may affect follicular miRNA expression and IVF efficacy. Epigenetic mechanisms in female infertility are complex and poorly studied. DNA methylation, histone modifications, miRNAs and nucleosome positioning influence cellular machinery through positive and negative feedback mechanisms either alone or interactively. miRNAs are important regulators during oogenesis, spermatogenesis and early embryogenesis, and are reported to play a role in regulating crosstalk between the oocyte and COCs. Although miRNome analysis has been performed in female human reproductive tissues (endometrium, myometrium, cervix and ovaries), epigenetic modifications in women with infertility have not been explored in detail. In addition, the impact of gonadotropin treatments during MAR on miRNA expression in COCs has not been fully investigated. This study was carried out in 53 COC samples obtained from mature metaphase II (MII) oocytes in 53 women undergoing MAR treatment. A total of 38 samples for assay development were pooled by maternal age and gonadotropin treatment into four predetermined subgroups: ≥36 years and recombinant human FSH (r-hFSH), n = 10; ≥36 years and r-hFSH+ recombinant human-luteinizing hormone (r-hLH), n = 10; ≤35 years and r-hFSH, n = 9; ≤35 years and r-hFSH+r-hLH, n = 9. miRNome profiles were determined and compared between subgroups. Expression of defined miRNAs was validated in the remaining fifteen samples, representative of each subgroup, by quantitative polymerase chain reaction (PCR). COCs were processed for miRNA-enriched total RNA extraction and pooled in homogeneous subgroups to obtain a sufficient amount and quality of starting material to perform the analysis. Each pooled sample underwent miRNA profiling using PCR assay system to examine expression of 752 human miRNAs without pre-amplification. Data were analyzed using the delta-delta Ct method for relative quantitation and prediction of target genes (with at least four algorithms predicting the same miRNA-gene interaction pair (HIT)>4). The miRSystem database provided functional annotation enrichment (raw P-value <0.05) of co-expressed miRNAs. We found distinctive miRNA expression profiles in each subgroup correlating with age and MAR stimulation. In addition, a number of selective and co-expressed miRNAs were revealed by comparative analysis. A cluster of 37 miRNAs were commonly but differentially expressed in all four pools. Significant differences were observed in expression regulation of 37 miRNAs between age groups (≤35 or ≥36) in women receiving r-hFSH+r-hLH compared to those receiving r-hFSH alone. Higher concentrations and increased numbers of miRNAs were recorded in younger than in older patients, regardless of treatment. Functional and expression studies performed to retrieve common miRNome profiles revealed an enrichment of biological functions in oocyte growth and maturation, embryo development, steroidogenesis, ovarian hyperstimulation, apoptosis and cell survival, glucagon and lipid metabolism, and cell trafficking. The highest scored pathways of target genes of the 37 common miRNAs were associated with mitogen-activated protein kinase (MAPK) signaling pathways, G alpha signaling, transcription regulation, tight junctions, RNA polymerase I and III, and mitochondrial transcription. We identified a potential age- and MAR stimulation-dependent signature in the miRNA landscape of COCs. We cannot rule out the possibility that other unknown individual genetic or clinical factors may have interfered with the reported results. Since miRNA profiling was conducted with a predefined array of target probes, other miRNA molecules, potentially modulated by age and hormonal stimulation, may have been missed in this study. miRNA expression in COCs is modulated by gonadotropin treatment and correlates strongly with age. A better understanding of the expression patterns and functions of miRNAs may lead to the development of novel therapeutics to treat ovarian dysfunction and improve fertility in older women. This study was funded by Merck KGaA, Darmstadt, Germany. All authors declared no competing interest, except SL and TD who are fully employed by Merck KGaA. N/A.
To investigate the influence of inappropriate gestational weight gain (GWG) on pregnancy outcomes in twin pregnant women with in vitro fertilization (IVF) treatment. This retrospective cohort study included 2992 twin pregnant women and categorized the participants as follows: (i) they were classified into spontaneous conception (SC) or IVF groups based on whether they received IVF treatment, and (ii) they were categorized into inadequate, optimal, or excessive GWG groups according to the International Organization for Migration Twin Pregnancy Guidelines. Initially, the study investigated the separate effects of IVF treatment and different levels of GWG on the outcomes of twin pregnancies. Subsequently, after adjusting for confounding factors, multifactorial logistic regression analysis was performed to further investigate the impact of IVF treatment and high GWG on twin pregnancy outcomes. Based on this, the analysis was stratified by whether IVF was used to explore the effects of different GWG levels on each subgroup (those who underwent IVF and those who conceived spontaneously). Finally, potential multiplicative interactions between IVF and different GWG categories were examined to identify their combined effect on pregnancy outcomes. The results showed that women with twin gestations conceived via IVF exhibited significantly higher maternal age, pre-pregnancy body mass index, and a greater incidence of GWG beyond recommended guidelines compared to the SC group. Furthermore, both IVF treatment and inappropriate GWG increased the risk of adverse pregnancy outcomes, respectively. Following adjustments for confounding variables through multifactorial logistic regression, it was demonstrated that both IVF treatment and high GWG significantly elevated the risk of adverse outcomes in twin pregnancies, such as admission to the neonatal intensive care unit. It is noteworthy that inappropriate GWG, combined with IVF treatment, will stepwise increase the incidence of intrahepatic cholestasis of pregnancy, respiratory failure, respiratory distress, pre-eclampsia, maternal intensive care unit admission, and postpartum hemorrhage risk. However, these outcomes were less affected by inappropriate GWG in the SC group. Lastly, this study did not unveil a significant interaction between the IVF procedure and disparate levels of GWG in relation to the adverse outcomes. A high incidence of inappropriate GWG in twin pregnancies with IVF treatment and inappropriate GWG conferred more adverse twin pregnancy outcomes in the IVF group relative to the SC group. This study indicates that proper management of GWG may be a breakthrough in reducing adverse outcomes in twin pregnancies associated with IVF. Therefore, implementing proactive interventions such as supervised exercise programs, prescribed physical or dietary plans, enhanced weight management, or personalized counseling, holds promise for lowering the risks associated with inappropriate GWG in twin pregnancies resulting from IVF.
Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.
Rising antimicrobial resistance of Helicobacter pylori is a public health challenge. Genomic-based susceptibility testing allows for the identification of resistance-associated mutations, complementing conventional diagnostics and advancing towards pathogen-based personalised therapies. Our study aimed to identify genes and mutations involved in antimicrobial resistance in H pylori and evaluate the extent to which these markers can be used as predictors of phenotypic resistance against clarithromycin and levofloxacin. In this retrospective phenotypic and genotypic observational study, we included 1011 H pylori whole-genome sequences and strains of known geographical origin from the H pylori Genome Project (HpGP) collection. We performed phenotypic clarithromycin and levofloxacin susceptibility testing on a subset of 419 HpGP strains using Etest at a centralised laboratory. A genomic analysis was conducted to identify 23S rRNA and gyrA variants and build a curated catalogue of mutations associated with resistance to clarithromycin (ie, 23S rRNA 2142A→G, 2142A→C, and 2143A→G) and levofloxacin (ie, gyrA A88V or A88P, N87K or N87I, and D91G, D91N, or D91Y). Genotype-phenotype concordance was assessed to estimate sensitivity and specificity, and the curated catalogue of resistance-associated mutations was applied to the complete HpGP set. Region-specific prevalence of resistance-associated mutations was calculated for a combined dataset including the HpGP genomes and 768 whole-genome sequences retrieved from the US National Center for Biotechnology Information Sequence Read Archive repository. Associations between resistance genotypes, H pylori subpopulations, and minimum inhibitory concentrations (MICs) were tested. Clarithromycin-resistant and levofloxacin-resistant HpGP strains were estimated with a sensitivity and specificity of 100%, with all confidence intervals ranging from 96% to 100%. The combined analysis (n=1779) found the highest prevalence of clarithromycin resistance in the western Pacific region (173 [51·2%] of 338 in southeast Asia and 75 [29·8%] of 252 in eastern Asia), north African region (seven [38·9%] of 18), and western Asian region (12 [31·6%] of 38), whereas the highest prevalence of levofloxacin resistance was found in south Asia (14 [51·85%] of 27), Central America (48 [38·7%] of 124), eastern Europe (four [36·4%] of 11), and southern Africa (three [33·3%] of nine). Similarly, 23S rRNA and gyrA genotypes are variable across H pylori subpopulations. MIC values changed depending on the specific mutation in 23S rRNA (mean clarithromycin MIC 24·61 mg/L [95% CI 12·27-36·96] for 2143A→G and 142·25 mg/L [95% CI 77·88-206·61] for 2142A→G) and gyrA (mean levofloxacin MIC 9·66 mg/L [95% CI 6·75-12·56] for mutations on codon 91, and 27·97 mg/L [95% CI 25·82-30·11] for mutations on codon 87). Mutations in specific genes are reliable indicators to clarithromycin and levofloxacin resistance in H pylori, making them useful markers for the development of diagnostic assays and molecular monitoring. Our results suggest that using clarithromycin and levofloxacin empirically, without previous susceptibility testing, is unsuitable in all geographical regions covered by this study. Intramural Research Program of the US National Cancer Institute, the European Research Council, and the Spanish Ministry of Science and Innovation.
During the past decade, China has witnessed a rapid increase in healthcare utilization. However, whether this surge in healthcare use is reasonable remains an urgent question to be answered, particularly for informing scientific policy design and adjustment in future health systems reform. We aimed to analyze the differences in healthcare utilization trends among Chinese adults aged 50 and above in comparison with other countries and regions, and to investigate the association between socioeconomic status (SES) and healthcare utilization in China. Participants aged 50 and over were drawn from the ageing surveys conducted in China, the United States, South Korea, and Europe. SES was measured using education level, total household income, and employment status. Random-effects negative binomial regression models were employed to examine the association between SES and healthcare utilization. From 2011 to 2020, the outpatient utilization rates in China showed no clear long-term upward or downward trend. The inpatient utilization rates in the United States (tau-b = - 0.02, P < 0.001) and South Korea (tau-b = - 0.05, P < 0.001) declined gradually, whereas inpatient utilization rates in China continuously grew (tau-b = 0.08, P < 0.001). In China, inpatient utilization rates across different SES groups generally showed an upward trend (P < 0.01). Elementary and lower education was positively associated with inpatient utilization rates compared to middle school and higher education (IRR = 1.11, 95% CI: 1.04-1.18, P = 0.003). Similar patterns were observed for low household income (IRR = 1.08, 95% CI: 1.02-1.14, P = 0.007), non-employment (IRR = 1.39, 95% CI: 1.32-1.47, P < 0.001) and retirement (IRR = 1.38, 95% CI: 1.26-1.52, P < 0.001). These associations remained significant even among individuals covered by the Urban and Rural Resident Basic Medical Insurance (URRBMI). Participants with lower SES were more likely to report having two or more chronic diseases and poor self-rated health (P < 0.001). Inpatient utilization rates among middle-aged and older adults in China have experienced excessive growth over the past decade. Low SES was associated with high inpatient utilization, likely attributable to the poorer health status of low-SES groups. This association persisted in people covered by URRBMI. Policy reforms should prioritize the development of primary care, targeted health management, and equitable adjustments to health insurance. These measures are essential for curbing unnecessary hospitalizations and advancing healthcare equity in China.
Subfertility affects 15% to 20% of couples trying to conceive. In vitro fertilisation (IVF) is one of the assisted reproduction techniques developed to improve chances of achieving pregnancy. In the standard IVF method with controlled ovarian hyperstimulation (COH), growth and development of multiple follicles are stimulated by using gonadotrophins, often combined with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist. Although it is an established method of conception for subfertile couples, the treatment is expensive and has a high risk of adverse effects. Studies have shown that IVF in a natural cycle (NC) or a modified natural cycle (MNC) might be a promising low risk and low cost alternative to the standard stimulated IVF treatment since the available dominant follicle of each cycle is used. In this review, we included available randomised controlled studies comparing natural cycle IVF (NC and MNC) with standard IVF. To compare the efficacy and safety of natural cycle IVF (including both NC-IVF and MNC-IVF) with controlled ovarian hyperstimulation IVF (COH-IVF) in subfertile couples. An extended search including of the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ClinicalTrials.gov, conference abstracts in the Web of Knowledge, the World Health Organization International Trials Registry Platform search portal, LILACS database, PubMed and the OpenSIGLE database was conducted according to Cochrane guidelines. The last search was on 31st July 2013. All randomised controlled trials (RCTs) comparing either natural cycle IVF or modified natural cycle IVF versus standard IVF in subfertile couples were included. Data selection and extraction and risk of bias assessment were carried out independently by two authors (TA and AC). The primary outcome measures were live birth rate and ovarian hyperstimulation syndrome (OHSS) rate per randomised woman. We calculated Mantel-Haenszel odds ratios for each dichotomous outcome and either the mean difference or the standardised mean difference (SMD) for continuous outcomes, with 95% confidence intervals (CIs). A fixed effect model was used unless there was substantial heterogeneity, in which case a random effects model was used. Six randomised controlled trials with a total of 788 women were included. The largest of these trials included 396 women eligible for this review.No evidence of a statistically significant difference was found between natural cycle and standard IVF in live birth rates (OR 0.68, 95% CI 0.46 to 1.01, two studies, 425 women, I(2)= 0%, moderate quality evidence). The evidence suggests that for a woman with a 53% chance of live birth using standard IVF, the chance using natural cycle IVF would range from 34% to 53%. There was no evidence of a statistically significant difference between natural cycle and standard IVF in rates of OHSS (OR 0.19, 95% CI 0.01 to 4.06, one study, 60 women, very low quality evidence), clinical pregnancy (OR 0.52 95% CI 0.17 to 1.61, 4 studies, 351 women, I(2)=63%, low quality evidence), ongoing pregnancy (OR 0.72, 95% CI 0.50 to 1.05, three studies, 485 women, I(2)=0%, moderate quality evidence), multiple pregnancy (OR 0.76, 95% CI 0.25 to 2.31, 2 studies, 527 women, I(2)=0%, very low quality evidence), gestational abnormalities (OR 0.44 95% CI 0.03 to 5.93, 1 study, 18 women, very low quality evidence) or cycle cancellations (OR 8.98, 95% CI 0.20 to 393.66, 2 studies, 159 women, I(2)=83%, very low quality evidence). One trial reported that the oocyte retrieval rate was significantly lower in the natural cycle group (MD -4.40, 95% CI -7.87 to -0.93, 60 women, very low quality evidence). There were insufficient data to draw any conclusions about rates of treatment cancellation. Findings on treatment costs were inconsistent and more data are awaited. The evidence was limited by imprecision. Findings for pregnancy rate and for cycle cancellation were sensitive to the choice of statistical model: for these outcomes, use of a fixed effect model suggested a benefit for the standard IVF group. Moreover the largest trial has not yet completed follow up, though data have been reported for over 95% of women. Further evidence from well conducted large trials is awaited on natural cycle IVF treatment. Future trials should compare natural cycle IVF with standard IVF. Outcomes should include cumulative live birth and pregnancy rates, the number of treatment cycles necessary to reach live birth, treatment costs and adverse effects.
More than 3 billion people do not have access to clean energy and primarily use solid fuels to cook. Use of solid fuels generates household air pollution, which was associated with more than 2 million deaths in 2019. Although local patterns in cooking vary systematically, subnational trends in use of solid fuels have yet to be comprehensively analysed. We estimated the prevalence of solid-fuel use with high spatial resolution to explore subnational inequalities, assess local progress, and assess the effects on health in low-income and middle-income countries (LMICs) without universal access to clean fuels. We did a geospatial modelling study to map the prevalence of solid-fuel use for cooking at a 5 km × 5 km resolution in 98 LMICs based on 2·1 million household observations of the primary cooking fuel used from 663 population-based household surveys over the years 2000 to 2018. We use observed temporal patterns to forecast household air pollution in 2030 and to assess the probability of attaining the Sustainable Development Goal (SDG) target indicator for clean cooking. We aligned our estimates of household air pollution to geospatial estimates of ambient air pollution to establish the risk transition occurring in LMICs. Finally, we quantified the effect of residual primary solid-fuel use for cooking on child health by doing a counterfactual risk assessment to estimate the proportion of deaths from lower respiratory tract infections in children younger than 5 years that could be associated with household air pollution. Although primary reliance on solid-fuel use for cooking has declined globally, it remains widespread. 593 million people live in districts where the prevalence of solid-fuel use for cooking exceeds 95%. 66% of people in LMICs live in districts that are not on track to meet the SDG target for universal access to clean energy by 2030. Household air pollution continues to be a major contributor to particulate exposure in LMICs, and rising ambient air pollution is undermining potential gains from reductions in the prevalence of solid-fuel use for cooking in many countries. We estimated that, in 2018, 205 000 (95% uncertainty interval 147 000-257 000) children younger than 5 years died from lower respiratory tract infections that could be attributed to household air pollution. Efforts to accelerate the adoption of clean cooking fuels need to be substantially increased and recalibrated to account for subnational inequalities, because there are substantial opportunities to improve air quality and avert child mortality associated with household air pollution. Bill & Melinda Gates Foundation.
High pathogenicity avian influenza (HPAI) is a highly infectious and lethal disease of birds that causes systemic symptoms and has been spreading globally, including in Japan. The Okinawa rail (Hypotaenidia okinawae), a flightless bird endemic to Japan, is classified as an endangered species on the Red List. In 2004, the Ministry of the Environment of Japan began implementing a conservation breeding program for Okinawa rails, focusing on maintaining the species' genetic diversity, captive breeding, and reintroduction to the wild. Given the potential for significant losses due to HPAI in Okinawa rails, the establishment of a treatment protocol as a preparedness measure is essential. The aim of this study was to determine an appropriate treatment method for HPAI in Okinawa rails using baloxavir marboxil (BXM), a drug shown to be effective in an avian laboratory model of HPAI virus infection. Single oral administration of BXM at 2.5 or 12.5 mg/kg did not produce plasma concentrations sufficient to achieve the expected therapeutic efficacy. Therefore, oral administration was deemed inadequate for generating the desired pharmacological effects. Consequently, subcutaneous administration of BXM to Okinawa rails at a dose of 2.5 or 7.5 mg/kg was explored as an alternative protocol, which resulted in higher systemic exposure compared with oral administration. Furthermore, plasma concentrations were maintained at therapeutically relevant levels up to 24 hours after subcutaneous administration at 7.5 mg/kg, with mild and reversible injection site irritation the main adverse effect. Based on these results, subcutaneous administration of BXM is proposed as a viable treatment protocol for HPAI in the conservation of endangered Okinawa rails.
Does a reduced FSH dose in women with a predicted hyper response, apparent from a high antral follicle count (AFC), who are scheduled for IVF/ICSI lead to a different outcome with respect to cumulative live birth rate and safety? Although in women with a predicted hyper response (AFC > 15) undergoing IVF/ICSI a reduced FSH dose (100 IU per day) results in similar cumulative live birth rates and a lower occurrence of any grade of ovarian hyperstimulation syndrome (OHSS) as compared to a standard dose (150 IU/day), a higher first cycle cancellation rate and similar severe OHSS rate were observed. Excessive ovarian response to controlled ovarian stimulation (COS) for IVF/ICSI may result in increased rates of cycle cancellation, the occurrence of OHSS and suboptimal live birth rates. In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can be used to predict response to COS. No consensus has been reached on whether ORT-based FSH dosing improves effectiveness and safety in women with a predicted hyper response. Between May 2011 and May 2014, we performed an open-label, multicentre RCT in women with regular menstrual cycles and an AFC > 15. Women with polycystic ovary syndrome (Rotterdam criteria) were excluded. The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. Secondary outcomes included the occurrence of OHSS and cost-effectiveness. Since this RCT was embedded in a cohort study assessing over 1500 women, we expected to randomize 300 predicted hyper responders. Women with an AFC > 15 were randomized to an FSH dose of 100 IU or 150 IU/day. In both groups, dose adjustment was allowed in subsequent cycles (maximum 25 IU in the reduced and 50 IU in the standard group) based on pre-specified criteria. Both effectiveness and cost-effectiveness were evaluated from an intention-to-treat perspective. We randomized 255 women to a daily FSH dose of 100 IU and 266 women to a daily FSH dose of 150 IU. The cumulative live birth rate was 66.3% (169/255) in the reduced versus 69.5% (185/266) in the standard group (relative risk (RR) 0.95 [95%CI, 0.85-1.07], P = 0.423). The occurrence of any grade of OHSS was lower after a lower FSH dose (5.2% versus 11.8%, RR 0.44 [95%CI, 0.28-0.71], P = 0.001), but the occurrence of severe OHSS did not differ (1.3% versus 1.1%, RR 1.25 [95%CI, 0.38-4.07], P = 0.728). As dose reduction was not less expensive (€4.622 versus €4.714, delta costs/woman €92 [95%CI, -479-325]), there was no dominant strategy in the economic analysis. Despite our training programme, the AFC might have suffered from inter-observer variation. Although strict cancellation criteria were provided, selective cancelling in the reduced dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as first cycle live birth rates did not differ from the cumulative results, the open design probably did not mask a potential benefit for the reduced dosing group. As this RCT was embedded in a larger cohort study, the power in this study was unavoidably lower than it should be. Participants had a relatively low BMI from an international perspective, which may limit generalization of the findings. In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose did reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS. Future research into ORT-based dosing in women with a predicted hyper response should compare various safety management strategies and should be powered on a clinically relevant safety outcome while assessing non-inferiority towards live birth rates. This trial was funded by The Netherlands Organization for Health Research and Development (ZonMW, Project Number 171102020). SCO, TCvT and HLT received an unrestricted research grant from Merck Serono (the Netherlands). CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV and Merck Serono for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657. 20 December 2010. 12 May 2011.
Are there differences in levels of parental wellbeing (parental stress, psychological adjustment and partner relationship satisfaction) between gay-father families with infants born through surrogacy, lesbian-mother families with infants born through donor insemination, and heterosexual-parent families with infants born through IVF? There were no differences in parental wellbeing. The only other study of parental wellbeing in gay-father families formed through surrogacy (mean age children: 4 years old) found no difference in couple relationship satisfaction between these families and lesbian-mother families formed through donor insemination and heterosexual-parent families formed without assisted reproductive technologies. This cross-sectional study is part of an international research project involving 38 gay-father families, 61 lesbian-mother families and 41 heterosexual-parent families with 4-month-olds. In each country (the UK, the Netherlands and France), participants were recruited through several sources, such as specialist lawyers with expertise in surrogacy (for the recruitment of gay fathers), lesbian and gay parenting support groups, fertility clinics (for the recruitment of lesbian and heterosexual parents), and/or online forums and magazines. During a home visit when their infants were between 3.5 and 4.5 months old, participants completed standardized measures of parental stress, parental psychological adjustment (anxiety and depression) and partner relationship satisfaction. All parents reported relatively low levels of parental stress, anxiety and depression, and were all relatively satisfied with their intimate relationships. After controlling for caregiver role (primary or secondary caregiver role), there were no significant family type differences in parental stress, P = 0.949, depression, P = 0.089, anxiety, P = 0.117, or relationship satisfaction, P = 0.354. The findings cannot be generalized to all first-time ART parents with infants because only families from relatively privileged backgrounds participated. Our findings may have implications for the development of policy and legislation in relation to these new family forms, as well as the regulation of surrogacy in the Netherlands and France. In addition, our findings might encourage professional organizations of obstetricians and gynecologists in these countries to recommend that requests for assisted reproduction should be considered regardless of the applicants' sexual orientation. This research was supported, under the auspices of the Open Research Area (Application BO 3973/1-1; Principal Investigator, Michael E Lamb), by grants from the UK Economic and Social Research Council (ESRC; Grant ES/K006150/1; Principal Investigator, Michael E. Lamb), The Netherlands Organisation for Scientific Research (NWO; Grant NWO 464-11-001, Principal Investigator, Henny W.M. Bos) and the French Agence Nationale de Recherche (ANR; Grant ANR-12-ORAR-00005-01, Principal Investigator, Olivier Vecho) whose support is gratefully acknowledged. There were no competing interests.
China's economic involvement in Latin America has increased dramatically in the twenty-first century, often due to China's demand for natural resources. Chinese President Xi Jinping and his government have actively courted Latin America to pave the way for economic interactions. Chinese leaders have been working to foster China's "soft power" abroad. Nonetheless, we know relatively little about how Latin Americans perceive China and how Latin Americans' experiences with Chinese firms over the past two decades have shaped their views. Have Chinese efforts at cultivating "soft power" worked? Or have the actions of Chinese mining firms damaged China's reputation? Using the Latin American Public Opinion Project (LAPOP) coupled with data on Chinese investments in Peru, I examine Peruvians' views of China and whether Peruvians think China should be a model for their country. I find that while Peruvians generally trust the Chinese government, only a small proportion prefers China as a model for Peru. The relationship between Chinese investment and public opinion is mixed. However, Peruvians who strongly value democracy are less likely to prefer China as a model for their country. The data also suggest that China still has an opportunity to shape public opinion in Peru, despite conflicts with Peruvian communities over mining projects.
Non-mucinous bronchioloalveolar carcinoma (BAC) is considered the early stage of lung adenocarcinoma and is classified as the lung adenocarcioma in situ (AIS) by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. This study was designed to investigate the gene expression differences between AIS (formerly non-mucinous BAC) and invasive lepidic predominant adenocarcinoma (LPA, formerly non-mucinous BAC pattern with >5 mm invasion, mixed type adenocarcinoma with BAC features) and to investigate the mechanism of the progression of lung adenocarcinoma in situ to invasive adenocarcinoma. Gene expression analysis was performed by using Agilent 4 × 44 K Whole Human Genome Oligo Microarray on 10 fresh frozen tissue samples of AIS and LPA, respectively. Real time RT-PCR was used to validate the differential expression of 13 genes selected by cDNA microarray on fresh frozen tissue samples from 41 patients with lung adenocarcinoma and 4 genes were confirmed. These 4 genes were then validated by western blotting. Immunohistochemical staining for these validated genes was performed on formalin-fixed, paraffin-embedded tissue samples from 81 cases of lung adenocarcinomna. We identified a 13 gene expression signature by comparative analysis of gene expression. Expression of these genes strongly differed between AIS and LPA. Four genes (MMP-2, c-fos, claudin 1 (CLDN1) and claudin 10(CLDN10)) were correlated with the results of microarray and real time RT-PCR analyses for the gene-expression data in samples from 41 patients with lung adenocarcinoma. As confirmed by western blotting, the expression levels of MMP-2 and c-fos were higher in LPA than those in AIS; the expression levels of CLDN1 and CLDN10 in LPA were lower than those in AIS. Immunohistochemical staining for these genes in samples from 81 cases of lung adenocarcinoma demonstrated the expressions of CLDN1 and CLDN10 were correlated with overall survival of patients with lung adenocarcinoma. CLDN1 and CLDN10 may play important roles in the development of AIS to LPA. Overexpression of CLDN1 and CLDN10 indicates a favorable prognosis for overall survival in some patients with lung adenocarcinoma. Expression of CLDN10 may be regulated by the c-fos pathway.
BACKGROUND: Chronic endometritis (CE) has two principal subtypes—non-specific chronic endometritis (NSCE) and endometrial tuberculosis (ETB). Both can adversely affect embryo implantation. Although ETB is generally more severe, its low incidence has limited comparative data on assisted reproductive outcomes versus NSCE. A direct comparison of pregnancy outcomes following in vitro fertilization (IVF) or intracytoplasmic sperm injection-embryo transfer (ICSI-ET) between patients with ETB and those with NSCE would help clarify whether differential management strategies are warranted and provide more precise guidance for clinical practice. METHODS: In this single-center retrospective study, clinical data were collected from infertile patients who underwent IVF/ICSI-ET at West China Second University Hospital, Sichuan University, between January 2019 and December 2024. All patients were diagnosed via hysteroscopic endometrial biopsy. ETB was verified through histopathology along with positive nucleic acid testing for the Mycobacterium tuberculosis complex, whereas NSCE was diagnosed by histopathology in combination with CD138 immunohistochemical staining. RESULTS: A total of 409 patients were included: 27 in the ETB group and 382 in the NSCE group. No significant differences were observed between the two groups in age, duration of infertility, baseline FSH level, or number of embryos transferred (P > 0.05). The clinical pregnancy rate was comparable between the ETB group (51.9%) and the NSCE group (49.0%) (P > 0.05). However, the live birth rate was numerically lower in the ETB group (30.0%) than in the NSCE group (42.4%), though this difference was not statistically significant (P > 0.05). A significant difference was found in the miscarriage rate between the two groups with the ETB group having a higher miscarriage rate (P < 0.05). Multivariate regression analysis identified ETB as an independent risk factor for miscarriage after IVF/ICSI-ET. CONCLUSIONS: In patients undergoing IVF/ICSI-ET, ETB is associated with a significantly higher risk of miscarriage compared to NSCE, despite similar clinical pregnancy rates. This underscores the need for distinct clinical management and counseling in ETB cases.
Is DNA methyltransferase 1 (DNMT1) dysfunction involved in epigenetic deregulation of placentae from embryos obtained by assisted reproduction technologies (ARTs)? DNMT1 expression in growing placentae of in vitro produced (IVP) embryos is compromised and associated with pregnancy loss. DNMT1 maintains the methylation profile of genes during cell division. The methylation status of genes involved in placenta development is altered in embryos obtained in vitro. Disturbances in the epigenetic regulation of gene expression during placentogenesis could be involved in the frequent developmental arrest and loss of IVP embryos. Forty sheep were naturally mated (Group 1, CTR). IVP blastocysts (2-4 per ewe) were surgically transferred to the remaining 46 recipient sheep 6 days after oestrus (Group 2). Twenty-one recipients from Group 1 and 27 recipients from Group 2 were allowed to deliver in order to compare embryo survival in both groups at term (150 days). From the remaining recipients (n = 38), fetuses and placentae of both groups were recovered by paramedian laparotomy at Days 20, 22, 24, 26 and 28 of gestation. Immediately after collection, early placental tissues (chorion-allantois) were snap frozen in liquid nitrogen and DNMT1 expression and activity was evaluated. mRNA levels (for DNMT1, HDAC2, PCNA, DMAP1, MEST, IGF2, CDKN1C, H19) and the methylation status of H19 were also analyzed. Furthermore, embryo size and survival rate were measured. Our study shows that DNMT1 expression was reduced in early placentae from sheep IVP embryos. This reduction was associated with growth arrest and subsequent death of the sheep embryos. Conversely, normal levels of DNMT1 and its cofactors were observed in placentae from IVP embryos that survived this developmental bottleneck. Although DNA methylation machinery was severely compromised in IVP placentae only up to Day 24, the low DNMT1 enzymatic activity that persisted after this stage in IVP placentae was not lethal for the developing embryos. The studied genes represent only a small fraction of genes regulating DNA methylation. Further studies are needed to evaluate changes in the expression and methylation status of other genes that may lead to developmental arrest of IVP embryos. As this is the only study evaluating the functionality of DNMT1 machinery in placentae from ART embryos, studies on other species are needed to confirm if our observation may be applicable to all mammalian embryos produced in vitro. The knowledge about compromised activity of DNMT1 in placentae obtained from IVP embryos should stimulate detailed studies on the metabolic requirements of oocytes and embryos in order to adequately enrich the culture media.
Anabolic androgenic steroids are synthetic substances related to the male sex hormones (androgens). These agents promote the growth of skeletal muscle (anabolic effects) and the development of male sexual characteristics (androgenic effects). Anabolic steroids have been illegally used for many years as performance-enhancing drugs in human, equine, and canine sports and as growth promoters in livestock reared to provide meat for human consumption. The analytical challenge to developing effective means of control within these fields has been exacerbated by the reported endogenous nature of some of these steroids. Anabolic steroids have been employed extensively in equine practice over the past 50 years. Their usefulness is largely dependent on subjective opinions, as only minimal studies investigating pharmacodynamics have been carried out in horses. Therefore, their use will vary markedly between practitioners depending on their personal experiences and pressures by trainers to use them. They form part of rational therapy in a variety of conditions. In addition to their use for increasing muscle mass, they are used to varying extents in the raising of yearlings and in the training and racing of horses with the view of improving performance. The use of these agents is prohibited in the horseracing industry by the Association of Racing Commissioners International (ARCI), International Federation of Horseracing Authorities (IFHA), and Fédération Equestre Internationale (FEI).
Background: A spray pattern (SP) test is one of the most challenging in vitro tests for nasal spray products (NSPs) associated with a high degree of variation. The total results variation observed in such studies should be in major part representative of product performance to assure high confidence when making conclusions based on obtained results. Analytical methods should be developed in a way to minimize variation contribution of random factors. A systematic statistical assessment of sources of variation is encouraged to be performed during any method development. Methods: This study includes the development of a product-shaking procedure, definition of in vivo relevant actuation parameters, and the development of a robust SP method considering NSP behavior. The final SP method is tested on different days and in different laboratories to evaluate the contribution of individual factors and interactions to the observed variance in SP using a gauge repeatability and reproducibility (GRR) model. Results: It was found that the time lag between consecutive actuations significantly influences the variability of the SP area, suggesting the importance of determining a recovery period. Factor analyst was not found to be important. Factor day was found to have the potential to impact results, mostly through interactions with other factors, suggesting that one should pay attention when performing any comparative studies within the same laboratory on different days. Significant differences were observed when the same product was tested in different laboratories. Conclusion: Key random factors, which significantly contribute to total variation, were identified using a GRR approach. By applying an appropriate control strategy over these factors, one can assure that assessed total variation can be representative of product performance. The same general approach is not only applicable to development of SP method for NSP but to all types of analytical testing as well.
Adolescent migrant girls face unique challenges to their sexual and reproductive health and rights (SRHR) due to their intersecting identities as women, young people, and migrants. Since the first International Conference on Population and Development (ICPD) in 1994, reports have increasingly emphasized the prioritization of SRHR for marginalized groups. In this article, I examine the response to contraceptive care needs through the case study of Venezuelan adolescent migrant girls in Colombia, utilizing Reproductive Justice as an analytical framework. I evaluate how state and non-state actors' responses address the intersections of gender, age, and migration to create environments that discourage contraceptive care access. I collected qualitative data through multi-perspective interviews conducted during ethnographic fieldwork in 2022. The sample includes 30 adolescent migrant girls and key informants involved in designing and delivering policies or programs for Venezuelan migrants in Colombia. Overall, the findings show that both state and non-state actors favored short-term, "urgent" interventions over access to adolescent-friendly, migrant-inclusive contraceptive care. I conclude that responses fragment aspects of SRH, deprioritizing contraceptive care and other longer-term intersectional responses in favor of urgent responses, which, in turn, further marginalize adolescent migrant girls. To overcome this, the post-ICPD agenda must recognize SRHR as a continuum and shape responses, aligning responses with the reproductive realities of adolescent migrant girls.
One of the major issues in international development is how disadvantaged populations mobilize in response to state repression. Whether in the Black Lives Movement or in the 2011 Arab Spring, digital exposures of police abuse have spurred social movements when people took to social media to expose it. Yet, in authoritarian regimes, citizens cannot easily initiate or participate in social movements. In such cases, how do victims of police violence express their dissatisfaction? This study examines this question in contemporary China, where repression of protesters is well documented. Based on a dataset of microblogs-Chinese tweets-documenting 74,415 protest events in the early Xi administration (2013-2016), this study analyzes how ordinary protestors, including migrant workers, peasants, and the urban poor, expose police abuse in social media. A close reading of microblogs documenting 150 randomly sampled events finds that Chinese protestors adopt three distinct narrative types: citizenship, solidarity, and confrontational. An accompanying quantitative analysis of the wider dataset further finds that ordinary protestors frequently expose police abuse online and that mentions of police abuse are closely associated with the above three narratives. Overall, this study contributes to understanding how abused protestors discursively contest authorities in the world's most powerful authoritarian regime.
There is a paucity of research on socioeconomic factors associated with intravitreal injection use or type of anti-vascular endothelial growth factor (anti-VEGF) use. The purpose of this cross-sectional analysis is to examine the association between demographic and socioeconomic factors and intravitreal injections and type of anti-VEGF (bevacizumab, aflibercept, and ranibizumab) use for patients with diabetic macular edema, proliferative diabetic retinopathy, retinal vein occlusion, and wet age-related macular degeneration in the AllofUs Database, which is a nationwide health database initiative conducted by the National Institutes of Health in the United States to enroll participants from groups that are considered to be historically underrepresented in biomedical research. The study population included patients diagnosed with diabetic macular edema, proliferative diabetic retinopathy, retinal vein occlusion, or wet age-related macular degeneration based on the International Classification of Diseases Ninth/10th Revision, Clinical Modification diagnosis codes. Exposures included age, sex, race/ethnicity, income, and education. Outcomes included IVI use based on the Current Procedural Terminology 4 codes and anti-VEGF type based on RxNorm codes. Of 3010 participants, 25.9% ever had IVI use. In multivariate logistic regression analyses, those with older age (adjusted odds ratio [aOR] = 1.27; 95% CI, 1.18-1.37) and income >$150,000 (aOR = 1.71; CI, 1.27-2.32) were more likely to have had IVI use. Those with older age (aOR = 1.46; CI, 1.22-1.75), Asian/other race/ethnicity (aOR = 3.81; CI, 1.09-13.34), Hispanic race/ethnicity (aOR = 3.16; CI, 1.59-6.26), income >$150,000 (aOR = 3.20; CI, 1.45-7.06), and college graduate/advanced degree (aOR = 1.83; CI, 1.01-3.31) were more likely to have aflibercept/ranibizumab only versus bevacizumab use. Interventions are needed to increase health literacy and access to IVI for at-risk, low-income populations. Future research should investigate patient and provider decision-making for anti-VEGF drug choice, which may have implications for cost-saving measures and policies.
This study examines the impact of institutional shifts on the strategic choices of Russian firms. It proposes and tests hypotheses of how a shift from a weak to a strong institutional context is likely to affect firms' knowledge accumulation, absorptive capacities and internalisation of operations. Using discriminant analysis, the econometric investigation demonstrates that firms tend to allocate greater resources towards improving their knowledge and absorptive capacity and make more efforts to vertically integrate-in line with improvements in the institutional environment. These investments ensure the survivability and competitiveness of firms in the long term. Furthermore, the study demonstrates that the long-term strategic orientation of firms goes hand in hand with rising resource allocations by the nation-state towards economic development. The findings align with the institutionalist political economy views that institutions are the ultimate overseers that allow the market to operate efficiently, especially in emerging market environments. The paper is also instructive to other developing economies about the need to strengthen their institutional environments, which supports the long-term orientation of firms and has a positive impact on economic development. The analysis does not take into account the impact of sanctions on Russian business and economy, post the annexation of Crimea and the armed conflict with Ukraine. Nor does it consider the impact of COVID-19 on the economy. As such, the study attempts to constitute an untainted comparison of two paths of transition on Russian firms-shock therapy, vis-à-vis, an institutional political economy approach.