Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 ...cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.
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•51 cell subsets in colon mucosa of 18 ulcerative colitis and 12 healthy individuals•M-like cells, inflammatory monocytes and fibroblasts, and CD8+IL-17+ T cells expand in disease•Oncostatin M circuit in inflammatory monocytes and fibroblasts may affect drug response•Co-expression of genes within cells allows inference of causal genes across risk loci
Single-cell analyses of colon biopsy specimens from patients with ulcerative colitis delineate how expression patterns and shifting cell populations may shape disease and drug resistance, and provide a framework for linking GWAS risk loci with specific cell types and functional pathways.
Objective To compare the duration of parenteral nutrition, growth, and morbidity in extremely premature infants fed exclusive diets of either bovine milk–based preterm formula (BOV) or donor human ...milk and human milk-based human milk fortifier (HUM), in a randomized trial of formula vs human milk. Study design Multicenter randomized controlled trial. The authors studied extremely preterm infants whose mothers did not provide their milk. Infants were fed either BOV or an exclusive human milk diet of pasteurized donor human milk and HUM. The major outcome was duration of parenteral nutrition. Secondary outcomes were growth, respiratory support, and necrotizing enterocolitis (NEC). Results Birth weight (983 vs 996 g) and gestational age (27.5 vs 27.7 wk), in BOV and HUM, respectively, were similar. There was a significant difference in median parenteral nutrition days: 36 vs 27, in BOV vs HUM, respectively ( P = .04). The incidence of NEC in BOV was 21% (5 cases) vs 3% in HUM (1 case), P = .08; surgical NEC was significantly higher in BOV (4 cases) than HUM (0 cases), P = .04. Conclusions In extremely preterm infants given exclusive diets of preterm formula vs human milk, there was a significantly greater duration of parenteral nutrition and higher rate of surgical NEC in infants receiving preterm formula. This trial supports the use of an exclusive human milk diet to nourish extremely preterm infants in the neonatal intensive care unit.
To present updated national birthweight percentiles by gestational age for male and female singleton infants born in Australia.
Cross-sectional population-based study of 2.53 million singleton live ...births in Australia between 1998 and 2007.
Birthweight percentiles by gestational age and sex.
Between 1998 and 2007, women in Australia gave birth to 2 539 237 live singleton infants. Of these, 2 537 627 had a gestational age between 20 and 44 weeks, and sex and birthweight data were available. Birthweight percentiles are presented by sex and gestational age for a total of 2 528 641 births, after excluding 8986 infants with outlying birthweights. Since the publication of the previous Australian birthweight percentiles in 1999, median birthweight for term babies has increased between 0 and 25 g for boys and between 5 g and 45 g for girls.
There has been only a small increase in birthweight percentiles for babies of both sexes and most gestational ages since 1991-1994. These national percentiles provide a current Australian reference for clinicians and researchers assessing weight at birth.
Amniotic fluid embolism (AFE) remains one of the principal reported causes of direct maternal mortality in high-income countries. However, obtaining robust information about the condition is ...challenging because of its rarity and its difficulty to diagnose. This study aimed to pool data from multiple countries in order to describe risk factors, management, and outcomes of AFE and to explore the impact on the findings of considering United Kingdom, international, and United States AFE case definitions.
A population-based cohort and nested case-control study was conducted using the International Network of Obstetric Survey Systems (INOSS). Secondary data on women with AFE (n = 99-218, depending on case definition) collected prospectively in population-based studies conducted in Australia, France, the Netherlands, Slovakia, and the UK were pooled along with secondary data on a sample of control women (n = 4,938) collected in Australia and the UK. Risk factors for AFE were investigated by comparing the women with AFE in Australia and the UK with the control women identified in these countries using logistic regression. Factors associated with poor maternal outcomes (fatality and composite of fatality or permanent neurological injury) amongst women with AFE from each of the countries were investigated using logistic regression or Wilcoxon rank-sum test. The estimated incidence of AFE ranged from 0.8-1.8 per 100,000 maternities, and the proportion of women with AFE who died or had permanent neurological injury ranged from 30%-41%, depending on the case definition. However, applying different case definitions did not materially alter findings regarding risk factors for AFE and factors associated with poor maternal outcomes amongst women with AFE. Using the most liberal case definition (UK) and adjusting for the severity of presentation when appropriate, women who died were more likely than those who survived to present with cardiac arrest (89% versus 40%, adjusted odds ratio aOR 10.58, 95% confidence interval CI 3.93-28.48, p < 0.001) and less likely to have a source of concentrated fibrinogen (40% versus 56%, aOR 0.44, 95% CI 0.21-0.92, p = 0.029) or platelets given (24% versus 49%, aOR 0.23, 95% CI 0.10-0.52, p < 0.001). They also had a lower dose of tranexamic acid (median dose 0.7 g versus 2 g, p = 0.035) and were less likely to have had an obstetrician and/or anaesthetist present at the time of the AFE (61% versus 75%, aOR 0.38, 95% CI 0.16-0.90, p = 0.027). Limitations of the study include limited statistical power to examine factors associated with poor maternal outcome and the potential for residual confounding or confounding by indication.
The findings of our study suggest that when an AFE is suspected, initial supportive obstetric care is important, but having an obstetrician and/or anaesthetist present at the time of the AFE event and use of interventions to correct coagulopathy, including the administration of an adequate dose of tranexamic acid, may be important to improve maternal outcome. Future research should focus on early detection of the coagulation deficiencies seen in AFE alongside the role of tranexamic acid and other coagulopathy management strategies.
Objective To compare regulatory and economic aspects of assisted reproductive technologies (ART) in developed countries. Design Comparative policy and economic analysis. Patient(s) Couples undergoing ...ART treatment in the United States, Canada, United Kingdom, Scandinavia, Japan, and Australia. Outcome Measure(s) Description of regulatory and financing arrangements, cycle costs, cost-effectiveness ratios, total expenditure, utilization, and price elasticity. Result(s) Regulation and financing of ART share few general characteristics in developed countries. The cost of treatment reflects the costliness of the underlying healthcare system rather than the regulatory or funding environment. The cost (in 2006 United States dollars) of a standard IVF cycle ranged from $12,513 in the United States to $3,956 in Japan. The cost per live birth was highest in the United States and United Kingdom ($41,132 and $40,364, respectively) and lowest in Scandinavia and Japan ($24,485 and $24,329, respectively). The cost of an IVF cycle after government subsidization ranged from 50% of annual disposable income in the United States to 6% in Australia. The cost of ART treatment did not exceed 0.25% of total healthcare expenditure in any country. Australia and Scandinavia were the only country/region to reach levels of utilization approximating demand, with North America meeting only 24% of estimated demand. Demand displayed variable price elasticity. Conclusion(s) Assisted reproductive technology is expensive from a patient perspective but not from a societal perspective. Only countries with funding arrangements that minimize out-of-pocket expenses met expected demand. Funding mechanisms should maximize efficiency and equity of access while minimizing the potential harm from multiple births.
The innate immune mechanisms by which adjuvants enhance the potency and protection of vaccine-induced adaptive immunity are largely unknown. We introduce a model to delineate the steps of how ...adjuvant-driven innate immune activation leads to priming of vaccine responses using rhesus macaques. Fluorescently labeled HIV-1 envelope glycoprotein (Env) was administered together with the conventional aluminum salt (alum) adjuvant. This was compared to Env given with alum with preabsorbed Toll-like receptor 7 (TLR7) ligand (alum-TLR7) or the emulsion MF59 because they show superiority over alum for qualitatively and quantitatively improved vaccine responses. All adjuvants induced rapid and robust immune cell infiltration to the injection site in the muscle. This resulted in substantial uptake of Env by neutrophils, monocytes, and myeloid and plasmacytoid dendritic cells (DCs) and migration exclusively to the vaccine-draining lymph nodes (LNs). Although less proficient than monocytes and DCs, neutrophils were capable of presenting Env to memory CD4
T cells. MF59 and alum-TLR7 showed more pronounced cell activation and overall higher numbers of Env
cells compared to alum. This resulted in priming of higher numbers of Env-specific CD4
T cells in the vaccine-draining LNs, which directly correlated with increased T follicular helper cell differentiation and germinal center formation. Thus, strong innate immune activation promoting efficient vaccine antigen delivery to infiltrating antigen-presenting cells in draining LNs is an important mechanism by which superior adjuvants enhance vaccine responses.
Objective To analyze information on assisted reproductive technology (ART) performed worldwide, and trends in outcomes over successive years. Design Cross-sectional survey on access, efficiency, and ...safety of ART procedures performed in 55 countries during 2007. Setting Not applicable. Patient(s) Infertile women and men undergoing ART globally. Intervention(s) Collection and analysis of international ART data. Main Outcome Measure(s) Number of cycles performed, by country and region, including pregnancies, single and multiple birth rates, and perinatal mortality. Result(s) Overall, >1,251,881 procedures with ART were reported, and resulted in 229,442 reported babies born. The availability of ART varied by country, from 12 to 4,140 treatments per million population. Of all aspiration cycles, 65.2% (400,617 of 614,540) were intracytoplasmic sperm injection. The overall delivery rate per fresh aspiration was 20.3%, and for frozen-embryo transfer (FET), 18.4%, with a cumulative delivery rate of 25.8%. With wide regional variations, single-embryo transfer represented 23.4% of fresh transfers, and the proportion of deliveries with twins and triplets from fresh transfers was 22.3% and 1.2%, respectively. The perinatal mortality rate was 19.9 per 1,000 births for fresh in vitro fertilization using intracytoplasmic sperm injection, and 9.6 per 1,000 for FET. The proportion of women aged ≥40 years increased to 19.8% from 15.5% in 2006. Conclusion(s) The international trend toward <3 transferred embryos continued, as did the wider uptake of FET. This was achieved without compromising delivery rates. The application of ART for women aged >40 years was a major component of ART services in some regions and countries.
Limited research in high-income countries (HICs) examines adolescent abortion care-seeking pathways. This review aims to examine the pathways and experiences of adolescents when seeking abortion ...care, and service delivery processes in provision of such care. We undertook a systematic search of the literature to identify relevant studies in HICs (2000-2020). A directed content analysis of qualitative and quantitative studies was conducted. Findings were organised to one or more of three domains of an a priori conceptual framework: context, components of abortion care and access pathway. Thirty-five studies were included. Themes classified to the Context domain included adolescent-specific and restrictive abortion legislation, mostly focused on the United States. Components of abortion care themes included confidentiality, comprehensive care, and abortion procedure. Access pathway themes included delays to access, abortion procedure information, decision-making, clinic operation and environments, and financial and transportation barriers. This review highlights issues affecting access to abortion that are particularly salient for adolescents, including additional legal barriers and challenges receiving care due to their age. Opportunities to enhance abortion access include removing legal barriers, provision of comprehensive care, enhancing the quality of information, and harnessing innovative delivery approaches offered by medical abortion.
Objectives
To determine the prevalence and impact of common co‐occurring symptoms among community‐dwelling older adults in the United States.
Design
The National Health and Aging Trends Study is a ...nationally representative, prospective study with annual data collection between 2011 and 2017.
Setting
Community‐based, in‐person interviews (survey response rates, 71%–96%).
Participants
A total of 7,609 community‐dwelling Medicare beneficiaries, 65 years or older.
Measurements
Symptoms assessed at baseline include pain, fatigue, breathing difficulty, sleeping difficulty, depressed mood, and anxiety. Total symptom count ranged from zero to six. Several outcomes were examined, including grip strength, gait speed, and overall lower‐extremity function as well as incidence of recurrent falls (two or more per year), hospitalization, disability, nursing home admission, and mortality.
Results
Prevalence of zero, one, two, three, and four or more symptoms was 25.0%, 26.6%, 20.7%, 14.0%, and 13.6%, respectively. Symptom count increased with advancing age and was higher in women than in men. Pain and fatigue were the most common co‐occurring symptoms. Higher symptom count was associated with decreased physical capacity. For example, participants with one, two, three, and four or more symptoms had gait speeds that were 0.04, 0.06, 0.09, and 0.13 m/s slower, respectively, than those with no symptoms, adjusting for specific diseases, total number of diseases, and other potential confounders (P < .001). The risk of several adverse outcomes also increased with greater symptom count. For example, compared with those with no symptoms, the adjusted risk ratios for recurrent falls were 1.48 (95% confidence interval CI = 1.30–1.70), 1.54 (95% CI = 1.32–1.80), 1.90 (95% CI = 1.55–2.32), and 2.38 (95% CI = 2.00–2.83) for older adults with one, two, three, and four or more symptoms, respectively.
Conclusions
Symptoms frequently co‐occur among community‐dwelling older adults and are strongly associated with increased risk of a range of adverse outcomes. Symptoms represent a potential treatment target for improving outcomes and should be systematically captured in health records. J Am Geriatr Soc 67:223–231, 2019.
See related Editorial by Hunt et al. in this issue.
Abstract
Purpose
Cardiac disease is a leading cause of maternal morbidity and mortality yet there is limited research on women’s experiences and quality of life (QoL) outcomes. The aim of this study ...is to explore the general and health-related QoL (HRQoL) and mental health outcomes for women who have experienced cardiac disease in pregnancy and the first 12 months postpartum (CDPP).
Methods
This exploratory descriptive study recruited 43 women with acquired, genetic and congenital CDPP. Patient reported outcomes measures (PROMs) used were: WHOQoL-Bref, a Kansas City Cardiac Questionnaire (KCCQ), the Depression, Anxiety and Stress Scales-21 (DASS-21), the Cardiac Anxiety Questionnaire (CAQ) plus newly developed questions.
Results
Women reported low health satisfaction (51.7/100), physical health (55.2/100) and low HRQoL (63.1/100). Women had clinically significant scores for depression (24%), anxiety (22%) and stress (19.5%) (DASS-21) and 44.5% scored at least moderate anxiety on the CAQ. Most women (83.7%) were advised to avoid pregnancy which 88.9% found “upsetting” to “devastating”; 10.0% were offered counselling. Most women were concerned about reduced longevity (88.1%), offspring developing a cardiac condition (73.8%), and the limitations on enjoyment of life (57.1%). Women missed medical appointments due to cost (25.03%) and difficulty arranging childcare (45.5%).
Conclusion
The majority of women reported inadequate information and counselling support, with women with CDPP having sustained impaired QoL and mental health outcomes. The new and modified questions relating to mothering and children reflected the primacy of mothering to women’s identity and needs.
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