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IL-33 is a member of the IL-1 family and was first identified as an alarmin that acts at mucosal barrier sites. However, IL-33 is now understood to be a pleiotropic cytokine that acts on a variety of immune and non-immune cell types to promote type 2 T helper cell (T

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from −90% to +30%, were reported in many countries following early COVID-19 pandemic response measures (‘lockdowns’). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95–0.98, P value

Objective To determine the involvement of the endocannabinoid (EC) family member in the pathophysiology of endometriosis (EMS). Design Mass spectrometry analysis of plasma and tissue samples from patients with EMS, controls, and a mouse model of EMS and messenger RNA and immunohistochemistry analysis of the samples from patients with EMS and controls. Setting Academic teaching hospital and university. Patient(s) Patients with EMS and healthy fertile control subjects. Intervention(s) None. Main Outcome Measure(s) Endocannabinoid analysis in patient plasma, EMS lesions, and healthy endometrial samples. Result(s) Circulating ECs were detected in the plasma samples, whereas no significant changes were observed in patients with EMS compared with healthy fertile controls. However, the palmitoylethanolamide levels were significantly higher in the EMS lesions than in the endometrium from patients with EMS. Similarly, genes involved in the EC signaling pathways were differentially expressed in the EMS lesions. Analysis of cannabinoid 1 and 2 receptors in the EMS lesions revealed a significantly lower cannabinoid 2 receptor expression, whereas no significant changes were observed in cannabinoid 1 receptor expression compared with those in the endometrium from both patients with EMS and healthy fertile controls. The palmitoylethanolamide levels were significantly elevated in plasma from EMS mice compared with that from sham controls and in EMS lesions compared with uterine samples. Conclusion(s) Together, we provide evidence toward dysregulation of members of the ECs in both patients with EMS and the mouse model of EMS. These findings will advance the knowledge of the role of ECs in EMS and their potential implications as therapeutic targets.

Background Infectious diseases are a leading cause of hospitalization during childhood. The various mitigation strategies implemented to control the coronavirus disease (COVID-19) pandemic could have additional, unintended benefits for limiting the spread of other infectious diseases and their associated burden on the health care system. Methods We conducted an interrupted time-series analysis using population-wide hospitalization data for the state of Victoria, Australia. Infection-related hospitalizations for children and adolescents (aged Results Over 2015–19, the mean annual incidence of hospitalization with infection among children less than 18 years was 37 per 1000 population. There was an estimated 65% (95% CI 62-67%) reduction in the incidence of overall infection-related hospitalizations associated with the introduction of pandemic restrictions. The reduction was most marked in younger children (at least 66% in those less than 5 years of age) and for lower respiratory tract infections (relative reduction 85%, 95% CI 85-86%). Conclusions The wider impacts of pandemic mitigation strategies on non-COVID-19 infection-related hospitalizations are poorly understood. We observed marked and rapid decreases in hospitalized childhood infection. In tandem with broader consequences, sustainable measures, such as improved hand hygiene, could reduce the burden of severe childhood infection post-pandemic and the social and economic costs of hospitalization.

Background and objectiveAs caesarean delivery and childhood allergy continue to rise, their inter-relationships may change. We examined whether caesarean delivery predicts allergic disease and impaired lung function in two contemporary harmonised population-based cohorts.MethodsParent-reported asthma and eczema data were drawn from two prospective Australian infant cohorts, HealthNuts (n=5276, born 2006–2010) and the Longitudinal Study of Australian Children (LSAC, n=5107, born 2003–2004) at age 6–7 years, and spirometric lung function from LSAC’s Child Health CheckPoint (n=1756) at age 11–12 years. Logistic regression estimated associations between delivery mode and current asthma and eczema at 6–7 years, and linear regression examined lung function at 11–12 years. Models were adjusted for potential confounding factors.ResultsComplete case analysis included 3135 HealthNuts and 3654 LSAC children (32.2% and 30.9% born by caesarean, respectively). An association was evident between caesarean delivery and asthma at age 6–7 years in HealthNuts (adjusted OR (aOR) 1.25, 95% CI 1.00 to 1.57) but not in LSAC (aOR 1.05, 95% CI 0.86 to 1.28), while neither study showed clear associations with eczema (HealthNuts: aOR 1.09, 95% CI 0.88 to 1.35; LSAC: aOR 0.89, 95% CI 0.69 to 1.15). Spirometric lung function parameters at age 11–12 years were similar by delivery mode. Associations were not modified by duration of breast feeding, maternal history of asthma/eczema, childcare attendance, number of older siblings or pet exposure.ConclusionsIn two unselected populations using harmonised protocols, the likely association of caesarean delivery with developing childhood allergy was small.

Chronic inflammation and localized alterations in immune cell function are suspected to contribute to the progression of endometriosis and its associated symptoms. In particular, the alarmin, Interleukin (IL)-33 is elevated in the plasma, peritoneal fluid, and endometriotic lesions from endometriosis patients; however, the exact role of IL-33 in the pathophysiology of endometriosis is not well understood. In this study, we demonstrate, in both human patients and a murine model, that IL-33 contributes to the expansion of the novel group 2 innate lymphoid cells (ILC2s) and this IL-33 induced ILC2 expansion modulates the endometriosis lesion microenvironment. Importantly, we show that IL-33 drives hallmarks of severe endometriosis including elevated inflammation, lesion proliferation, and fibrosis and that this IL-33 induced aggravation is mediated by ILC2s. Finally, we demonstrate the functionality of IL-33 neutralization as a promising and novel therapeutic avenue for treating the debilitating symptoms of endometriosis.

To identify immune cells, cytokines, and immune cell transcriptome in the menstrual effluent (ME) of women with endometriosis compared with that of healthy donors.Live immune cells were isolated from human ME samples and were analyzed by flow cytometry to identify various immune cell populations. Selected cytokines from the same patients were evaluated using multiplex cytokine analyses. The transcriptome of the immune cell population was subsequently profiled using NanoString nCounter's PanCancer Immune panel.Academic institution.Surgically confirmed endometriosis patients (n = 14) and healthy fertile donors (n = 19).None.In-depth immune cell profiling of ME obtained from women with endometriosis compared with that of healthy donors.ME analysis revealed that the number of T helper 17 (TWe demonstrate for the first time that the levels of T

Endometriosis (EM) is characterized by the growth of endometrium-like tissue outside the uterus, leading to chronic inflammation and pelvic pain. Lesion proliferation, vascularization, and associated inflammation are the hallmark features of EM lesions. The legalization of recreational cannabinoids has garnered interest in the patient community and is contributing to a greater incidence of self medication; however, it remains unknown if cannabinoids possess marked disease-modifying properties. In this study, we assess the effects of synthetic cannabinoid, WIN 55212-2 (WIN 55), in EM-representative in vitro and in vivo syngeneic mouse models. WIN 55 reduced proliferation and angiogenesis in vitro, via MAPK/Akt-mediated apoptosis. These findings were corroborated in a mouse model of EM, where we found reduced TRPV1 expression in the dorsal root ganglia of the EM mouse model exposed to WIN 55, suggesting reduced signaling of pain stimuli. Ultimately, these pieces of evidence support the use of cannabinoid receptor agonists as a potential therapeutic intervention for EM associated pain and inflammation.

ObjectiveTo investigate whether antibiotic exposure during pregnancy was associated with childhood asthma and if this relationship was conditional on timing of exposure and mode of delivery.DesignA cohort study using multivariable logistic regression models adjusting for a priori defined confounders. Pregnant women were recruited from 1996 to 2002.SettingThe Danish National Birth Cohort.PatientsOf the 96 832 children in the cohort, 32 651 children were included in the study population.Main outcome measureParent-reported childhood asthma at 11 years.ResultsA total of 5522 (17%) children were born to mothers exposed to antibiotics during pregnancy. In adjusted analyses, children born to exposed mothers had higher odds of asthma (OR 1.14, 95% CI 1.05 to 1.24). There was no association with antibiotic exposure in the first trimester (OR 1.02, 95% CI 0.83 to 1.26), but higher odds were observed for antibiotic exposure in the second to third trimester (OR 1.17, 95% CI 1.06 to 1.28), compared with unexposed children. The overall association between antibiotics during pregnancy and childhood asthma was only observed in vaginally born children (OR 1.17, 95% CI 1.07 to 1.28) but not in caesarean section born children (planned caesarean section: OR 0.95, 95% CI 0.66 to 1.37; caesarean emergency: OR 0.96, 95% CI 0.73 to 1.28). In exposed vaginally born children, the odds for childhood asthma requiring treatment during the preceding year were 34% higher (OR 1.34, 95% CI 1.21 to 1.49), compared with unexposed vaginally born children.ConclusionsAntibiotic exposure in mid-to-late pregnancy is associated with higher odds of childhood asthma in vaginally born children. Mode of delivery may modify the association.

Summary Background/Objectives Current research suggests an association between antibiotic use in early life and later obesity. Less is known about prenatal antibiotic exposure and foetal growth. We investigated the association between prenatal antibiotic exposure and birth weight. Methods Data from the Danish National Birth Cohort were linked to the Danish National Medical Birth Registry. Exposure was self-reported antibiotic use in pregnancy. Outcome was registered birth weight. Multivariable linear regression models were adjusted for confounders defined a priori. Results A total of 63?300 mother?child dyads from 1996 to 2002 were included. Overall, prenatal antibiotic exposure was not associated with birth weight (?8.90?g, 95%CI: ?19.5? +1.64?g, p = 0.10). Findings were similar for those born term and preterm. Antibiotic exposure in second to third trimester, compared to no exposure, was associated with lower birth weight (?12.6 g, 95%CI: ?24.1 to ?1.1 g, p = 0.03). In sex-stratified analyses, there were no observed associations between antibiotics and birth weight. With further stratifications, prenatal antibiotic exposure and birth weight were associated in boys who were preterm (+91.0 g, 95%CI: +6.8 g? +175.2 g, p = 0.03) but not among girls who were preterm (?44.0 g, 95%CI: ?128.1 to +40.0 g, p = 0.30). Conclusions Prenatal antibiotic exposure is not consistently associated with birth weight.

OBJECTIVE Obesity is an established risk factor for severe coronavirus disease 2019 (COVID-19) but the contribution of overweight and/or diabetes remain unclear. In a multi-center international study, we investigated if overweight, obesity and diabetes were independently associated with COVID-19 severity, and whether the body mass index (BMI)-associated risk was increased among those with diabetes. RESEARCH DESIGN & METHODS We retrospectively extracted data from health care records and regional databases of hospitalized adult patients with COVID-19 from 18 sites in 11 countries. We used standardized definitions and analyses to generate site-specific estimates, modelling the odds of each outcome (supplemental oxygen/non-invasive ventilation, invasive mechanical ventilation, and in-hospital mortality) by BMI category (reference, overweight, obese) adjusting for age, sex, and pre-specified co-morbidities. Subgroup analysis was performed on patients with pre-existing diabetes. Site-specific estimates were combined in a meta-analysis. RESULTS Among 7244 patients (65.6% overweight/obese), those with overweight were more likely to require oxygen/non-invasive ventilation (random effects adjusted odds ratio [aOR] 1.44 [95% CI 1.15-1.80]) and invasive mechanical ventilation (aOR 1.22 [CI 1.03-1.46]). There was no association between overweight and in-hospital mortality (aOR 0.88 [CI 0.74-1.04]). Similar effects were observed in patients with obesity or diabetes. In the subgroup analysis, the aOR for any outcome was not additionally increased in those with diabetes and overweight or obesity. CONCLUSIONS In adults hospitalized with COVID-19, overweight as well as obesity and diabetes were associated with increased odds of respiratory support but not mortality. In patients with diabetes, the odds of severe COVID-19 were not increased above the BMI-associated risk.

Spontaneous fetal loss is one of the most important challenges that commercial pig industry is still facing in North America. Research over the decade provided significant insights into some of the associated mechanisms including uterine capacity, placental efficiency, deficits in vasculature, and immune-inflammatory alterations at the maternal-fetal interface. Pigs have unique epitheliochorial placentation where maternal and fetal layers lay in opposition without any invasion. This has provided researchers opportunities to accurately tease out some of the mechanisms associated with maternal-fetal interface adaptations to the constantly evolving needs of a developing conceptus. Another unique feature of porcine pregnancy is the conceptus derived recruitment of immune cells during the window of conceptus attachment. These immune cells in turn participate in pregnancy associated vascular changes and contribute toward tolerance to the semi-allogeneic fetus. However, the precise mechanism of how maternal-fetal cells communicate during the critical times in gestation is not fully understood. Recently, it has been established that bi-directional communication between fetal trophoblasts and maternal cells/tissues is mediated by extracellular vesicles (EVs) including exosomes. These EVs are detected in a variety of tissues and body fluids and their role has been described in modulating several physiological and pathological processes including vascularization, immune-modulation, and homeostasis. Recent literature also suggests that these EVs (exosomes) carry cargo (nucleic acids, protein, and lipids) as unique signatures associated with some of the pregnancy associated pathologies. In this review, we provide overview of important mechanisms in porcine pregnancy success and failure and summarize current knowledge about the unique cargo containing biomolecules in EVs. We also discuss how EVs (including exosomes) transfer their contents into other cells and regulate important biological pathways critical for pregnancy success.

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread “natural experiment” of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic.

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread “natural experiment” of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic.

Aims Public health responses to reduce SARS-CoV-2 transmission have profoundly affected the epidemiology and management of other infections. We examined the impact of COVID-19 restrictions on antibiotic dispensing in Australia. Methods We used national claims data to investigate antibiotic dispensing trends from November 2015 to October 2020 and whether changes reflected reductions in primary care consultations. We used interrupted time series analysis to quantify changes in monthly antibiotic dispensing and face-to-face and telehealth GP consultations and examined changes by recipient age, pharmacy State and prescriber specialty. Results Over the study period, an estimated 19 921 370 people had 125 495 137 antibiotic dispensings, 71% prescribed by GPs. Following COVID-19 restrictions, we observed a sustained 36% (95% CI: 33-40%) reduction in antibiotic dispensings from April 2020. Antibiotics recommended for managing respiratory tract infections showed large reductions (range 51-69%), whereas those recommended for non-respiratory infections were unchanged. Dispensings prescribed by GPs decreased from 63.5 per 1000 population for April-October 2019 to 37.0 per 1000 for April-October 2020. Total GP consultation rates remained stable, but from April 2020, 31% of consultations were telehealth. Conclusion In a setting with a low COVID-19 incidence, restrictions were associated with a substantial reduction in community dispensings of antibiotics primarily used to treat respiratory infections, coincident with reported reductions in respiratory viral infections. Our findings are informative for post-pandemic antimicrobial stewardship and highlight the potential to reduce inappropriate prescribing by GPs and specialists for respiratory viral infections.

Background The proportion of births via cesarean section (CS) varies worldwide and in many countries exceeds WHO-recommended rates. Long-term health outcomes for children born by CS are poorly understood, but limited data suggest that CS is associated with increased infection-related hospitalisation. We investigated the relationship between mode of birth and childhood infection-related hospitalisation in high-income countries with varying CS rates. Methods and findings We conducted a multicountry population-based cohort study of all recorded singleton live births from January 1, 1996 to December 31, 2015 using record-linked birth and hospitalisation data from Denmark, Scotland, England, and Australia (New South Wales and Western Australia). Birth years within the date range varied by site, but data were available from at least 2001 to 2010 for each site. Mode of birth was categorised as vaginal or CS (emergency/elective). Infection-related hospitalisations (overall and by clinical type) occurring after the birth-related discharge date were identified in children until 5 years of age by primary/secondary International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes. Analysis used Cox regression models, adjusting for maternal factors, birth parameters, and socioeconomic status, with results pooled using meta-analysis. In total, 7,174,787 live recorded births were included. Of these, 1,681,966 (23%, range by jurisdiction 17%–29%) were by CS, of which 727,755 (43%, range 38%–57%) were elective. A total of 1,502,537 offspring (21%) had at least 1 infection-related hospitalisation. Compared to vaginally born children, risk of infection was greater among CS-born children (hazard ratio (HR) from random effects model, HR 1.10, 95% confidence interval (CI) 1.09–1.12, p < 0.001). The risk was higher following both elective (HR 1.13, 95% CI 1.12–1.13, p < 0.001) and emergency CS (HR 1.09, 95% CI 1.06–1.12, p < 0.001). Increased risks persisted to 5 years and were highest for respiratory, gastrointestinal, and viral infections. Findings were comparable in prespecified subanalyses of children born to mothers at low obstetric risk and unchanged in sensitivity analyses. Limitations include site-specific and longitudinal variations in clinical practice and in the definition and availability of some data. Data on postnatal factors were not available. Conclusions In this study, we observed a consistent association between birth by CS and infection-related hospitalisation in early childhood. Notwithstanding the limitations of observational data, the associations may reflect differences in early microbial exposure by mode of birth, which should be investigated by mechanistic studies. If our findings are confirmed, they could inform efforts to reduce elective CS rates that are not clinically indicated.

Objectives To outline which infectious diseases in the pre-covid-19 era persist in children and adolescents in China and to describe recent trends and variations by age, sex, season, and province. Design National surveillance studies, 2008-17. Setting 31 provinces in mainland China. Participants 4 959 790 Chinese students aged 6 to 22 years with a diagnosis of any of 44 notifiable infectious diseases. The diseases were categorised into seven groups: quarantinable; vaccine preventable; gastrointestinal and enteroviral; vectorborne; zoonotic; bacterial; and sexually transmitted and bloodborne. Main outcome measures Diagnosis of, and deaths from, 44 notifiable infectious diseases. Results From 2008 to 2017, 44 notifiable infectious diseases were diagnosed in 4 959 790 participants (3 045 905 males, 1 913 885 females) and there were 2532 deaths (1663 males, 869 females). The leading causes of death among infectious diseases shifted from rabies and tuberculosis to HIV/AIDS, particularly in males. Mortality from infectious diseases decreased steadily from 0.21 per 100 000 population in 2008 to 0.07 per 100 000 in 2017. Quarantinable conditions with high mortality have effectively disappeared. The incidence of notifiable infectious diseases in children and adolescents decreased from 280 per 100 000 in 2008 to 162 per 100 000 in 2015, but rose again to 242 per 100 000 in 2017, largely related to mumps and seasonal influenza. Excluding mumps and influenza, the incidence of vaccine preventable diseases fell from 96 per 100 000 in 2008 to 7 per 100 000 in 2017. The incidence of gastrointestinal and enterovirus diseases remained constant, but typhoid, paratyphoid, and dysentery continued to decline. Vectorborne diseases all declined, with a particularly noticeable reduction in malaria. Zoonotic infections remained at low incidence, but there were still unpredictable outbreaks, such as pandemic A/H1N1 2009 influenza. Tuberculosis remained the most common bacterial infection, although cases of scarlet fever doubled between 2008 and 2017. Sexually transmitted diseases and bloodborne infections increased significantly, particularly from 2011 to 2017, among which HIV/AIDS increased fivefold, particularly in males. Difference was noticeable between regions, with children and adolescents in western China continuing to carry a disproportionate burden from infectious diseases. Conclusions China’s success in infectious disease control in the pre-covid-19 era was notable, with deaths due to infectious diseases in children and adolescents aged 6-22 years becoming rare. Many challenges remain around reducing regional inequalities, scaling-up of vaccination, prevention of further escalation of HIV/AIDS, renewed efforts for persisting diseases, and undertaking early and effective response to highly transmissible seasonal and unpredictable diseases such as that caused by the novel SARS-CoV-2 virus.

INTRODUCTION Infections are a leading cause of mortality and morbidity in preschool children. We aimed to assess the impact of the co-occurrence of cesarean section, early birth and formula feeding on hospitalization with infection in early childhood. MATERIAL AND METHODS Population-based retrospective record-linkage cohort study of 488 603 singleton livebirths ≥32 weeks' gestational age in New South Wales, Australia, 2007-2012. Multivariable Cox-regression was used to estimate independent and combined adjusted associations of gestational age, mode of birth (vaginal or cesarean section by labor onset) and formula feeding with time to first and repeat hospitalization with infection for children less than five years of age. RESULTS In all, 95 346 (19.5%) children were hospitalized with infection, and of these 24.8% (23 615) more than once. Median age at first and repeat hospitalization was 1.1 and 1.7 years, respectively. Earlier gestation, modes of birth other than spontaneous vaginal, and formula feeding were independently associated with an increased risk of first and repeat hospitalization with infection. At 32-36 weeks' gestation, co-occurrence of perinatal factors (cf. spontaneous vaginal birth at 39+ weeks without formula feeding) was associated with a 2-fold and 1.5-fold increased risk of first and repeat hospitalization, respectively. For births at 37-38 weeks, the increased risk was 1.5-fold and 1.25-fold for first and repeat hospitalization, respectively. CONCLUSIONS Cesarean section, labor induction, birth at

Endometriosis affects 176 million women worldwide and is defined by the growth of endometrial (uterine) tissue outside of the uterus. Endometriosis is considered a multifactorial disease known for chronic inflammation and estrogen dependence; however, there is no consensus as to the cause. An overall lack of knowledge surrounding the disease has led to substantial challenges in classification, diagnosis, and treatment for endometriosis patients. The use of large-scale molecular profiles, including genomic, epigenetic, transcriptomic, and proteomic profiles, has been conducted to further understand the pathology of endometriosis with the hopes that this information could help improve the current challenges. Interestingly, these studies have clearly revealed unique immune-inflammatory gene signatures in endometriosis patients compared to healthy fertile women. Since immune pathways are redundant and converge at multiple cellular and molecular levels, further study is required to carefully dissect how these specific immune pathways are contributing to the disease and if therapeutic targets can be revealed. Additionally, further study of specific lesion types, disease stage, and associated symptoms in the context of an immune gene signature could lead to the design of novel classification systems and diagnostic procedures. Here, we provide a comprehensive overview of the alterations in immune-inflammatory gene signatures and their functional significance in endometriosis.

Endometriosis is a debilitating gynecological disease characterized by the extrauterine presence of endometrial-like tissues located on the peritoneal membrane and organs of the pelvic cavity. Notably, dysfunctional immune activation in women with endometriosis could also contribute to the development of disease. In particular, alternatively activated (M2) peritoneal macrophages are shown to aid peritoneal lesion development by promoting remodeling of extracellular matrix and neovascularization of lesions. However, the stimuli responsible for polarizing M2 macrophages in endometriosis remain elusive. Interleukin-17A (IL-17A) can induce M2 macrophage polarization in other disease models and IL-17A is elevated in the plasma and endometriotic lesions of women with endometriosis. In this study, we investigated whether IL-17A could induce macrophage recruitment and M2 polarization, while promoting endometriotic lesion growth through enhanced vascularization. By utilizing a co-culture of macrophage-like THP-1 cells with an endometriotic epithelial cell line, our in vitro results suggest that IL-17A indirectly induces M2 markers CCL17 and CD206 by interacting with endometriotic epithelial cells. Further, in a syngeneic mouse model of endometriosis, IL-17A treatment increased macrophages in the peritoneum, which were also M2 in phenotype. However, IL-17A treatment did not augment proliferation or vascularization of the lesion in the study time frame. These findings suggest that IL-17A may be a stimulus inducing the pathogenic polarization of macrophages into the M2 phenotype by first acting on the endometriotic lesion itself.

With multifactorial etiologies, combined with disease heterogeneity and a lack of suitable diagnostic markers and therapy, endometriosis remains a major reproductive health challenge. Extracellular vesicles (EVs) have emerged as major contributors of disease progression in several conditions, including a variety of cancers; however, their role in endometriosis pathophysiology has remained elusive. Using next-generation sequencing of EVs obtained from endometriosis patient tissues and plasma samples compared with controls, we have documented that patient EVs carry unique signatures of miRNAs and long noncoding RNAs (lncRNAs) reflecting their contribution to disease pathophysiology. Mass spectrophotometry–based proteomic analysis of EVs from patient plasma and peritoneal fluid further revealed enrichment of specific pathways, as well as altered immune and metabolic processes. Functional studies in endometriotic epithelial and endothelial cell lines using EVs from patient plasma and controls clearly indicate autocrine uptake and paracrine cell proliferative roles, suggestive of their involvement in endometriosis. Multiplex cytokine analysis of cell supernatants in response to patient and control plasma–derived EVs indicate robust signatures of important inflammatory and angiogenic cytokines known to be involved in disease progression. Collectively, these findings suggest that endometriosis-associated EVs carry unique cargo and contribute to disease pathophysiology by influencing inflammation, angiogenesis, and proliferation within the endometriotic lesion microenvironment.

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Introduction: Chronic inflammation drives endometriosis (EM) and its associated symptoms. Interleukin (IL)-33, has gained therapeutic interest as it is elevated in the plasma, peritoneal fluid (PF), and lesions of EM patients. However, how IL-33 contributes to EM is largely unknown. For the first time, we demonstrate, using both human samples and murine models, that IL-33 expands local group 2 innate lymphoid cells (ILC2s) and that IL-33 activated ILC2s modulate hallmark features of EM. Methods: We identified ILC2s (CD45+Lin−CRTH2+CD127+ST2+) in the PF of EM patients using flow cytometry. Using immunofluorescence, we determine whether IL-33 forms epithelial or stromal cell niches within the EM lesion. Then, using our well established EM model, we induced EM in female C57Bl/6 mice and treated with PBS or IL-33. Hallmark features of EM were assessed including inflammation (using multiplex cytokine analysis), immune cell profiling (using flow cytometry), and lesion architecture (using immunohistochemistry and Nanostring transcriptomic profiling). To establish cause and effect, we treated ILC2 deficient mice with PBS (n=5) or IL-33 (n=5). Unpaired t-tests and one-way ANOVAs were done when appropriate. Results/Discussion: In humans, ILC2s are present and elevated in EM patients (n=5) compared to healthy donors (n=3) and IL-33 colocalized with both epithelial and stromal cells within the EM lesion. Using murine models, IL-33 drove hallmark features of EM including increased inflammation, alterations in PF immune cells (including eosinophils, T cells, macrophages and ILC2s), as well as increased lesion proliferation, neurogenesis and fibrosis. Using ILC2 deficient mice, we show that IL-33 induced pathology is ILC2 dependent.

Objective To assess the risk of severe childhood infections within families, we conducted a sibling analysis in a population-based cohort study with genealogical linkage. We investigated the sibling risk of hospitalization with common infections, a marker of severity. We hypothesized that having siblings hospitalized for infection would increase the proband’s risk of admission with infection. Study design We used population data on Western Australian live-born singletons and their siblings between 1980 and 2014. Measures of infection were infection-related hospitalizations from discharge diagnostic codes. Exposure was having a sibling who had an infection-related hospitalization. Outcomes were infection-related hospitalizations in the child/proband. Probands were followed until an infection-related hospitalization admission (up to the first three), death, 18th birthday, or end of 2014, whichever occurred first. Infection risks were estimated by adjusted Cox proportional hazard models for multiple events. Results Of 512,279 probands, 142,915 (27.9%) had infection-related hospitalizations; 133,322 (26.0%) had a sibling with a previous infection-related hospitalization (i.e. exposed). Median interval between sibling and proband infection-related hospitalizations was 1.4 years (inter-quartile range 0.5–3.7). Probands had a dose-dependent increase in risk if sibling/s had 1, 2, or 3+ infection-related hospitalizations (adjusted hazard ratio, aHR 1.41, 95% CI 1.39–1.43; aHR 1.65, 1.61–1.69; aHR 1.83, 1.77–1.90, respectively). Among siblings with the same clinical infection type, highest sibling risks were for genitourinary (aHR 2.06, 1.68–2.53), gastrointestinal (aHR 2.07, 1.94–2.19), and skin/soft tissue infections (aHR 2.34, 2.15–2.54). Overall risk of infection-related hospitalization was higher in children with more siblings and with older siblings. Conclusion In this population-based study, we observed an increased risk of infection-related hospitalization in children whose siblings were previously hospitalized for infection. Public health interventions may be particularly relevant in families of children hospitalized with infection.

Endometriosis is a chronic, inflammatory, estrogen-dependent disease characterized by the growth of endometrial tissue outside of the uterine cavity. Although the etiology of endometriosis remains elusive, immunological dysfunction has been proposed as a critical facilitator of ectopic lesion growth following retrograde menstruation of endometrial debris. However, it is not clear whether this immune dysfunction is a cause or consequence of endometriosis. Thus, here we provide in-depth insights into our current understanding of the immunopathophysiology of endometriosis and highlight challenges and opportunities for future research. With the explosion of successful immune-based therapies targeting various chronic inflammatory conditions, it is crucial to determine whether immune dysfunction can be therapeutically targeted in endometriosis.

Background: The early life microbiome contributes to immune development. Antibiotics during pregnancy alter the microbiome and may influence disease risks in the offspring. We investigated the relationship between maternal antibiotic exposure before and during pregnancy, and risk of childhood hospitalization with infection.Methods: We used population-based Danish national databases for pregnancies between 1995 and 2009. Infants were followed from birth until their first infection-related hospitalization, death, 14th birthday, emigration or end-2009. Exposure was maternal antibiotics prescribed before and during pregnancy. Outcome was infection-related hospitalization.Results: 141 359 (18%) mothers had at least one antibiotic prescription during pregnancy, 230 886 (29.4% of those with complete data) in the 18 months before pregnancy. Of 776 657 live-born singletons, 443 546 infection-related hospitalizations occurred in 222 524 (28.6%) children. Pregnancy antibiotic exposure was associated with increased risk of childhood infection-related hospitalization [hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.17-1.19]. In mothers prescribed antibiotics only during pregnancy whose child did not receive pre-hospitalization antibiotics, this association was present only in those born vaginally. Higher risks of infection-related hospitalization occurred when pregnancy antibiotic prescriptions were closer to birth and in mothers receiving more pregnancy antibiotics. Children born to mothers exposed to antibiotics before (but not during) pregnancy also had increased risk of infection-related hospitalization (HR 1.10, 95% CI 1.07-1.12).Conclusions: Antibiotic exposure before or during pregnancy was associated with increased risk of childhood hospitalized infections. Alteration of the maternally derived microbiome and shared heritable and environmental determinants are possible contributory mechanisms.

Objective Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by both genes and environment. However, the environmental factors remain largely unknown. The hygiene hypothesis suggests that exposure to siblings, as a marker of exposure to microbes in early life, may protect against the development of later immune disorders. Some prior evidence suggests this may also be true for JIA. The present study was undertaken to test this hypothesis in detail. Methods We conducted a comprehensive analysis of the role of sibling exposure in JIA risk within the Childhood Arthritis Risk Factor Identification Study JIA case–hospital control sample (302 cases and 676 controls) from Victoria, Australia. Results We found that, compared to being an only child, having any siblings was protective against JIA, with an adjusted odds ratio (OR) of 0.46 (95% confidence interval [95% CI] 0.28–0.74) (P = 0.001). The protective association appeared to increase with increasing number of siblings (e.g., for ≥3 siblings, adjusted OR 0.25 [95% CI 0.13–0.48], P

Endometriosis is a debilitating condition that is categorized by the abnormal growth of endometrial tissue outside the uterus. Although the pathogenesis of this disease remains unknown, it is well established that endometriosis patients exhibit immune dysfunction. Interleukin (IL)-33 is a danger signal that is a critical regulator of chronic inflammation. Although plasma and peritoneal fluid levels of IL-33 have been associated with deep infiltrating endometriosis, its contribution to the disease pathophysiology is unknown. We investigated the role of IL-33 in the pathology of endometriosis using patient samples, cell lines and a syngeneic mouse model. We found that endometriotic lesions produce significantly higher levels of IL-33 compared to the endometrium of healthy, fertile controls. In vitro stimulation of endometrial epithelial, endothelial and endometriotic epithelial cells with IL-33 led to the production of pro-inflammatory and angiogenic cytokines. In a syngeneic mouse model of endometriosis, IL-33 injections caused systemic inflammation, which manifested as an increase in plasma pro-inflammatory cytokines compared to control mice. Furthermore, endometriotic lesions from IL-33 treated mice were highly vascularized and exhibited increased proliferation. Collectively, we provide convincing evidence that IL-33 perpetuates inflammation, angiogenesis and lesion proliferation, which are critical events in the lesion survival and progression of endometriosis.

RNA-binding proteins are key regulatory molecules involved primarily in post-transcriptional gene regulation of RNAs. Post-transcriptional gene regulation is critical for adequate cellular growth and survival. Recent reports have shown key interactions between these RNA-binding proteins and other regulatory elements, such as miRNAs and long noncoding RNAs, either enhancing or diminishing their response to RNA stabilization. Many RNA-binding proteins have been reported to play a functional role in mediation of cytokines involved in inflammation and immune dysfunction, and some have been classified as global post-transcriptional regulators of inflammation. The ubiquitous expression of RNA-binding proteins in a wide variety of cell types and their unique mechanisms of degradative action provide evidence that they are involved in reproductive tract pathologies. Aberrant inflammation and immune dysfunction are major contributors to the pathogenesis and disease pathophysiology of many reproductive pathologies, including ovarian and endometrial cancers in the female reproductive tract. Herein, we discuss various RNA-binding proteins and their unique contributions to female reproductive pathologies with a focus on those mediated by aberrant inflammation and immune dysfunction.

Introduction Endometriosis (EM) is a chronic inflammatory disease categorized by the growth of endometrial tissue on the ovaries, peritoneal wall and other internal organs. Despite it’s prevalence (176 million women worldwide), the etiology is unknown. Currently, there is a significant knowledge gap regarding how the immune microenvironment contributes to the progression of EM (specifically inflammation, pain and fibrosis). We have shown that interleukin(IL)-33 is produced by EM lesions and drives pathology in a mouse model of EM. We are now investigating, mechanistically, how IL-33 contributes to EM and whether IL-33 neutralization could alleviate the pathology. Methods Female C57BL/6 mice were induced with EM and were treated with PBS (n=10) or IL-33 (n=10) every other day. After 2 weeks, the mice were euthanized and plasma, peritoneal fluid (PF) and EM lesions were collected. Cytokines in the plasma and PF were analyzed using a multiplex array. Immune cell populations in the PF were evaluated using CyTOF. Finally, sectioned lesions were stained for markers of innervation, proliferation and fibrosis. To establish cause and effect, mice were induced with EM and treated with IL-33+anti-IL-33 antibody (n=10) or IL-33+isotype control (n=10). Results Mice treated with IL-33 had elevated cytokines (e.g. IL-5) in the plasma and PF and EM lesions exhibited drastic changes in morphology. Additionally, both innate and adaptive immune cells were altered in the PF of IL- 33 treated mice. Neutralizing IL-33 reduced inflammation and immune cell recruitment. Conclusions Overall, these results show that IL-33 drives hallmark pathologies of endometriosis and neutralization of IL-33 could provide a novel therapeutic target for EM.

Background Cerebral palsy (CP) is a common motor disability in childhood. We examined the association between maternal infections during pregnancy and the risk of congenital CP in the child.

// Jessica E. Miller 1 , Soo Hyun Ahn 1 , Stephany P. Monsanto 1 , Kasra Khalaj 1 , Madhuri Koti 1 and Chandrakant Tayade 1 1 Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario, Canada Correspondence to: Chandrakant Tayade, email: // Keywords : inflammation, cytokines, oxidative stress, infertility, endometriosis Received : September 09, 2016 Accepted : October 05, 2016 Published : October 11, 2016 Abstract Endometriosis is a complex, inflammatory disease that affects 6-10% of reproductive-aged women. Almost half of the women with endometriosis experience infertility. Despite the excessive prevalence, the pathogenesis of endometriosis and its associated infertility is unknown and a cure is not available. While many theories have been suggested to link endometriosis and infertility, a consensus among investigators has not emerged. In this extensive review of the literature as well as research from our laboratory, we provide potential insights into the role of immune dysfunction in endometriosis associated infertility. We discuss the implication of the peritoneal inflammatory microenvironment on various factors that contribute to infertility such as hormonal imbalance, oxidative stress and how these could further lead to poor oocyte, sperm and embryo quality, impaired receptivity of the endometrium and implantation failure.

Author(s): Miller, Jessica E; Molnar, Miklos Z; Kovesdy, Csaba P; Zaritsky, Joshua J; Streja, Elani; Salusky, Isidro; Arah, Onyebuchi A; Kalantar-Zadeh, Kamyar | Abstract: PurposeSeveral observational studies have indicated that vitamin D receptor activators (VDRA), including paricalcitol, are associated with greater survival in maintenance hemodialysis (MHD) patients. However, patients with higher serum parathyroid hormone, a surrogate of higher death risk, are usually given higher VDRA doses, which can lead to confounding by indication and attenuate the expected survival advantage of high VDRA doses.MethodsWe examined mortality-predictability of low (g1 but l10 µg/week) versus high (≥10 µg/week) dose of administered paricalcitol over time in a contemporary cohort of 15 442 MHD patients (age 64 ± 15 years, 55% men, 44% diabetes, 35% African-Americans) from all DaVita dialysis clinics across the USA (7/2001-6/2006 with survival follow-ups until 6/2007) using conventional Cox regression, propensity score (PS) matching, and marginal structural model (MSM) analyses.ResultsIn our conventional Cox models and PS matching models, low dose of paricalcitol was not associated with mortality either in baseline (hazard ratio (HR): 1.03, 95% confidence interval (CI): (0.97-1.09)) and (HR: 0.99, 95%CI:(0.86-1.14)) or time-dependent (HR: 1.04, 95%CI: (0.98-1.10)) and (HR: 1.12, 95%CI: (0.98-1.28)) models, respectively. In contrast, compared to high dose of paricalcitol, low dose was associated with a 26% higher risk of mortality (HR: 1.26, 95%CI: (1.19-1.35)) in MSM. The association between dose of paricalcitol and mortality was robust in almost all subgroups of patients using MSMs.ConclusionsHigher dose of paricalcitol appears causally associated with greater survival in MHD patients. Randomized controlled trials need to verify the survival effect of paricalcitol dose in MHD patients are indicated.

Background: Maternal infections during pregnancy have been associated with an increased risk for neurological outcomes in the child, including epilepsy. We examined cystitis antibiotics commonly used during pregnancy, as a marker of cystitis, and the risk of childhood epilepsy in a population-based cohort in Denmark. Methods: We examined all liveborn singletons born in Denmark between January 1996 and September 2004, identified from the Danish National Birth Registry. Epilepsy diagnoses were obtained from the Danish National Hospital Register and maternal antibiotic use from the National Register of Medicinal Product Statistics. Cystitis antibiotics consisted of pivmecillinam, sulphamethizole and nitrofurantoin. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated with Cox proportional hazard regression models. Results: The study followed 447 629 singletons for up to 9.9 years and identified 2848 children diagnosed with epilepsy. We found slightly increased risks of epilepsy in children whose mothers had redeemed prescriptions during pregnancy for pivmecillinam HR = 1.2 [95% CI 1.0, 1.4], sulphamethizole HR = 1.2 [95% CI 1.1, 1.4] or nitrofurantoin HR = 1.1 [95% CI 0.8, 1.5], compared with those unexposed. Among mothers with multiple redeemed prescriptions during pregnancy, adjusted HR were for pivmecillinam HR = 1.3 [95% CI 1.1, 1.5], sulphamethizole HR = 1.3 [95% CI 1.1, 1.5] and nitrofurantoin HR = 1.3 [95% CI 1.0, 1.8]. Conclusions: Similar magnitudes of associations between chemically different drugs, used almost exclusively to treat cystitis, may suggest an impact of maternal infection on the fetal brain. However, direct drug effects or confounding factors are also possible explanations.

Blacks have high rates of chronic kidney disease, are overrepresented among the US dialysis patients, have higher parathyroid hormone levels, but greater survival compared to nonblacks. We hypothesized that mineral and bone disorders (MBDs) have a bearing on survival advantages of black hemodialysis patients. In 139,328 thrice-weekly treated hemodialysis patients, including 32% blacks, in a large dialysis organization, where most laboratory values were measured monthly for up to 60 months (July 2001 to June 2006), we examined differences across races in measures of MBDs and survival predictabilities of these markers and administered the active vitamin D medication paricalcitol. Across each age increment, blacks had higher serum calcium and parathyroid hormone (PTH) levels and almost the same serum phosphorus and alkaline phosphatase levels and were more likely to receive injectable active vitamin D in the dialysis clinic, mostly paricalcitol, at higher doses than nonblacks. Racial differences existed in mortality predictabilities of different ranges of serum calcium, phosphorus, and PTH but not alkaline phosphatase. Blacks who received the highest dose of paricalcitol (>10 µg/week) had a demonstrable survival advantage over nonblacks (case-mix-adjusted death hazard ratio = 0.87, 95% confidence level 0.83–0.91) compared with those who received lower doses (

Background: The outcome-predictability of baseline and instantaneously changing serum calcium in hemodialysis patients has been examined. We investigated the mortality-predictability of time-averaged calcium values to reflect the ‘cumulative’ effect of calcium burden over time. Methods: We employed a Cox model using up-to-5-year (7/2001–6/2006) time-averaged values to examine the mortality-predictability of cumulative serum calcium levels in 107,200 hemodialysis patients prior to the use of calcimimetics, but during the time where other calcium-lowering interventions, including lower dialysate calcium, were employed. Results: Both low (10.0 mg/dl) calcium levels were associated with increased mortality (reference: 9.0 to 3.5 mg/dl) and PTH levels (>150 pg/ml). Higher paricalcitol doses shifted the calcium range associated with the greatest survival to the right, i.e. from 9.0 to Conclusions: Whereas in hemodialysis patients cumulatively high or low calcium levels are associated with higher death risk, subtle but meaningful interactions with phosphorus, PTH, paricalcitol dose and race exist.

Summary Background Reduced gestational age and low birthweight are associated with an increased risk of neonatal infections. However, the long-term risk of infection, especially in late preterm infants or those at near-normal birthweight, is unknown. We estimated whether rates of infection-related admissions to hospital for children in Western Australia were associated with age, gestational age, birthweight, and birth length. Methods We did a population-based, data-linkage study using total-linked, registry data from the Western Australia Birth Register of all liveborn, non-Indigenous Australian singleton births recorded from Jan 1, 1980, to Dec 31, 2010. We followed up individuals from birth-related hospital discharge to age 18 years, death, or end of 2010, and linked to data about subsequent admissions to hospital or death registrations. Gestational age was assessed from both the last menstrual period and from estimates based on ultrasonography. We categorised birthweight by 500 g bands and birth length by 5 cm bands, and approximated the reference ranges for both to the 50th percentile. Because size at birth and gestational age are strongly associated, we calculated Z scores for gestational-specific and sex-specific birthweight, birth length, and ponderal index. Our primary outcomes were the number and type of infection-related admissions to hospital. We used multilevel negative binomial regression to generate rate ratios (RR) for such admissions, identified by codes from the International Classification of Diseases, versions 9 and 10-AM. We adjusted the RRs for maternal age at delivery, birth year, birth season, parity, sex, 5-min Apgar score, delivery method, socioeconomic status, and bronchopulmonary dysplasia. Findings Of 719 311 liveborn singletons included in the analysis and followed up for 8 824 093 person-years, 365 867 infection-related admissions to hospital occurred for 213 683 (30%) children. Of the 719 311 children included in the analysis, 137 124 (19%) had one infection-related admission to hospital, 43 796 (6%) had two, 16 679 (2%) had three, and 16 084 (2%) had four or more. The 365 867 admissions to hospital included a diagnosis of infection of the upper respiratory tract for 174 653 (48%), the lower respiratory tract for 74 297 (20%), the gastrointestinal tract for 44 755 (12%), and a viral infection for 37 213 (10%). Infection-related rates of admissions to hospital increased by 12% for each week reduction in gestational age less than 39–40 weeks (RR 1·12, 95% CI 1·12–1·13), by 19% for each 500 g reduction in birthweight less than 3000–3500 g (1·19, 1·18–1·21), and by 41% for each 5 cm reduction in birth length less than 45–50 cm (1·41, 1·38–1·45). Gestational age-specific and sex-specific birthweight Z scores lower than the 25th to 50th percentile and birth length Z scores lower than the 10th to 25th percentile were associated with increased rates of infection-related admissions to hospital (eg, 1st–5th percentile RR 1·15, 95% CI 1·12–1·19, and 1·11, 1·07–1·14, respectively). Ponderal index Z scores lower than the 25th to 50th percentile were also associated with increased rates of infection-related admissions (eg, 1st–5th percentile RR 1·08, 95% CI 1·04–1·12). A gestational age of 41 weeks or later, a birthweight or birth length Z score above the 50th percentile, or a ponderal index Z score between the 75th and 95th percentile, were associated with modestly reduced rates of infection-related admissions to hospital. Interpretation Children who were born with reduced gestational age, birthweight, and birth length have persistently increased rates of infection-related admissions to hospital until age 18 years. Pregnancy outcomes should be optimised to prevent infection occurring in this population, especially in resource-limited settings where suboptimum intrauterine growth and moderate prematurity are common. Funding Australian National Health and Medical Research Council.