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To effectively inform infectious disease control strategies, accurate knowledge of the pathogen’s transmission dynamics is required. Since the timings of infections are rarely known, estimates of the infection incidence, which is crucial for understanding the transmission dynamics, often rely on measurements of other quantities amenable to surveillance. Case-based surveillance, in which infected individuals are identified by a positive test, is the predominant form of surveillance for many pathogens, and was used extensively during the COVID-19 pandemic. However, there can be many biases present in case-based surveillance indicators due to, for example test sensitivity, changing testing behaviours and the co-circulation of pathogens with similar symptom profiles. Here, we develop a mathematical description of case-based surveillance of infectious diseases. By considering realistic epidemiological parameters and situations, we demonstrate many of the potential biases in common surveillance indicators based on case-based surveillance data. Crucially, we find that many of these common surveillance indicators (e.g. case numbers, test-positive proportion) are heavily biased by circulating pathogens with similar symptom profiles. Future surveillance strategies could be designed to minimize these sources of bias and uncertainty, providing more accurate estimates of a pathogen’s transmission dynamics and, ultimately, more targeted application of public health measures.

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

To support the ongoing management of viral respiratory diseases while transitioning out of the acute phase of the COVID-19 pandemic, many countries are moving toward an integrated model of surveillance for SARS-CoV-2, influenza virus, and other respiratory pathogens. Although many surveillance approaches catalyzed by the COVID-19 pandemic provide novel epidemiologic insight, continuing them as implemented during the pandemic is unlikely to be feasible for nonemergency surveillance, and many have already been scaled back. Furthermore, given anticipated cocirculation of SARS-CoV-2 and influenza virus, surveillance activities in place before the pandemic require review and adjustment to ensure their ongoing value for public health. In this report, we highlight key challenges for the development of integrated models of surveillance. We discuss the relative strengths and limitations of different surveillance practices and studies as well as their contribution to epidemiologic assessment, forecasting, and public health decision-making.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

The time-varying reproduction number R(t) measures the number of new infections per infectious individual and is closely correlated with the time series of infection incidence by definition. The timings of actual infections are rarely known, and analysis of epidemics usually relies on time series data for other outcomes such as symptom onset. A common implicit assumption, when estimating R(t) from an epidemic time series, is that R(t) has the same relationship with these downstream outcomes as it does with the time series of incidence. However, this assumption is unlikely to be valid given that most epidemic time series are not perfect proxies of incidence. Rather they represent convolutions of incidence with uncertain delay distributions. Here we define the apparent time-varying reproduction number, RA(t), the reproduction number calculated from a downstream epidemic time series and demonstrate how differences between RA(t) and R(t) depend on the convolution function. The mean of the convolution function sets a time offset between the two signals, whilst the variance of the convolution function introduces a relative distortion between them. We present the convolution functions of epidemic time series that were available during the SARS-CoV-2 pandemic. Infection prevalence, measured by random sampling studies, presents fewer biases than other epidemic time series. Here we show that additionally the mean and variance of its convolution function were similar to that obtained from traditional surveillance based on mass-testing and could be reduced using more frequent testing, or by using stricter thresholds for positivity. Infection prevalence studies continue to be a versatile tool for tracking the temporal trends of R(t), and with additional refinements to their study protocol, will be of even greater utility during any future epidemics or pandemics.

Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

The REACT-1 study measures the community prevalence of SARS-CoV-2 in England through repeated cross-sectional surveys. Here, the authors present data from REACT-1 that document the increase in infection prevalence, particularly among children, associated with the Omicron variant in January 2022.

This study presents data from the REACT-1 SARS-CoV-2 community sampling study in England from November 2021 to March 2022. They show that the Omicron variant peaked in January with a prevalence of ~7% and that the BA.2 sublineage had a 1.5x higher reproduction number compared to other Omicron sublineages.

Abstract Background Since the emergence of SARS-CoV-2, evolutionary pressure has driven large increases in the transmissibility of the virus. However, with increasing levels of immunity through vaccination and natural infection the evolutionary pressure will switch towards immune escape. Genomic surveillance in regions of high immunity is crucial in detecting emerging variants that can more successfully navigate the immune landscape. Methods We present phylogenetic relationships and lineage dynamics within England (a country with high levels of immunity), as inferred from a random community sample of individuals who provided a self-administered throat and nose swab for rt-PCR testing as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. During round 14 (9 September–27 September 2021) and 15 (19 October–5 November 2021) lineages were determined for 1322 positive individuals, with 27.1% of those which reported their symptom status reporting no symptoms in the previous month. Results We identified 44 unique lineages, all of which were Delta or Delta sub-lineages, and found a reduction in their mutation rate over the study period. The proportion of the Delta sub-lineage AY.4.2 was increasing, with a reproduction number 15% (95% CI 8–23%) greater than the most prevalent lineage, AY.4. Further, AY.4.2 was less associated with the most predictive COVID-19 symptoms (p = 0.029) and had a reduced mutation rate (p = 0.050). Both AY.4.2 and AY.4 were found to be geographically clustered in September but this was no longer the case by late October/early November, with only the lineage AY.6 exhibiting clustering towards the South of England. Conclusions As SARS-CoV-2 moves towards endemicity and new variants emerge, genomic data obtained from random community samples can augment routine surveillance data without the potential biases introduced due to higher sampling rates of symptomatic individuals.

The relationship between prevalence of infection and severe outcomes such as hospitalisation and death changed over the course of the COVID-19 pandemic. Reliable estimates of the infection fatality ratio (IFR) and infection hospitalisation ratio (IHR) along with the time-delay between infection and hospitalisation/death can inform forecasts of the numbers/timing of severe outcomes and allow healthcare services to better prepare for periods of increased demand. The REal-time Assessment of Community Transmission-1 (REACT-1) study estimated swab positivity for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in England approximately monthly from May 2020 to March 2022. Here, we analyse the changing relationship between prevalence of swab positivity and the IFR and IHR over this period in England, using publicly available data for the daily number of deaths and hospitalisations, REACT-1 swab positivity data, time-delay models, and Bayesian P-spline models. We analyse data for all age groups together, as well as in 2 subgroups: those aged 65 and over and those aged 64 and under. Additionally, we analysed the relationship between swab positivity and daily case numbers to estimate the case ascertainment rate of England's mass testing programme. During 2020, we estimated the IFR to be 0.67% and the IHR to be 2.6%. By late 2021/early 2022, the IFR and IHR had both decreased to 0.097% and 0.76%, respectively. The average case ascertainment rate over the entire duration of the study was estimated to be 36.1%, but there was some significant variation in continuous estimates of the case ascertainment rate. Continuous estimates of the IFR and IHR of the virus were observed to increase during the periods of Alpha and Delta's emergence. During periods of vaccination rollout, and the emergence of the Omicron variant, the IFR and IHR decreased. During 2020, we estimated a time-lag of 19 days between hospitalisation and swab positivity, and 26 days between deaths and swab positivity. By late 2021/early 2022, these time-lags had decreased to 7 days for hospitalisations and 18 days for deaths. Even though many populations have high levels of immunity to SARS-CoV-2 from vaccination and natural infection, waning of immunity and variant emergence will continue to be an upwards pressure on the IHR and IFR. As investments in community surveillance of SARS-CoV-2 infection are scaled back, alternative methods are required to accurately track the ever-changing relationship between infection, hospitalisation, and death and hence provide vital information for healthcare provision and utilisation.

BackgroundFollowing rapidly rising COVID-19 case numbers, England entered a national lockdown on 6 January 2021, with staged relaxations of restrictions from 8 March 2021 onwards.AimWe characterise how the lockdown and subsequent easing of restrictions affected trends in SARS-CoV-2 infection prevalence.MethodsOn average, risk of infection is proportional to infection prevalence. The REal-time Assessment of Community Transmission-1 (REACT-1) study is a repeat cross-sectional study of over 98,000 people every round (rounds approximately monthly) that estimates infection prevalence in England. We used Bayesian P-splines to estimate prevalence and the time-varying reproduction number (Rt) nationally, regionally and by age group from round 8 (beginning 6 January 2021) to round 13 (ending 12 July 2021) of REACT-1. As a comparator, a separate segmented-exponential model was used to quantify the impact on Rt of each relaxation of restrictions.ResultsFollowing an initial plateau of 1.54% until mid-January, infection prevalence decreased until 13 May when it reached a minimum of 0.09%, before increasing until the end of the study to 0.76%. Following the first easing of restrictions, which included schools reopening, the reproduction number Rt increased by 82% (55%, 108%), but then decreased by 61% (82%, 53%) at the second easing of restrictions, which was timed to match the Easter school holidays. Following further relaxations of restrictions, the observed Rt increased steadily, though the increase due to these restrictions being relaxed was offset by the effects of vaccination and also affected by the rapid rise of Delta. There was a high degree of synchrony in the temporal patterns of prevalence between regions and age groups.ConclusionHigh-resolution prevalence data fitted to P-splines allowed us to show that the lockdown was effective at reducing risk of infection with school holidays/closures playing a significant part.

Summary: Background: The Omicron wave of COVID-19 in England peaked in January 2022 resulting from the rapid transmission of the Omicron BA.1 variant. We investigate the spread and dynamics of the SARS-CoV-2 epidemic in the population of England during February 2022, by region, age and main SARS-CoV-2 sub-lineage. Methods: In the REal-time Assessment of Community Transmission-1 (REACT-1) study we obtained data from a random sample of 94,950 participants with valid throat and nose swab results by RT-PCR during round 18 (8 February to 1 March 2022). Findings: We estimated a weighted mean SARS-CoV-2 prevalence of 2.88% (95% credible interval [CrI] 2.76–3.00), with a within-round effective reproduction number (R) overall of 0.94 (0·91–0.96). While within-round weighted prevalence fell among children (aged 5 to 17 years) and adults aged 18 to 54 years, we observed a level or increasing weighted prevalence among those aged 55 years and older with an R of 1.04 (1.00–1.09). Among 1,616 positive samples with sublineages determined, one (0.1% [0.0–0.3]) corresponded to XE BA.1/BA.2 recombinant and the remainder were Omicron: N=1047, 64.8% (62.4–67.2) were BA.1; N=568, 35.2% (32.8–37.6) were BA.2. We estimated an R additive advantage for BA.2 (vs BA.1) of 0.38 (0.34–0.41). The highest proportion of BA.2 among positives was found in London. Interpretation: In February 2022, infection prevalence in England remained high with level or increasing rates of infection in older people and an uptick in hospitalisations. Ongoing surveillance of both survey and hospitalisations data is required. Funding: Department of Health and Social Care, England.

The time-varying reproduction number (Rt) can change rapidly over the course of a pandemic due to changing restrictions, behaviours, and levels of population immunity. Many methods exist that allow the estimation of Rtfrom case data. However, these are not easily adapted to point prevalence data nor can they infer Rtacross periods of missing data. We developed a Bayesian P-spline model suitable for fitting to a wide range of epidemic time-series, including point-prevalence data. We demonstrate the utility of the model by fitting to periodic daily SARS-CoV-2 swab-positivity data in England from the first 7 rounds (May 2020–December 2020) of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Estimates of Rtover the period of two subsequent rounds (6–8 weeks) and single rounds (2–3 weeks) inferred using the Bayesian P-spline model were broadly consistent with estimates from a simple exponential model, with overlapping credible intervals. However, there were sometimes substantial differences in point estimates. The Bayesian P-spline model was further able to infer changes in Rtover shorter periods tracking a temporary increase above one during late-May 2020, a gradual increase in Rtover the summer of 2020 as restrictions were eased, and a reduction in Rtduring England’s second national lockdown followed by an increase as the Alpha variant surged. The model is robust against both under-fitting and over-fitting and is able to interpolate between periods of available data; it is a particularly versatile model when growth rate can change over small timescales, as in the current SARS-CoV-2 pandemic. This work highlights the importance of pairing robust methods with representative samples to track pandemics.

Summary: Background: Prevalence of SARS-CoV-2 infection with Delta variant was increasing in England in late summer 2021 among children aged 5 to 17 years, and adults who had received two vaccine doses. In September 2021, a third (booster) dose was offered to vaccinated adults aged 50 years and over, vulnerable adults and healthcare/care-home workers, and a single vaccine dose already offered to 16 and 17 year-olds was extended to children aged 12 to 15 years. Methods: SARS-CoV-2 community prevalence in England was available from self-administered throat and nose swabs using reverse transcriptase polymerase chain reaction (RT-PCR) in round 13 (24 June to 12 July 2021, N = 98,233), round 14 (9 to 27 September 2021, N = 100,527) and round 15 (19 October to 5 November 2021, N = 100,112) from the REACT-1 study randomised community surveys. Linking to National Health Service (NHS) vaccination data for consenting participants, we estimated vaccine effectiveness in children aged 12 to 17 years and compared swab-positivity rates in adults who received a third dose with those who received two doses. Findings: Weighted SARS-CoV-2 prevalence was 1.57% (1.48%, 1.66%) in round 15 compared with 0.83% (0.76%, 0.89%) in round 14, and the previously observed link between infections and hospitalisations and deaths had weakened. Vaccine effectiveness against infection in children aged 12 to 17 years was estimated (round 15) at 64.0% (50.9%, 70.6%) and 67.7% (53.8%, 77.5%) for symptomatic infections. Adults who received a third vaccine dose were less likely to test positive compared to those who received two doses, with adjusted OR of 0.36 (0.25, 0.53). Interpretation: Vaccination of children aged 12 to 17 years and third (booster) doses in adults were effective at reducing infection risk. High rates of vaccination, including booster doses, are a key part of the strategy to reduce infection rates in the community. Funding: Department of Health and Social Care, England.

Abstract Interpersonal difficulties are often implicated in the onset of depressive disorders, and typically exacerbate depressive symptoms. This is particularly true for young people, given rapid changes in, and the increased importance of, their social relationships. The purpose of this narrative review was to identify empirically supported interventions that aim to prevent or treat depression in young people by facilitating improvements in their social environment. We conducted a search of controlled trials, systematic reviews and meta-analyses of such interventions, published between 1980 and June 2020. Our literature search and interpretation of results was informed by consultations with clinical experts and youth consumers and advocates. A number of promising approaches were identified with respect to prevention and treatment. Preliminary evidence was identified suggesting that school- and Internet-based approaches present a viable means to prevent the worsening of depressive symptoms in young people. Notably, delivering interpersonal psychotherapy—adolescent skills training (IPT-AST) in schools appears to be a promising early intervention strategy for young people at risk of full-threshold depressive disorder. In terms of treating depressive disorders in young people, there is strong evidence for the efficacy of interpersonal psychotherapy for adolescents (IPT-A), and preliminary evidence in favour of attachment-based family therapy (ABFT). Results are discussed with respect to recommendations for future research and practice.

BackgroundRapid detection, isolation, and contact tracing of community COVID-19 cases are essential measures to limit the community spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to identify a parsimonious set of symptoms that jointly predict COVID-19 and investigated whether predictive symptoms differ between the B.1.1.7 (Alpha) lineage (predominating as of April 2021 in the US, UK, and elsewhere) and wild type.Methods and findingsWe obtained throat and nose swabs with valid SARS-CoV-2 PCR test results from 1,147,370 volunteers aged 5 years and above (6,450 positive cases) in the REal-time Assessment of Community Transmission-1 (REACT-1) study. This study involved repeated community-based random surveys of prevalence in England (study rounds 2 to 8, June 2020 to January 2021, response rates 22%-27%). Participants were asked about symptoms occurring in the week prior to testing. Viral genome sequencing was carried out for PCR-positive samples with N-gene cycle threshold value < 34 (N = 1,079) in round 8 (January 2021). In univariate analysis, all 26 surveyed symptoms were associated with PCR positivity compared with non-symptomatic people. Stability selection (1,000 penalized logistic regression models with 50% subsampling) among people reporting at least 1 symptom identified 7 symptoms as jointly and positively predictive of PCR positivity in rounds 2-7 (June to December 2020): loss or change of sense of smell, loss or change of sense of taste, fever, new persistent cough, chills, appetite loss, and muscle aches. The resulting model (rounds 2-7) predicted PCR positivity in round 8 with area under the curve (AUC) of 0.77. The same 7 symptoms were selected as jointly predictive of B.1.1.7 infection in round 8, although when comparing B.1.1.7 with wild type, new persistent cough and sore throat were more predictive of B.1.1.7 infection while loss or change of sense of smell was more predictive of the wild type. The main limitations of our study are (i) potential participation bias despite random sampling of named individuals from the National Health Service register and weighting designed to achieve a representative sample of the population of England and (ii) the necessary reliance on self-reported symptoms, which may be prone to recall bias and may therefore lead to biased estimates of symptom prevalence in England.ConclusionsWhere testing capacity is limited, it is important to use tests in the most efficient way possible. We identified a set of 7 symptoms that, when considered together, maximize detection of COVID-19 in the community, including infection with the B.1.1.7 lineage.

Background: Since early March 2020, the COVID-19 epidemic across the United Kingdom has led to a range of social distancing policies, which have resulted in reduced mobility across different regions. Crowd level data on mobile phone usage can be used as a proxy for actual population mobility patterns and provide a way of quantifying the impact of social distancing measures on changes in mobility. Methods: Here, we use two mobile phone-based datasets (anonymised and aggregated crowd level data from O2 and from the Facebook app on mobile phones) to assess changes in average mobility, both overall and broken down into high and low population density areas, and changes in the distribution of journey lengths. Results: We show that there was a substantial overall reduction in mobility, with the most rapid decline on the 24th March 2020, the day after the Prime Minister’s announcement of an enforced lockdown. The reduction in mobility was highly synchronized across the UK. Although mobility has remained low since 26th March 2020, we detect a gradual increase since that time. We also show that the two different datasets produce similar trends, albeit with some location-specific differences. We see slightly larger reductions in average mobility in high-density areas than in low-density areas, with greater variation in mobility in the high-density areas: some high-density areas eliminated almost all mobility. Conclusions: These analyses form a baseline from which to observe changes in behaviour in the UK as social distancing is eased and inform policy towards the future control of SARS-CoV-2 in the UK.

Green products are appealing. Thus, labeling products as environmentally friendly is an effective strategy to increase sales. However, the labels often promise more than the products can actually deliver. In the present research, we examined the expectation that consumers with high ecological motivation have strong preferences for green-labeled products – even when presented product information contradicts the label’s image. This unsettling hypothesis is grounded in the labels’ potential to create a cognitive match between the labeled product and consumers’ motives. For labels indicating environmental friendliness (green product labels), this link should be strongest when consumers’ ecological motivation is high. Findings in a series of three experiments support our assumption, showing that consumers with high ecological motivation had strong preferences (i.e. product evaluations, purchase intentions, and simulated purchase decisions) for green-labeled products as compared to consumers with low ecological motivation (Studies 1-3). Crucially, these preferences were robust, despite contradicting environmental product information (Studies 1 and 2). We extended our findings by additionally examining the impact of product labels and motivation on moral self-regulation processes. This was established by assessing participants’ pro-social behavior after the purchase task: participants with high ecological motivation acted, consistent with their motives, more pro-socially in post-decision occasions. In accordance with moral cleansing effects, pro-social behavior was intensified after purchasing conventional products (Studies 2 and 3). Green labels protected participants with high ecological motivation from moral threats due to the purchase, thus making pro-social behavior less likely. Findings suggest that highly ecologically motivated consumers are most susceptible to green labels, which may override detailed product information.

Background: A portion of obstetrical randomized clinical trials registered on ClinicalTrials.gov are not published in peer-reviewed journals., Objective: This study aimed to compare the characteristics of completed published vs unpublished randomized clinical trials in obstetrics registered on ClinicalTrials.gov and to identify barriers to publication., Study Design: This cross-sectional study queried ClinicalTrials.gov for all completed obstetrical randomized clinical trials registered between January 1, 2009, and December 31, 2018. For each completed obstetrical randomized clinical trial, we abstracted the following registration fields from ClinicalTrials.gov: ClinicalTrials.gov identifier, recruitment status, trial start and completion dates, study results, type of intervention, study phase, enrollment size, funder type, location, and facilities. Calculated variables included time to completion. In May 2021, we used PubMed and Google Scholar to identify the publication status of completed trials, and we compared the characteristics of published vs unpublished randomized clinical trials. The corresponding authors' e-mail addresses for the unpublished studies were collected from ClinicalTrials.gov and departmental websites. Between September 2021 and March 2022, the authors of these completed but unpublished obstetrical randomized clinical trials were contacted and invited to respond to a survey examining perceptions of barriers to publication, responses of which were collected and presented as counts and percentages., Results: Of the 647 obstetrical randomized clinical trials marked as completed on ClinicalTrials.gov, 378 (58%) were published, and 269 (42%) were unpublished. Unpublished trials were more likely to have an enrollment size of <50 participants (14.5% published vs 25.3% unpublished; P<.001) and less likely to be conducted at multiple sites (25.4% published vs 17.5% unpublished; P<.02). The main barriers to publication reported in the survey by authors whose trials were not published included lack of time (30%), change in employment or completion of training (25%), and results that were not of statistical significance (15%)., Conclusion: Among the obstetrical randomized clinical trials registered and marked as completed on ClinicalTrials.gov, more than 40% were unpublished. Unpublished trials were more likely to be smaller studies, conducted by researchers who reported experiencing a lack of time as the most common barrier to study publication., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To compare stillbirth rates per week of expectant management stratified by birth weight in pregnancies complicated by gestational diabetes mellitus (GDM) or pregestational diabetes mellitus., Methods: A national population-based retrospective cohort study of singleton, nonanomalous pregnancies complicated by pregestational diabetes or GDM was performed using national birth and death certificate data from 2014 to 2017. Stillbirth rates per 10,000 patients (stillbirth incidence at gestational age week/ongoing pregnancies-[0.5×live births at gestational age week]) were determined for each week of pregnancy from 34 to 39 completed weeks of gestation. Pregnancies were stratified by birth weight, categorized as having small-for-gestational-age (SGA), appropriate-for-gestational-age (AGA), or large-for-gestational-age (LGA) fetuses, assigned by sex-based Fenton criteria. Relative risk (RR) and 95% CI for stillbirth were calculated for each gestational age week compared with the GDM-related AGA group., Results: We included 834,631 pregnancies complicated by either GDM (86.9%) or pregestational diabetes (13.1%) in the analysis, with a total of 3,033 stillbirths. Stillbirth rates increased with advancing gestational age for pregnancies complicated by both GDM and pregestational diabetes regardless of birth weight. Compared with pregnancies with AGA fetuses, those with both SGA and LGA fetuses were significantly associated with an increased risk of stillbirth at all gestational ages. Ongoing pregnancies at 37 weeks of gestation complicated by pregestational diabetes with LGA or SGA fetuses had respective stillbirth rates of 64.9 and 40.1 per 10,000 patients. Pregnancies complicated by pregestational diabetes had an RR of stillbirth of 21.8 (95% CI 17.4-27.2) for LGA fetuses and 13.5 (95% CI 8.5-21.2) for SGA fetuses compared with GDM-related AGA at 37 weeks of gestation. The greatest absolute risk of stillbirth was in pregnancies complicated by pregestational diabetes at 39 weeks of gestation with LGA fetuses (97/10,000)., Conclusion: Pregnancies complicated by both GDM and pregestational diabetes affected by pathologic fetal growth have an increased risk of stillbirth with advancing gestational age. This risk is significantly higher with pregestational diabetes, especially pregestational diabetes with LGA fetuses., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To identify rates of fetal autopsy in the United States as well as demographic and clinical characteristics related to consent to autopsy after stillbirth., Methods: This is a population-based retrospective cohort study using U.S. fetal death certificates for stillborn fetuses (20 weeks of gestation or more) delivered between January 2014 and December 2016. Multiple gestations were excluded. Fetal autopsy rates were calculated by gestational age, maternal age, self-reported race and ethnicity, education, and having at least one living child. Multivariate logistic regression to adjust for potential confounders was performed., Results: There were 60,328 stillbirths meeting inclusion criteria. Overall, fetal autopsy was performed in 20.9% of stillbirths. Non-Hispanic Black women had the highest rate of fetal autopsy (22.9%, 95% CI 22.3-23.6%), compared with non-Hispanic White women (20.4%, 95% CI 20.0-20.9%) and Hispanic women (19.6%, 95% CI 19.0-20.3%) ( P &lt;.001). After adjusting for potential confounders, maternal non-Hispanic Black race (adjusted odds ratio [aOR] 1.22, 95% CI 1.16-1.29), higher education (graduate degree: aOR 1.62, 95% CI 1.47-1.79), and higher gestational age (term: aOR 2.08, 95% CI 1.95-2.23) were associated with increased aORs for fetal autopsy. Maternal age 40 years or older (aOR 0.77 95% CI 0.63-0.92) and having at least one living child (aOR 0.74, 95% CI 0.71-0.78) were associated with a decreased aOR of having a fetal autopsy. Women of American Indian or Alaska Native decent had decreased uptake of fetal autopsy compared with non-Hispanic White women (aOR 0.72, 95% CI 0.58-0.90)., Conclusion: Fetal autopsy rates are low throughout the United States. The reasons for low autopsy rates warrant further exploration to inform strategies to increase availability and uptake., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Initial studies on COVID-19 in pregnancy have demonstrated a range of neutralizing activity, but little has been published on the full profile of SARS CoV-2 related antibodies in maternal and cordblood., Objective: This study aimed to describe the profile and specificity of maternal and neonatal cord blood antibody profiles in response to SARS-CoV-2 virus exposure., Study Design: This was a prospective cohort study of delivering patients at Thomas Jefferson University Hospital from April 2020 to February 2021. The primary objective was to describe unique maternal and fetal antibody epitope titers and specificity in patients with COVID-19 history. Serologic profile was assessed with a multiplex platform. Antigens used were hemagglutinin trimer influenza A (Hong Kong H3); spike trimers for SARS-CoV-2, SARS-CoV-1, Middle East respiratory syndrome coronavirus, and betacoronaviruses HKU-1 and OC43; and spike N-terminal domain, spike receptor-binding domain, and nucleocapsid protein (full length) for SARS-CoV-2., Results: Here, 112 maternal samples and 101 maternal and cord blood pairs were analyzed. Of note, 37 patients had a known history of COVID-19 (positive polymerase chain reaction test) during pregnancy. Of 36 patients, 16 (44%) were diagnosed with COVID-19 within 7 days of delivery. Moreover, 15 of the remaining 76 patients (20%) without a known diagnosis had positive maternal serology. For those with a history of COVID-19, we identified robust immunoglobulin G response in maternal blood to CoV-2 nucleocapsid, spike (full length), and spike (receptor-binding domain) antigens with more modest responses to the spike (N-terminal domain) antigen. In contrast, the maternal blood immunoglobulin M response seemed more specific to spike (full length) epitopes than nucleocapsid, spike (receptor-binding domain), or spike (N-terminal domain) epitopes. There were significantly higher maternal and cord blood immunoglobulin G responses not only to CoV-2 spike (127.1-fold; standard deviation, 2.0; P <.00001) but also to CoV-1 spike (21.1-fold higher; standard deviation, 1.8; P <.00001) and Middle East respiratory syndrome spike (6.9-fold higher; standard deviation, 2.5; P <.00001). In contrast, maternal immunoglobulin M responses were more specific to CoV-2 spike (15.8-fold; standard deviation, 2.1; P <.00001) but less specific to CoV-1 (2.5-fold higher; standard deviation, 0.71; P <.00001) and no significant difference for Middle East respiratory syndrome. Maternal and cord blood immunoglobulin G antibodies were highly correlated for both spike and nucleocapsid (R 2 =0.96 and 0.94, respectively)., Conclusion: Placental transfer was efficient, with robust nucleocapsid and spike responses. Both nucleocapsid and spike antibody responses should be studied for a better understanding of COVID-19 immunity. Immunoglobulin G antibodies were cross-reactive with related CoV-1 and Middle East respiratory syndrome spike epitopes, whereas immunoglobulin M antibodies, which cannot cross the placenta to provide neonatal passive immunity, were more SARS-CoV-2 specific. Neonatal cord blood may have significantly different fine specificity than maternal blood, despite the high efficiency of immunoglobulin G transfer., (© 2021 The Authors.)

Objective: Our objective was to evaluate the compliance with a patient-safety bundle for placenta accreta spectrum (PAS) by comparing the implementation of the components of the patient-safety bundle in the pre- and post-protocol time periods as a quality improvement project., Study Design: This is a before and after retrospective cohort study as a quality improvement report examining compliance with a multidisciplinary delivery approach for patients with suspected PAS between 2007 and 2018. This bundle involved a multidisciplinary approach with maternal-fetal medicine, gynecologic oncology, intervention radiology, obstetric anesthesia, neonatology, and blood bank. The primary outcome was incorporation of all six of the components of the bundle into a PAS procedure: (1) betamethasone, (2) gynecologic oncology intraoperative consult, (3) preoperative balloon catheters, (4) cell salvage technology in the operating room, (5) vertical skin incision, and (6) fundal or high transverse hysterotomy. Demographic, delivery, and patient outcome data were also collected., Results: There were 39 patients included in the study, 17 were pre-protocol and 22 were post-protocol. Patients were more likely to have a PAS suspected in the antenatal period during post protocol period (23.5 versus 90.9%, p  < .0001), as well as having a placenta previa (35.3 versus 81.8%, p  = .003), and receive betamethasone prior to delivery (23.5 versus 86.3%, p  < .0001). Patients were delivered at an earlier gestational age in post protocol period (36.8 ± 2.52 versus 33.87 ± 2.4, p  = .001). The primary outcome, adherence to all components of the patient-safety bundle, was more likely to occur in the post protocol period (0 versus 40.9%, p  < .0001). Maternal and postoperative outcomes were not significantly different between groups., Conclusions: We have successfully implemented a patient-safety bundle for PAS and have standardized the execution of multidisciplinary management for PAS at our institution.

Objective: To investigate the association between meconium-stained amniotic fluid (MSAF) and postcesarean surgical site infections., Methods: This was a secondary analysis of the Maternal-Fetal Medicine Units Network (MFMU) Cesarean Registry. Women with a singleton pregnancy attempting labor or induction of labor, who ultimately had a cesarean delivery, were included in the study. Pregnancies complicated by MSAF ( n  = 4262) and those who did not have MSAF ( n  = 13,850) were compared. The primary outcome was the incidence of SSI., Results: A total of 18,112 patients were included in the study. 4262 (38%) had meconium-stained amniotic fluid. After accounting for potential confounders in a multivariable logistic regression, meconium-stained amniotic fluid was associated with an increased risk of postoperative surgical site infection (odds ratio 1.16, 95% CI 1.03-1.30)., Conclusions: Meconium-stained amniotic fluid may be associated with an increased risk of postoperative surgical site infection.

Objective: This study aimed to compare neonatal outcomes for delivery at 36 weeks compared with 37 weeks in women with prior classical cesarean delivery (CCD)., Study Design: This was a secondary analysis of the prospective observational cohort of the Eunice Kennedy National Institute for Child and Human Development's Maternal-Fetal Medicine Unit Network Cesarean Registry. Data on cases of repeat cesarean delivery (RCD) in the setting of a prior CCD were abstracted and used for analysis. This study compared outcomes of women who delivered at 36 0/7 to 36 6/7 versus 37 0/7 to 37 6/7 weeks. The primary outcome was a composite of adverse neonatal outcomes that included neonatal intensive care unit (NICU) admission, respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), hypoglycemia, mechanical ventilation, sepsis, length of stay ≥5 days, and neonatal death. A composite of maternal outcomes that included uterine rupture, blood transfusion, general anesthesia, cesarean hysterectomy, venous thromboembolism, maternal sepsis, intensive care unit admission, and surgical complications was also evaluated., Results: There were 436 patients included in the analysis. Women who delivered at 36 weeks ( n  = 176) were compared those who delivered at 37 weeks ( n  = 260). There were no differences in baseline characteristics. Delivery at 37 weeks was associated with a reduction in composite neonatal morbidity (24 vs. 34%, adjusted odds ratio [aOR] = 0.61 [0.31-0.94]), including a decrease in NICU admission rates (20 vs. 29%, aOR = 0.63 [0.40-0.99]), hospitalization ≥5 days (13 vs. 24%, aOR = 0.48 [0.29-0.8]), and RDS or TTN (9 vs. 19%, aOR = 0.43 [0.24-0.77]). There was no difference in adverse maternal outcomes (7 vs. 7%, aOR = 0.98 [0.46-2.09])., Conclusion: Delivery at 37 weeks for women with a history of prior CCD is associated with a decrease in adverse neonatal outcomes, compared with delivery at 36 weeks., Key Points: · Classical cesarean section may have increased risk of uterine rupture in future pregnancies.. · This study compares outcomes of delivery at 370/7 to 376/7 versus 360/7 to 366/7 weeks.. · Delivery at 370/7 to 376/7 weeks was associated with decreased neonatal morbidity.., Competing Interests: None declared., (Thieme. All rights reserved.)

Obstetric anal sphincter injuries (OASIS) are one of the most common causes of anal incontinence (AI) in women of reproductive age and can have a significant impact on quality of life. However, many women do not report symptoms to their physicians because of embarrassment and shame. Therefore, prevention and diagnosis of the tear is essential. Diagnostic strategies have evolved considerably in recent years, with an increase in prevalence of OASIS as a consequence. The use of 3D endoanal (3D-EAUS) and 4D transperineal ultrasound (4D-TPUS), in addition to standard clinical examination have enhanced the detection of OASIS. Once identified, adequate repair by a skilled practitioner and optimal postpartum management should be ensured in order to reduce the risk of anal incontinence. This review presents the available evidence on strategies for prevention, diagnosis, and management of OASIS.

Objectives: To compare cholecystectomy (CCY) and nonoperative treatment (no-CCY) for acute cholecystitis in pregnancy., Summary of Background Data: Current Society of Gastrointestinal and Endoscopic Surgery guidelines recommend CCY over nonoperative management of acute cholecystitis during pregnancy, and the American College of Obstetricians and Gynecologists recommend medically necessary surgery regardless of trimester. This approach has been recently questioned., Methods: Pregnant women admitted with acute cholecystitis were identified using the Nationwide Readmission Database 2010-2015. Propensity-score adjusted logistic regression models were used to compare CCY and no-CCY. The primary outcome was a composite measure of adverse maternal-fetal outcomes (intrauterine death/stillbirth, poor fetal growth, abortion, preterm delivery, C-section, obstetric bleeding, infection of the amniotic fluid, venous thromboembolism)., Results: There were 6390 pregnant women with acute cholecystitis: 38.2% underwent CCY, of which 5.1% were open. Patients were more likely to be managed operatively in their second trimester (First 43.9%, Second 59.1%, Third 34.2%; P < 0.01). Patients managed with CCY did not differ in age, insurance, income, Charlson Comorbidity Index, diabetes or obesity when compared to no-CCY (all P > 0.05), but were less likely to have a previous C-section, gestational diabetes, preeclampsia/eclampsia or be in the third trimester (P ≤ 0.01). Risk-adjusted analyses showed that no-CCY was associated with significantly increased maternal-fetal complications during the index admission [odds ratio 3.0 (95% confidence interval 2.08-4.34), P < 0.01] and 30-day readmissions [odds ratio 1.61 (confidence interval % CI 1.12-2.32), P < 0.01]., Conclusions: Contrary to current guidelines, most pregnant women admitted in the US with acute cholecystitis are managed nonoperatively. This is associated with over twice the odds of maternal-fetal complications in addition to increased readmissions., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

This document addresses the current coronavirus disease 2019 (COVID-19) pandemic for providers and patients in labor and delivery (L&D). The goals are to provide guidance regarding methods to appropriately screen and test pregnant patients for COVID-19 prior to, and at admission to L&D reduce risk of maternal and neonatal COVID-19 disease through minimizing hospital contact and appropriate isolation; and provide specific guidance for management of L&D of the COVID-19-positive woman, as well as the critically ill COVID-19-positive woman. The first 5 sections deal with L&D issues in general, for all women, during the COVID-19 pandemic. These include Section 1: Appropriate screening, testing, and preparation of pregnant women for COVID-19 before visit and/or admission to L&D Section 2: Screening of patients coming to L&D triage; Section 3: General changes to routine L&D work flow; Section 4: Intrapartum care; Section 5: Postpartum care; Section 6 deals with special care for the COVID-19-positive or suspected pregnant woman in L&D and Section 7 deals with the COVID-19-positive/suspected woman who is critically ill. These are suggestions, which can be adapted to local needs and capabilities., (© 2020 Elsevier Inc. All rights reserved.)

Objective: To assess the association of fetal movement counting with perinatal mortality., Data Sources: Electronic databases (ie, MEDLINE, ClinicalTrials.gov, ScienceDirect, the Cochrane Library at the CENTRAL Register of Controlled Trials) were searched from inception until May 2019. Search terms used were: "fetal movement," "fetal movement counting," "fetal kick counting," "stillbirth," "fetal demise," "fetal mortality," and "perinatal death.", Methods of Study Selection: We included all randomized controlled trials comparing perinatal mortality in those women randomized to receive instructions for fetal movement counting compared with a control group of women without such instruction., Tabulation, Integration and Results: The primary outcome was perinatal mortality. Five of 1,290 identified articles were included, with 468,601 fetuses. Definitions of decreased fetal movement varied. In four of five studies, women in the intervention group were asked to contact their health care providers if they perceived decreased fetal movement; the fifth study did not provide details. Reported reduction in fetal movement usually resulted in electronic fetal monitoring and ultrasound assessment of fetal well-being. There was no difference in the incidence of perinatal outcome between groups. The incidence of perinatal death was 0.54% (1,252/229,943) in the fetal movement counting group and 0.59% (944/159,755) in the control group (relative risk [RR] 0.92, 95% CI 0.85-1.00). There were no statistical differences for other perinatal outcomes as stillbirths, neonatal deaths, birth weight less than 10th percentile, reported decreased fetal movement, 5-minute Apgar score less than 7, neonatal intensive care unit admission or perinatal morbidity. There were weak but significant increases in preterm delivery (7.6% vs 7.1%; RR 1.07, 95% CI 1.05-1.10), induction of labor (36.6% vs 31.6%; RR 1.15, 95% CI 1.09-1.22), and cesarean delivery (28.2% vs 25.3%; RR 1.11, 95% CI 1.10-1.12)., Conclusion: Instructing pregnant women on fetal movement counting compared with no instruction is not associated with a clear improvement in pregnancy outcomes. There are weak associations with some secondary outcomes such as preterm delivery, induction of labor, and cesarean delivery., Systematic Review Registration: PROSPERO, CRD42019123264.

Objective: To investigate whether women using intravaginal progesterone suppositories for preterm birth prevention during pregnancy will have lower rates of group B streptococcus (GBS) colonisation at term, compared with women receiving intramuscular 17-alpha-hydroxyprogesterone caproate., Design: This was a retrospective observational cohort study of women who were prescribed a progestogen during their pregnancy for preterm birth prevention, and who delivered at term., Setting: A tertiary referral hospital in central Ohio., Population: Patients who were prescribed a progestogen during their pregnancy for preterm birth prevention between 2004 and 2017 were included in the study. Patients who delivered at <37 weeks of pregnancy, switched progestogen type during the pregnancy, or had a pessary or cerclage placed were excluded., Methods: Baseline characteristics were compared using Mann-Whitney U-test or Chi-square test as appropriate. The association between type of progestogen and GBS colonisation was assessed using bivariate and multivariable analyses., Main Outcome Measures: The primary outcome was GBS colonisation., Results: In all, 565 patients were included in the study, of whom 173 received intravaginal progesterone, and 392 17-alpha-hydroxyprogesterone caproate. Patients receiving intravaginal progesterone were less likely to be colonised with GBS (19.7 versus 28.1%). After adjustments for potential confounders were made in a multivariable logistic regression analysis, receiving intravaginal progesterone suppositories (adjusted odds ratio [OR] 0.61, 95% CI 0.39-0.95) was associated with reduced GBS colonisation., Conclusions: Intravaginal progesterone is associated with a decreased prevalence of rectovaginal GBS colonisation at term., Tweetable Abstract: Vaginal progesterone is associated with a lower incidence of rectovaginal GBS colonisation, compared with 17α-hydroxyprogesterone caproate., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Preterm prelabor rupture of membranes (PPROM), which can precede or follow intra-amniotic infection/inflammation (IAI), is a poorly understood pregnancy complication. Tenascin-X (TNX) is a connective tissue extracellular matrix protein that regulates fibrillogenesis of collagens I, III, and V. Our goal was to investigate the presence and level of soluble TNX (sTNX) in amniotic fluid (AF) and TNX expression in reproductive tissues of pregnancies complicated by PPROM and IAI. We prospectively recruited 334 women pregnant with singletons who had a clinically indicated amniocentesis for genetic karyotyping, lung maturity testing, or rule-out IAI in the presence or absence of PPROM. We quantified TNX expression in fetal membranes, myometrium, cervix, and placenta using immunological methods and qRT-PCR. In pregnancies with normal outcomes, AF sTNX levels were GA-regulated with lower levels toward term. IAI significantly upregulated AF sTNX levels independent of membrane status. AF sTNX levels inversely correlated with fetal membranes tenascin XB (TNXB) mRNA level, which was significantly downregulated by IAI. Western blotting identified characteristic ∼75 and ∼140 kDa sTNX forms in both AF and fetal membranes. Fetal membranes, placenta, and cervix constitutively express TNX with the highest abundance in the amnion. Amnion TNX richness is significantly lost in the setting of IAI. Our results suggest that fetal membranes may be a source of AF sTNX whereby protein and mRNA expression seem to be significantly impacted by inflammation independent of fetal membrane status. A more thorough understanding of TNX changes may be valuable for understanding spontaneous PPROM and to potentially develop therapeutic targets., (© The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)

Objective: To compare preterm birth rates and gestational length in four race-nativity groups including Somali Americans., Methods: Using a retrospective cohort study design of Ohio birth certificates, we analyzed all singleton births between 2000 and 2015 from four groups of women categorized as U.S.-born, non-Hispanic white (USBW), U.S.-born, non-Hispanic black (USBB), African-born black (ABB, primarily of West African birth country), and Somalia-born (SB). An algorithm trained on maternal names was used to confirm Somali ethnicity. Gestational length was analyzed as completed weeks or aggregated by clinically relevant periods. Risk of spontaneous and health care provider-initiated preterm birth was calculated in a competing risk model., Results: Births to women in the designated groups accounted for 1,960,693 births (USBW n=1,638,219; USBB n=303,028; ABB n=10,966, and SB n=8,480). Women in the SB group had a lower preterm birth rate (5.9%) compared with women in the USBB (13.0%), ABB (8.4%), and USBW (7.9%) groups (P<.001). Women in the SB group had a higher frequency of postterm pregnancy (5.8% vs less than 1%, P<.001 for all groups). The lower rate of preterm birth in the SB group was unrelated to differences in parity or smoking or whether preterm birth was spontaneous or health care provider-initiated. The lower rate of preterm birth and tendency for prolonged gestation was attenuated in ethnic Somali women born outside Somalia., Conclusion: We report a positive disparity in preterm birth and a tendency for prolonged gestation for ethnic Somali women in Ohio. Etiologic studies in multiethnic cohorts aimed to uncover the sociobiological determinants of gestational length may lead to practical approaches to reduce prematurity in the general population.

Objective  To evaluate current patterns in empiric antibiotic use for early-onset neonatal sepsis (EONS). Study Design  Retrospective population-based cohort study of newborns admitted on postnatal day 0 to 1 and discharged from NICUs participating in the Pediatric Health Information System (PHIS 2006-2013). Analyses included frequency of antibiotic initiation within 3 days of birth, duration of first course, and variation among hospitals. Results  Of 158,907 newborns, 118,624 (74.7%) received antibiotics on or before postnatal day 3. Within 3 days of treatment, 49.4% ( n  = 58,610) were discharged home or remained hospitalized without antibiotics. There was marked interhospital variation in the proportion of infants receiving antibiotics (range: 52.3-90.9%, mean 77.9%, SD 11.0%) and in treatment days (range: 3.2-8.6, mean 5.3, SD 1.4). Facilities with higher number of newborns started on antibiotics had longer courses ( r  = 0.643, p  < 0.001). The cost of admissions for infants born at ≥35 weeks started on antibiotics and discharged home after no more than 3 days of antibiotics was $76,692,713. Conclusion  Site variation in antibiotic utilization suggests antibiotic overtreatment of infants with culture unconfirmed EONS is common and costly., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Homeless people have complex problems. GP enhanced care (Pathway) has shown benefits. We performed a randomised, -parallel arm trial at two large inner city hospitals. Inpatient homeless adults were randomly allocated to either standard care (all management by the hospital-based clinical team) or enhanced care with input from a homeless care team. The hospital data system provided healthcare usage information, and we used questionnaires to assess quality of life. 206 patients were allocated to enhanced care and 204 to usual care. Length of stay (up to 90 days after admission) did not differ between groups (standard care 14.0 days, enhanced care 13.3 days). Average reattendance at the emergency department within a year was 5.8 visits in the standard care group and 4.8 visits with enhanced care, but this decrease was not significant. -Quality of life scores after discharge (in 108 patients) improved with enhanced care (EQ-5D-5L score increased by 0.12 [95% CI 0.032 to 0.22] compared wtih 0.03 [-0.1 to 0.15; p=0.076] with standard care). The proportion of people sleeping on the streets after discharge was 14.6% in the standard care arm and 3.8% in the enhanced care arm (p=0.034). The quality-of-life cost per quality-adjusted life-year was £26,000. The Pathway approach doesn't alter length of stay but improves quality of life and reduces street -homelessness., (© 2016 Royal College of Physicians.)

Background: High Mobility Group Box-1 (HMGB1) is considered a prototype alarmin molecule. Upon its extracellular release, HMGB1 engages pattern recognition receptors and the Receptor for Advanced Glycation End-products (RAGE) followed by an outpouring of inflammatory cytokines, including interleukin (IL)-6., Methods: We assayed the amniotic fluid (AF) levels of HMGB1 and IL-6 in 255 women that either had a normal pregnancy outcome or delivered preterm. Immunohistochemistry on fetal membranes was used for cellular localization and validation of immunoassay findings. HMGB1 also was analyzed in amniochorion tissue explants subjected to endotoxin., Results: AF HMGB1 levels are not gestational age regulated but are increased in women with intra-amniotic inflammation and preterm birth. The likely source is the damaged amniochorion, as demonstrated by immunohistochemistry and explant experiments., Conclusions: Our research supports a role for HMGB1 in the inflammatory response leading to preterm birth. As a delayed phase cytokine, in utero exposure to elevated AF HMGB1 levels may have an impact on the newborn beyond the time of birth., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Determining whether initiation of preterm birth was spontaneous, or through labour induction or caesarean without labour or membrane rupture is critical in surveillance and aetiological research on preterm birth, although this information is not explicitly included on the US Birth Certificate. Algorithms combining several fields from birth certificates have been developed to infer the initiating event, but none has been validated against manual review of original obstetric records. Our objective was to develop a birth certificate-based algorithm to determine initiation of preterm birth and validate it by manual review of original records., Methods: We developed an algorithm from the 2003 US Standard Birth Certificate to determine spontaneous vs. indicated preterm birth. The algorithm was first tested on obstetrical records from 80 preterm (<37 weeks) births in Columbus OH (2006-12) abstracted by an obstetrics research nurse and reviewed by an obstetrician-gynecologist. Onset of delivery was spontaneous if the initiating event was premature rupture of membranes (PROM) or contractions, or indicated if the initiating event was induction or caesarean without labour or PROM. The algorithm was validated in an independent sample of 100 preterm births from four hospitals., Results: Codes for tocolysis, fetal intolerance of labour, and anaesthesia during labour did not predict labour and were dropped. The final algorithm correctly classified 73/80 cases, kappa = 0.83. In the validation, 86/100 cases were correctly classified. The kappa statistic was 0.68 (0.52, 0.83); predictive values for spontaneous and indicated onset were 85% (75%, 92%) and 89% (71%, 98%)., Conclusions: The algorithm distinguished spontaneous from indicated preterm birth, using birth certificates, with good accuracy., (© 2016 John Wiley & Sons Ltd.)

Introduction: Universal health coverage (UHC) has its roots in the Universal Declaration of Human Rights and has recently gained momentum. Out-of-pocket payments (OPP) remain a significant barrier to care. There is an increasing global prevalence of non-communicable diseases, many of which are surgically treatable. We sought to provide a comparative analysis of the inclusion of surgical care in operating plans for UHC in low- and middle-income countries (LMIC)., Methods: We systematically searched PubMed and Google Scholar using pre-defined criteria for articles published in English, Spanish, or French between January 1991 and November 2013. Keywords included "insurance," "OPP," "surgery," "trauma," "cancer," and "congenital anomalies." World Health Organization (WHO), World Bank, and Joint Learning Network for UHC websites were searched for supporting documents. Ministries of Health were contacted to provide further information on the inclusion of surgery., Results: We found 696 articles and selected 265 for full-text review based on our criteria. Some countries enumerated surgical conditions in detail (India, 947 conditions). Other countries mentioned surgery broadly. Obstetric care was most commonly covered (19 countries). Solid organ transplantation was least covered. Cancer care was mentioned broadly, often without specifying the therapeutic modality. No countries were identified where hospitals are required to provide emergency care regardless of insurance coverage. OPP varied greatly between countries. Eighty percent of countries had OPP of 60% or more, making these services, even if partially covered, largely inaccessible., Conclusion: While OPP, delivery, and utilization continue to represent challenges to health care access in many LMICs, the inclusion of surgery in many UHC policies sets an important precedent in addressing a growing global prevalence of surgically treatable conditions. Barriers to access, including inequalities in financial protection in the form of high OPP, remain a fundamental challenge to providing surgical care in LMICs.

Problem: TLR4 mediates host responses to pathogens through a mechanism that involves protein myeloid differentiation-2 (MD-2) and its soluble form sMD-2. The role of sMD2 in intra-amniotic inflammation-induced preterm birth has not been previously explored., Method of Study: Human amniotic fluid (AF) sMD-2 was studied by Western blotting in 152 AF samples of patients who had an amniocentesis to rule-out infection (yes infection, n = 50; no infection, n = 50) or women with normal pregnancy outcome (second trimester genetic karyotyping, n = 26; third trimester lung maturity testing, n = 26). Histological localization and mRNA expression of MD2 in fetal membranes were studied by immunohistochemistry and RT-PCR. The ability of fetal membrane to release sMD-2 and inflammatory cytokines was studied in vitro., Results: Human AF contains three sMD-2 proteoforms whose levels of expression were lower at term. Intra-amniotic infection upregulated sMD-2. MD-2 mRNA and immunohistochemistry findings concurred. In vitro, LPS and monensin increased, while cycloheximide decreased sMD-2 production. Recombinant sMD-2 modulated TNF-α and IL-6 levels in a dose- and time-dependent fashion., Conclusion: sMD2 proteoforms are constitutively present in human AF. The intensity of the intra-amniotic inflammatory response to bacteria or perhaps to other TLR4 ligands may be facilitated through synthesis and release of sMD2 by the amniochorion., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Previous narrative reviews in this area have concluded that there are few interventions that are likely to be beneficial and that further high-quality research is required. Our objective was to perform a review of systematic reviews of the effectiveness of interventions for the prevention of small-for-gestational age (SGA) fetuses and perinatal mortality, to summarize the most up-to-date evidence and assess quality. Searches were carried out by using Medline, Embase, Cochrane Library and DARE (inception to September 2011), by hand searching of journal and reference lists and by contact with experts. Systematic reviews of randomized controlled trials were selected. Two reviewers independently selected articles and assessed the methodological and reporting quality. Data were extracted on study characteristics, quality and results. Summary data were presented as relative risks (RRs) and 95% confidence intervals (CIs). There were 834 randomized controlled trials (>668 672 participants), reporting on 45 different interventions. The most effective interventions to prevent the SGA fetus were antiplatelets at <16 weeks in women at risk of pre-eclampsia (RR 0.47; CI 0.30-0.74) and progesterone therapy for prevention of preterm birth (RR 0.64; CI 0.49-0.83). For the prevention of perinatal mortality in high-risk women, antiplatelets (RR 0.69; CI 0.53-0.90) and antenatal corticosteroids (RR 0.77; CI 0.67-0.89) were effective interventions. It is concluded that effective interventions are available for reducing the occurrence of SGA fetuses and preventing related perinatal mortality. Some are effective in all women, while others target specific co-morbidities. There is a need to consider a comprehensive approach to primary prevention that targets SGA along with pre-eclampsia and preterm birth., (© 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.)

A 27-year-old Ghanaian primigravida with a known triamniotic trichorionic triplet pregnancy presented at 17 weeks gestation following a miscarriage of one triplet at home. Examination and investigation revealed no signs of imminent delivery or infection. After careful counselling with regard to prognosis and options available for management, the couple opted for intervention including rescue cerclage. The patient received antibiotic prophylaxis for five days and daily progesterone suppositories until delivery. An ultrasound scan was performed every three weeks to monitor fetal growth and cervical length. At 24 weeks corticosteroids for fetal lung maturity were given. At 31 weeks gestation she experienced spontaneous rupture of membranes followed by active labour and forceps delivery. There were no maternal complications. Both babies were born in a good condition, but required ventilatory support for 72 h.

Problem: Activins and inhibins are important modulators of inflammatory processes. We explored activation of amniotic fluid (AF) activin-A and inhibin-A system in women with intra-amniotic infection and preterm premature rupture of the membranes (PPROM)., Method of Study: We analyzed 78 AF samples: '2nd trimester-control' (n=12), '3rd trimester-control' (n=14), preterm labor with intact membranes [positive-AF-cultures (n=13), negative-AF-cultures (n=13)], and PPROM [positive-AF-cultures (n=13), negative-AF-cultures (n=13)]. Activin-A levels were evaluated ex-vivo following incubation of amniochorion and placental villous explants with Gram-negative lipopolysaccharide (LPS) or Gram-positive (Pam3Cys) bacterial mimics. Ability of recombinant activin-A and inhibin-A to modulate inflammatory reactions in fetal membranes was explored through explants' IL-8 release., Results: Activin-A and inhibin-A were present in human AF and were gestational age-regulated. Activin-A was significantly upregulated by infection. Lower inhibin-A levels were seen in PPROM. LPS elicited release of activin-A from amniochorion, but not from villous explants. Recombinant activin-A stimulated IL-8 release from amniochorion, an effect that was not reversed by inhibin-A., Conclusion: Human AF activin-A and inhibin-A are involved in biological processes linked to intra-amniotic infection/inflammation-induced preterm birth., (© 2011 John Wiley & Sons A/S.)

Objective: To evaluate cord blood erythropoietin (EPO) and interleukin-6 (IL-6) levels to predict preterm infants at risk of developing intraventricular hemorrhage (IVH)., Methods: Levels of umbilical cord EPO, acid-base status and IL-6 were analyzed in 116 consecutive, preterm newborns (GA at delivery: 29 [23-34 ] weeks) born to mothers who had a clinically indicated amniocentesis to rule out infection. Early-onset neonatal sepsis (EONS) was diagnosed using symptoms, hematological criteria and blood cultures., Results: IVH was diagnosed by cranial ultrasounds. The prevalence of IVH in our population was 25% (29/116). There was a direct relationship between cord blood EPO and cord blood IL-6 concentration (r = 0.225, p = 0.014), independent of GA at birth. Elevated cord blood EPO levels (r = 0.182, p = 0.016) and GA at birth (r =  -0.236, p = 0.004) remained significant independent factors associated with the risk of IVH, when evaluated with stepwise logistic regression analyses. Cord blood IL-6, pH, and EONS were not associated with IVH. These relationships remained following correction for GA at birth (p = 0.027)., Conclusions: Our results suggest that elevation in cord blood EPO may predict newborns at risk for IVH, independent of fetal inflammatory status. Further studies are warranted to confirm this association.