Apocalypse Now: War and Religion in Late Colonial and Early Republic America

ABSTRACT French “Idolators,” British “Heretics,” Native “Heathens”: The Seven Years’ War in North America as a Religious Conflict With France and Great Britain as its primary belligerents, the Seven Years\u27 War was an international conflict with a decidedly religious dimension, one based on the longstanding rivalry between Catholicism and Protestantism. In North America, the conflict galvanized clergymen in both the British and French colonies to frame the war as a religious struggle with potentially apocalyptic consequences. This discourse remains understudied by historians, and efforts to address religion\u27s role in America during the Seven Years\u27 War is usually one-sided, focusing either on the French or British experience. This paper aims to fill this historiographic gap by analyzing both sermons produced by Protestant ministers from across the American colonies and pastoral letters issued by the Catholic Bishop of Quebec between 1755 and 1763. Moreover, this paper argues that both French and British religious leaders viewed the Seven Years\u27 War as an extension of the Catholic-Protestant European religious wars of the previous century, and believed that the conflict\u27s outcome would determine the survival of their respective religions in North America. This paper also describes how Native Americans figured in this discourse, employing a combination of captivity narratives written by Protestant ministers and the reports of Jesuit missionaries to further illustrate the war\u27s perceived apocalyptic significance. ABSTRACT “The English Establishment Is, Itself, of a Beastly Nature”: Catholicizing Great Britain in Pro-War American Discourse During the War of 1812 In order to catalyze support for their cause against the British during the War of 1812, pro-war writers in the United States revived a rhetorical device that had once served their Revolutionary predecessors: the casting of Great Britain as an anti-Protestant and practically Catholic agent. Specifically, these writers were reacting to claims made by certain New England religious and political authorities shortly after the war’s inception that Great Britain was Protestantism’s “bulwark,” and as a result should be viewed as an American ally rather than as an enemy. An examination of pro-war newspaper articles and published sermons ranging in origin from Vermont to Maryland demonstrates how pro-war writers deconstructed Great Britain’s historically accepted role as Protestantism’s defender. It also reveals how this rhetorical strategy intensified in comparison to its brief employment during the Revolutionary period, thanks to the manner in which Napoleonic France was perceived as an effective check against the Papacy. Finally, these sources demonstrate the extent to which pro-war writers employed apocalyptic imagery from the biblical Book of Revelation to bolster their denunciation of Great Britain, which they argued stood alongside the Catholic Church as one of the beasts of the Apocalypse

Risk of Adverse Obstetric and Neonatal Outcomes by Maternal Age: Quantifying Individual and Population Level Risk Using Routine UK Maternity Data.

OBJECTIVE: The objective of this study was to investigate whether moderately increased maternal age is associated with obstetric and neonatal outcome in a contemporary population, and to consider the possible role of co-morbidities in explaining any increased risk. STUDY DESIGN: Secondary analysis of routinely collected data from a large maternity unit in London, UK. Data were available on 51,225 singleton deliveries (≥22 weeks) occurring to women aged ≥20 between 2004 and 2012. Modified Poisson regression was used to estimate risk ratios for the association between maternal age and obstetric and neonatal outcome (delivery type, postpartum haemorrhage, stillbirth, low birthweight, preterm birth, small for gestational age, neonatal unit admission), using the reference group 20-24 years. Population attributable fractions were calculated to quantify the population impact. RESULTS: We found an association between increasing maternal age and major postpartum haemorrhage (≥1000ml blood loss) (RR 1.36 95% CI 1.18-1.57 for age 25-29 rising to 2.41 95% CI 2.02-2.88 for age ≥40). Similar trends were observed for caesarean delivery, most notably for elective caesareans (RR 1.64 95% CI 1.36-1.96 for age 25-29 rising to 4.94 95% CI 4.09-5.96 for age ≥40). There was evidence that parity modified this association, with a higher prevalence of elective caesarean delivery in older nulliparous women. Women aged ≥35 were at increased risk of low birthweight and preterm birth. We found no evidence that the risk of stillbirth, small for gestational age, or neonatal unit admission differed by maternal age. CONCLUSIONS: Our results suggest a gradual increase in the risk of caesarean delivery and postpartum haemorrhage from age 25, persisting after taking into account maternal BMI, hypertension and diabetes. The risk of low birthweight and preterm birth was elevated in women over 35. Further research is needed to understand the reasons behind the high prevalence of elective caesarean delivery in nulliparous older mothers

Ethnic variation in stillbirth risk and the role of maternal obesity: analysis of routine data from a London maternity unit.

BACKGROUND: Approximately 5 in 1,000 deliveries in England and Wales result in stillbirth, with little improvement in figures over the last few decades. The aim of this study was to investigate the association between clinical and socio-demographic factors and stillbirth, with a particular focus on ethnicity and obesity. METHODS: Analysis of routine maternity data on 53,293 singleton births occurring in a large London teaching hospital between 2004 and 2012. Logistic regression was used to investigate risk factors for stillbirth and to explore potential effect modification. RESULTS: 53,293 deliveries occurred during the time period, of which 329 resulted in a stillbirth (6.2 per 1,000 births). Compared to White women, non-White ethnicity was associated with a doubling of the odds of stillbirth (aOR for Black women 2.15, 95% CI 1.56-2.97; aOR for South Asian women 2.33, 95% CI 1.42-3.83). Obese women had a trend towards higher odds of stillbirth compared to women of recommended BMI (aOR 1.38, 95% CI 0.98-1.96), though this was not significant (p 0.07). Both higher parity (≥2 compared to para 1) and hypertension were associated with a higher odds of stillbirth (parity ≥2 aOR 1.65, 95% CI 1.13-2.39; hypertension aOR 1.84, 95% CI 1.22-2.78) but there was no evidence that area deprivation or maternal age were independently associated with stillbirth in this population. There was some evidence of effect modification between ethnicity and obesity (p value for interaction 0.06), with obesity a particularly strong risk factor for stillbirth in South Asian women (aOR 4.64, 95% CI 1.84-11.70). CONCLUSIONS: There was a high prevalence of stillbirth in this multi-ethnic urban population. The increased risk of stillbirth observed in non-White women remains after adjusting for other factors. Our finding of possible effect modification between ethnicity and obesity suggests that further research should be conducted in order to improve understanding of the interplay between ethnicity, obesity and stillbirth

Identifying Community-Engaged Translational Research Collaboration Experience and Health Interests of Community-Based Organizations Outside of Metropolitan Atlanta

Background: While rural health research has increased over the last two decades, there is limited understanding of the self-reported health priorities and research interests of rural and suburban community-based representatives and residents. These insights can be used to inform more successful intervention strategies that are responsive to the lived experiences of local residents and leaders who are the gatekeepers to buy-in and sustainability of community engaged research. The Georgia Clinical and Translational Science Alliance, a collaboration between four academic institutions includes a Community Engagement Program (CE) designed to facilitate community-academic research partnerships. This study aimed to assess the health priorities, community-academic research experience, and interests of community respondents outside of Metropolitan Atlanta through the Community Engagement Facilitation Survey (CEFS). Methods: CE Program and Community Steering Board created the CEFS to assess the health topic priorities, research experience, and interests of community-based representatives and community members across the state of Georgia. The 11-item survey was administered (paper and electronic surveys) statewide at community events and professional organization meetings. Descriptive statistics were analyzed, and geospatial mapping was conducted. Data were analyzed in SPSS and Microsoft Excel software systems to clean data and to calculate data counts and percentages. Three maps were created in Tableau Version 19.2 depicting all counties represented by the survey sample superimposed with the counties from which at least one respondent indicated each of the top three health priorities for this sample. Results: Four-hundred six (406) surveys were analyzed, representing 83.6% of rural and suburban Georgia counties. The most frequently identified health priorities and research interests were diabetes, cancer, high blood pressure, and mental health

Sense of agency and mentalizing: Dissociation of subdomains of social cognition in patients with schizophrenia

The sense of agency, i.e., the sense that “I am the one who is causing an action”, and mentalizing, the ability to understand the mental states of other individuals, are key domains of social cognition. It has been hypothesized that an intact sense of agency is an important precondition for higher-level mentalizing abilities. A substantial body of evidence shows that both processes rely on similar brain areas and are severely impaired in schizophrenia, suggesting a close link between agency and mentalizing. Yet this relationship has not been explicitly tested. We investigated 40 individuals with schizophrenia and 40 healthy controls on an agency and mentalizing task. On the agency task, participants carried out simple mouse movements and judged the partially manipulated visual feedback as either self- or other-generated. On the mentalizing task, participants inferred mental states from pictures that depicted others' eyes (“Reading the mind in the eyes test”). Neuropsychological, psychopathological and social functioning levels were also evaluated. Both sense of agency and mentalizing were impaired in schizophrenia patients compared to healthy controls. However, testing for a relationship revealed no significant correlations between the two processes, either in the schizophrenia or the control group. The present findings demonstrate a dissociation of agency and mentalizing deficits in schizophrenia, suggesting that the multifaceted construct of social cognition consists of independent subdomains in healthy and psychiatrically ill individuals

Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Background: Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high. Methods: We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa. Healthy adult community volunteers who were aged 18–50 years, had received BCG vaccination as infants, were HIV negative, had negative interferon-¿ release assay (IGRA) results, and had no personal history of tuberculosis or current household contact with someone with tuberculosis were enrolled in a safety cohort. Infants born to HIV-negative women with no personal history of tuberculosis or current household contact with a person with tuberculosis and who were 96 h old or younger, generally healthy, and had not yet received routine BCG vaccination were enrolled in a separate infant cohort. Eligible adults were randomly assigned (1:1) to receive either BCG Vaccine SSI (5 × 105 colony forming units [CFU] of Danish strain 1331 in 0·1 mL diluent) or MTBVAC (5 × 105 CFU in 0·1 mL) intradermally in the deltoid region of the arm. After favourable review of 28-day reactogenicity and safety data in the adult cohort, infants were randomly assigned (1:3) to receive either BCG Vaccine SSI (2·5 × 105 CFU in 0·05 mL diluent) or MTBVAC in three sequential cohorts of increasing MTBVAC dose (2·5 × 103 CFU, 2·5 × 104 CFU, and 2·5 × 105 CFU in 0·05 mL) intradermally in the deltoid region of the arm. QuantiFERON-TB Gold In-Tube IGRA was done on days 180 and 360. For both randomisations, a pre-prepared block randomisation schedule was used. Participants (and their parents or guardians in the case of infant participants), investigators, and other clinical and laboratory staff were masked to intervention allocation. The primary outcomes, which were all measured in the infant cohort, were solicited and unsolicited local adverse events and serious adverse events until day 360; non-serious systemic adverse events until day 28 and vaccine-specific CD4 and CD8 T-cell responses on days 7, 28, 70, 180, and 360. Secondary outcomes measured in adults were local injection-site and systemic reactions and haematology and biochemistry at study day 7 and 28. Safety analyses and immunogenicity analyses were done in all participants who received a dose of vaccine. This trial is registered with ClinicalTrials.gov, number NCT02729571. Findings: Between Sept 29, 2015, and Nov 16, 2015, 62 adults were screened and 18 were enrolled and randomly assigned, nine each to the BCG and MTBVAC groups. Between Feb 12, 2016, and Sept 21, 2016, 36 infants were randomly assigned—eight to the BCG group, nine to the 2·5 × 103 CFU MTBVAC group, nine to the 2·5 × 104 CFU group, and ten to the 2·5 × 105 CFU group. Mild injection-site reactions occurred only in infants in the BCG and the 2·5 × 105 CFU MTBVAC group, with no evidence of local or regional injection-site complications. Systemic adverse events were evenly distributed across BCG and MTBVAC dose groups, and were mostly mild in severity. Eight serious adverse events were reported in seven vaccine recipients (one adult MTBVAC recipient, one infant BCG recipient, one infant in the 2·5 × 103 CFU MTBVAC group, two in the 2·5 × 104 CFU MTBVAC group, and two in the 2·5 × 105 CFU MTBVAC group), including one infant in the 2·5 × 103 CFU MTBVAC group treated for unconfirmed tuberculosis and one in the 2·5 × 105 CFU MTBVAC group treated for unlikely tuberculosis. One infant died as a result of possible viral pneumonia. Vaccination with all MTBVAC doses induced durable antigen-specific T-helper-1 cytokine-expressing CD4 cell responses in infants that peaked 70 days after vaccination and were detectable 360 days after vaccination. For the highest MTBVAC dose (ie, 2·5 × 105 CFU), these responses exceeded responses induced by an equivalent dose of the BCG vaccine up to 360 days after vaccination. Dose-related IGRA conversion was noted in three (38%) of eight infants in the 2·5 × 103 CFU MTBVAC group, six (75%) of eight in the 2·5 × 104 CFU MTBVAC group, and seven (78%) of nine in the 2·5 × 105 CFU MTBVAC group at day 180, compared with none of seven infants in the BCG group. By day 360, IGRA reversion had occurred in all three infants (100%) in the 2·5 × 103 CFU MTBVAC group, four (67%) of the six in the 2·5 × 104 CFU MTBVAC group, and three (43%) of the seven in the 2·5 × 105 CFU MTBVAC group. Interpretation: MTBVAC had acceptable reactogenicity, and induced a durable CD4 cell response in infants. The evidence of immunogenicity supports progression of MTBVAC into larger safety and efficacy trials, but also confounds interpretation of tests for M tuberculosis infection, highlighting the need for stringent endpoint definition. Funding: Norwegian Agency for Development Cooperation, TuBerculosis Vaccine Initiative, UK Department for International Development, and Biofabri

Validation of a host blood transcriptomic biomarker for pulmonary tuberculosis in people living with HIV: a prospective diagnostic and prognostic accuracy study.

BACKGROUND: A rapid, blood-based triage test that allows targeted investigation for tuberculosis at the point of care could shorten the time to tuberculosis treatment and reduce mortality. We aimed to test the performance of a host blood transcriptomic signature (RISK11) in diagnosing tuberculosis and predicting progression to active pulmonary disease (prognosis) in people with HIV in a community setting. METHODS: In this prospective diagnostic and prognostic accuracy study, adults (aged 18-59 years) with HIV were recruited from five communities in South Africa. Individuals with a history of tuberculosis or household exposure to multidrug-resistant tuberculosis within the past 3 years, comorbid risk factors for tuberculosis, or any condition that would interfere with the study were excluded. RISK11 status was assessed at baseline by real-time PCR; participants and study staff were masked to the result. Participants underwent active surveillance for microbiologically confirmed tuberculosis by providing spontaneously expectorated sputum samples at baseline, if symptomatic during 15 months of follow-up, and at 15 months (the end of the study). The coprimary outcomes were the prevalence and cumulative incidence of tuberculosis disease confirmed by a positive Xpert MTB/RIF, Xpert Ultra, or Mycobacteria Growth Indicator Tube culture, or a combination of such, on at least two separate sputum samples collected within any 30-day period. FINDINGS: Between March 22, 2017, and May 15, 2018, 963 participants were assessed for eligibility and 861 were enrolled. Among 820 participants with valid RISK11 results, eight (1%) had prevalent tuberculosis at baseline: seven (2·5%; 95% CI 1·2-5·0) of 285 RISK11-positive participants and one (0·2%; 0·0-1·1) of 535 RISK11-negative participants. The relative risk (RR) of prevalent tuberculosis was 13·1 times (95% CI 2·1-81·6) greater in RISK11-positive participants than in RISK11-negative participants. RISK11 had a diagnostic area under the receiver operating characteristic curve (AUC) of 88·2% (95% CI 77·6-96·7), and a sensitivity of 87·5% (58·3-100·0) and specificity of 65·8% (62·5-69·0) at a predefined score threshold (60%). Of those with RISK11 results, eight had primary endpoint incident tuberculosis during 15 months of follow-up. Tuberculosis incidence was 2·5 per 100 person-years (95% CI 0·7-4·4) in the RISK11-positive group and 0·2 per 100 person-years (0·0-0·5) in the RISK11-negative group. The probability of primary endpoint incident tuberculosis was greater in the RISK11-positive group than in the RISK11-negative group (cumulative incidence ratio 16·0 [95% CI 2·0-129·5]). RISK11 had a prognostic AUC of 80·0% (95% CI 70·6-86·9), and a sensitivity of 88·6% (43·5-98·7) and a specificity of 68·9% (65·3-72·3) for incident tuberculosis at the 60% threshold. INTERPRETATION: RISK11 identified prevalent tuberculosis and predicted risk of progression to incident tuberculosis within 15 months in ambulant people living with HIV. RISK11's performance approached, but did not meet, WHO's target product profile benchmarks for screening and prognostic tests for tuberculosis. FUNDING: Bill & Melinda Gates Foundation and the South African Medical Research Council

Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial.

BACKGROUND: Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design. METHODS: Adult volunteers aged 18-59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590. FINDINGS: 20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI -145 to 65). INTERPRETATION: The RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months. FUNDING: Bill and Melinda Gates Foundation, South African Medical Research Council

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)