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International audience; Colistin is a critically important antimicrobial for human medicine, and colistin-resistant Escherichia coli are commonly found in poultry and poultry products in Southeast Asia. Here, we aim at disentangling the within-farm and outside-farm drivers of colistin resistance in small-scale chicken farms of the Mekong delta of Vietnam. Nineteen Vietnamese chicken farms were followed up along a whole production cycle, during which weekly antimicrobial use data were recorded. At the beginning, middle and end of each production cycle, commensal E. coli samples from birds were collected, pooled and tested for colistin resistance. Twelve models were fitted to the data using an expectation-maximization algorithm and compared. We further tested the spatial clustering of the occurrence of resistance importations from external sources using the local Moran's I statistic. In the best model, colistin resistance in E. coli from chickens was found to be mostly affected by importations of resistance, and, to a lesser extent, by the use of antimicrobials in the last 1.73 weeks [0.00; 2.90], but not by the use of antimicrobials in day-olds, nor their colistin resistance carriage from hatchery. The occurrence of external source importations proved to be sometimes spatially clustered, suggesting a role of local environmental sources of colistin resistance.

We studied the immunogenicity of the Oxford-AstraZeneca vaccine in health-care workers of a major infectious diseases hospital in Vietnam. We measured neutralizing antibodies before and 14 days after each dose, and at day 28 and month 3 after dose 1. A total of 554 workers (136 men and 418 women; age range, 22–71 years; median age, 36 years) participated with the study. Of the 144 participants selected for follow-up after dose 1, 104 and 94 gave blood for antibody measurement at weeks 6 and 8, and at month 3 after dose 1, respectively. The window time between the two doses was 6 weeks. At baseline, none had detectable neutralizing antibodies. After dose 1, the proportion of participants with detectable neutralizing antibodies increased from 27.3% (151 of 554) at day 14 to 78.0% (432 of 554) at day 28. Age correlated negatively with the development and the levels of neutralizing antibodies. However, at day 28, these differences were less profound, and women had a greater seroconversion rate and greater levels of neutralizing antibodies than men. After dose 2, these age and gender associations were not observable. In addition, the proportion of study participants with detectable neutralizing antibodies increased from 70.2% (73 of 104) before dose 2 (week 6, after dose 1) to 98.1% (102 of 104) 14 days later. At month 3, neutralizing antibodies decreased and 94.7% (89 of 94) of the study participants remained seropositive. The Oxford-AstraZeneca COVID-19 vaccine is immunogenic in Vietnamese health-care workers. These data are critical to informing the deployment of the COVID-19 vaccine in Vietnam and in Southeast Asia, where vaccination coverage remains inadequate.

IntroductionCarpal tunnel syndrome (CTS) is the most common peripheral neuropathy. The optimal treatment strategy is still unknown. The objective of the Dutch Injection versus Surgery TRIal in patients with CTS (DISTRICTS) is to investigate if initial surgery of CTS results in a better clinical outcome and is more cost-effective when compared with initial treatment with corticosteroid injection.Methods and analysisThe DISTRICTS is an ongoing multicenter, open-label randomised controlled trial. Participants with CTS are randomised to treatment with surgery or with a corticosteroid injection. If needed, any additional treatments after this first treatment are allowed and these are not dictated by the study protocol. The primary outcome is the difference between the groups in the proportion of participants recovered at 18 months. Recovery is defined as having no or mild symptoms as measured with the 6-item carpal tunnel symptoms scale. Secondary outcome measurements are among others: time to recovery, hand function, patient satisfaction, quality of life, additional treatments, adverse events, and use of care and health-related costs.Ethics and disseminationThe study was approved by the Medical Ethical Committee of the Amsterdam University Medical Centers (study number 2017-171). Study results will be disseminated in peer-reviewed journals and conferences.Trial registration numberISRCTN Registry: 13164336.

The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a data compendium of 12,289 Mycobacterium tuberculosis global clinical isolates, all of which have undergone whole-genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured in a single assay. It is the largest matched phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a summary detailing the breadth of data collected, along with a description of how the isolates were selected, collected, and uniformly processed in CRyPTIC partner laboratories across 23 countries. The compendium contains 6,814 isolates resistant to at least 1 drug, including 2,129 samples that fully satisfy the clinical definitions of rifampicin resistant (RR), multidrug resistant (MDR), pre-extensively drug resistant (pre-XDR), or extensively drug resistant (XDR). The data are enriched for rare resistance-associated variants, and the current limits of genotypic prediction of resistance status (sensitive/resistant) are presented by using a genetic mutation catalogue, along with the presence of suspected resistance-conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid, and linezolid. Finally, a case study of rifampicin monoresistance demonstrates how this compendium could be used to advance our genetic understanding of rare resistance phenotypes. The data compendium is fully open source and it is hoped that it will facilitate and inspire future research for years to come.

[Purpose]: Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study. [Methods]: POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case–control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. [Results]: Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies, This work was funded by the Spanish Ministry of Science and Innovation, cofunded by FEDER funds (SAF2016-80888-R, SAF2015-68016-R, Severo Ochoa SVP-2014-068895 contract [L.M.-P.]); Instituto de Salud Carlos III (PI16/00563, PI16/00588, PI14/00613, PI19/00553, CIBERONC CB16/12/00234, CIBERESP, Sara Borrell contract [P.M.]); Government of Catalonia [AGAUR 2017SGR1282, CERCA Program]; and Fundación Olga Torres. This study was facilitated by COST Action CA17118, supported by COST (European Cooperation in Science and Technology).

BackgroundDespite reported injury rates of up to 3 per 1000 hours exposure, there are no evidence-based prevention programmes in tennis.PurposeTo evaluate the effectiveness of an e-health prevention programme for reducing tennis injury prevalence.Study designTwo-arm, researcher-blinded randomised controlled trial.MethodsAdult tennis players of all playing levels were randomised in an unsupervised programme lasting 12 weeks (TennisReady group or control group). The primary outcome was the overall injury prevalence over a 16-week period, measured at 2 weekly intervals with the Oslo Sports and Trauma Research Centre questionnaire. Estimates for the primary outcome and associated 95% CIs were obtained using generalised estimating equation models. Secondary outcome scores included prevalence of substantial injuries, overall incidence, adherence and time-loss injuries.ResultsA total of 579 (83%) (TennisReady n=286, control n=293) participants were included in the primary analysis. The mean injury prevalence was 37% (95% CI 33% to 42%) in the TennisReady vs 38% (95% CI 34% to 42%) in the control group (adjusted p-value 0.93). The prevalence of substantial injuries was 11% (95% CI 9% to 14%) in the TennisReady vs 12% (95% CI 9% to 15%) in the control group (p value of 0.79). Analysis of the secondary outcome scores showed no difference between groups. The mean prevalence rates between high (8%) and low (92%) adherent groups were 32% (95% CI 23% to 44%) and 37% (95% CI 33% to 42%), respectively (p value 0.36).ConclusionProviding an unsupervised e-health tennis-specific exercise programme did not reduce the injury rates and should not be implemented.Trial registration numberNTR6443.

Because of comorbidities and polypharmacy, older patients with cancer have a greater risk of iatrogenic events. We aimed to characterize potential drug-drug interactions (PDIs) and the risk of unplanned hospitalization in older patients with cancer treated with antineoplastic agents (ANAs).We analyzed all older patients (≥70 years) from the prospective ELCAPA cohort referred for geriatric assessment (2007-2014) prior to treatment with ANA at Henri Mondor Hospital (Créteil, France). PDIs were identified using Lexicomp®, and Theriaque® for French medications. Factors associated with PDIs, and association between PDIs and unplanned hospitalization in the 6 months following geriatric assessment were analyzed using ordered multivariate logistic regression (MLR).We included 442 patients (median [interquartile range] age: 77 years [74-80]); number of medications/patient/day: 6 [3-8]); ECOG-PS ≤ 2: 79%; metastasis: 70%). Most patients had a digestive tract cancer (colorectal: 22%; upper digestive tract: 23%). We identified 1742 PDIs; 76.5% of patients had ≥1 PDI; 13% of the PDIs involved an ANA. In a multivariate analysis, cardiovascular disorders (ischemic heart disease, heart failure, atrial fibrillation and/or arterial hypertension) were independently associated with PDIs (p .001, after adjustment for polypharmacy and tumor site/stage). A high number of PDIs between two daily medications was independently associated with the risk of unplanned hospitalization (adjusted-odds ratio [95% confidence interval] per PDI: 1.05 [1.00;1.11], p = .05), while polypharmacy was not.Patients with cardiovascular comorbidities were more likely to have a PDI. A higher number of PDIs may be an independent risk factor for early unplanned hospitalization.

International audience; In the Mekong Delta region of Vietnam, small-scale chicken farming is common. However, high levels of disease or mortality in such flocks impair eco- nomic development and challenge the livelihoods of many rural households. We investigated 61 diseased small-scale flocks (122 chickens) for evidence of infec- tion with 5 bacteria, 4 viruses, and helminths. Sero- logical profiles (ELISA) were also determined against 6 of these pathogens. The aims of this study were the following: (1) to investigate the prevalence of different pathogens and to compare the probability of detection of bacterial pathogens using PCR and culture; (2) to investigate the relationship between detection of or- ganisms in birds’ tissues and the observed morbidity and mortality, as well as their antibody profile; and (3) to characterize risk factors for infection with specific viral or bacterial pathogens. We used PCR to test for viral (viruses causing infectious bronchitis [IB], highly pathogenic avian influenza [HPAI], Newcastle disease, and infectious bursal disease [IBD]) and bacterial pathogens (Mycoplasma gallisepticum, Pas- teurella multocida, Avibacterium paragallinarum, and Ornithobacterium rhinotracheale [ORT]). The latter two were also investigated in respiratory tissues by conventional culture. Colisepticemic Escherichia coli was investigated by liver or spleen culture. In 49 of 61 (80.3%) flocks, at least one bacterial or viral pathogen was detected, and in 29 (47.5%) flocks, more than one pathogen was detected. A. paragallinarum was detected in 62.3% flocks, followed by M. gallisepticum (26.2%), viruses causing IBD (24.6%) and IB (21.3%), septicemic E. coli (14.8%), ORT (13.1%), and HPAI viruses (4.9%). Of all flocks, 67.2% flocks were colonized by helminths. Mortality was highest among flocks infected with HPAI (100%, interquartile range [IQR]: 81.6– 100%) and lowest with flocks infected with ORT (5.3%, IQR: 1.1–9.0%). The results indicated slight agreement (kappa 0.167) between detection by PCR and culture for both A. paragallinarum and ORT, as well as be- tween the presence of cestodes and ORT infection (kappa 5 0.317). Control of A. paragallinarum, viruses causing HPAI, IBD, and IB, M. gallisepticum, and gastrointestinal helminths should be a priority in small- scale flocks.

Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features. ispartof: NATURE MEDICINE vol:28 issue:2 pages:303-+ ispartof: location:United States status: published

Aims The role of diuretics in patients with intermediate-risk pulmonary embolism (PE) is controversial. In this multicentre, double-blind trial, we randomly assigned normotensive patients with intermediate-risk PE to receive either a single 80 mg bolus of furosemide or a placebo. Methods and results Eligible patients had at least a simplified PE Severity Index (sPESI) ≥1 with right ventricular dysfunction. The primary efficacy endpoint assessed 24 h after randomization included (i) absence of oligo-anuria and (ii) normalization of all sPESI items. Safety outcomes were worsening renal function and major adverse outcomes at 48 hours defined by death, cardiac arrest, mechanical ventilation, or need of catecholamine. A total of 276 patients underwent randomization; 135 were assigned to receive the diuretic, and 141 to receive the placebo. The primary outcome occurred in 68/132 patients (51.5%) in the diuretic and in 49/132 (37.1%) in the placebo group (relative risk = 1.30, 95% confidence interval 1.04–1.61; P = 0.021). Major adverse outcome at 48 h occurred in 1 (0.8%) patients in the diuretic group and 4 patients (2.9%) in the placebo group (P = 0.19). Increase in serum creatinine level was greater in diuretic than placebo group [+4 µM/L (−2; 14) vs. −1 µM/L (−11; 6), P Conclusion In normotensive patients with intermediate-risk PE, a single bolus of furosemide improved the primary efficacy outcome at 24 h and maintained stable renal function. In the furosemide group, urine output increased, without a demonstrable improvement in heart rate, systolic blood pressure, or arterial oxygenation. ClinicalTrials.gov identifier NCT02268903.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vaginal intraepithelial neoplasia (VaIN). The management of VaIN varies according to the grade of the lesion: VaIN 1 (low grade vaginal squamous intraepithelial lesions (SIL)) can be subjected to follow-up, while VaIN 2–3 (high-grade vaginal SIL) should be treated. Treatment needs individualization according to the patient’s characteristics, disease extension and previous therapeutic procedures. Surgical excision is the mainstay of treatment and should be performed if invasion cannot be excluded. Total vaginectomy is used only in highly selected cases of extensive and persistent disease. Carbon dioxide (CO2) laser may be used as both an ablation method and an excisional one. Reported cure rates after laser excision and laser ablation are similar. Topical agents are useful for persistent, multifocal lesions or for patients who cannot undergo surgical treatment. Imiquimod was associated with the lowest recurrence rate, highest human papillomavirus (HPV) clearance, and can be considered the best topical approach. Trichloroacetic acid and 5-fluorouracil are historical options and should be discouraged. For VaIN after hysterectomy for cervical intraepithelial neoplasia (CIN) 3, laser vaporization and topical agents are not the best options, since they cannot reach epithelium buried in the vaginal scar. In these cases surgical options are preferable. Brachytherapy has a high overall success rate but due to late side effects should be reserved for poor surgical candidates, having multifocal disease, and with failed prior treatments. VaIN tends to recur and ensuring patient adherence to close follow-up visits is of the utmost importance. The first evaluation should be performed at 6 months with cytology and an HPV test during 2 years and annually thereafter. The implementation of vaccination against HPV infection is expected to contribute to the prevention of VaIN and thus cancer of the vagina. The effects of treatment can have an impact on quality of life and result in psychological and psychosexual issues which should be addressed. Patients with VaIN need clear and up-to-date information on a range of treatment options including risks and benefits, as well as the need for follow-up and the risk of recurrence.

International audience; Abstract Objective: To explore the relationships between dental problems and underweight status among rural women in Burkina Faso by using nationally representative data. Design: This was a cross-sectional secondary study of primary data obtained by the 2013 World Health Organization Stepwise Approach to Surveillance survey conducted in Burkina Faso. Descriptive and analytical analyses were performed using Student’s t test, ANOVA, the chi-square test, Fisher’s exact test and logistic regression. Setting: All 13 Burkinabè regions were categorized using quartiles of urbanization rates. Participants: The participants were 1730 rural women aged 25-64 years. Results: The prevalence of underweight was 16.0%, and 24.1% of participants experienced dental problems during the 12-month period. The women with dental problems were more frequently underweight (19.9% and 14.7%; p49 years old) and smokeless tobacco users. Age >49 years, professions with inconsistent income, a lack of education, smokeless tobacco use and low BMI were factors that were significantly associated with dental problems, while residency in a low-urbanization area was a protective factor. Conclusion: The prevalence of underweight in rural Burkinabè women is among the highest in sub-Saharan Africa, and women with dental problems are more frequently affected than those without dental problems. Public health measures for the prevention of these disorders should specifically target women aged over 49 years and smokeless tobacco users.

The relationship between SARS-CoV-2 viral load and infectiousness is poorly known. Using data from a cohort of cases and high-risk contacts, we reconstructed viral load at the time of contact and inferred the probability of infection. The effect of viral load was larger in household contacts than in non-household contacts, with a transmission probability as large as 48% when the viral load was greater than 1010 copies per mL. The transmission probability peaked at symptom onset, with a mean probability of transmission of 29%, with large individual variations. The model also projects the effects of variants on disease transmission. Based on the current knowledge that viral load is increased by two- to eightfold with variants of concern and assuming no changes in the pattern of contacts across variants, the model predicts that larger viral load levels could lead to a relative increase in the probability of transmission of 24% to 58% in household contacts, and of 15% to 39% in non-household contacts.

Background Nutritional impairment is common in cancer patients and is associated with poor outcomes. Only few studies focused on cachexia. We assessed the prevalence of cachexia in older cancer patients, identified associated risk factors, and evaluated its impact on 6 month overall mortality. Methods A French nationwide cross‐sectional survey (performed in 55 geriatric oncology clinics) of older cancer patients aged ≥70 referred for geriatric assessment prior to treatment choice and initiation. Demographic, clinical, and nutritional data were collected. The first outcome was cachexia, defined as loss of more than 5% of bodyweight over the previous 6 months, or a body mass index below 20 kg/m2 with weight loss of more than 2%, or sarcopenia (an impaired Strength, Assistance with walking, Rise from chair, Climb stairs and Falls score) with weight loss of more than 2%. The second outcome was 6 month overall mortality. Results Of the 1030 patients included in the analysis [median age (interquartile range): 83 (79–87); males: 48%; metastatic cancer: 42%; main cancer sites: digestive tract (29%) and breast (16%)], 534 [52% (95% confidence interval: 49–55%)] had cachexia. In the multivariate analysis, patients with breast (P

Background Biological control programs involving Wolbachia-infected Aedes aegypti are currently deployed in different epidemiological settings. New Caledonia (NC) is an ideal location for the implementation and evaluation of such a strategy as the only proven vector for dengue virus (DENV) is Ae. aegypti and dengue outbreaks frequency and severity are increasing. We report the generation of a NC Wolbachia-infected Ae. aegypti strain and the results of experiments to assess the vector competence and fitness of this strain for future implementation as a disease control strategy in Noumea, NC. Methods/principal findings The NC Wolbachia strain (NC-wMel) was obtained by backcrossing Australian AUS-wMel females with New Caledonian Wild-Type (NC-WT) males. Blocking of DENV, chikungunya (CHIKV), and Zika (ZIKV) viruses were evaluated via mosquito oral feeding experiments and intrathoracic DENV challenge. Significant reduction in infection rates were observed for NC-wMel Ae. aegypti compared to WT Ae. aegypti. No transmission was observed for NC-wMel Ae. aegypti. Maternal transmission, cytoplasmic incompatibility, fertility, fecundity, wing length, and insecticide resistance were also assessed in laboratory experiments. Ae. aegypti NC-wMel showed complete cytoplasmic incompatibility and a strong maternal transmission. Ae. aegypti NC-wMel fitness seemed to be reduced compared to NC-WT Ae. aegypti and AUS-wMel Ae. aegypti regarding fertility and fecundity. However further experiments are required to assess it accurately. Conclusions/significance Our results demonstrated that the NC-wMel Ae. aegypti strain is a strong inhibitor of DENV, CHIKV, and ZIKV infection and prevents transmission of infectious viral particles in mosquito saliva. Furthermore, our NC-wMel Ae. aegypti strain induces reproductive cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, supporting field-releases in Noumea, NC., Author summary Dengue represents a risk for almost half of the world’s population, especially throughout the tropics. In New Caledonia, dengue outbreaks have become more frequent in the past decade along with the recent circulation of chikungunya and Zika viruses. The opportunity to use the biocontrol method involving the release of Wolbachia-infected Ae. aegypti mosquitoes has been investigated as an alternative solution to the traditional control methods, like elimination of larval habitats and pyrethroid insecticide application to kill adults, which are becoming insufficient. A local strain of Ae. aegypti carrying Wolbachia (NC-wMel) has been generated and tested to evaluate its pathogen blocking capacity for the four dengue virus serotypes as well as chikungunya and Zika viruses. The fitness of NC-wMel strain has also been assessed to estimate its ability to compete with the wild-type strain in the field. Noumea city, where a third of the population of New Caledonia resides, has been chosen as the first site to implement the method in New Caledonia. As Ae. aegypti is the only proven vector in New Caledonia, we expect a significant impact on dengue outbreaks occurring in Noumea as soon as a high frequency of NC-wMel is established in the population.

Coronavirus disease (COVID-19) was detected in Wuhan, China in 2019 and spread worldwide within few weeks. The COVID-19 epidemic started to gain traction in France in March 2020. Sub-national hospital admissions and deaths were then recorded daily and served as the main policy indicators. Concurrently, mobile phone positioning data have been curated to determine the frequency of users being colocalized within a given distance. Contrarily to individual tracking data, these can provide a proxy of human contact networks between subnational administrative units. Motivated by numerous studies correlating human mobility data and disease incidence, we developed predictive time series models of hospital incidence between July 2020 and April 2021. Adding human contact network analytics such as clustering coefficients, contact network strength, null links or curvature as regressors, we found that predictions can be improved substantially (more than 50%) both at the national and sub-national for up to two weeks. Our sub-national analysis also revealed the importance of spatial structure, as incidence in colocalized administrative units improved predictions. This original application of network analytics from co-localisation data to epidemic spread opens new perspectives for epidemics forecasting and public health.HighlightsWe use novel human contact network analytics based on colocation data of mobile app users to follow the dynamics of disease incidence and interventions of COVID-19 in France.Time series predictions of hospital incidence are greatly improved by adding these analytics as regressors.Sub-national analysis highlights both spatial correlations of incidence and network analytics to obtain high-precision predictions.

Background Visual hallucinations are common in patients with Parkinson's disease and represent probably the major independent predictor for cognitive deterioration and nursing home placement. Objective To investigate if treatment of minor visual hallucinations in Parkinson's disease with rivastigmine delays the progression to psychosis. Methods A multicenter, randomized, double‐blind, placebo‐controlled trial was conducted which aimed to recruit 168 patients with Parkinson's disease reporting minor visual hallucinations 4 weeks before it. Important exclusion criteria were Parkinson's disease dementia, current delirium, and treatment with antipsychotics or drugs that have significant anti‐cholinergic side effects. Subjects were randomized to rivastigmine capsules, 3–6 mg twice a day, or placebo for 24 months. The primary outcome was the time to Parkinson's disease psychosis, which was defined as the need to start with antipsychotics. Results The trial was stopped prematurely because of slow recruitment. Ninety‐one patients were randomized: 46 patients were assigned to rivastigmine and 45 patients to placebo. No effect of rivastigmine could be demonstrated on the transition time to psychosis or dementia during the 24‐month follow‐up period. After 6 months of study treatment, cognition, mood, motor performance, and non‐motor performance did not differ significantly between the rivastigmine‐group and the placebo‐group. Conclusions Because the study was terminated early, it was insufficiently powered to properly evaluate the primary outcome. The limited data of the study favor a wait and see approach instead of early treatment with rivastigmine in PD patients with minor VH., A randomized controlled trial was conducted to investigate if treatment of minor visual hallucinations in Parkinson's disease with rivastigmine delays the progression to psychosis. The limited data of our study favor a wait and see approach instead of early treatment.

BackgroundDevelopment of antimicrobial use (AMU) surveillance systems in humans and animals is a priority for many low- and middle-income countries; however accurate estimations are hampered by a diversity of animal production systems and metrics. The Mekong Delta region of Vietnam is a ‘hotspot’ of antimicrobial resistance and is home to a high density of humans and animal populations.ObjectivesTo measure and compare AMU using different metrics (standing population, biomass and population correction unit) in the Mekong Delta, and to explore the potential of field-based data collection methods in the design of AMU surveillance systems.MethodsWe collected AMU data from humans and animals (chickens, ducks, Muscovy ducks, pigs) from 101 small-scale farms in the Mekong Delta over a fixed period (90 days in humans, 7 days in animals).ResultsHumans used 7.1 DDDkg, or 175.9 mg of antimicrobial active ingredients (AAIs) per kg of standing body mass annually; animals consumed 60.9 ADDkg or 1324 mg. In the Mekong Delta humans represented 79.3% of the total body mass but consumed 29.6% of AAIs by weight. AAIs regarded of critical importance by WHO represented 56.9% and 50.2% of doses consumed by animals and humans, respectively.ConclusionsUsing a One Health approach, we show that AMU can potentially be estimated from cross-sectional surveys, although results are hypothetical due to small sample size and are sensitive to the chosen population denominator. The methodology proposed here can potentially be scaled up be applied to design AMU surveillance in low-resource settings, allowing AMU reduction efforts to be focused on particular animal species.

Researchers have extensively studied fatigue, depression and anxiety in cancer patients. Several risk and protective factors have been identified for these symptoms. As most studies address these constructs, independently from other symptoms and potential risk and protective factors, more insight into the complex relationships among these constructs is needed. This study used the multivariate network approach to gain a better understanding of how patients’ symptoms and risk and protective factors (i.e. physical symptoms, social withdrawal, illness cognitions, goal adjustment and partner support) are interconnected. We used cross-sectional data from a sample of cancer patients seeking psychological care (n = 342). Using network modelling, the relationships among symptoms of fatigue, depression and anxiety, and potential risk and protective factors were explored. Additionally, centrality (i.e. the number and strength of connections of a construct) and stability of the network were explored. Among risk factors, the relationship of helplessness and physical symptoms with fatigue stood out as they were stronger than most other connections in the network. Among protective factors, illness acceptance was most centrally embedded within the network, indicating it had more and stronger connections than most other variables in the network. The network identified key connections with risk factors (helplessness, physical symptoms) and a key protective factor (acceptance) at the group level. Longitudinal studies should explore these risk and protective factors in individual dynamic networks to further investigate their causal role and the extent to which such networks can inform us on what treatment would be most suitable for the individual cancer patient. Electronic supplementary material The online version of this article (10.1007/s10865-019-00084-7) contains supplementary material, which is available to authorized users.

Background Antimicrobials are used by poultry farmers in Vietnam as a tool to treat and prevent infectious diseases. We aimed to determine the fraction of disease episodes likely to remain untreated due to the administration of antimicrobials on non-susceptible pathogens in chicken flocks in the Mekong Delta of Vietnam. Weekly data on antimicrobial use and clinical signs were collected from 88 randomly chosen chicken flocks over 124 full production cycles (i.e. time between restocking flocks with day-old chicks and sale for slaughter). A naïve Bayes model was trained to infer the probabilities of disease episodes having been caused by each of 24 pathogens, given the observed clinical sign profile, and expert knowledge on their relative incidence. Results A total of 224 disease episodes were observed, of which 44.8% were attributed to viruses (95% CI 31.1–58.4%), 54.6% (CI 40.4–68.7%) to bacteria, and 0.6% (CI 0–1.7%) to a protozoan (Eimeria spp.). Antimicrobials were more frequently administered on weeks with disease than on weeks without disease (43.3% vs. 17.8%; p

IMPORTANCE: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking. OBJECTIVE: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017. INTERVENTIONS: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age. RESULTS: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%). CONCLUSIONS AND RELEVANCE: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication. TRIAL REGISTRATION: Netherlands National Trial Register Identifier: NTR2768. ispartof: JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION vol:321 issue:4 pages:354-363 ispartof: location:United States status: published

A cornerstone of antimicrobial stewardship programs (ASPs) is monitoring quantitative antibiotic use. Frequently used metrics are defined daily dose (DDD) and days of therapy (DOT). The purpose of this study was (1) to explore for the hospital setting the possibilities of quantitative data retrieval on the level of medical specialty and (2) to describe factors affecting the usability and interpretation of these quantitative metrics. We performed a retrospective observational study, measuring overall systemic antibiotic use at specialty level over a 1-year period, from December 1st 2014 to December 1st 2015, in one university and 13 non-university hospitals in the Netherlands. We distinguished surgical and non-surgical adult specialties. The association between DDDs, calculated from aggregated dispensing data, and DOTs, calculated from patient-level prescription data, was explored descriptively and related to organizational factors, data sources (prescription versus dispensing data), data registration, and data extraction. Twelve hospitals were able to extract dispensing data (DDD), three of which on the level of medical specialty; 13 hospitals were able to extract prescription data (DOT), 11 of which by medical specialty. A large variation in quantitative antibiotic use was found between hospitals and the correlation between DDDs and DOTs at specialty level was low. Differences between hospitals related to organizational factors, data sources, data registration, and data extraction procedures likely contributed to the variation in quantitative use and the low correlation between DDDs and DOTs. The differences in healthcare organization, data sources, data registration, and data extraction procedures contributed to the variation in reported quantitative use between hospitals. Uniform registration and extraction procedures are necessary for appropriate measurement and interpretation and benchmarking of quantitative antibiotic use.

Aims This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation. Methods and results We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1–2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0–3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality. Conclusion Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed.

IntroductionLess than one-third of bladder cancers are non-pure urothelial carcinoma [with variant histological (VH) or non-urothelial carcinoma (non-UC)] for which no treatment guidelines are available. We aim to evaluate the efficacy of systemic treatments in VH or non-UC bladder cancers.MaterialsMulticenter retrospective analysis of patients treated for advanced or metastatic VH or non-UC bladder cancers. Primary endpoint was overall response rate (ORR) according to treatment line, regimen and histology subtype. Secondary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsBetween 2005 and 2020, 46 patients from seven centers were included. The median age was 66 years (58.75; 74.75), 65.2% were male and 67.2% presented VH. At first line, the ORR for the entire population was 54.4% and median OS was 21.6 months (95% confidence interval [CI]: 14.2-38.6). The ORR of the 37 patients treated with chemotherapy at first line was 62.2% with median PFS and OS of 7.3 (95% CI: 4.5-8.6) and 21.6 months (95% CI: 14.2-35.7), respectively. Dose dense MVAC and platinum doublet chemotherapy had the highest ORR (71.4% and 65.2%). The 9 patients treated with immunotherapy at first line had an ORR of 22.2%, a median PFS of 3.3 months (95% CI:2.3-NR) and the median OS was not reached (95% CI:13.8-NR). Response to treatment varied depending on the histological sub-types and on the treatment type.ConclusionChemotherapy and immunotherapy have shown to be effective in VH or non-UC cancers, a rare histological subtype for which we currently have very little data in the literature.

Dengue outbreaks have regularly been recorded in Lao People&rsquo, s Democratic Republic (PDR) since the first detection of the disease in 1979. In 2012, an integrated arbovirus surveillance network was set up in Lao PDR and an entomological surveillance has been implemented since 2016 in Vientiane Capital. Here, we report a study combining epidemiological, phylogenetic, and entomological analyzes during the largest DENV-4 epidemic ever recorded in Lao PDR (2015&ndash, 2019). Strikingly, from 2015 to 2019, we reported the DENV-4 emergence and spread at the country level after two large epidemics predominated by DENV-3 and DENV-1, respectively, in 2012&ndash, 2013 and 2015. Our data revealed a significant difference in the median age of the patient infected by DENV-4 compared to the other serotypes. Phylogenetic analysis demonstrated the circulation of DENV-4 Genotype I at the country level since at least 2013. The entomological surveillance showed a predominance of Aedesaegypti compared to Aedesalbopictus and high abundance of these vectors in dry and rainy seasons between 2016 and 2019, in Vientiane Capital. Overall, these results emphasized the importance of an integrated approach to evaluate factors, which could impact the circulation and the epidemiological profile of dengue viruses, especially in endemic countries like Lao PDR.

Background The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from

Background One third of primary prevention implantable cardioverter‐defibrillator patients receive appropriate therapy, but all remain at risk of defibrillator complications. Information on these complications in contemporary cohorts is limited. This study assessed complications and their risk factors after defibrillator implantation in a Dutch nationwide prospective registry cohort and forecasts the potential reduction in complications under distinct scenarios of updated indication criteria. Methods and Results Complications in a prospective multicenter registry cohort of 1442 primary implantable cardioverter‐defibrillator implant patients were classified as major or minor. The potential for reducing complications was derived from a newly developed prediction model of appropriate therapy to identify patients with a low probability of benefitting from the implantable cardioverter‐defibrillator. During a follow‐up of 2.2 years (interquartile range, 2.0–2.6 years), 228 complications occurred in 195 patients (13.6%), with 113 patients (7.8%) experiencing at least one major complication. Most common ones were lead related (n=93) and infection (n=18). Minor complications occurred in 6.8% of patients, with lead‐related (n=47) and pocket‐related (n=40) complications as the most prevailing ones. A surgical reintervention or additional hospitalization was required in 53% or 61% of complications, respectively. Complications were strongly associated with device type. Application of stricter implant indication results in a comparable proportional reduction of (major) complications. Conclusions One in 13 patients experiences at least one major implantable cardioverter‐defibrillator–related complication, and many patients undergo a surgical reintervention. Complications are related to defibrillator implantations, and these should be discussed with the patient. Stricter implant indication criteria and careful selection of device type implanted may have significant clinical and financial benefits.

BackgroundAlthough it is accepted that long-lasting insecticidal net (LLIN) use is an effective means to prevent malaria, children aged 5 to 15 years do not appear to be sufficiently protected in Madagascar; the malaria prevalence is highest in this age group. The purpose of this research is to summarize recent qualitative studies describing LLIN use among the Malagasy people with a focus on children aged 5–15 years.MethodsQualitative data from three studies on malaria conducted between 2012 and 2016 in 10 districts of Madagascar were analysed. These studies cover all malaria epidemiological profiles and 10 of the 18 existing ethnic groups in Madagascar. A thematic analysis was conducted on the collected data from semi-structured interviews, direct observation data, and informal interviews.ResultsA total of 192 semi-structured interviews were conducted. LLINs are generally perceived positively because they protect the health and well-being of users. However, regional representations of mosquito nets may contribute to LLIN lower use by children over 5 years of age including the association between married status and LLIN use, which leads to the refusal of unmarried young men to sleep under LLINs; the custom of covering the dead with a mosquito net, which leads to fear of LLIN use; and taboos governing sleeping spaces for siblings of opposite sexes, which leads to LLIN shortages in households. Children under 5 years of age are known to be the most vulnerable age group for acquiring malaria and, therefore, are prioritized for LLIN use when there are limited supplies in households. In contrast, children over 5 years of age, who are perceived to be at less risk for malaria, often sleep without LLINs.ConclusionsPerceptions, social practices and regional beliefs regarding LLINs and vulnerability to malaria contribute to the nonuse of LLINs among children over 5 years of age in Madagascar. Modifying LLIN policies to account for these factors may increase LLIN use in this age group and reduce disease burden.

The ongoing COVID-19 pandemic emphasizes the importance of understanding exposures to zoonotic reservoirs, active surveillance for pathogens and novel viruses and having feasible testing for quick identification of emerging viruses in future outbreaks. A cohort of 581 individuals working with animals in Vietnam was established (2013–2016). Nasal-throat swabs of the participants and their animals were collected at beginning of each year (no any respiratory symptoms) for baseline data, and whenever the participants reported any respiratory symptom and fever. The analysis shows that the participants were frequently exposed to zoonotic sources by both occupational activities and non-occupational activities (e.g. farming animals surrounding their house, consuming of raw animal blood or meat), or by no or limited use of personal protective equipment, or by exposure to a large variety of animal species. Multiplex RT-PCRs screening for 15 common respiratory viral viruses reveals that enteroviruses and rhinoviruses were predominant viruses detected throughout the study. mNGS analysis of 91 disease-episodes swabs in 2013 successfully detected rhinovirus, enterovirus, influenza A virus, coronavirus OC43, and RSV A in 13 of 15 (86.7%) RT-PCR positive samples (positive controls). Additionally, rotavirus, torque teno virus, human papillomavirus and human betaherpesvirus 7 were also detected. Notably, a vientovirus of a recently discovered Redondoviridae family, a novel cyclovirus, a novel gemycircularvirus and a novel statovirus were also detected and genetically characterized. The results offer important insights into the virome of acute respiratory infections in individuals at high risk of zoonotic infections. The mNGS protocol used here is highly sensitive for sequence-independent detection of a wide range of viruses. Using PCR to screen in all mNGS samples, the virus detection of mNGS were successfully replicated by PCR. However, redondoviruses were additionally detected in 29, the novel cyclovirus in 5, the novel gemycircularvirus in 12 mNGS-negative samples. This result reveals the prevalence of these viruses and emphasizes that standard PCR remains a more sensitive diagnostic test for known viruses than mNGS. No evidence of redondoviruses was found by PCR screenings in nasal-throat swabs of pigs, chicken, Muscovy ducks, ducks and dogs that the virus-positive participants were exposed to. Similarly, the novel statovirus was not detected in animal samples. In contrast, sequences of the novel cyclovirus and gemycircularvirus were found in pig swabs. However, passive contamination in respiratory tracts of both humans and their animals cannot be excluded. Additionally, the same replication gene sequence of redondoviruses was detected in longitudinal samples of several participants, indicating likelihood of redondovirus persistence in the human nasopharynx. Phylogenetic analysis suggests a wide geographic distribution and diversity of redondoviruses. Collectively, these data provided new insights into the high prevalence, widespread, possible chronic shedding in human respiratory tracts and lack of evidence about zoonotic origin of redondoviruses -.

This study was supported by grants PI17/02276 and PI20/01845 from Fondo de Investigaciones Sanitarias (Madrid, Spain) and by intramural funds of GENYO and FIBAO foundation (Granada, Spain). This study was also supported by the Novo Nordisk Fonden (NNF15OC0016932, VA) and Knud og Edith Eriksens Mindefond (VA) and Gigtforeningen (A2037, A3570, VA). JS and KB-K were supported by the grant No. 2016/21/B/NZ5/01901 from the National Science Centre (Poland). MGN was supported by a Spinoza grant from the Netherlands Organization for Scientific Research. YL was supported by an ERC Starting Grant (948207) and the Radboud University Medical Centre Hypatia Grant (2018) for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (DDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (perallele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the metaanalysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated., Instituto de Salud Carlos III PI17/02276 PI20/01845, GENYO foundation (Granada, Spain), FIBAO foundation (Granada, Spain), Novo Nordisk Foundation NNF15OC0016932, Knud og Edith Eriksens Mindefond, Gigtforeningen A2037 A3570, National Science Centre, Poland 2016/21/B/NZ5/01901, Spinoza grant from the Netherlands Organization for Scientific Research, European Research Council (ERC) European Commission 948207, Radboud University Medical Centre Hypatia Grant (2018)

Background: Prolonged or excessive bleeding after cardiac surgery can lead to a broad spectrum of secondary complications. One of the underlying causes is incomplete wound drainage, with subsequent accumulation of blood and clots in the pericardium. We developed the continuous postoperative pericardial flushing (CPPF) therapy to improve wound drainage and reduce postoperative blood loss and bleeding-related complications after cardiac surgery. This study compared CPPF to standard care in patients after coronary artery bypass grafting (CABG).Methods: This is a single center, open label, randomized trial that enrolled patients at the Amsterdam UMC, location AMC, Amsterdam, the Netherlands. The study was registered at the 'Netherlands Trial Register', study identifier NTR5200 [1]. Adults undergoing CABG were randomly assigned to receive CPPF therapy or standard care, participants and investigators were not masked to group assignment. The primary end point was postoperative blood loss in the first 12-hours after surgery.Findings: Between the January 15, 2014 and the March 13, 2017, 169 patients were enrolled and assigned to CPPF therapy (study group; n = 83) or standard care (control group; n = 86). CPPF reduced postoperative blood loss when compared to standard care (median differences -385 ml, reduction 76% p=

BACKGROUND Although evidence-based practice (EBP) has been spreading since the 1990s, it has not yet been sufficiently implemented. AIM Following the reform of initial training for healthcare professions in France 2012, we sought to determine whether the new curriculum was associated with more frequent use of EBP. METHODS We performed an online, cross-sectional survey of nurses, occupational therapists, and podiatrists (divided into pre- and post-reform groups) in June 2018. The questionnaire covered demographic data, use of EBP, and the perception of EBP. As holding a master's degree may enhance knowledge and use of EBP, we adjusted for this variable. Categories to analyze qualitative data were created regarding the five steps in EBP and its definition. RESULTS The total sample was N = 595 (pre-reform group n = 301; post-reform group n = 294). The proportion of respondents who frequently read the professional literature was lower in the post-reform group than in the pre-reform group (33% vs. 54%, respectively; OR [95% CI] = .52 [.37-.73]; p

International audience; Aim Although well documented in randomised trials, the efficacy of prophylaxis against respiratory syncytial virus (RSV) in real-word conditions is less studied. The objective was to assess the impact of partial versus full RSV prophylaxis for acute respiratory infections (ARIs) and ARI-related hospital admissions in preterm children.Methods This study included children born preterm in 2011 in France who were eligible for RSV prophylaxis and received at least one palivizumab dose from October 2011 to March 2012. Full prophylaxis was defined as receiving at least one palivizumab dose for each month of RSV exposure in the community. Children with full and partial prophylaxis were matched, and odds of ARIs and ARI-related hospital admission were compared by logistic regression.Results Full prophylaxis concerned 861/1083 (80%) children. As compared with full prophylaxis, partial prophylaxis was not associated with ARI occurrence (odds ratio OR 1.3, 95% confidence interval CI 0.9-1.9) but was significantly associated with ARI-related hospital admission during the RSV epidemic (OR 1.9, 95% CI 1.2-2.9).Conclusion During the 2011-2012 RSV epidemic, hospital admission rates were higher for preterm children with partial than full RSV prophylaxis. Improving compliance could help alleviate the burden of RSV on healthcare systems.

Objectives To estimate the prevalence of understated cognitive impairment by administering the Clock-Drawing Test (CDT) to community-dwelling individuals aged ≥50 years and to investigate the associated clinical phenotype. Design A cross-sectional analysis of baseline data on community-dwelling individuals assessed at an outpatient clinic in the Paris region of France. Setting and Participants Participants aged ≥50 years (n = 488, median age: 62.1 years) prospectively included in the SUCCessful agEing outpatiEnt's Department survey between 2010 and 2014. Methods A multidimensional geriatric assessment, including cognition [7-point CDT, Mini-Mental State Examination (MMSE), the 5-word screening test (5-WT), and the Frontal Assessment Battery (FAB)], gait speed in dual tasks, mood [the Geriatric Depression Scale (GDS)], balance, physical functions (gait speed and handgrip strength), nutrition, bone density, and comorbidities; major cardiovascular risk factors, and Scheltens and Fazekas scores on brain magnetic resonance imaging. Baseline characteristics were analyzed as a function of the CDT score ( Results The prevalence of impairment in the CDT was 23.6%; higher than the values for the MMSE (12.7%), 5-WT (2.3%), and FAB (16.6%). In age-adjusted analyses, a lower educational level (odds ratio [95% confidence interval] = 0.72 [0.58‒0.89]), diabetes (2.57 [1.14‒5.79]), metabolic syndrome (1.93 [1.05‒3.56]), lower gait speed in the cognitive dual task (1.27 [1.05‒1.53]), a poorer Geriatric Depression Scale score (1.86 [1.04‒3.32]), a poorer MMSE score (2.56 [1.35‒4.88]), a poorer FAB score (1.79 [1.01‒3.16]), impaired episodic memory in the 5-WT (4.11 [1.12‒15.02]), and a higher Scheltens score (P = .001) were significantly associated with CDT impairment. Conclusions and Implications Understated cognitive impairment is common among young seniors and is associated with factors known to be linked to a higher risk of cognitive decline and dementia. These findings suggest that the CDT may be of value for identifying high-risk individuals who may then benefit from targeted multidomain prevention actions (diet, exercise, cognitive training, and vascular risk factor management).

Background Ischemic stroke patients with a good outcome in terms of motor functioning and communication are likely to be discharged home without further rehabilitation. A significant number of these patients experience cognitive and emotional problems resulting in lower quality of life and decreased participation in society. This paper presents the protocol of a study examining the clinical effectiveness, cost-effectiveness and implementation of an intervention focused on screening and patient-tailored care for cognitive and emotional problems as compared to usual care in patients discharged home after ischemic stroke. Methods / design A multicenter, patient-blinded, cluster randomized controlled trial will be performed. Centers will be randomized (1:1) to the intervention group or the usual care group. Patients (> 18 years old) with a neurological confirmed diagnosis of ischemic stroke who can be discharged home without follow-up treatment at an outpatient rehabilitation clinic will be included. In the intervention group, patients will receive a short, individualized, semi-structured consultation by specialized nurses in addition to usual care. This consultation includes 1) screening for cognitive and emotional problems, 2) screening for restrictions in participation, 3) promotion of self-management strategies and 4) a decision tool for referral to rehabilitation services. The intervention will be performed approximately 6 weeks after the stroke at the neurology outpatient clinics and will take approximately 60 min. The control group will receive care as usual. Both groups will be followed-up at 6 weeks, 3 months and 12 months after stroke. The primary outcome will be the level of participation measured with the Restriction subscale of the Utrecht Scale for Evaluation of Rehabilitation on the level of Participation (USER-Participation-R) at 12 months. A cost-effectiveness analysis and process evaluation will be performed alongside. Discussion This trial is the first to evaluate clinical effectiveness, cost-effectiveness and implementation of screening and patient-tailored care for cognitive and emotional problems compared to care as usual in patients discharged home after ischemic stroke. Potentially, this will improve the outcomes for patients with frequently occurring cognitive and emotional problems after stroke. Trial registration Netherlands Trial Register: NL7295, registered 25 September 2018

Objectives Men engaged in high-risk sexual behaviour, such as MSM, are likely to be infected by resistant Mycoplasma genitalium strains. Understanding the transmission dynamics is challenging. We aimed to investigate the molecular epidemiology of M. genitalium in men visiting sexually transmitted infection (STI) clinics. Patients and methods Between June 2017 and February 2018, 95 M. genitalium-positive specimens from 78 men, including 76.9% MSM, visiting two STI clinics in Montpellier, France, were analysed for SNPs in the mgpB adhesin gene and number of tandem repeats in the MG_309 gene. Macrolide and fluoroquinolone resistance were determined. Typing results were compared with antibiotic resistance, sexual behaviour, sampling site, HIV pre-exposure prophylaxis (PrEP) usage and HIV status. Results Thirty-eight mgpB STs were identified, including 23 new STs, with ST4 being most prevalent. The mgpB/MG_309 typing method identified 52 genetic profiles, resulting in a discriminatory index of 0.979. Macrolide and fluoroquinolone resistance-associated mutations were detected in 58.3% and 10.8% of patients, respectively. The macrolide resistance rate was higher among MSM than among men who have sex with women only (68.4% versus 9.1%; adjusted OR, 1.57; 95% CI, 1.13–2.18; P = 0.007). A lower mgpB diversity of 0.870 was found among macrolide-resistant strains in comparison with 0.978 in macrolide-susceptible strains, with an over-representation of mgpB ST62 and ST153. Conclusions Although macrolide resistance spread appears polyclonal in M. genitalium, the lower diversity of mgpB types among macrolide-resistant strains may reflect the easier spread of a few specific mgpB types or the occurrence of sexual networks among MSM.

Avian influenza outbreaks have been occurring on smallholder poultry farms in Asia for two decades. Farmer responses to these outbreaks can slow down or accelerate virus transmission. We used a longitudinal survey of 53 small-scale chicken farms in southern Vietnam to investigate the impact of outbreaks with disease-induced mortality on harvest rate, vaccination, and disinfection behaviors. We found that in small broiler flocks (≤16 birds/flock) the estimated probability of harvest was 56% higher when an outbreak occurred, and 214% higher if an outbreak with sudden deaths occurred in the same month. Vaccination and disinfection were strongly and positively correlated with the number of birds. Small-scale farmers – the overwhelming majority of poultry producers in low-income countries – tend to rely on rapid sale of birds to mitigate losses from diseases. As depopulated birds are sent to markets or trading networks, this reactive behavior has the potential to enhance onward transmission., eLife digest The past few decades have seen the circulation of avian influenza viruses increase in domesticated poultry, regularly creating outbreaks associated with heavy economic loss. In addition, these viruses can sometimes ‘jump’ into humans, potentially allowing new diseases – including pandemics – to emerge. The Mekong river delta, in southern Vietnam, is one of the regions with the highest circulation of avian influenza. There, a large number of farmers practice poultry farming on a small scale, with limited investments in disease prevention such as vaccination or disinfection. Yet, it was unclear how the emergence of an outbreak could change the behavior of farmers. To learn more, Delabouglise et al. monitored 53 poultry farms, with fewer than 1000 chickens per farm, monthly for over a year and a half. In particular, they tracked when outbreaks occurred on each farm, and how farmers reacted. Overall, poultry farms with more than 17 chickens were more likely to vaccinate their animals and use disinfection practices than smaller farms. However, disease outbreaks did not affect vaccination or disinfection practices. When an outbreak occurred, farmers with fewer than 17 chickens tended to sell their animals earlier. For instance, they were 214% more likely to send their animals to market if an outbreak with sudden deaths occurred that month. Even if they do not make as much money selling immature individuals, this strategy may allow them to mitigate economical loss: they can sell animals that may die soon, saving on feeding costs and potentially avoiding further contamination. However, as animals were often sold alive in markets or to itinerant sellers, this practice increases the risk of spreading diseases further along the trade circuits. These data could be most useful to regional animal health authorities, which have detailed knowledge of local farming systems and personal connections in the communities where they work. This can allow them to effect change. They could work with small poultry farmers to encourage them to adopt efficient disease management strategies. Ultimately, this could help control the spread of avian influenza viruses, and potentially help to avoid future pandemics.

The severe respiratory distress syndrome linked to the new coronavirus disease (COVID-19) includes unbearable dyspneic suffering which contributes to the deterioration of the prognosis of patients in intensive care unit (ICU). Patients are put on mechanical ventilation to reduce respiratory suffering and preserve life. Despite this mechanical ventilation, most patients continue to suffer from dyspnea. Dyspnea is a major source of suffering in intensive care and one of the main factors that affect the prognosis of patients. The development of innovative methods for its management, especially non-drug management is more than necessary. In recent years, numerous studies have shown that transcranial direct current stimulation (tDCS) could modulate the perception of acute or chronic pain. In the other hand, it has been shown that the brain zones activated during pain and dyspnea are close and/or superimposed, suggesting that brain structures involved in the integration of aversive emotional component are shared by these two complex sensory experiences. Therefore, it can be hypothesized that stimulation by tDCS with regard to the areas which, in the case of pain have activated one or more of these brain structures, may also have an effect on dyspnea. In addition, our team recently demonstrated that the application of tDCS on the primary cortical motor area can modulate the excitability of the respiratory neurological pathways. Indeed, tDCS in anodal or cathodal modality reduced the excitability of the diaphragmatic cortico-spinal pathways in healthy subjects. We therefore hypothesized that tDCS could relieve dyspnea in COVID-19 patients under mechanical ventilation in ICU. This study was designed to evaluate effects of two modalities of tDCS (anodal and cathodal) vs. placebo, on the relief of dyspnea in COVID-19 patients requiring mechanical ventilation in ICU. Trial Registration: This protocol is derived from the tDCS-DYSP-REA project registered on ClinicalTrials.gov NCT03640455. It will however be registered under its own NCT number.

Objectives:Recruitment to pragmatic trials is often difficult, and little is known about factors associated with key participation and treatment decisions. These were explored in the Prostate cancer testing and Treatment (ProtecT) study. Study Design and Setting:Baseline sociodemographic, patient-reported outcome, clinical history, and prostate cancer biopsy data were collected for all patients eligible to take part in the ProtecT trial, in a comprehensive cohort design. Men who rejected randomization specified a preferred option and were followed up identically to the randomized cohort. Factors associated with participation decisions, patient preferences, and reasons for changing treatment were explored. Results:Of 2,664 men with clinically localized prostate cancer, 997 (37%) rejected randomization. Their treatment preferences and subsequent treatment choices/changes in both randomized and treatment choice cohorts were strongly associated with prostate cancer risk features: toward active monitoring for low-risk disease and toward radical options with higher risk prostate cancer. Among many factors measured, only a small number of weak associations were found for occupation groups and some patient symptoms. Similar percentages changed from the random allocation and initially stated preference. Conclusion:The comprehensive cohort design provided new insights into trial recruitment and participation decisions. Opportunities to improve recruitment by supporting recruiters with equipoise and patient preferences were identified.

Importance: To date, only uncontrolled studies have evaluated the efficacy and safety of endovascular treatment (EVT) in patients with cerebral venous thrombosis (CVT), leading to the lack of recommendations on EVT for CVT.Objective: To evaluate the efficacy and safety of EVT in patients with a severe form of CVT.Design, Setting, and Participants: TO-ACT (Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis) was a multicenter, open-label, blinded end point, randomized clinical trial conducted in 8 hospitals in 3 countries (the Netherlands, China, and Portugal). Patients were recruited from September 2011 to October 2016, and follow-up began in March 2012 and was completed in December 2017. Adult patients with radiologically confirmed CVT who had at least 1 risk factor for a poor outcome (mental status disorder, coma state, intracerebral hemorrhage, or thrombosis of the deep venous system) were included. Data were analyzed according to the intention-to-treat principle from March 2018 to February 2019. The trial was halted after the first interim analysis for reasons of futility.Interventions: Patients were randomized to receive either EVT with standard medical care (intervention group) or guideline-based standard medical care only (control group). The EVT consisted of mechanical thrombectomy, local intrasinus application of alteplase or urokinase, or a combination of both strategies. Patients in the intervention group underwent EVT as soon as possible but no later than 24 hours after randomization.Main Outcomes and Measures: Primary end point was the proportion of patients with a good outcome at 12 months (recovered without a disability; modified Rankin Scale [mRS] score of 0-1). Secondary end points were the proportion of patients with an mRS score of 0 to 1 at 6 months and an mRS score of 0 to 2 at 6 and 12 months, outcome on the mRS across the ordinal continuum at 12 months, recanalization rate, and surgical interventions in relation to CVT. Safety end points included symptomatic intracranial hemorrhage.Results: Of the 67 patients enrolled and randomized, 33 (49%) were randomized to the intervention group and 34 (51%) were randomized to the control group. Patients in the intervention group vs those in the control group were slightly older (median [interquartile range (IQR)] age, 43 [33-50] years vs 38 [23-48] years) and comprised fewer women (23 women [70%] vs 27 women [79%]). The median (IQR) baseline National Institutes of Health Stroke Scale score was 12 (7-20) in the EVT group and 12 (5-20) in the standard care group. At the 12-month follow-up, 22 intervention patients (67%) had an mRS score of 0 to 1 compared with 23 control patients (68%) (relative risk ratio, 0.99; 95% CI, 0.71-1.38). Mortality was not statistically significantly higher in the EVT group (12% [n = 4] vs 3% [n = 1]; P = .20). The frequency of symptomatic intracerebral hemorrhage was not statistically significantly lower in the intervention group (3% [n = 1] vs 9% [n = 3]; P = .61).Conclusions and Relevance: The TO-ACT trial showed that EVT with standard medical care did not appear to improve functional outcome of patients with CVT. Given the small sample size, the possibility exists that future studies will demonstrate better recovery rates after EVT for this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204333.

Background: Excessive bleeding, incomplete wound drainage, and subsequent accumulation of blood and clots in the pericardium have been associated with a broad spectrum of bleeding-related complications after cardiac surgery. We developed and studied the continuous postoperative pericardial flushing (CPPF) method to improve wound drainage and reduce blood loss and bleeding-related complications.Methods: We conducted a single-center, open-label, ITT, randomized controlled trial at the Academic Medical Center Amstserdam. Adults undergoing cardiac surgery for non-emergent valvular or congenital heart disease (CHD) were randomly assigned (1:1) to receive CPPF method or standard care. The primary outcome was actual blood loss after 12-hour stay in the intensive care unit (ICU). Secondary outcomes included bleeding-related complications and clinical outcome after six months follow-up.Findings: Between May 2013 and February 2016, 170 patients were randomly allocated to CPPF method (study group; n = 80) or to standard care (control group; n = 90). CPPF significantly reduced blood loss after 12-hour stay in the ICU (-41%) when compared to standard care (median differences -155 ml, 95% confidence interval (CI) -310 to 0; p=0.001). Cardiac tamponade and reoperation for bleeding did not occur in the study group versus one and three in the control group, respectively. At discharge from hospital, patients in the study group were less likely to have pleural effusion in a surgically opened pleural cavity (22% vs. 36%; p = 0.043).Interpretation: Our study results indicate that CPPF is a safe and effective method to improve chest tube patency and reduce blood loss after cardiac surgery. Larger trials are needed to draw final conclusions concerning the effectiveness of CPPF on clinically relevant outcomes. (C) 2020 The Author(s). Published by Elsevier B.V.

Objectives: To investigate whether antibiotic treatment of 6 days' duration is non-inferior to treatment for 12 days in patients hospitalized for cellulitis. Methods: This multicentre, randomized, double-blind, placebo-controlled, non-inferiority trial enrolled adult patients hospitalized for severe cellulitis who were treated with intravenous flucloxacillin. At day 6 participants with symptom improvement who were afebrile were randomized between an additional 6 days of oral flucloxacillin or placebo in a 1:1 ratio, stratified for diabetes and hospital. The primary outcome was cure by day 14, without relapse by day 28. Secondary outcomes included a modified cure assessment and relapse rate by day 90. Results: Between August 2014 and June 2017, 151 of 248 included participants were randomized. The intention-to-treat population consisted of 76 and 73 participants allocated to 12 and 6 days of antibiotic therapy, respectively (mean age 62 years, 67% males, 24% diabetics); 38/76 (50.0%) and 36/73 (49.3%) were cured in the 12- and 6-day groups respectively (ARR 0.7 percentage points, 95%CI: –15.0 to 16.3). Cure rates were 56/76 (73.7%) and 49/73 (67.1%) with the modified cure assessment (ARR 6.6, 95%CI: –8.0 to 20.8). After initial cure without relapse, day 90 relapse rates were higher in the 6-day group (6% versus 24%, p < 0.05). Conclusions: Given the wide confidence intervals, we can neither confirm nor refute our hypothesis that 6 days of therapy is non-inferior to 12 days of therapy. However, a 6-day course resulted in significantly more frequent relapses by day 90. These findings require confirmation in future studies.

32 páginas, 7figuras, 9 tablas. This project contains European Nucleotide Archive accession numbers for Illumina sequence data and associated metatdata, Two billion people are infected with Mycobacterium tuberculosis, leading to 10 million new cases of active tuberculosis and 1.5 million deaths annually. Universal access to drug susceptibility testing (DST) has become a World Health Organization priority. We previously developed a software tool, Mykrobe predictor, which provided offline species identification and drug resistance predictions for M. tuberculosis from whole genome sequencing (WGS) data. Performance was insufficient to support the use of WGS as an alternative to conventional phenotype-based DST, due to mutation catalogue limitations. Here we present a new tool, Mykrobe, which provides the same functionality based on a new software implementation. Improvements include i) an updated mutation catalogue giving greater sensitivity to detect pyrazinamide resistance, ii) support for user-defined resistance catalogues, iii) improved identification of non-tuberculous mycobacterial species, and iv) an updated statistical model for Oxford Nanopore Technologies sequencing data. Mykrobe is released under MIT license at https://github.com/mykrobe-tools/mykrobe. We incorporate mutation catalogues from the CRyPTIC consortium et al. (2018) and from Walker et al. (2015), and make improvements based on performance on an initial set of 3206 and an independent set of 5845 M. tuberculosis Illumina sequences. To give estimates of error rates, we use a prospectively collected dataset of 4362 M. tuberculosis isolates. Using culture based DST as the reference, we estimate Mykrobe to be 100%, 95%, 82%, 99% sensitive and 99%, 100%, 99%, 99% specific for rifampicin, isoniazid, pyrazinamide and ethambutol resistance prediction respectively. We benchmark against four other tools on 10207 (=5845+4362) samples, and also show that Mykrobe gives concordant results with nanopore data. We measure the ability of Mykrobe-based DST to guide personalized therapeutic regimen design in the context of complex drug susceptibility profiles, showing 94% concordance of implied regimen with that driven by phenotypic DST, higher than all other benchmarked tools., ZI was funded by a Wellcome Trust/Royal Society Sir Henry Dale Fellowship, grant number 102541. MH was supported by Wellcome Trust/Newton Fund-MRC Collaborative Award [200205]; and Bill & Melinda Gates Foundation Trust [OPP1133541]. TMW is a Wellcome Trust Clinical Career Development Fellow, grant number 214560. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background Tuberculosis (TB) is a major global health burden, with an estimated quarter of the world’s population being infected. The World Health Organization (WHO) launched the “End TB Strategy” in 2014 emphasising knowing the epidemic. WHO ranks Vietnam 12th in the world of high burden countries. TB spatial and temporal patterns have been observed globally with evidence of Vitamin D playing a role in seasonality. We explored the presence of temporal and spatial clustering of TB in Vietnam and their determinants to aid public health measures. Methods Data were collected by the National TB program of Vietnam from 2010 to 2015 and linked to the following datasets: socio-demographic characteristics; climatic variables; influenza-like-illness (ILI) incidence; geospatial data. The TB dataset was aggregated by province and quarter. Descriptive time series analyses using LOESS regression were completed per province to determine seasonality and trend. Harmonic regression was used to determine the amplitude of seasonality by province. A mixed-effect linear model was used with province and year as random effects and all other variables as fixed effects. Results There were 610,676 cases of TB notified between 2010 and 2015 in Vietnam. Heat maps of TB incidence per quarter per province showed substantial temporal and geospatial variation. Time series analysis demonstrated seasonality throughout the country, with peaks in spring/summer and troughs in autumn/winter. Incidence was consistently higher in the south, the three provinces with the highest incidence per 100,000 population were Tay Ninh, An Giang and Ho Chi Minh City. However, relative seasonal amplitude was more pronounced in the north. Mixed-effect linear model confirmed that TB incidence was associated with time and latitude. Of the demographic, socio-economic and health related variables, population density, percentage of those under 15 years of age, and HIV infection prevalence per province were associated with TB incidence. Of the climate variables, absolute humidity, average temperature and sunlight were associated with TB incidence. Conclusion Preventative public health measures should be focused in the south of Viet Nam where incidence is highest. Vitamin D is unlikely to be a strong driver of seasonality but supplementation may play a role in a package of interventions.

About 10–20% of patients with Kawasaki disease (KD) are unresponsive to intravenous immunoglobulin (IVIg) and are at increased risk of coronary artery abnormalities (CAAs). Early identification is critical to initiate aggressive therapies, but available scoring systems lack sensitivity in non-Japanese populations. We investigated the accuracy of 3 Japanese scoring systems and studied factors associated with IVIg unresponsiveness in a large multiethnic French population of children with KD to build a new scoring system. Children admitted for KD between 2011–2014 in 65 centers were enrolled. Factors associated with second line-treatment; i.e. unresponsiveness to initial IVIg treatment, were analyzed by multivariate regression analysis. The performance of our score and the Kobayashi, Egami and Sano scores were compared in our population and in ethnic subgroups. Overall, 465 children were reported by 84 physicians; 425 were classified with KD (55% European Caucasian, 12% North African/Middle Eastern, 10% African/Afro-Caribbean, 3% Asian and 11% mixed). Eighty patients (23%) needed second-line treatment. Japanese scores had poor performance in our whole population (sensitivity 14–61%). On multivariate regression analysis, predictors of secondary treatment after initial IVIG were hepatomegaly, ALT level ≥30 IU/L, lymphocyte count 3 and time to treatment

STUDY QUESTIONIs there a difference in the risk of serious maternal complications during pregnancy and the postpartum in twin pregnancies according to mode of conception: natural conception, non-IVF fertility treatment, IVF, ICSI or oocyte donation?SUMMARY ANSWERWomen with twin pregnancies after medically assisted reproduction (MAR) had an overall risk of serious maternal complications 30% higher compared with women with natural twin pregnancies, and this association varied according to the MAR procedure; the risk was increased by 50% with IVF using autologous oocytes and by 270% with oocyte donation.WHAT IS KNOWN ALREADYIVF has been reported as a risk factor for serious maternal complications in several concordant studies of singleton pregnancies. For twin pregnancies, this association is less well documented with imprecise categorisation of the mode of conception, and results are contradictory.STUDY DESIGN, SIZE, DURATIONThis is a secondary analysis of the national, observational, prospective, population-based cohort study of twin pregnancies (JUmeaux Mode d’Accouchement), which took place in France from 10 February 2014 through 1 March 2015. All French maternity units performing more than 1500 annual deliveries were invited to participate, regardless of their academic, public or private status or level of care. Of the 191 eligible units, 176 (92%) participated.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen with a twin pregnancy who gave birth at or after 22 weeks of gestation were eligible (N = 8823 women included). We excluded women whose mode of conception was unknown (n = 75). Serious maternal complications were regrouped within the recently emerged concept of severe acute maternal morbidity (SAMM), as a binary composite outcome. The exposure of interest was the mode of conception, studied in five classes: natural conception (reference group), non-IVF fertility treatment including insemination and ovarian stimulation, IVF with autologous oocyte, ICSI with autologous oocyte and oocyte donation. To assess the association between the mode of conception and SAMM, we used multivariate logistic regression to adjust for confounders. Structural equation modelling (SEM) was used to explore the contribution to this association of potential intermediate factors, i.e. factors possibly caused by the mode of conception and responsible for SAMM: non-severe pre-eclampsia, placenta praevia and planned mode of delivery.MAIN RESULTS AND THE ROLE OF CHANCEAmong the 8748 women of the study population, 5890 (67.3%) conceived naturally, 854 (9.8%) had non-IVF fertility treatment, 1307 (14.9%) had IVF with autologous oocytes, 368 (4.2%) had ICSI with autologous oocytes and 329 (3.8%) used oocyte donation. Overall, 538 (6.1%) developed SAMM. Women with twin pregnancy after any type of MAR had a higher risk of SAMM than those with a natural twin pregnancy, after adjustment for confounders (7.9% (227/2858) compared to 5.3% (311/5890), adjusted odds ratio (aOR) 1.3, 95% CI 1.1–1.6). This association varied according to the MAR procedure. The risk of SAMM was higher among women with IVF using either autologous oocytes (8.3%; 108/1307) or oocyte donation (14.0%; 46/329) compared with the reference group (respectively aOR 1.5, 95% CI 1.1–1.9 and aOR 2.7, 95% CI 1.8–4.1) and higher after oocyte donation compared with autologous oocytes (aOR 1.7, 95% CI 1.1–2.6). Conversely, the risk of SAMM for women with non-IVF fertility treatment (6.2%; 53/854) and with ICSI using autologous oocytes (5.4%; 20/368) did not differ from that of the reference group (5.3%; 311/5890) (respectively aOR 1.1, 95% CI 0.8–1.5 and aOR 0.9, 95% CI 0.6–1.5). The tested intermediate factors poorly explained these increased risks.LIMITATIONS, REASONS FOR CAUTIONBeyond the confounders and intermediate factors considered in our analysis, specific causes of infertility and specific aspects of infertility treatments may explain the differences in the risk of SAMM by mode of conception. However, these data were not available.WIDER IMPLICATIONS OF THE FINDINGSOur study showed an increased risk of SAMM in women with twin pregnancies after MAR, notably after IVF using autologous oocytes and particularly after oocyte donation. To avoid unnecessary exposure to the high-risk combination of MAR and multiple pregnancies, transfer of a single embryo should be encouraged whenever possible. Knowledge of these differential risks may inform discussions between clinicians and women about the mode of conception and help to optimise obstetric care for women in subgroups at higher risk.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique, AOM2012). There are no competing interests.TRIAL REGISTRATION NUMBERNot applicable.

Objective To determine risk factors of severe acute maternal morbidity in women with twin pregnancies and identify subgroups at high risk. Methods In a prospective, population-based study of twin deliveries, the JUMODA cohort, all women with twin pregnancies at or after 22 weeks of gestation were recruited in 176 French hospitals. Severe acute maternal morbidity was a composite criterion. We determined its risk factors by multilevel multivariate Poisson regression modeling and identified high-risk subgroups by classification and regression tree (CART) analysis, in two steps: first considering only characteristics known at the beginning of pregnancy and then adding factors arising during its course. Results Among the 8,823 women with twin pregnancies, 542 (6.1%, 95% confidence interval (CI) 5.6–6.6) developed severe acute maternal morbidity. Risk factors for severe maternal morbidity identified at the beginning of pregnancy were maternal birth in sub-Saharan Africa (adjusted relative risk (aRR) 1.6, 95% CI 1.1–2.3), preexisting insulin-treated diabetes (aRR 2.2, 95% CI 1.1–4.4), nulliparity (aRR 1.6, 95% CI 1.3–2.0), IVF with autologous oocytes (aRR, 1.3, 95% CI, 1.0–1.6), and oocyte donation (aRR 2.0, 95% CI 1.4–2.8); CART analysis identified nulliparous women with oocyte donation as the subgroup at highest risk (SAMM rate: 14.7%, 95% CI, 10.3–19.1). At the end of pregnancy, additional risk factors identified were placenta praevia (aRR 3.5, 95% CI 2.3–5.3), non-severe preeclampsia (aRR 2.5, 95% CI 1.9–3.2), and macrosomia for either twin (aRR 1.7, 95% CI 1.3–2.1); CART analysis identified women with both oocyte donation and non-severe preeclampsia (SAMM rate: 28.9%, 95% CI, 19.9–37.9) and sub-Saharan nulliparous women with non-severe preeclampsia (SAMM rate: 26.9%, 95% CI, 9.9–43.9) as the two subgroups at highest risk. Conclusion In woman with twin pregnancy, rates of severe acute maternal morbidity vary between subgroups from 4.6% to 14.7% and from 3.8% to 28.9% at the beginning and at the end of pregnancy respectively, depending on the combined presence of risk factors.

Author(s): Phommasone, Koukeo; van Leth, Frank; Peto, Thomas J; Landier, Jordi; Nguyen, Thuy-Nhien; Tripura, Rupam; Pongvongsa, Tiengkham; Lwin, Khin Maung; Kajeechiwa, Ladda; Thwin, May Myo; Parker, Daniel M; Wiladphaingern, Jacher; Nosten, Suphak; Proux, Stephane; Nguon, Chea; Davoeung, Chan; Rekol, Huy; Adhikari, Bipin; Promnarate, Cholrawee; Chotivanich, Kesinee; Hanboonkunupakarn, Borimas; Jittmala, Podjanee; Cheah, Phaik Yeong; Dhorda, Mehul; Imwong, Mallika; Mukaka, Mavuto; Peerawaranun, Pimnara; Pukrittayakamee, Sasithon; Newton, Paul N; Thwaites, Guy E; Day, Nicholas PJ; Mayxay, Mayfong; Hien, Tran Tinh; Nosten, Francois H; Cobelens, Frank; Dondorp, Arjen M; White, Nicholas J; von Seidlein, Lorenz | Abstract: BackgroundMass administrations of antimalarial drugs (MDA) have reduced the incidence and prevalence of P. falciparum infections in a trial in the Greater Mekong Subregion. Here we assess the impact of the MDA on P. vivax infections.MethodsBetween May 2013 and July 2017, four villages in each Myanmar, Vietnam, Cambodia and Lao PDR were selected based on high prevalence of P. falciparum infections. Eight of the 16 villages were randomly assigned to receive MDA consisting of three-monthly rounds of three-day courses of dihydroartemisinin-piperaquine and, except in Cambodia, a single low-dose of primaquine. Cross-sectional surveys were conducted at quarterly intervals to detect Plasmodium infections using ultrasensitive qPCR. The difference in the cumulative incidence between the groups was assessed through a discrete time survival approach, the difference in prevalence through a difference-in-difference analysis, and the difference in the number of participants with a recurrence of P. vivax infection through a mixed-effect logistic regression.Results3,790 (86%) residents in the intervention villages participated in at least one MDA round, of whom 2,520 (57%) participated in three rounds. The prevalence of P. vivax infections fell from 9.31% to 0.89% at month 3 but rebounded by six months to 5.81%. There was no evidence that the intervention reduced the cumulative incidence of P.vivax infections (95% confidence interval [CI] Odds ratio (OR): 0.29 to 1.36). Similarly, there was no evidence of MDA related reduction in the number of participants with at least one recurrent infection (OR: 0.34; 95% CI: 0.08 to 1.42).ConclusionMDA with schizontocidal drugs had a lasting effect on P. falciparum infections but only a transient effect on the prevalence of P. vivax infections. Radical cure with an 8-aminoquinoline will be needed for the rapid elimination of vivax malaria.