Transforming Growth Factor β Receptor Type 1 Is Essential for Female Reproductive Tract Integrity and Function

The transforming growth factor β (TGFβ) superfamily proteins are principle regulators of numerous biological functions. Although recent studies have gained tremendous insights into this growth factor family in female reproduction, the functions of the receptors in vivo remain poorly defined. TGFβ type 1 receptor (TGFBR1), also known as activin receptor-like kinase 5, is the major type 1 receptor for TGFβ ligands. Tgfbr1 null mice die embryonically, precluding functional characterization of TGFBR1 postnatally. To study TGFBR1–mediated signaling in female reproduction, we generated a mouse model with conditional knockout (cKO) of Tgfbr1 in the female reproductive tract using anti-Müllerian hormone receptor type 2 promoter-driven Cre recombinase. We found that Tgfbr1 cKO females are sterile. However, unlike its role in growth differentiation factor 9 (GDF9) signaling in vitro, TGFBR1 seems to be dispensable for GDF9 signaling in vivo. Strikingly, we discovered that the Tgfbr1 cKO females develop oviductal diverticula, which impair embryo development and transit of embryos to the uterus. Molecular analysis further demonstrated the dysregulation of several cell differentiation and migration genes (e.g., Krt12, Ace2, and MyoR) that are potentially associated with female reproductive tract development. Moreover, defective smooth muscle development was also revealed in the uteri of the Tgfbr1 cKO mice. Thus, TGFBR1 is required for female reproductive tract integrity and function, and disruption of TGFBR1–mediated signaling leads to catastrophic structural and functional consequences in the oviduct and uterus

Establishment and cryptic transmission of Zika virus in Brazil and the Americas

University of Oxford. Department of Zoology, Oxford, UK / Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.University of Birmingham. Institute of Microbiology and Infection. Birmingham, UK.University of Oxford. Department of Zoology. Oxford UK.University of Oxford. Department of Zoology. Oxford, UK / Harvard Medical School. Boston, MA, USA / Boston Children's Hospital. Boston, MA, USA.University of Oxford. Department of Zoology. Oxford, UK.Fred Hutchinson Cancer Research Center. Vaccine and Infectious Disease Division. Seattle, WA, USA / University of Washington. Department of Epidemiology. Seattle, WA, USA.University of São Paulo. School of Medicine &Institute of Tropical Medicine. Department of Infectious Disease. São Paulo, SP, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.University of Oxford. Department of Statistics. Oxford, UK.University of Oxford. Department of Zoology. Oxford, UK.Institut Pasteur. Biostatistics and Integrative Biology. Mathematical Modelling of Infectious Diseases and Center of Bioinformatics. Paris, FR / Centre National de la Recherche Scientifique. Paris, FR.University of Oxford. Department of Zoology. Oxford, UK.Ministry of Health. Coordenação dos Laboratórios de Saúde. Brasília, DF, Brazil.Ministry of Health. Coordenação Geral de Vigilância e Resposta às Emergências em Saúde Pública. Brasília, DF, Brazil / Fundação Oswaldo Cruz. Center of Data and Knowledge Integration for Health. Salvador, BA, Brazil.Ministry of Health. Departamento de Vigilância das Doenças Transmissíveis. Brasilia, DF, Brazil.Ministry of Health. Coordenação Geral dos Programas de Controle e Prevenção da Malária e das Doenças Transmitidas pelo Aedes. Brasília, DF, Brazil / Pan American Health Organization (PAHO). Buenos Aires, AR.Ministry of Health. Coordenação Geral dos Programas de Controle e Prevenção da Malária e das Doenças Transmitidas pelo Aedes. Brasília, DF, Brazil / Fundação Oswaldo Cruz. Rio de Janeiro, RJ, Brazil.Ministry of Health. Coordenação Geral dos Programas de Controle e Prevenção da Malária e das Doenças Transmitidas pelo Aedes. Brasília, DF, BrazilMinistry of Health. Departamento de Vigilância das Doenças Transmissíveis. Brasilia, DF, Brazil.Ontario Institute for Cancer Research. Toronto, ON, Canada.University of Nottingham. Nottingham, UKThe Scripps Research Institute. Department of Immunology and Microbial Science. La Jolla, CA, USA.The Scripps Research Institute. Department of Immunology and Microbial Science. La Jolla, CA, USA.University of California. Departments of Laboratory Medicine and Medicine & Infectious Diseases. San Francisco, CA, USA.University of California. Departments of Laboratory Medicine and Medicine & Infectious Diseases. San Francisco, CA, USA.Instituto Mexicano del Seguro Social. División de Laboratorios de Vigilancia e Investigación Epidemiológica. Ciudad de México, MC.Instituto Mexicano del Seguro Social. División de Laboratorios de Vigilancia e Investigación Epidemiológica. Ciudad de México, MC.Universidad Nacional Autónoma de México. Instituto de Biotecnología. Cuernavaca, MC.Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brazil.Paul-Ehrlich-Institut. Langen, Germany.Laboratório Central de Saúde Pública Noel Nutels. Rio de Janeiro, RJ, Brazil.Laboratório Central de Saúde Pública Noel Nutels. Rio de Janeiro, RJ, Brazil.Laboratório Central de Saúde Pública Noel Nutels. Rio de Janeiro, RJ, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Fundação Oswaldo Cruz. Salvador, BA, Brazil.Laboratório Central de Saúde Pública. Natal, RN, Brazil.Laboratório Central de Saúde Pública. Natal, RN, Brazil / Universidade Potiguar. Natal, RN, Brazil.Laboratório Central de Saúde Pública. Natal, RN, Brazil / Faculdade Natalense de Ensino e Cultura. Natal, RN, Brazil.Laboratório Central de Saúde Pública. João Pessoa, PB, Brazil.Laboratório Central de Saúde Pública. João Pessoa, PB, Brazil.Laboratório Central de Saúde Pública. João Pessoa, PB, Brazil.Laboratório Central de Saúde Pública. João Pessoa, PB, Brazil.Fundação Oswaldo Cruz. Recife, PE, Brazil.Fundação Oswaldo Cruz. Recife, PE, Brazil.Fundação Oswaldo Cruz. Recife, PE, Brazil / Colorado State University. Department of Microbiology, Immunology &Pathology. Fort Collins, CO, USA.Fundação Oswaldo Cruz. Recife, PE, Brazil.Heidelberg University Hospital. Department for Infectious Diseases. Section Clinical Tropical Medicine. Heidelberg, Germany.Fundação Oswaldo Cruz. Recife, PE, Brazil.Laboratório Central de Saúde Pública. Maceió, AL, Brazil.Laboratório Central de Saúde Pública. Maceió, AL, Brazil.Laboratório Central de Saúde Pública. Maceió, AL, Brazil.Universidade Estadual de Feira de Santana. Feira de Santana, BA, Brazil.Secretaria de Saúde de Feira de Santana. Feira de Santana, BA, Brazil.Universidade Federal do Amazonas. Manaus, AM, Brazil.University of São Paulo. School of Medicine &Institute of Tropical Medicine. Department of Infectious Disease. São Paulo, SP, Brazil.University of São Paulo. School of Medicine &Institute of Tropical Medicine. Department of Infectious Disease. São Paulo, SP, Brazil.Hospital São Francisco. Ribeirão Preto, SP, Brazil.University of São Paulo. School of Medicine &Institute of Tropical Medicine. Department of Infectious Disease. São Paulo, SP, Brazil.Universidade Federal do Tocantins. Palmas, TO, Brazil.University of São Paulo. School of Medicine &Institute of Tropical Medicine. Department of Infectious Disease. São Paulo, SP, Brazil.University of Sydney. Sydney, Australia.University of Edinburgh. Institute of Evolutionary Biology. Edinburgh, UK / National Institutes of Health. Fogarty International Center. Bethesda, MD, USA.Fred Hutchinson Cancer Research Center. Vaccine and Infectious Disease Division. Seattle, WA, USA.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil / University of Texas Medical Branch. Department of Pathology. Galveston, TX, USA.University of São Paulo. School of Medicine &Institute of Tropical Medicine. Department of Infectious Disease. São Paulo, SP, Brazil.Fundação Oswaldo Cruz. Salvador, BA, Brazil.University of Birmingham. Institute of Microbiology and Infection. Birmingham, UK.University of Oxford. Department of Zoology, Oxford, UK / Metabiota. San Francisco, CA, USA.University of São Paulo. School of Medicine &Institute of Tropical Medicine. Department of Infectious Disease. São Paulo, SP, Brazil.Fundação Oswaldo Cruz. Salvador, BA, Brazil.Fundação Oswaldo Cruz. Salvador, BA, Brazil / University of Rome Tor Vergata. Rome, Italy.Transmission of Zika virus (ZIKV) in the Americas was first confirmed in May 2015 in northeast Brazil. Brazil has had the highest number of reported ZIKV cases worldwide (more than 200,000 by 24 December 2016) and the most cases associated with microcephaly and other birth defects (2,366 confirmed by 31 December 2016). Since the initial detection of ZIKV in Brazil, more than 45 countries in the Americas have reported local ZIKV transmission, with 24 of these reporting severe ZIKV-associated disease. However, the origin and epidemic history of ZIKV in Brazil and the Americas remain poorly understood, despite the value of this information for interpreting observed trends in reported microcephaly. Here we address this issue by generating 54 complete or partial ZIKV genomes, mostly from Brazil, and reporting data generated by a mobile genomics laboratory that travelled across northeast Brazil in 2016. One sequence represents the earliest confirmed ZIKV infection in Brazil. Analyses of viral genomes with ecological and epidemiological data yield an estimate that ZIKV was present in northeast Brazil by February 2014 and is likely to have disseminated from there, nationally and internationally, before the first detection of ZIKV in the Americas. Estimated dates for the international spread of ZIKV from Brazil indicate the duration of pre-detection cryptic transmission in recipient regions. The role of northeast Brazil in the establishment of ZIKV in the Americas is further supported by geographic analysis of ZIKV transmission potential and by estimates of the basic reproduction number of the virus

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien–Dindo classification system. Results: A total of 3288 patients were included in the analysis, of whom 301 (9·2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4–7) and 7 (6–8) days respectively (P < 0·001). There were no significant differences in rates of readmission between these groups (6·6 versus 8·0 per cent; P = 0·499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0·90, 95 per cent c.i. 0·55 to 1·46; P = 0·659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34·7 versus 39·5 per cent; major 3·3 versus 3·4 per cent; P = 0·110). Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Safety and efficacy of non-steroidal anti-inflammatory drugs to reduce ileus after colorectal surgery

Background: Ileus is common after elective colorectal surgery, and is associated with increased adverse events and prolonged hospital stay. The aim was to assess the role of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing ileus after surgery. Methods: A prospective multicentre cohort study was delivered by an international, student- and trainee-led collaborative group. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The primary outcome was time to gastrointestinal recovery, measured using a composite measure of bowel function and tolerance to oral intake. The impact of NSAIDs was explored using Cox regression analyses, including the results of a centre-specific survey of compliance to enhanced recovery principles. Secondary safety outcomes included anastomotic leak rate and acute kidney injury. Results: A total of 4164 patients were included, with a median age of 68 (i.q.r. 57\u201375) years (54\ub79 per cent men). Some 1153 (27\ub77 per cent) received NSAIDs on postoperative days 1\u20133, of whom 1061 (92\ub70 per cent) received non-selective cyclo-oxygenase inhibitors. After adjustment for baseline differences, the mean time to gastrointestinal recovery did not differ significantly between patients who received NSAIDs and those who did not (4\ub76 versus 4\ub78 days; hazard ratio 1\ub704, 95 per cent c.i. 0\ub796 to 1\ub712; P = 0\ub7360). There were no significant differences in anastomotic leak rate (5\ub74 versus 4\ub76 per cent; P = 0\ub7349) or acute kidney injury (14\ub73 versus 13\ub78 per cent; P = 0\ub7666) between the groups. Significantly fewer patients receiving NSAIDs required strong opioid analgesia (35\ub73 versus 56\ub77 per cent; P < 0\ub7001). Conclusion: NSAIDs did not reduce the time for gastrointestinal recovery after colorectal surgery, but they were safe and associated with reduced postoperative opioid requirement

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system. Results A total of 3288 patients were included in the analysis, of whom 301 (9 center dot 2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P < 0 center dot 001). There were no significant differences in rates of readmission between these groups (6 center dot 6 versus 8 center dot 0 per cent; P = 0 center dot 499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0 center dot 90, 95 per cent c.i. 0 center dot 55 to 1 center dot 46; P = 0 center dot 659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34 center dot 7 versus 39 center dot 5 per cent; major 3 center dot 3 versus 3 center dot 4 per cent; P = 0 center dot 110). Conclusion Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function.Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system.Results: A total of 3288 patients were included in the analysis, of whom 301 (9.2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P < 0.001). There were no significant differences in rates of readmission between these groups (6.6 versus 8.0 per cent; P = 0.499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0.90, 95 per cent c.i. 0.55 to 1.46; P = 0.659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34.7 versus 39.5 per cent; major 3.3 versus 3.4 per cent; P = 0.110).Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Timing of nasogastric tube insertion and the risk of postoperative pneumonia: an international, prospective cohort study

Aim: Aspiration is a common cause of pneumonia in patients with postoperative ileus. Insertion of a nasogastric tube (NGT) is often performed, but this can be distressing. The aim of this study was to determine whether the timing of NGT insertion after surgery (before versus after vomiting) was associated with reduced rates of pneumonia in patients undergoing elective colorectal surgery. Method: This was a preplanned secondary analysis of a multicentre, prospective cohort study. Patients undergoing elective colorectal surgery between January 2018 and April 2018 were eligible. Those receiving a NGT were divided into three groups, based on the timing of the insertion: routine NGT (inserted at the time of surgery), prophylactic NGT (inserted after surgery but before vomiting) and reactive NGT (inserted after surgery and after vomiting). The primary outcome was the development of pneumonia within 30 days of surgery, which was compared between the prophylactic and reactive NGT groups using multivariable regression analysis. Results: A total of 4715 patients were included in the analysis and 1536 (32.6%) received a NGT. These were classified as routine in 926 (60.3%), reactive in 461 (30.0%) and prophylactic in 149 (9.7%). Two hundred patients (4.2%) developed pneumonia (no NGT 2.7%; routine NGT 5.2%; reactive NGT 10.6%; prophylactic NGT 11.4%). After adjustment for confounding factors, no significant difference in pneumonia rates was detected between the prophylactic and reactive NGT groups (odds ratio 1.03, 95% CI 0.56\u20131.87, P = 0.932). Conclusion: In patients who required the insertion of a NGT after surgery, prophylactic insertion was not associated with fewer cases of pneumonia within 30 days of surgery compared with reactive insertion

Timing of nasogastric tube insertion and the risk of postoperative pneumonia: an international, prospective cohort study

Aim: Aspiration is a common cause of pneumonia in patients with postoperative ileus. Insertion of a nasogastric tube (NGT) is often performed, but this can be distressing. The aim of this study was to determine whether the timing of NGT insertion after surgery (before versus after vomiting) was associated with reduced rates of pneumonia in patients undergoing elective colorectal surgery. Method: This was a preplanned secondary analysis of a multicentre, prospective cohort study. Patients undergoing elective colorectal surgery between January 2018 and April 2018 were eligible. Those receiving a NGT were divided into three groups, based on the timing of the insertion: routine NGT (inserted at the time of surgery), prophylactic NGT (inserted after surgery but before vomiting) and reactive NGT (inserted after surgery and after vomiting). The primary outcome was the development of pneumonia within 30 days of surgery, which was compared between the prophylactic and reactive NGT groups using multivariable regression analysis. Results: A total of 4715 patients were included in the analysis and 1536 (32.6%) received a NGT. These were classified as routine in 926 (60.3%), reactive in 461 (30.0%) and prophylactic in 149 (9.7%). Two hundred patients (4.2%) developed pneumonia (no NGT 2.7%; routine NGT 5.2%; reactive NGT 10.6%; prophylactic NGT 11.4%). After adjustment for confounding factors, no significant difference in pneumonia rates was detected between the prophylactic and reactive NGT groups (odds ratio 1.03, 95% CI 0.56–1.87, P = 0.932). Conclusion: In patients who required the insertion of a NGT after surgery, prophylactic insertion was not associated with fewer cases of pneumonia within 30 days of surgery compared with reactive insertion