RESUMEN
OBJECTIVE: To investigate the effect of interpregnancy interval (IPI) on preterm birth (PTB) according to whether the previous birth was preterm or term. DESIGN: Cohort study. SETTING: USA (California), Australia, Finland, Norway (1980-2017). POPULATION: Women who gave birth to first and second (n = 3 213 855) singleton livebirths. METHODS: Odds ratios (ORs) for PTB according to IPIs were modelled using logistic regression with prognostic score stratification for potential confounders. Within-site ORs were pooled by random effects meta-analysis. OUTCOME MEASURE: PTB (gestational age <37 weeks). RESULTS: Absolute risk of PTB for each IPI was 3-6% after a previous term birth and 17-22% after previous PTB. ORs for PTB differed between previous term and preterm births in all countries (P-for-interaction ≤ 0.001). For women with a previous term birth, pooled ORs were increased for IPI <6 months (OR 1.50, 95% CI 1.43-1.58); 6-11 months (OR 1.10, 95% CI 1.04-1.16); 24-59 months (OR 1.16, 95% CI 1.13-1.18); and ≥ 60 months (OR 1.72, 95%CI 1.60-1.86), compared with 18-23 months. For previous PTB, ORs were increased for <6 months (OR 1.30, 95% CI 1.18-1.42) and ≥60 months (OR 1.29, 95% CI 1.17-1.42), but were less than ORs among women with a previous term birth (P < 0.05). CONCLUSIONS: Associations between IPI and PTB are modified by whether or not the previous pregnancy was preterm. ORs for short and long IPIs were higher among women with a previous term birth than a previous PTB, which for short IPI is consistent with the maternal depletion hypothesis. Given the high risk of recurrence and assuming a causal association between IPI and PTB, IPI remains a potentially modifiable risk factor for women with previous PTB. TWEETABLE ABSTRACT: Short versus long interpregnancy intervals associated with higher ORs for preterm birth (PTB) after a previous PTB.
Asunto(s)
Intervalo entre Nacimientos , Nacimiento Prematuro/epidemiología , Adolescente , Adulto , California/epidemiología , Estudios de Cohortes , Países Desarrollados , Femenino , Finlandia/epidemiología , Humanos , Estudios Longitudinales , Nueva Gales del Sur/epidemiología , Noruega/epidemiología , Oportunidad Relativa , Embarazo , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: To investigate preterm birth (PTB) phenotypes in women with different autoimmune rheumatic diseases in a large population-based cohort. DESIGN: Retrospective cohort study. SETTING: California, USA. POPULATION: All live singleton births in California between 2007 and 2011 were analysed. Patients with autoimmune disease at delivery were identified by International Classification of Diseases, Ninth Revision , Clinical Modification (ICD-9-CM), codes for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and juvenile idiopathic arthritis (JIA). METHODS: Maternally linked hospital and birth certificate records of 2 481 516 deliveries were assessed (SLE n = 2272, RA n = 1501, SSc n = 88, JIA n = 187, DM/PM n = 38). Multivariable Poisson regression models estimated the risk ratios (RRs) for different PTB phenotypes (relative to term deliveries) for each autoimmune disease compared with the general obstetric population, adjusting for maternal age, race/ethnicity, body mass index, smoking, education, payer, parity, and prenatal care. MAIN OUTCOME MEASURES: Preterm birth (PTB) was assessed overall (20-36 weeks of gestation) and by subphenotype: preterm prelabour rupture of membranes (PPROM), spontaneous birth, or medically indicated PTB. The risk of PTB overall and for each phenotype was partitioned by gestational age: early (20-31 weeks of gestation) and late (32-36 weeks of gestation). RESULTS: Risks for PTB were elevated for each autoimmune disease evaluated: SLE (RR 3.27, 95% CI 3.01-3.56), RA (RR 2.04, 95% CI 1.79-2.33), SSc (RR 3.74, 95% CI 2.51-5.58), JIA (RR 2.23, 95% CI 1.54-3.23), and DM/PM (RR 5.26, 95% CI 3.12-8.89). These elevated risks were observed for the majority of PTB phenotypes as well. CONCLUSIONS: Women with systemic autoimmune diseases appear to have an elevated risk of various PTB phenotypes. Therefore, preconception counselling and close monitoring during pregnancy is crucial. TWEETABLE ABSTRACT: This study found that women with systemic autoimmune diseases have an elevated risk of preterm birth phenotypes.
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Enfermedades Autoinmunes/epidemiología , Complicaciones del Embarazo/epidemiología , Nacimiento Prematuro/epidemiología , Enfermedades Reumáticas/epidemiología , Adulto , California/epidemiología , Femenino , Edad Gestacional , Humanos , Paridad , Fenotipo , Preeclampsia/epidemiología , Embarazo , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: To investigate the distribution of known factors for preterm birth (PTB) by severity of maternal underweight; to investigate the risk-adjusted relation between severity of underweight and PTB, and to assess whether the relation differed by gestational age. DESIGN: Retrospective cohort study. SETTING: State of California, USA. METHODS: Maternally linked hospital and birth certificate records of 950 356 California deliveries in 2007-2010 were analysed. Singleton live births of women whose prepregnancy body mass index (BMI) was underweight (<18.5 kg/m2 ) or normal (18.50-24.99 kg/m2 ) were analysed. Underweight BMI was further categorised as: severe (<16.00), moderate (16.00-16.99) or mild (17.00-18.49). PTB was grouped as 22-27, 28-31, 32-36 or <37 weeks (compared with 37-41 weeks). Adjusted multivariable Poisson regression modeling was used to estimate relative risk for PTB. MAIN OUTCOME MEASURES: Risk of PTB. RESULTS: About 72 686 (7.6%) women were underweight. Increasing severity of underweight was associated with increasing percent PTB: 7.8% (n = 4421) in mild, 9.0% (n = 1001) in moderate and 10.2% (475) in severe underweight. The adjusted relative risk of PTB also significantly increased: adjusted relative risk (aRR) = 1.22 (95% CI 1.19-1.26) in mild, aRR = 1.41 (95% CI 1.32-1.50) in moderate and aRR = 1.61 (95% CI 1.47-1.76) in severe underweight. These findings were similar in spontaneous PTB, medically indicated PTB, and the gestational age groupings. CONCLUSION: Increasing severity of maternal prepregnancy underweight BMI was associated with increasing risk-adjusted PTB at <37 weeks. This increasing risk was of similar magnitude in spontaneous and medically indicated births and in preterm delivery at 28-31 and at 32-36 weeks of gestation. TWEETABLE ABSTRACT: Increasing severity of maternal underweight BMI was associated with increasing risk of preterm birth.
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Nacimiento Prematuro/diagnóstico , Nacimiento Prematuro/etiología , Delgadez/diagnóstico , Adulto , Índice de Masa Corporal , California/epidemiología , Femenino , Edad Gestacional , Humanos , Recién Nacido , Paridad , Embarazo , Nacimiento Prematuro/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Delgadez/epidemiologíaRESUMEN
OBJECTIVES: We assessed whether interpregnancy interval (IPI) length after live birth and after pregnancy termination was associated with preterm birth (PTB). DESIGN: Multiyear birth cohort. SETTINGS: Fetal death, birth and infant death certificates in California merged with Office of Statewide Health Planning and Development. POPULATION: One million California live births (2007-10) after live birth and after pregnancy termination. METHODS: Logistic regression was used to estimate odds ratios (ORs) of PTB of 20-36 weeks of gestation and its subcategories for IPIs after a live birth and after a pregnancy termination. We used conditional logistic regression (two IPIs/mother) to investigate associations within mothers. MAIN OUTCOME MEASURE: PTB relative to gestations of ≥ 37 weeks. RESULTS: Analyses included 971 211 women with IPI after live birth, and 138 405 women with IPI after pregnancy termination with 30.6% and 74.6% having intervals of <18 months, respectively. IPIs of <6 months or 6-11 months after live birth showed increased odds of PTB adjusted ORs for PTB of 1.71 (95% CI 1.65-1.78) and 1.20 (95% CI 1.16-1.24), respectively compared with intervals of 18-23 months. An IPI >36 months (versus 18-23 months) was associated with increased odds for PTB. Short IPI after pregnancy termination showed a decreased OR of 0.87 (95% CI 0.81-0.94). The within-mother analysis showed the association of increased odds of PTB for short IPI, but not for long IPI. CONCLUSIONS: Women with IPI <1 or >3 years after a live birth were at increased odds of PTB-an important group for intervention to reduce PTB. Short IPI after pregnancy termination was associated with reduced odds for PTB and needs to be further explored. TWEETABLE ABSTRACT: Short and long IPI after live birth, but not after pregnancy termination, showed increased odds for PTB.
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Aborto Inducido/efectos adversos , Intervalo entre Nacimientos/estadística & datos numéricos , Muerte Fetal/etiología , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/etiología , Adulto , Índice de Masa Corporal , California/epidemiología , Estudios de Cohortes , Femenino , Edad Gestacional , Humanos , Incidencia , Lactante , Mortalidad Infantil , Recién Nacido , Nacimiento Vivo/epidemiología , Edad Materna , Obesidad/epidemiología , Embarazo , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Cough suppression is part of the pharmacodynamic profile of opioids. We investigated the impact of clinical doses of fentanyl on suppressing the cough reflex. Thirteen volunteers received 2 µg.kg(-1) of fentanyl in a divided administration protocol. Three minutes after each administration and at 10 min intervals during washout, suppressed cough reflex testing with nebulised citric acid was performed and compared with fentanyl effect-site concentration. Mean (SD) citric acid concentration provoking cough increased from 0.5 (0.28) mol.l(-1) at baseline to 1.2 (0.50) mol.l(-1) after 2 µg.kg(-1) of fentanyl (p = 0.01). Mean (SD) fentanyl effect-site concentration after the final dose of fentanyl was 1.89 (0.05) ng.ml(-1) . A strong positive correlation was found between suppressed cough reflex thresholds and fentanyl effect-site concentrations during both fentanyl administration and washout phases of the study (r(2) = 0.79, p = 0.01). The mean (SD) length of time for return of suppressed cough response was 44.6 (18.8) min. Clinically relevant doses of fentanyl produced cough reflex suppression in healthy volunteers.
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Analgésicos Opioides/farmacología , Tos/tratamiento farmacológico , Fentanilo/farmacología , Reflejo/efectos de los fármacos , Adolescente , Adulto , Anciano , Ácido Cítrico , Tos/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Voluntarios Sanos , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Objective Studies have reported an increased risk of spontaneous preterm birth associated with elevated prepregnancy body mass index (BMI) among nulliparous but not multiparous women. We examined whether changes in BMI and weight between pregnancies contributed to risk of preterm birth among obese (BMI > 29 kg/m(2)) women. Study Design This study utilized maternally linked California birth records of sequential singleton births between 2007 and 2010. Preterm birth was defined as 20 to 31 or 32 to 36 weeks of gestation. BMI was examined as category change and by tertile of weight change. Primary analyses included women without diabetes or hypertensive disorders; these women were compared with those without prior preterm birth, women with preterm deliveries preceded by spontaneous preterm labor, and women without any exclusions (i.e., diabetes or hypertensive disorders). Results Analyses showed that obesity was not associated with increased risk of spontaneous preterm birth among multiparous women. Women whose BMI increased had a decreased risk of spontaneous preterm birth at 32 to 36 weeks. Change in BMI or weight between pregnancies did not substantively alter results. Conclusion Among multiparous women, obesity was associated with reduced risk of spontaneous preterm delivery. This observed association is complex and may be influenced by maternal age, gestational age, placental insufficiency, and altered immune response.
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Índice de Masa Corporal , Obesidad/complicaciones , Obesidad/epidemiología , Nacimiento Prematuro/epidemiología , Adulto , California/epidemiología , Femenino , Edad Gestacional , Humanos , Recién Nacido , Embarazo , Nacimiento Prematuro/etiología , Análisis de Regresión , Factores de Riesgo , Aumento de Peso , Adulto JovenRESUMEN
Thyroid disease is a common problem among women of reproductive age but often goes undiagnosed. Maternal thyroid disease has been associated with increased risk of craniosynostosis. We hypothesized that known risk factors for thyroid disease would be associated with risk of craniosynostosis among women not diagnosed with thyroid disease. Analyses included mothers of 1,067 cases and 8,494 population-based controls who were interviewed for the National Birth Defects Prevention Study. We used multivariable logistic regression to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI). After excluding women with diagnosed thyroid disease, younger maternal age (AOR 0.7, 95% CI 0.6-0.9, for <25 years versus 25-29), black or other race-ethnicity (AOR 0.3, 95% CI 0.2-0.4 and AOR 0.6, 95% CI 0.4-0.8, respectively, relative to non-Hispanic whites), fertility medications or procedures (AOR 1.5, 95% CI 1.2-2.0), and alcohol consumption (AOR 0.8, 95% CI 0.7-0.9) were associated with risk of craniosynostosis, based on confidence intervals that excluded 1.0. These associations with craniosynostosis are consistent with the direction of their association with thyroid dysfunction (i.e., younger age, black race-ethnicity and alcohol consumption are associated with reduced risk and fertility problems are associated with increased risk of thyroid disease). This study thus provides support for the hypothesis that risk factors associated with thyroid dysfunction are also associated with risk of craniosynostosis. Improved understanding of the potential association between maternal thyroid function and craniosynostosis among offspring is important given that craniosynostosis carries significant morbidity and that thyroid disease is under-diagnosed and potentially modifiable.
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Craneosinostosis/etiología , Complicaciones del Embarazo/etiología , Enfermedades de la Tiroides/complicaciones , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Embarazo , Factores de Riesgo , Glándula Tiroides , Adulto JovenRESUMEN
OBJECTIVE: To examine the relationship between maternal characteristics, serum biomarkers and preterm birth (PTB) by spontaneous and medically indicated subtypes. DESIGN: Population-based cohort. SETTING: California, United States of America. POPULATION: From a total population of 1 004 039 live singleton births in 2009 and 2010, 841 665 pregnancies with linked birth certificate and hospital discharge records were included. METHODS: Characteristics were compared for term and preterm deliveries by PTB subtype using logistic regression and odds ratios adjusted for maternal characteristics and obstetric factors present in final stepwise models and 95% confidence intervals. First-trimester and second-trimester serum marker levels were analysed in a subset of 125 202 pregnancies with available first-trimester and second-trimester serum biomarker results. MAIN OUTCOME MEASURE: PTB by subtype. RESULTS: In fully adjusted models, ten characteristics and three serum biomarkers were associated with increased risk in each PTB subtype (Black race/ethnicity, pre-existing hypertension with and without pre-eclampsia, gestational hypertension with pre-eclampsia, pre-existing diabetes, anaemia, previous PTB, one or two or more previous caesarean section(s), interpregnancy interval ≥ 60 months, low first-trimester pregnancy-associated plasma protein A, high second-trimester α-fetoprotein, and high second-trimester dimeric inhibin A). These risks occurred in 51.6-86.2% of all pregnancies ending in PTB depending on subtype. The highest risk observed was for medically indicated PTB <32 weeks in women with pre-existing hypertension and pre-eclampsia (adjusted odds ratio 89.7, 95% CI 27.3-111.2). CONCLUSIONS: Our findings suggest a shared aetiology across PTB subtypes. These commonalities point to targets for further study and exploration of risk reduction strategies. TWEETABLE ABSTRACT: Findings suggest a shared aetiology across preterm birth subtypes. Patterns may inform risk reduction efforts.
Asunto(s)
Nacimiento Prematuro/sangre , Nacimiento Prematuro/epidemiología , Adolescente , Adulto , Anemia/epidemiología , Biomarcadores/sangre , Intervalo entre Nacimientos , California/epidemiología , Cesárea/estadística & datos numéricos , Estudios de Cohortes , Diabetes Mellitus/epidemiología , Femenino , Humanos , Hipertensión/epidemiología , Inhibinas/sangre , Modelos Logísticos , Embarazo/sangre , Complicaciones del Embarazo/epidemiología , Primer Trimestre del Embarazo/sangre , Segundo Trimestre del Embarazo/sangre , Proteína Plasmática A Asociada al Embarazo/análisis , Nacimiento Prematuro/clasificación , Grupos Raciales , Factores de Riesgo , Adulto Joven , alfa-Fetoproteínas/análisisRESUMEN
BACKGROUND: Associations between maternal periconceptional exposure to disinfection by-products (DBPs) in drinking water and neural tube defects (NTDs) in offspring are inconclusive, limited in part by exposure misclassification. METHODS: Maternal interview reports of drinking water sources and consumption from the National Birth Defects Prevention Study were linked with DBP concentrations in public water system monitoring data for case children with an NTD and control children delivered during 2000-2005. DBPs analyzed were total trihalomethanes, the five most common haloacetic acids combined, and individual species. Associations were estimated for all NTDs combined and selected subtypes (spina bifida, anencephaly) with maternal periconceptional exposure to DBPs in public water systems and with average daily periconceptional ingestion of DBPs accounting for individual-level consumption and filtration information. Mixed effects logistic regression models with maternal race/ethnicity and educational attainment at delivery as fixed effects and study site as a random intercept were applied. RESULTS: Overall, 111 case and 649 control children were eligible for analyses. Adjusted odds ratios for maternal exposure to DBPs in public water systems ranged from 0.8-1.5 for all NTDs combined, 0.6-2.0 for spina bifida, and 0.7-1.9 for anencephaly; respective ranges for average daily maternal ingestion of DBPs were 0.7-1.1, 0.5-1.5, and 0.6-1.8. Several positive estimates (≥1.2) were observed, but all confidence intervals included the null. CONCLUSIONS: Using community- and individual-level data from a large, US, population-based, case-control study, we observed statistically nonsignificant associations between maternal periconceptional exposure to total and individual DBP species in drinking water and NTDs and subtypes.
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Desinfección , Agua Potable , Exposición Materna , Defectos del Tubo Neural , Humanos , Femenino , Agua Potable/efectos adversos , Defectos del Tubo Neural/etiología , Defectos del Tubo Neural/epidemiología , Embarazo , Exposición Materna/efectos adversos , Exposición Materna/estadística & datos numéricos , Desinfección/métodos , Adulto , Estudios de Casos y Controles , Desinfectantes/efectos adversos , Desinfectantes/análisis , Purificación del Agua/métodos , Trihalometanos/análisis , Trihalometanos/efectos adversos , Masculino , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Disrafia Espinal/etiología , Disrafia Espinal/epidemiologíaRESUMEN
The HIV-1-specific cytotoxic T lymphocyte (CTL) response is temporally associated with the decline in viremia during primary HIV-1 infection, but definitive evidence that it is of importance in virus containment has been lacking. Here we show that in a patient whose early CTL response was focused on a highly immunodominant epitope in gp 160, there was rapid elimination of the transmitted virus strain and selection for a virus population bearing amino acid changes at a single residue within this epitope, which conferred escape from recognition by epitope-specific CTL. The magnitude (> 100-fold), kinetics (30-72 days from onset of symptoms) and genetic pathways of virus escape from CTL pressure were comparable to virus escape from antiretroviral therapy, indicating the biological significance of the CTL response in vivo. One aim of HIV-1 vaccines should thus be to elicit strong CTL responses against multiple codominant viral epitopes.
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Síndrome de Inmunodeficiencia Adquirida/virología , VIH-1/inmunología , Linfocitos T Citotóxicos/inmunología , Viremia/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Proteínas gp160 de Envoltorio del VIH/inmunología , Humanos , Epítopos Inmunodominantes/inmunología , Sondas de OligonucleótidosRESUMEN
Plasma HIV RNA determinations are an important prognostic marker of disease progression and, when used appropriately, provide a valuable tool for the management of individual patients. But what constitutes appropriate use?
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Infecciones por VIH/etiología , Infecciones por VIH/genética , ARN Viral/sangre , Antivirales/uso terapéutico , Recolección de Muestras de Sangre , Infecciones por VIH/terapia , Humanos , Valor Predictivo de las Pruebas , Pronóstico , ARN Viral/efectos de los fármacos , Resultado del TratamientoRESUMEN
T-20, a synthetic peptide corresponding to a region of the transmembrane subunit of the HIV-1 envelope protein, blocks cell fusion and viral entry at concentrations of less than 2 ng/ml in vitro. We administered intravenous T-20 (monotherapy) for 14 days to sixteen HIV-infected adults in four dose groups (3, 10, 30 and 100 mg twice daily). There were significant, dose-related declines in plasma HIV RNA in all subjects who received higher dose levels. All four subjects receiving 100 mg twice daily had a decline in plasma HIV RNA to less than 500 copies/ml, by bDNA assay. A sensitive RT-PCR assay (detection threshold 40 copies/ml) demonstrated that, although undetectable levels were not achieved in the 14-day dosing period, there was a 1.96 log10 median decline in plasma HIV RNA in these subjects. This study provides proof-of-concept that viral entry can be successfully blocked in vivo. Short-term administration of T-20 seems safe and provides potent inhibition of HIV replication comparable to anti-retroviral regimens approved at present.
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Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Proteína gp41 de Envoltorio del VIH/sangre , Proteína gp41 de Envoltorio del VIH/fisiología , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/uso terapéutico , Replicación Viral/efectos de los fármacos , Adulto , Fármacos Anti-VIH/sangre , Recuento de Linfocito CD4 , Relación Dosis-Respuesta a Droga , Enfuvirtida , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/aislamiento & purificación , Semivida , Humanos , Tasa de Depuración MetabólicaRESUMEN
Quantitative analysis of the relationship between virus expression and disease outcome has been critical for understanding HIV-1 pathogenesis. Yet the amount of viral RNA contained within an HIV-expressing cell and the relationship between the number of virus-producing cells and plasma virus load has not been established or reflected in models of viral dynamics. We report here a novel strategy for the coordinated analysis of virus expression in lymph node specimens. The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status. In addition, there was a significant but nonlinear direct correlation between the frequency of vRNA+ lymph node cells and plasma vRNA. As predicted from this relationship, residual cells expressing this same mean copy number are detectable (frequency <2/10(6) cells) in tissues of treated patients who have plasma vRNA levels below the current detectable threshold (<50 copies/ml). These data suggest that fully replication-active cells are responsible for sustaining viremia after initiation of potent antiretroviral therapy and that plasma virus titers correlate, albeit in a nonlinear fashion, with the number of virus-expressing cells in lymphoid tissue.
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Infecciones por VIH/sangre , VIH-1/patogenicidad , Ganglios Linfáticos/virología , ARN Viral/sangre , Antivirales/uso terapéutico , Biopsia , Recuento de Células , Humanos , Ganglios Linfáticos/efectos de los fármacos , Monocitos , ARN Viral/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Carga Viral , Viremia/genética , Replicación Viral/genéticaRESUMEN
Identifying the specific genetic characteristics of successfully transmitted variants may prove central to the development of effective vaccine and microbicide interventions. Although human immunodeficiency virus transmission is associated with a population bottleneck, the extent to which different factors influence the diversity of transmitted viruses is unclear. We estimate here the number of transmitted variants in 69 heterosexual men and women with primary subtype C infections. From 1,505 env sequences obtained using a single genome amplification approach we show that 78% of infections involved single variant transmission and 22% involved multiple variant transmissions (median of 3). We found evidence for mutations selected for cytotoxic-T-lymphocyte or antibody escape and a high prevalence of recombination in individuals infected with multiple variants representing another potential escape pathway in these individuals. In a combined analysis of 171 subtype B and C transmission events, we found that infection with more than one variant does not follow a Poisson distribution, indicating that transmission of individual virions cannot be seen as independent events, each occurring with low probability. While most transmissions resulted from a single infectious unit, multiple variant transmissions represent a significant fraction of transmission events, suggesting that there may be important mechanistic differences between these groups that are not yet understood.
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Variación Genética , Infecciones por VIH/transmisión , Infecciones por VIH/virología , VIH-1/fisiología , Adulto , Análisis por Conglomerados , Femenino , VIH-1/clasificación , VIH-1/genética , Humanos , Masculino , Datos de Secuencia Molecular , Filogenia , ARN Viral/genética , Análisis de Secuencia de ADN , Homología de Secuencia , Adulto JovenRESUMEN
BACKGROUND: Average paternal age in the United States has increased substantially in the last few decades. Children of advanced age fathers have a higher incidence of early onset cancer and neuropsychiatric disease. OBJECTIVES: To quantify the number of population adjusted cases of early-onset cancer and neuropsychiatric disease in children attributable to increasing paternal age in the United States. METHODS: Paternal age in the United States from 1972 to 2015 was collected using the National Vital Statistics System (NVSS). Population attributable fraction and paternal age-specific cumulative incidence rates of several cancers and neuropsychiatric disorders were obtained from peer-reviewed publications. Paternal age-specific birth rates were correlated with paternal age-specific cumulative incidence rates to determine the number of attributable cases of disease caused by advancing age of fathers in the United States. RESULTS: The 2015 birth cohort in the United States is estimated to expect 9.2% more cases of acute lymphoblastic leukemia (ALL) diagnosed before 16 years of age (157 additional cases), 13.2% more cases of embryonal tumors in children <5 years of age (209 additional cases), and 13.0% more cases of breast cancer in females younger than 40 years old (424 additional cases) compared to the 1972 birth cohort. We can estimate to expect 10.5% more cases of schizophrenia diagnosed before 21 years of age (2864 additional cases), 6.3% more cases of autism spectrum disorder (ASD) in adolescents <17 years of age (2934 additional cases), 4.5% more cases of anorexia nervosa (AN) in females 8-30 years old (620 additional cases), and 9.2% more cases of bipolar disorder in young patients 16-25 years old (252 additional cases) in the 2015 birth cohort compared to the 1972 birth cohort. CONCLUSION: Increasing paternal age in the United States is associated with a substantial increase in the number of cases of early-onset cancer and neuropsychiatric disease in offspring.
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Costo de Enfermedad , Trastornos Mentales/epidemiología , Neoplasias/epidemiología , Padres , Adolescente , Adulto , Niño , Preescolar , Padre , Humanos , Incidencia , Lactante , Masculino , Factores de Riesgo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Patients are required to support their cheeks during breath-occluding lung function tests. This prevents cheek expansion which would alter pressure measured at the mouth, and, consequently, lung mechanics measurements. To date, the effect of cheek support on airway resistance measurements has been assessed. However other lung mechanics have not been studied as thoroughly, and no algorithm to account for the effect of missing cheek support on lung mechanics measurements has been developed. METHODS: Lung mechanics were assessed with a breath occlusion test during light panting in healthy subjects with and without cheek support in a body plethysmograph. Average model-based airway resistance, lung elastance, and a parameter representing the viscoelastic were measured. Results were compared to quantify the effect of cheek support on these three parameters. RESULTS: In the nine healthy subjects (5 Female, 4 Male) recruited for this study, all mechanics tended to be underestimated when cheeks were unsupported. Changes in elastance, resistance, and viscoelastic parameter ranged between 1.6-66.8 %, -4.5-21.8 %, and -4.7-68.2 %, respectively, when cheek support was added. The underestimation was due to reduced mouth pressure during cheek expansion when the breath was occluded. The variance of lung mechanics parameters did not change with cheek support in all subjects. CONCLUSIONS: The error in lung mechanics measurement caused by unsupported cheeks was subject dependent. Hence, no rule-of-thumb could be identified to reconstruct missing cheek support. For correct lung mechanics measurements during breath-occluding lung tests, patients must have adequate cheek support. ABBREVIATIONS: ROCC: Occlusion resistance; COPD: Chronic Obstructive Pulmonary Disorder; SB: spontaneous breathing.
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Resistencia de las Vías Respiratorias , Pulmón , Mejilla , Femenino , Humanos , Masculino , Pruebas de Función Respiratoria , Mecánica RespiratoriaRESUMEN
BACKGROUND AND OBJECTIVE: Model-based lung mechanics monitoring can provide clinically useful information for guiding mechanical ventilator treatment in intensive care. However, many methods of measuring lung mechanics are not appropriate for both fully and partially sedated patients, and are unable provide lung mechanics metrics in real-time. This study proposes a novel method of using lung mechanics identified during passive expiration to estimate inspiratory lung mechanics for spontaneously breathing patients. METHODS: Relationships between inspiratory and expiratory modeled lung mechanics were identified from clinical data from 4 fully sedated patients. The validity of these relationships were assessed using data from a further 4 spontaneously breathing patients. RESULTS: For the fully sedated patients, a linear relationship was identified between inspiratory and expiratory elastance, with slope 1.04 and intercept 1.66. The r value of this correlation was 0.94. No cohort-wide relationship was determined for airway resistance. Expiratory elastance measurements in spontaneously breathing patients were able to produce reasonable estimates of inspiratory elastance after adjusting for the identified difference between them. CONCLUSIONS: This study shows that when conventional methods fail, typically ignored expiratory data may be able to provide clinicians with the information needed about patient condition to guide MV therapy.
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Espiración , Inhalación , Respiración , Resistencia de las Vías Respiratorias , Humanos , Modelos Biológicos , Respiración ArtificialRESUMEN
Congenital diaphragmatic hernia (CDH) is a common birth defect for which few causative genes have been identified. Several candidate regions containing genes necessary for normal diaphragm development have been identified, including a 4-5 Mb deleted region at chromosome 1q41-1q42 from which the causative gene(s) has/have not been cloned. We selected the HLX gene from this interval as a candidate gene for CDH, as the Hlx homozygous null mouse has been reported to have diaphragmatic defects and the gene was described as being expressed in the murine diaphragm. We re-sequenced HLX in 119 CDH patients and identified four novel single nucleotide substitutions that predict amino acid changes: p.S12F, p.S18L, p.D173Y and p.A235V. These sequence alterations were all present in patients with isolated CDH, although patients with both isolated CHD and CDH with additional anomalies were studied. The single-nucleotide substitutions were absent in more than 186 control chromosomes. In-situ hybridization studies confirmed expression of Hlx in the developing murine diaphragm at the site of the junction of the diaphragm and the liver. Although functional studies to determine if these novel sequence variants altered the inductive activity of Hlx on the alpha-smooth muscle actin and SM22alpha promoters showed no significant differences between the variants and wild-type Hlx, sequence variants in HLX may still be relevant in the pathogenesis of CDH in combination with additional genetic and environmental factors.
Asunto(s)
Cromosomas Humanos Par 1/genética , Variación Genética , Hernia Diafragmática/genética , Proteínas de Homeodominio/genética , Factores de Transcripción/genética , Animales , Secuencia de Bases , Embrión de Mamíferos , Humanos , Hibridación in Situ , Cariotipificación , Ratones , Datos de Secuencia Molecular , Fenotipo , Análisis de Secuencia de ADNRESUMEN
This study compared the prevalence of cardiovascular defects in twin and singleton births and explored the influences of zygosity (monozygotic and dizygotic) and maternal age (<35 and >or=35 years of age) on concordance. Data on twin and singleton infants with (n = 628 twin pairs and n = 14,078 singletons) and without (n = 53,974 twin pairs and n = 4,858,255 singletons) cardiovascular defects were obtained from the California Birth Defects Monitoring Program and the California vital statistics birth and fetal death records during the period 1983-2003. Prevalence ratios (PR) (prevalence of twin/singleton) and approximate 95% confidence intervals were calculated for 16 congenital cardiovascular categories. Poisson regression techniques using log-linear models were employed to assess whether the probability of concordance of defects within each cardiovascular category varied by zygosity or maternal age. An increased prevalence was observed in twins compared to singletons in all 16 cardiovascular categories. Seven of the cardiovascular categories had at least double the prevalence in twins compared to singletons. Like-sex twins, as a proxy of monozygosity, had an increased prevalence of cardiovascular defects compared to unlike sex twins. Probabilities of concordance for flow lesions were higher among monozygotic than dizygotic twins. Our study provides evidence that twinning is associated with more cardiovascular defects than singletons. Increased concordance for flow lesions in monozygotic twins was observed, an observation that is in agreement with findings from familial recurrence studies of cardiovascular defects.
Asunto(s)
Anomalías Cardiovasculares/epidemiología , Enfermedades en Gemelos/epidemiología , Adolescente , Adulto , California/epidemiología , Anomalías Cardiovasculares/clasificación , Enfermedades en Gemelos/clasificación , Femenino , Humanos , Masculino , Edad Materna , Persona de Mediana Edad , Prevalencia , Gemelos Dicigóticos , Gemelos Monocigóticos , Adulto JovenRESUMEN
Evidence of simian immunodeficiency virus (SIV) infection has been reported for 26 different species of African nonhuman primates. Two of these viruses, SIVcpz from chimpanzees and SIVsm from sooty mangabeys, are the cause of acquired immunodeficiency syndrome (AIDS) in humans. Together, they have been transmitted to humans on at least seven occasions. The implications of human infection by a diverse set of SIVs and of exposure to a plethora of additional human immunodeficiency virus-related viruses are discussed.