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Improving understanding of the pathogen-specific seasonality of enteric infections is critical to informing policy on the timing of preventive measures and to forecast trends in the burden of diarrhoeal disease. Data obtained from active surveillance of cohorts can capture the underlying infection status as transmission occurs in the community. The purpose of this study was to characterise rotavirus seasonality in eight different locations while adjusting for age, calendar time and within-subject clustering of episodes by applying an adapted Serfling model approach to data from a multi-site cohort study. In the Bangladesh and Peru sites, within-subject clustering was high, with more than half of infants who experienced one rotavirus infection going on to experience a second and more than 20% experiencing a third. In the five sites that are in countries that had not introduced the rotavirus vaccine, the model predicted a primary peak in prevalence during the dry season and, in three of these, a secondary peak during the rainy season. The patterns predicted by this approach are broadly congruent with several emerging hypotheses about rotavirus transmission and are consistent for both symptomatic and asymptomatic rotavirus episodes. These findings have practical implications for programme design, but caution should be exercised in deriving inferences about the underlying pathways driving these trends, particularly when extending the approach to other pathogens. [ABSTRACT FROM AUTHOR]

Background: Oropharyngeal carriage studies of Haemophilus influenzae type b (Hib) and the rapid drop in Hib invasive disease in countries with widespread Hib conjugate vaccine immunization programmes for infants have indicated there may be significant indirect effects (herd immunity) associated with these vaccines. Our goal was to quantify the magnitude of these effects in an American Indian population during its early years of Hib immunization.Methods: In a synthetic case-cohort study, we combined data from an efficacy trial, an immunization uptake records survey, and ongoing surveillance for Hib disease on the Navajo Nation from 1988 to 1992. Decline in the incidence of invasive Hib disease among children <2 years old was estimated via proportional hazards survival models as a function of individual immunization status and the proportion of immunized children in a community.Results: The predominant vaccine during the study period was Hib-OMPC (92% of immunizations). The effectiveness of receipt of at least one dose was 97.2%. Compared to communities with 0-20% coverage with at least one dose, residence in communities with 20-40% and 40-60% coverage was associated with risk reductions of 56.5% and 73.2%, respectively.Conclusions: The results indicate substantial indirect effects of Hib-OMPC immunization may occur even at relatively low levels of immunization coverage. Countries that implement Hib immunization programmes may receive greater benefits at the community level than those due to the direct protection conferred to the individual through vaccination. [ABSTRACT FROM AUTHOR]

Abstract Background In epidemiological studies, subjects are often followed for a period during which study outcomes are measured at selected time points, such as by diagnostic testing performed on biological samples collected at each visit. Although test results may indicate the presence or absence of a disease or condition, they cannot provide information on when exactly it occurred. Such study designs generate arbitrarily censored time-to-event data, which can include left, interval and right censoring. Adding to this complexity, the data may be clustered such that observations within the same cluster are not independent, such as time to recovery of an infectious disease of family or community members. This data structure is observed when evaluating circumcision's effect on clearance of penile high risk human papillomavirus (HR-HPV) infections using data collected from the male circumcision(MC) trial conducted in Rakai, Uganda, where the multiple infections within individual and HPV testings performed at trial follow-up visits gave rise to the clustered data with arbitrary censoring. Methods We describe the use of parametric proportional hazards frailty models and accelerated failure time frailty models to examine the relationship between explanatory variables and the survival outcomes that are subject to arbitrary censoring, while accounting for the correlation within clusters. Standard software such as SAS can be used for parameter estimation. Results Circumcision's effect on HPV infection was a secondary end point in the Rakai MC trial, and HPV genotyping was conducted for penile samples of a subset of trial participants collected at enrollment, 6, 12 and 24-month follow up visits. At enrollment, 36.7% intervention arm men (immediate circumcision) and 36.6% control arm men (delayed circumcision at 2 years) were infected with HR-HPV, with the number of infections per man being 1-5. The proposed models were used to examine whether MC facilitated clearance of the prevalent infections. Results show that clearance of multiple infections within each man is highly correlated, and clearance was 60% faster if a man was circumcised. Conclusions Parametric frailty models provide viable ways to study the relationship between exposure variables and clustered survival outcome that is subject to arbitrary censoring, as is often observed in HPV epidemiology studies.

Uncertainty regarding the basis for the >50 ms jump used to define dual AV nodal physiology prompted us to calculate the threshold for significant change in the A1H1 and V1A1 intervals during decremental pacing. From this, we sought to establish whether ranges of AH and VA intervals are unique to the fast (FP) and slow (SP) AV nodal pathways among 100 pts. undergoing routine EP testing.The jump, defined as 2 STD beyond the mean increment in the A1H1 or V1A1 interval during decremental pacing, was ≥35 ms or ≥25ms, respectively. Among 61 pts. with ≥35ms jump, none had longest pre-jump A1H1intervals >200ms and none had shortest post-jump A1H1intervals <150ms. Among 89 pts. with intact retrograde conduction, 26 had ≥25ms jump in V1A1interval. In all 26, V1A1intervals ≥150ms corresponded to earliest atrial activation at the coronary sinus os while those <150ms had earliest activation in the His recording. Using 200ms to define minimum SP AH interval, SP prevalence was 92%.The data suggest that 200 ms may be a minimum SP AH interval and 150 ms is a maximum FP AH interval with values between 150-200 indeterminate. V1A1 intervals <150 ms and those ≥150 ms suggest FP and SP conduction time limits, respectively. [ABSTRACT FROM PUBLISHER]

Background: Venous thromboembolism is an important patient safety issue in thoracic surgery patients. The optimal enoxaparin dose remains unclear. This multicenter pre/post clinical trial compared the pharmacokinetics of fixed versus weight-tiered enoxaparin, and their impact on 90-day venous thromboembolism and bleeding., Methods: Thoracic surgery patients were prospectively enrolled using a pre/post study design. Cohort 1 received enoxaparin 40 mg daily, and cohort 2 received a weight-tiered regimen: less than 70 kg received 30 mg daily; 70 kg to 89.9 kg received 40 mg once daily; and 90 kg or more received 50 mg daily. The primary study outcome was peak anti-factor Xa levels in response to fixed or weight-tiered enoxaparin. Secondary outcomes included trough anti-factor Xa, 90-day symptomatic venous thromboembolism, and 90-day clinically relevant bleeding., Results: One hundred thirty-one patients were prospectively enrolled, including 65 in the fixed-dose cohort and 66 in the weight-tiered cohort. No patient was lost to follow-up. Weight-tiered enoxaparin was not significantly more likely to produce adequate anticoagulation (peak anti-factor Xa 0.3 IU/mL or greater) when compared with fixed-dose enoxaparin (44.3% vs 48.2%, P = .67). Weight-tiered enoxaparin was not more likely to avoid over-anticoagulation (peak anti-factor Xa 0.5 IU/mL or greater) when compared with fixed-dose enoxaparin (3.3% vs 3.6%, P = 1.00). The groups had no significant difference in trough anti-factor Xa. Observed rates of 90-day symptomatic venous thromboembolism and clinically relevant bleeding were low (0% and 3.1%, respectively) and were not significantly different between groups., Conclusions: This multicenter pre/post clinical trial did not show a pharmacokinetic advantage to weight-tiered enoxaparin, when compared with fixed-dose enoxaparin, in thoracic surgery patients. (Clinicaltrials.gov identifier: NCT03251963.)., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Dementia and other chronic conditions can compromise a person's ability to make independent personal and financial decisions. In the wake of an ageing population and rising incidence of chronic conditions, the number of persons who may require Decision-Making Capacity Assessments (DMCAs) is likely to increase. Legislation (e.g., Trusteeship, Guardianship, Medical Assistance in Dying) also necessitates that DMCAs adhere to legislative requirements and principles. An intentional, explicit and systematic means of implementing standardized DMCA best-practices is advisable. This single exploratory case-study examined the perspectives of senior leaders and clinical experts regarding the utility of using the National Implementation Research Network (NIRN) Model to facilitate implementation, spread and sustainability of a DMCA Model. Participants learned about the NIRN Model and discussed its application during working and focus groups, all of which were audio-recorded, transcribed, and analyzed using thematic analysis., Results: Participants found that the NIRN Model aligned well with the DMCA Model, and offered utility to support implementation, spread and sustainability of DMCA best-practices. Participants also noted barriers related to its language, inability to capture personal change, resource requirements, and complexity. It was recommended that a NIRN-informed DMCA-specific implementation framework and toolkit be developed and NIRN-champions be available to guide implementation.

Background: Many patients undergoing thoracic surgical procedures have venous thromboembolism (VTE) events despite the receipt of chemical prophylaxis. Enoxaparin's pharmacologic impact can be quantified by using anti-Factor Xa (aFXa) levels. We hypothesized that enoxaparin 40 mg once daily would be inadequate for most inpatients undergoing thoracic surgical procedures and that a real-time dose adjustment algorithm would be effective., Methods: This prospective clinical trial enrolled inpatients who were to undergo a thoracic surgical procedure and placed on enoxaparin 40 mg once daily for VTE prophylaxis after surgical procedures. aFXa levels were used to measure the anticoagulant effect of enoxaparin once steady state had been reached. Patients whose aFXa levels were out of range received real-time enoxaparin dose adjustment and had repeat aFXa levels drawn., Results: Ninety-three inpatients undergoing thoracic surgical procedures were prospectively enrolled. The majority of patients (67.4%) had low peak aFXa levels (<0.3 IU/mL), indicative of inadequate enoxaparin prophylaxis, and 30.3% of patients had in-range aFXa levels (0.3 to 0.5 IU/mL). Patient weight had a moderate correlation (r 2 0.38) with peak aFXa level. Patient weight, female sex, and preoperative creatinine were independent predictors of peak aFXa in a linear regression model. Real-time, protocol-driven enoxaparin dose adjustment allowed a significantly increased proportion of patients to achieve in-range aFXa levels (30.3% vs 97.6%, p < 0.001)., Conclusions: Enoxaparin 40 mg once daily is inadequate for most inpatients undergoing thoracic surgical procedures, based on a pharmacodynamic study of aFXa levels. Future research should examine the impact of weight-based once daily enoxaparin dosing versus twice daily enoxaparin dosing on prophylaxis adequacy., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Diet-induced obesity (DIO) is a significant health concern which has been linked to structural and functional changes in the gut microbiota. Exercise (Ex) is effective in preventing obesity, but whether Ex alters the gut microbiota during development with high fat (HF) feeding is unknown., Objective: Determine the effects of voluntary Ex on the gastrointestinal microbiota in LF-fed mice and in HF-DIO., Methods: Male C57BL/6 littermates (5 weeks) were distributed equally into 4 groups: low fat (LF) sedentary (Sed) LF/Sed, LF/Ex, HF/Sed and HF/Ex. Mice were individually housed and LF/Ex and HF/Ex cages were equipped with a wheel and odometer to record Ex. Fecal samples were collected at baseline, 6 weeks and 12 weeks and used for bacterial DNA isolation. DNA was subjected both to quantitative PCR using primers specific to the 16S rRNA encoding genes for Bacteroidetes and Firmicutes and to sequencing for lower taxonomic identification using the Illumina MiSeq platform. Data were analyzed using a one or two-way ANOVA or Pearson correlation., Results: HF diet resulted in significantly greater body weight and adiposity as well as decreased glucose tolerance that were prevented by voluntary Ex (p<0.05). Visualization of Unifrac distance data with principal coordinates analysis indicated clustering by both diet and Ex at week 12. Sequencing demonstrated Ex-induced changes in the percentage of major bacterial phyla at 12 weeks. A correlation between total Ex distance and the ΔCt Bacteroidetes: ΔCt Firmicutes ratio from qPCR demonstrated a significant inverse correlation (r2 = 0.35, p = 0.043)., Conclusion: Ex induces a unique shift in the gut microbiota that is different from dietary effects. Microbiota changes may play a role in Ex prevention of HF-DIO.

Objectives: Clinical algorithms can be helpful in decisions about treatment and feeding options in infancy, but have had limited exposure to real data. This analysis uses data from a large clinical trial to test such algorithms, and thereby develop a successor which performs usefully in poor countries with high HIV-prevalence., Methods: The ZVITAMBO trial followed 14 110 mother-baby pairs through infancy. 32% of mothers were HIV-positive. Infants were HIV tested regularly using DNA PCR. Clinical signs were evaluated in terms of identifying HIV-infection at 6 weeks, 6 and 12 months, using Zimbabwean, South African, and WHO generic adaptations of the WHO integrated management of childhood illness HIV algorithm. A modification, in which HIV-exposed infants are first divided into being at least or less than median weight-for-age, was derived and evaluated., Results: At 6 weeks 65% of all infected babies are less than median weight-for-age. Adding at least two clinical signs reduces sensitivity to 20% but those identified are 1.5 (95% CI 1.1-2.1) times more likely to die by 6 months than other infected infants. At 6 months, 86% of uninfected babies of HIV-infected mothers can be identified by selecting those whose weight is greater than median or, if less than median, who exhibit <2 clinical signs., Conclusions: In poor settings a simple clinical algorithm can identify children with probable HIV infection, especially those at risk of early death, who can then be referred for further testing and care, including highly active antiretroviral therapy. Most infants who are HIV-uninfected can be identified at 6 months and provided with support to maintain infection-free survival, including focussed infant-feeding counselling.

Background: C-Reactive protein (CRP) can provide prognostic information about risk of future coronary events in apparently healthy subjects. This application requires higher sensitivity assays than have traditionally been available in the clinical laboratory., Methods: Nine high-sensitivity CRP (hs-CRP) methods from Dade Behring, Daiichi, Denka Seiken, Diagnostic Products Corporation, Iatron, Kamiya, Olympus, Roche, and Wako were evaluated for limit of detection, linearity, precision, prozone effect, and comparability with samples from 388 apparently healthy individuals., Results: All methods had limits of detection that were lower than the manufacturers' claimed limit of quantification except for the Kamiya, Roche, and Wako methods. All methods were linear at 0.3-10 mg/L. The Diagnostic Products Corporation, Kamiya, Olympus, and Wako methods had imprecision (CVs) >10% at 0.15 mg/L. The Iatron, Olympus, and Wako methods demonstrated prozone effects at hs-CRP concentrations of 12, 206, and 117 mg/L, respectively. hs-CRP concentrations demarcating each quartile in a healthy population were method-dependent. Ninety-two to 95% of subjects were classified into the same quartile of hs-CRP established by the Dade Behring method by the Denka Seiken, Diagnostic Products Corporation, Iatron, and Wako methods. In contrast, 68-77% of subjects were classified into the same quartile by the Daiichi, Kamiya, Olympus, and Roche methods. No subject varied by more than one quartile by any method., Conclusions: Four of the nine examined hs-CRP methods classified apparently healthy subjects into quartiles of hs-CRP similar to the classifications assigned by the comparison method. Additional standardization efforts are required because an individual patient's results will be interpreted using population-based cutpoints.