Haptoglobin phenotype and intensive glycemic control for coronary artery disease risk reduction in people with type two diabetes: The Veterans Affairs Diabetes Trial.

Background: Intensive glycemic control reduced the risk of coronary artery disease (CAD) events among White ACCORD study participants with the haptoglobin (Hp)2-2 phenotype, and not among participants without the Hp2-2 phenotype. It is unknown whether these results persist in a population with more severe diabetes. Methods: Haptoglobin phenotype was measured in 1746 (97 %) samples from the Veterans Affairs Diabetes Trial (VADT) randomized controlled trial. Multivariable-adjusted Cox regression models assessed the effect of intensive therapy on CAD risk among participants with and without the Hp2-2 phenotype separately and when stratified within pre-specified race/ethnicity-based subgroups. Time-varying (achieved) HbA1c data (<7.0 % or ≥8.0 % compared to 7.0-7.9, updated every 3 months) were also analyzed in relation to CAD risk within each phenotype. Results: 567 (32.5 %) participants had the Hp2-2 phenotype. Compared to standard therapy, intensive glycemic control was not associated with risk of CAD among participants with the non-Hp2-2 or the Hp2-2 phenotype or for any race/ethnicity-based group. Compared to HbA1c of 7.0-7.9 %, having HbA1c <7.0 % was not associated with CAD risk for either phenotype or among any race/ethnicity-based group. Having HbA1c ≥8.0 % was associated with an increased risk of CAD among Hispanic participants without the Hp2-2 phenotype (HR= 3.61, 95 % CI: 1.54-8.41, p-interaction=0.53). Conclusion: The effect of intensive glycemic therapy on CAD events was not dependent on Hp phenotype in the VADT study of veterans with severe diabetes who may represent a population where Hp phenotype information would not be useful for personalizing diabetes management. However, further research is needed to determine if these results are conclusive.

Haptoglobin Phenotype and Intensive Glycemic Control for Coronary Artery Disease Risk Reduction in People With Type 2 Diabetes: The ADVANCE Study.

OBJECTIVE: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study participants with the haptoglobin (Hp)2-2 phenotype but not in participants without the Hp2-2 phenotype. It is unknown whether and how these results translate across different demographic/clinical characteristics and treatment strategies. RESEARCH DESIGN AND METHODS: Haptoglobin phenotype was measured in available samples from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) biomarker case-cohort study. Weighted multivariable-adjusted Cox regression models were used to evaluate the association between intensive glycemic control (HbA1c target of ≤6.5%) versus standard therapy (based on local guidelines) and major CAD events among participants with (n = 1,327) and without (n = 2,077) the Hp2-2 phenotype separately and within prespecified stratifications by sex, race, previous cardiovascular disease (CVD), diabetes duration, and HDL-cholesterol. RESULTS: While the hazard ratios (HRs) were in the hypothesized differing directions, compared with standard therapy, intensive glycemic control was not significantly associated with risk of CAD events among participants without (1.04, 95% CI 0.82-1.32) or with (0.84, 0.63-1.14, Pinteraction = 0.27) the Hp2-2 phenotype overall. Intensive therapy was associated with lower CAD risk among participants with the Hp2-2 phenotype who had no previous CVD (0.47, 0.29-0.76, Pinteraction = 0.01). CONCLUSIONS: Our findings suggest that intensive glycemic control contributes to the prevention of major CAD events among ADVANCE participants with the Hp2-2 phenotype and no previous CVD and are in alignment with our hypothesis that intensive glycemic control may be beneficial in a subset of people with the Hp2-2 phenotype.

Intensive lifestyle intervention in type 2 diabetes and risk of incident coronary artery disease for the common haptoglobin phenotypes: the Look AHEAD study.

BACKGROUND: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) participants with the haptoglobin (Hp) 2-2 phenotype only. It remains unknown whether Hp phenotype modifies the effect of an intensive lifestyle intervention (ILI) on CAD in type 2 diabetes. METHODS: Haptoglobin phenotype was measured in 4542 samples from the Action for Health in Diabetes (Look AHEAD) study. Cox regression models assessed the effect of ILI (focused on weight loss from caloric restriction and physical activity) versus diabetes support and education (DSE) on CAD events in each phenotype group, and within pre-specified subgroups including race/ethnicity, sex, history of cardiovascular disease, diabetes medication use, and diabetes duration. RESULTS: 1590 (35%) participants had the Hp2-2 phenotype. The ILI did not lower glycated hemoglobin (%HbA1c) to < 6.5% in either phenotype, with a peak significant difference between treatment arms of 0.5% [non-Hp2-2] and 0.6% [Hp2-2]. The cumulative CAD incidence was 13.4% and 13.8% in the DSE arm and 12.2% and 13.6% in the ILI arm for non-Hp2-2 and Hp2-2 groups, respectively. Compared to DSE, the ILI was not associated with CAD among participants without (HR = 0.95, 95% CI 0.78-1.17) or with (0.89, 0.68-1.19) the Hp2-2 phenotype (p-interaction between Hp phenotype and ILI = 0.58). After Bonferroni correction, there were no significant results among any subgroups. CONCLUSIONS: Hp phenotype did not modify the effect of the weight loss ILI on risk of CAD in Look AHEAD, potentially because it did not substantially impact glycemic control among participants with or without the Hp2-2 phenotype. Further research is needed to determine if these results are conclusive.

Relationship Between Time-Varying Achieved High-Density Lipoprotein Cholesterol and Risk of Coronary Events Depends on Haptoglobin Phenotype Within the ACCORD Lipid Study.

Background The Hp (haptoglobin)2-2 phenotype (~40% of people) is associated with dysfunctional high-density lipoprotein (HDL) that is heavily oxidized in hyperglycemia, which may explain why raising HDL-cholesterol (HDL-C) does not reliably prevent coronary artery disease (CAD) in diabetes. Methods and Results In this observational study using longitudinal data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) lipid trial, time-varying (achieved) HDL-C updated at 4, 8, and 12 months, and annually thereafter over a mean of 4.7 years, was analyzed in relation to risk of CAD and secondary outcomes using Cox proportional hazards regression with time-varying covariables among participants with (n=1781) and without (n=3191) the Hp2-2 phenotype. HDL-C did not differ between the phenotypes throughout the study. Having low HDL-C (<40 mg/dL for male participants and <50 mg/dL for female participants) was associated with a greater risk of CAD compared with non-low HDL-C among participants with the non-Hp2-2 phenotype (hazard ratio [HR], 1.48 [95% CI, 1.18-1.87]) but not among the Hp2-2 phenotype (HR, 0.97 [95% CI, 0.70-1.35]; P interaction=0.03). Similarly, an inverse relationship was observed between HDL-C quintiles and CAD risk among participants without the Hp2-2 phenotype, whereas no significant inverse relationship was observed among participants with the Hp2-2 phenotype (P interaction=0.38). Among the Hp2-2 phenotype group, having low HDL-C was associated with higher risk of CVD mortality (HR, 2.09 [95% CI, 1.05-4.13]), and compared with the lowest HDL-C quintile, higher quintiles were associated with lower risk of CVD mortality and congestive heart failure. Conclusions Hp phenotype modified the association between HDL-C and risk of CAD in the ACCORD lipid study, suggesting that HDL dysfunction in the Hp2-2 phenotype may hinder CAD-protective properties of HDL-C.

The Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Events Depends on Haptoglobin Phenotype Among White and Black ACCORD Participants.

OBJECTIVE: Intensive glycemic therapy reduced coronary artery disease (CAD) events among White participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with the haptoglobin (Hp)2-2 phenotype, while participants without the Hp2-2 phenotype had no CAD benefit. The association between achieved glycated hemoglobin (HbA1c) and CAD for each Hp phenotype remains unknown. RESEARCH DESIGN AND METHODS: Achieved HbA1c was similar in each phenotype throughout the study. Prospectively collected HbA1c data (categorized as <6.0%, 6.0-6.5%, 6.6-6.9%, or ≥8.0% compared with 7.0-7.9%) from the ACCORD study, updated every 4 months over a median of 4.7 years, were analyzed in relation to CAD in the Hp2-2 (n = 3,322) and non-Hp2-2 (n = 5,949) phenotypes separately overall, and within White (63%, 37% Hp2-2) and Black (19%, 26% Hp2-2) participants using Cox proportional hazards regression with time-varying covariables. RESULTS: Compared with HbA1c of 7.0-7.9%, having HbA1c ≥8.0% was associated with CAD risk among White (adjusted HR [aHR] 1.43, 95% CI 1.03-1.98) and Black (2.86, 1.09-7.51) participants with the Hp2-2 phenotype, but not when all Hp2-2 participants were combined overall (1.30, 0.99-1.70), and not among participants without the Hp2-2 phenotype. HbA1c <7.0% was not associated with a lower risk of CAD for any Hp phenotype. CONCLUSIONS: Achieving HbA1c >8.0% compared with 7.0-7.9% was consistently associated with incident CAD risk among White and Black ACCORD participants with the Hp2-2 phenotype, while no association was observed among participants without the Hp2-2 phenotype. We found no evidence that HbA1c concentration <7.0% prevents CAD in either Hp phenotype group.

Many authors of publicly available top-selling nutrition books in Canada are without clinical nutrition credentials, do not cite evidence, and promote their own services or products.

The accuracy of books as public nutrition resources varies substantially; whether authors of publicly available nutrition books possess related experience, cite scientific evidence, or have other financial incentives has not been assessed thoroughly. This study aimed to determine if publicly available top-selling nutrition books are written by authors who (1) have relevant expertise, (2) cite scientific evidence, and (3) benefit financially in other ways. Best-selling nutrition books were gathered from Amazon Canada. Differences in scientific citations and financial incentives were compared between authors with and without credentials. Authors who were Doctor of Medicine (MD), registered dietitians (RD), chiropractors, or naturopathic doctors had more in-text citations (56% versus 25%; p = 0.014) and cited more scientific articles (83% versus 50%; p = 0.0045) compared to all other authors. The majority of authors of publicly available top-selling nutrition books in Canada did not have MD/RD credentials. Many of the authors promoted their own services or products, regardless of credentials.

Eating Timing and Frequency as a Predictor of Hospitalization and/or Mortality From Coronary Artery Disease: The Linked CCHS-DAD-CMDB 2004-2013 Study.

Background: Coronary artery disease (CAD) is a major overlapping challenge in both clinical and public health realms due to high rates of hospitalization and mortality. Despite nutrition being a key risk factor for CAD, little is known about eating timing and frequency in Canadians or their relation to risk of hospitalization and/or mortality from CAD. Methods: Breakfast consumption, between-meal consumption, eating frequency, and established CAD risk factors were assessed at baseline in 13,328 adults free of cancer and CAD from the 2004 Canadian Community Health Survey, Cycle 2.2, Nutrition Focus and were linked to administrative health databases to determine incidence of hospitalization and/or mortality from CAD in the following 9 years. Multivariable-adjusted hazard ratios with 95% confidence intervals estimated from Cox proportional hazards models were computed to test for associations between eating timing/frequency and hospitalization and/or mortality from CAD (n = 746 cases). Results: Skipping breakfast (12.0% of participants) and engaging in between-meal consumption (90.2%) were common practices, as was eating 4-5 times per day (55.2%). Skipping breakfast, between-meal consumption, and eating more or less than 4-5 times/day were strongly and bi-directionally associated with many sociodemographic, lifestyle, and metabolic risk factors at baseline. No associations were observed between skipping breakfast, between-meal consumption, or eating frequency and risk of hospitalization and/or mortality from CAD. Conclusions: Skipping breakfast, between-meal consumption, and eating frequency were associated with numerous established risk and preventative factors for CAD at baseline but were not directly associated with the risk of hospitalization and/or mortality from CAD in this cohort of Canadian adults.

Introduction: La maladie coronarienne (MC) est un enjeu majeur chevauchant les domaines clinique et de santé publique en raison des taux élevés d'hospitalisation et de mortalité. Bien que la nutrition soit un facteur de risque fondamental de la MC, on en connaît peu sur le moment et la fréquence de la consommation d'aliments chez les Canadiens ou sur leur relation au risque d'hospitalisation et/ou de mortalité en raison de la MC. Méthodes: Nous avons initialement évalué la prise du déjeuner, la consommation entre les repas, la fréquence de la consommation d'aliments et les facteurs de risque établis de MC de 13 328 adultes indemnes de cancer et de MC de l'Enquête sur la santé dans les collectivités canadiennes de 2004, cycle 2.2, volet nutrition, et avons lié les bases de données administratives en santé pour déterminer la fréquence d'hospitalisation et/ou de mortalité en raison de la MC dans les neuf années subséquentes. Nous avons calculé les rapports de risque ajustés à plusieurs variables à intervalles de confiance à 95 % estimés à partir des modèles à risques proportionnels de Cox pour vérifier les associations entre le moment et la fréquence de la consommation d'aliments et l'hospitalisation et/ou la mortalité en raison de la MC (n = 746 cas). Résultats: L'absence du déjeuner (12,0 % des participants), la consommation d'aliments entre les repas (90,2 %) et la consommation d'aliments de 4 à 5 fois par jour (55,2 %) étaient des pratiques courantes. L'absence du déjeuner, la consommation d'aliments entre les repas et la consommation d'aliments plus ou moins 4-5 fois/jour étaient fortement et bidirectionnellement associées aux facteurs de risque sociodémographiques, liés au mode de vie et métaboliques initiaux. Nous n'avons observé aucune association entre l'absence du déjeuner, la consommation d'aliments entre les repas ou la fréquence de la consommation d'aliments, et le risque d'hospitalisation et/ou de mortalité en raison de la MC. Conclusions: L'absence du déjeuner, la consommation d'aliments entre les repas et la fréquence de la consommation d'aliments étaient associées à de nombreux risques établis et de facteurs préventifs initiaux de la MC, mais n'étaient pas directement associées au risque d'hospitalisation et/ou de mortalité en raison de la MC dans cette cohorte d'adultes canadiens.

Prospective study of breakfast frequency and timing and the risk of incident type 2 diabetes in community-dwelling older adults: the Cardiovascular Health Study.

BACKGROUND: No evidence-based recommendations regarding optimal breakfast frequency and timing and type 2 diabetes mellitus (T2DM) exist for older adults because of limited studies. OBJECTIVES: We sought to prospectively assess relations between breakfast frequency and timing and T2DM risk among older adults and determine whether these depended on sex or cardiometabolic risk factors. METHODS: Weekly breakfast frequency and usual daily breakfast time were assessed by questionnaire at baseline in 3747 older adults (aged ≥ 65 y) from the Cardiovascular Health Study (CHS) who were free of cancer and T2DM and followed for 17.6 y. Multivariable-adjusted hazard ratios (aHRs) with 95% CIs estimated from Cox proportional hazards models were used to quantify associations with T2DM. RESULTS: Most CHS participants (median age: 74 y; IQR: 71-78 y) consumed breakfast daily (85.5%), and 73% had their first daily eating occasion between 07:00 and 09:00, both of which were associated with higher socioeconomic status, factors that are indicative of a healthier lifestyle, and lower levels of cardiometabolic risk indicators at baseline. During follow-up, 547 T2DM cases were documented. No strong evidence was observed linking breakfast frequency and risk of T2DM. Compared with participants whose breakfast timing (first eating occasion of the day) was 07:00-09:00, those who broke fast after 09:00 had an aHR for T2DM of 0.71 (95% CI: 0.51, 0.99). This association was present in participants with impaired fasting glucose at baseline (aHR: 0.61; 95% CI: 0.39, 0.95) but not in those without (aHR: 0.83; 95% CI: 0.50, 1.38). No associations between eating frequency or timing and T2DM were observed within other prespecified subgroups. CONCLUSIONS: Eating breakfast daily was not associated with either higher or lower risk of T2DM in this cohort of older adults, whereas a later (after 09:00) daily first eating occasion time was associated with lower T2DM risk in participants with impaired fasting glucose at baseline.This trial was registered at clinicaltrials.gov as NCT00005133.

Haptoglobin Phenotype Modifies the Effect of Fenofibrate on Risk of Coronary Event: ACCORD Lipid Trial.

OBJECTIVE: The haptoglobin (Hp)2-2 phenotype (∼35-40% of people) is associated with increased oxidation and dysfunctional HDL in hyperglycemia and may explain why drugs designed to pharmacologically raise HDL cholesterol and lower triglycerides have not reliably prevented cardiovascular disease in diabetes. We aimed to determine whether the effect of adding fenofibrate versus placebo to simvastatin on the risk of coronary artery disease (CAD) events depends on Hp phenotype in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial. RESEARCH DESIGN AND METHODS: Cox proportional hazards regression models quantified the relationship between fenofibrate therapy and CAD events in the ACCORD lipid trial in participants with the Hp2-2 phenotype (n = 1,795) separately from those without (n = 3,201). RESULTS: Fenofibrate therapy successfully lowered the risk of CAD events in participants without the Hp2-2 phenotype (multivariable adjusted hazard ratio 0.74 [95% CI 0.60-0.90] compared with no fenofibrate therapy) but not in participants with the Hp2-2 phenotype (1.16 [0.87-1.56]; P interaction = 0.009). Subgroup analyses revealed that this protective effect of fenofibrate against CAD events among the non-Hp2-2 phenotype group was pronounced in participants with severe dyslipidemia (P interaction = 0.01) and in males (P interaction = 0.02) with an increased CAD risk from fenofibrate treatment observed in females with the Hp2-2 phenotype (P interaction = 0.002). CONCLUSIONS: The effect of fenofibrate added to simvastatin on risk of CAD events depends on Hp phenotype in the ACCORD lipid trial.

Comparison of Patient-Reported and Caregiver-Reported Swallowing-Related Quality of Life in Parkinson's Disease.

This pilot study explored agreement on swallowing-related quality-of-life scores reported by individuals with Parkinson's disease (PD) and their caregivers. Thirty-six patient-caregiver pairs completed the Swallowing Quality of Life Questionnaire (SWAL-QOL) using an online survey format. Additional background and clinical information was ascertained. A Wilcoxon signed-rank test was completed to compare the means of scores between individuals with PD and caregivers. Factors potentially influencing SWAL-QOL scores (age, employment status, sex, ethnicity, race, previous history of swallowing evaluation or treatment, caregiver concern about patient cognition, caregiver burden, and time since onset of disease) were explored using Spearman Coefficient Correlation tests. The Holm-Bonferroni method was used to adjust for multiple comparisons. Results did not reveal significant differences in SWAL-QOL scores between individuals with PD and caregiver pairs. There was a moderate degree of reliability and agreement between paired patient and caregiver scores, with the average ICC measures being 0.598 (95% CI [358, 0.748]) (F(71, 72) = 2.451, p < 0.0001). After adjusting for multiple comparisons, caregiver burden was found to be the only significant factor associated with caregivers' reported scores. No significant influential factor on reported scores by individuals with PD was found. These pilot results suggest individuals with PD and their caregivers may report similar swallowing-related quality-of-life scores. Further, caregiver burden appears to be an influential factor for caregiver-reported scores. Future studies should investigate the clinical benefits of including caregiver SWAL-QOL ratings in assessments, either as a supplement to patient scores to identify discrepancies across the dyad or in place of patient scores if needed. Further, caregiver burden and its influence on dysphagia identification and management should be explored, with targeted interventions to manage caregiver burden.

Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate.

Prospective Study of Skipping Meals to Lose Weight as a Predictor of Incident Type 2 Diabetes With Potential Modification by Cardiometabolic Risk Factors: The Canadian 1995 Nova Scotia Health Survey.

BACKGROUND: Skipping meals is an increasingly common practice to lose weight among North American adults. However, the long-term effect of this practice on incident type 2 diabetes mellitus (T2DM) remains unknown. We assessed whether skipping meals to lose weight is associated with T2DM risk and whether this association is modified by cardiometabolic risk factors. METHODS: Skipping meals to lose weight was assessed by questionnaire in 2,288 adults from the 1995 Nova Scotia Health Survey and was linked to administrative health databases to determine T2DM incidence in the following 23 years. Multivariable-adjusted Cox proportional hazards models estimated hazard ratios (aHRs) and 95% confidence intervals (CIs) for T2DM. RESULTS: During follow up, 378 T2DM cases were diagnosed. Compared with participants who did not skip meals to lose weight, those who did (2.2%) had a 125% higher risk of T2DM (aHR, 2.25; 95% CI, 1.31 to 3.86). This association was no longer present after further adjustment for baseline body mass index (BMI) (aHR, 1.66; 95% CI, 0.96 to 2.85). Skipping meals to lose weight was associated with T2DM among participants who were men (n=1,135; aHR, 2.09; 95% CI, 1.09 to 4.02) or had a BMI <30 kg/m2 (n=1,676; aHR, 2.64, 95% CI, 1.15 to 6.06), elevated cholesterol (n=1,146; aHR, 2.11; 95% CI, 1.06 to 4.22), high blood pressure (n=1,133; aHR, 2.10; 95% CI, 1.10 to 4.01) and restless sleep (n=1,186; aHR, 2.19; 95% CI, 1.13 to 4.25), but not among women, those with a BMI of ≥30 kg/m2 and those without elevated cholesterol, high blood pressure or restless sleep. CONCLUSIONS: Skipping meals to lose weight may be a predictive modifiable risk factor for developing T2DM over time, potentially working in connection with other T2DM risk factors.

Resident Memory B Cells.

In mammals, adaptive immunity is mediated by a broadly diverse repertoire of naive B and T lymphocytes that recirculate between secondary lymphoid organs. Initial antigen exposure promotes lymphocyte clonal expansion and differentiation, including the formation of memory cells. Antigen-specific memory cells are maintained at higher frequencies than their naive counterparts and have different functional and homing abilities. Importantly, a subset of memory cells, known as tissue-resident memory cells, is maintained without recirculating in nonlymphoid tissues, often at barrier surfaces, where they can be reactivated by antigen and rapidly perform effector functions that help protect the tissue in which they reside. Although antigen-experienced B cells are abundant at many barrier surfaces, their characterization as tissue-resident memory B (BRM) cells is not well developed. In this study, we describe the characteristics of memory B cells in various locations and discuss their possible contributions to immunity and homeostasis as bona fide BRM cells.

Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes.

BACKGROUND: Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia. OBJECTIVES: This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype. METHODS: Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers). RESULTS: Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908). CONCLUSIONS: Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.

Parent and Provider Preferences for Parenting Intervention Delivery in Rural Appalachia: A Qualitative Analysis Guiding Adaptation.

The public health impact of behavioral parent training (BPT) is limited, especially in underserved communities such as rural central Appalachia. To improve access to BPT in this region, we completed the first two steps of the ADAPT-ITT framework for systematic adaptation of evidence-based interventions: (1) assessing community perspectives about BPT delivery, and (2) deciding upon a specific intervention and adaptations needed to increase its acceptability and accessibility in rural central Appalachian counties. Guided by a community advisory board, we conducted key informant interviews with parents (N = 21) and three focus groups with child service providers to elicit stakeholders' perspectives about child behavior problems in their communities; existing resources; and preferences regarding four characteristics of BPT delivery: interventionist, modality, dose, and location. Results of directed content analysis led to the selection of local, trusted community health workers to deliver a brief, tailored BPT with flexibility in modality and location.

The establishment of resident memory B cells in the lung requires local antigen encounter.

Memory B cells are found in lymphoid and non-lymphoid tissues, suggesting that some may be tissue-resident cells. Here we show that pulmonary influenza infection elicited lung-resident memory B cells (BRM cells) that were phenotypically and functionally distinct from their systemic counterparts. BRM cells were established in the lung early after infection, in part because their placement required local antigen encounter. Lung BRM cells, but not systemic memory B cells, contributed to early plasmablast responses following challenge infection. Following secondary infection, antigen-specific BRM cells differentiated in situ, whereas antigen-non-specific BRM cells were maintained as memory cells. These data demonstrate that BRM cells are an important component of immunity to respiratory viruses such as influenza virus and suggest that vaccines designed to elicit BRM cells must deliver antigen to the lungs.

Impact of 'Ideal Clinic' implementation on patient waiting time in primary healthcare clinics in KwaZulu-Natal Province, South Africa: A before-and-after evaluation.

BACKGROUND: Long waiting times are a major source of dissatisfaction for patients attending public healthcare facilities in South Africa (SA). The National Department of Health has identified this as one of six priority areas for improvement. Health system-strengthening (HSS) interventions to improve patient waiting time are being implemented in public health facilities across SA as part of the 'Ideal Clinic' model. The effect of these interventions on patient waiting time needs to be assessed and evidence generated for system improvement. OBJECTIVES: To determine the effect of Ideal Clinic HSS intervention on patient waiting time in public health facilities in Amajuba District, KwaZulu-Natal Province, SA. METHODS: We implemented 12 months of HSS activity, including facility reorganisation and patient appointment scheduling. The major outcome of interest was the total time spent by patients in a facility during a visit. This was calculated as the median time spent, obtained through a 'before-and-after' intervention survey. Univariate and multivariate factors associated with waiting time were determined. RESULTS: A total of 1 763 patients from nine clinics were surveyed before and after the intervention (n=860 at baseline and n=903 at follow-up). The median overall waiting time after the intervention was 122 minutes (interquartile range (IQR) 81 - 204), compared with 116 minutes (IQR 66 - 168) before (p<0.05). Individual facility results after the intervention were mixed. Two facilities recorded statistically significant reductions in patient waiting time, while three recorded significant increases (p<0.05). Patient load per nurse, type of service received and time of arrival in facilities were all independently associated with waiting time. Patients' arrival patterns, which were determined by appointment scheduling, played a significant role in the results obtained. CONCLUSIONS: Implementation of the Ideal Clinic model in the selected facilities led to changes in patient waiting time. Observed changes were positive when a clinic appointment system was successfully implemented and negative when this was unsuccessful. We recommend strengthening of the appointment system component of the Ideal Clinic model to improve patient waiting time. Assessing facility waiting time performance in terms of average time spent by patients during a clinic visit was shown to be inadequate, and we suggest the inclusion of 'proportion of clients who spent above the national waiting time threshold during their visit' as a sensitive measure of performance.