The Cabarrus County COVID-19 Prevalence and Immunity (C3PI) Study: design, methods, and baseline characteristics.

OBJECTIVES: Coronavirus Disease 2019 (COVID-19) is a viral illness with public health importance. The Cabarrus County COVID-19 Prevalence and Immunity (C3PI) Study is a prospective, longitudinal cohort study designed to contribute valuable information on community prevalence of active COVID-19 infection and SARS-CoV-2 antibodies as the pandemic and responses to it have and continue to evolve. We present the rationale, study design, and baseline characteristics of the C3PI Study. METHODS: We recruited 1,426 participants between June 2020 and August 2020 from the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study Community Registry and Biorepository, a previously established, community-based, longitudinal cohort. Participants completed a baseline survey and follow-up surveys every two weeks. A nested weighted, random sub-cohort (n=300) was recruited to measure the incidence and prevalence of active COVID-19 infection and SARS-CoV-2 IgG antibodies. RESULTS: The sub-cohort was younger (56 vs 61 years), had more men (39.0% vs 30.9%), and a higher proportion of Hispanic (11.0% vs 5.1%) and Black participants (17.0% vs 8.2%) compared with the overall cohort. They had similar anthropometrics and medical histories, but a greater proportion of the sub-cohort had a higher educational degree (36.1% vs 31.3%) and reported a pre-pandemic annual household income of >$90,000 (57.1% vs 47.9%). CONCLUSION: This study is part of a multisite consortium that will provide critical data on the epidemiology of COVID-19 and community perspectives about the pandemic, behaviors and mitigation strategies, and individual and community burden in North Carolina.

Comparative Effectiveness of Medical Therapy, Supervised Exercise, and Revascularization for Patients With Intermittent Claudication: A Network Meta-analysis.

BACKGROUND: There are limited data on the comparative effectiveness of medical therapy, supervised exercise, and revascularization to improve walking and quality of life in patients with intermittent claudication (IC). HYPOTHESIS: Supervised exercise and revascularization was superior to medical therapy in IC. METHODS: We studied the comparative effectiveness of exercise training, medications, endovascular intervention, and surgical revascularization on outcomes including functional capacity (walking distance and timing), quality of life, and mortality. We searched PubMed, EMBASE, and the Cochrane Database of Systematic Reviews from January 1995 to August 2012 for relevant English-language studies. Two investigators independently collected data. Meta-analyses with random-effects models of direct comparisons were supplemented by mixed-treatment analyses to incorporate data from placebo comparisons, head-to-head comparisons, and multiple treatment arms. RESULTS: Thirty-five unique studies evaluated treatment modalities in 7475 patients with IC. Compared with usual care, only exercise training improved both maximal walking distance (150 meters; 95% confidence interval: 35-266 meters, P = 0.01) and initial claudication distance (39 meters; 95% confidence interval: 9-65 meters, P = 0.003). All modalities were associated with improved quality of life (Short Form-36 physical functioning score) compared with usual care, but there were no differences between treatments. There were insufficient safety data to assess treatment-related complications. All-cause mortality was not significantly different between modalities. CONCLUSIONS: Evidence is insufficient to determine treatment superiority for improving quality of life and walking parameters in IC patients. Further studies with attention to study design, standardized efficacy and safety endpoints, and appropriate subgroup reporting are necessary to determine comparative effectiveness.

Data-driven asthma endotypes defined from blood biomarker and gene expression data.

The diagnosis and treatment of childhood asthma is complicated by its mechanistically distinct subtypes (endotypes) driven by genetic susceptibility and modulating environmental factors. Clinical biomarkers and blood gene expression were collected from a stratified, cross-sectional study of asthmatic and non-asthmatic children from Detroit, MI. This study describes four distinct asthma endotypes identified via a purely data-driven method. Our method was specifically designed to integrate blood gene expression and clinical biomarkers in a way that provides new mechanistic insights regarding the different asthma endotypes. For example, we describe metabolic syndrome-induced systemic inflammation as an associated factor in three of the four asthma endotypes. Context provided by the clinical biomarker data was essential in interpreting gene expression patterns and identifying putative endotypes, which emphasizes the importance of integrated approaches when studying complex disease etiologies. These synthesized patterns of gene expression and clinical markers from our research may lead to development of novel serum-based biomarker panels.

Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review.

BACKGROUND: Discordant results have been reported on the effects of concomitant use of proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT) for cardiovascular outcomes. We conducted a systematic review comparing the effectiveness and safety of concomitant use of PPIs and DAPT in the postdischarge treatment of unstable angina/non-ST-segment-elevation myocardial infarction patients. METHODS AND RESULTS: We searched for clinical studies in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, from 1995 to 2012. Reviewers screened and extracted data, assessed applicability and quality, and graded the strength of evidence. We performed meta-analyses of direct comparisons when outcomes and follow-up periods were comparable. Thirty-five studies were eligible. Five (4 randomized controlled trials and 1 observational) assessed the effect of omeprazole when added to DAPT; the other 30 (observational) assessed the effect of PPIs as a class when compared with no PPIs. Random-effects meta-analyses of the studies assessing PPIs as a class consistently reported higher event rates in patients receiving PPIs for various clinical outcomes at 1 year (composite ischemic end points, all-cause mortality, nonfatal MI, stroke, revascularization, and stent thrombosis). However, the results from randomized controlled trials evaluating omeprazole compared with placebo showed no difference in ischemic outcomes, despite a reduction in upper gastrointestinal bleeding with omeprazole. CONCLUSIONS: Large, well-conducted observational studies of PPIs and randomized controlled trials of omeprazole seem to provide conflicting results for the effect of PPIs on cardiovascular outcomes when coadministered with DAPT. Prospective trials that directly compare pharmacodynamic parameters and clinical events among specific PPI agents in patients with unstable angina/non-ST-segment-elevation myocardial infarction treated with DAPT are warranted.

Dual antiplatelet therapy with or without oral anticoagulation in the postdischarge management of acute coronary syndrome patients with an indication for long term anticoagulation: a systematic review.

Currently, there is a lack of consensus among guidelines for the postdischarge treatment of patients presenting with acute coronary syndrome (ACS) who have a long-term indication for anticoagulation. We conducted a systematic review comparing the safety and effectiveness of dual antiplatelet therapy (DAPT) and triple therapy (TT; defined as DAPT plus an oral anticoagulant) in patients with ACS and a long-term indication for anticoagulation. We searched for clinical studies in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews published between January 1995 and September 2013. Each investigator screened and abstracted data, assessed applicability and quality, and graded the strength of evidence. Meta-analysis of direct comparison was performed when outcomes and follow-up periods were comparable. Fourteen observational studies were identified that contained comparative effectiveness data on DAPT versus TT. No difference in the odds of mortality (OR 1.04, 95% CI 0.59-1.83) or stroke (OR 1.01, 95% CI 0.38-2.67) at 1-5 years was found between TT and DAPT. Major bleeding at 1-5 years (OR 1.46, 95% CI 1.07-2.00) and nonfatal MI at 1-5 years (OR 1.85, 95% CI 1.13-3.02) occurred more frequently in patients receiving TT. The results of this systematic review demonstrate that treatment with TT was associated with increased rates of nonfatal MI and major bleeding when compared with treatment with DAPT in the postdischarge management of ACS patients with an indication for oral anticoagulation. Until results of ongoing randomized trials assessing antithrombotic therapies define optimal management strategies, the current analysis suggests using caution when prescribing TT to these patients.

Evaluating cough assessment tools: a systematic review.

BACKGROUND: Little is known about the comparative validity, reliability, or responsiveness of instruments for assessing cough frequency or impact, where the term impact encompasses both cough severity and the impact of cough on health-related quality of life. METHODS: We conducted a systematic review to evaluate instruments that assess cough frequency or impact in adults, adolescents, and children with acute or chronic cough. RESULTS: Seventy-eight studies were included, of which eight were randomized controlled trials and 70 were observational studies. In all age groups, audio and video electronic recording devices had good reliability compared with other methods of assessing cough frequency but had variable correlation with other cough assessments, such as visual analog scale scores, quality-of-life questionnaires, cough diaries, and tussigenic challenges. Among adult and adolescent patients, the Leicester Cough Questionnaire (LCQ) and the Cough-Specific Quality-of-Life Questionnaire (CQLQ) were valid and reliable, showing high intraclass and test-retest correlations. Among children, the Parent Cough-Specific Quality of Life Questionnaire and Pediatric Cough Questionnaire were valid and reliable. CONCLUSIONS: Electronic recording devices can be valid assessments of cough frequency. The LCQ and CQLQ for adults and the Parent Cough-Specific Quality of Life questionnaire for children are valid instruments for assessing cough impact. There is limited but insufficient evidence to determine the reliability or concurrent validity of the different types of cough diaries or visual analog scale scores. There are also limited data to support the responsiveness of recording devices. There is good responsiveness data for the LCQ and CQLQ, but more evidence is needed.

Efficacy and tolerability of treatments for chronic cough: a systematic review and meta-analysis.

BACKGROUND: Understanding the comparative effectiveness of treatments for patients with unexplained or refractory cough is important to increase awareness of proven therapies and their potential adverse effects in this unique population. METHODS: We performed a literature search for English-language studies published up to June 2012 that compared symptomatic therapies for chronic cough. Two investigators screened each abstract and full-text article for inclusion, abstracted data, and rated quality. Meta-analysis with random-effects models was used to summarize effects of treatments. RESULTS: We identified 49 studies (3,067 patients) comprising 68 therapeutic comparisons. Of the studied agents, opioid and certain nonopioid and nonanesthetic antitussives had demonstrated efficacy for chronic cough in adults. Compared with placebo, effect sizes (standardized mean differences for cough severity and rate ratios for cough frequency) for opioids were 0.55 (95% CI, 0.38-0.72; P < .0001) and 0.57 (95% CI, 0.36-0.91; P = .0260), respectively. For dextromethorphan, effect sizes were 0.37 (95% CI, 0.19-0.56; P = .0008) and 0.40 (95% CI, 0.18-0.85; P = .0248), respectively. The overall strength of evidence was limited by inconsistency and imprecision of results and by small numbers of direct comparisons. Nonpharmacologic therapies and the management of cough in children were infrequently studied. CONCLUSIONS: Although evidence is limited, opioid and certain nonopioid and nonanesthetic antitussives demonstrated efficacy for treating chronic cough in adults. There is a need for further studies in patients with unexplained or refractory cough as well as for more systematic study designs, assessment of patient-centered outcomes, and reporting.

The patient centered medical home. A systematic review.

BACKGROUND: The patient-centered medical home (PCMH) describes mechanisms for organizing primary care to provide high quality care across the full range of individuals' health care needs.It is being widely implemented by provider organizations and third party payers. PURPOSE: To describe approaches for PCMH implementation and summarize evidence for effects on patient and staff experiences,process of care, and clinical and economic outcomes. DATA SOURCES: PubMed (through 6 December 2011), Cumulative Index to Nursing & Allied Health Literature, and the Cochrane Database of Systematic Reviews (through 29 June 2012). STUDY SELECTION: English-language trials and longitudinal observational studies that met criteria for the PCMH, as defined by the Agency for Healthcare Research and Quality, and included populations with multiple conditions. DATA EXTRACTION: Information on study design, populations, interventions,comparators, financial models, implementation methods,outcomes, and risk of bias were abstracted by 1 investigator and verified by another. DATA SYNTHESIS: In 19 comparative studies, PCMH interventions had a small positive effect on patient experiences and small to moderate positive effects on the delivery of preventive care services(moderate strength of evidence). Staff experiences were also improved by a small to moderate degree (low strength of evidence).Evidence suggested a reduction in emergency department visits(risk ratio [RR], 0.81 [95% CI, 0.67 to 0.98]) but not in hospital admissions (RR, 0.96 [CI, 0.84 to 1.10]) in older adults (low strength of evidence). There was no evidence for overall cost savings. LIMITATION: Systematic review is challenging because of a lack of consistent definitions and nomenclature for PCMH. CONCLUSION: The PCMH holds promise for improving the experiences of patients and staff and potentially for improving care processes,but current evidence is insufficient to determine effects on clinical and most economic outcomes

Closing the quality gap: revisiting the state of the science (vol. 2: the patient-centered medical home).

OBJECTIVES: As part of the Closing the Quality Gap: Revisiting the State of the Science series of the Agency for Healthcare Research and Quality (AHRQ), this systematic review sought to identify completed and ongoing evaluations of the comprehensive patient-centered medical home (PCMH), summarize current evidence for this model, and identify evidence gaps. DATA SOURCES: We searched PubMed®, CINAHL®, and the Cochrane Database of Systematic Reviews for published English-language studies, and a wide variety of databases and Web resources to identify ongoing or recently completed studies. REVIEW METHODS: Two investigators per study screened abstracts and full-text articles for inclusion, abstracted data, and performed quality ratings and evidence grading. Our functional definition of PCMH was based on the definition used by AHRQ. We included studies that explicitly claimed to be evaluating PCMH and those that did not but which met our functional definition. RESULTS: Seventeen studies with comparison groups evaluated the effects of PCMH (Key Question [KQ] 1). Older adults in the United States were the most commonly studied population (8 of 17 studies). PCMH interventions had a small positive impact on patient experiences (including patient-perceived care coordination) and small to moderate positive effects on preventive care services (moderate strength of evidence [SOE]). Staff experiences were also improved by a small to moderate degree (low SOE). There were too few studies to estimate effects on clinical or most economic outcomes. Twenty-one of 27 studies reported approaches that addressed all 7 major PCMH components (KQ 2), including team-based care, sustained partnership, reorganized care or structural changes to care, enhanced access, coordinated care, comprehensive care, and a systems-based approach to quality. A total of 51 strategies were used to address the 7 major PCMH components. Twenty-two of 27 studies reported information on financial systems used to implement PCMH, implementation strategies, and/or organizational learning strategies for implementing PCMH (KQ 3). The 31 studies identified in the horizon scan of ongoing PCMH studies (KQ 4) were broadly representative of the U.S. health care system, both in geography and in the complexity of private and public health care payers and delivery networks. CONCLUSIONS: Published studies of PCMH interventions often have similar broad elements, but precise components of care varied widely. The PCMH holds promise for improving the experiences of patients and staff, and potentially for improving care processes. However, current evidence is insufficient to determine effects on clinical and most economic outcomes. Ongoing studies identified through the horizon scan have potential to greatly expand the evidence base relating to PCMH.

Comparative microarray analysis and pulmonary changes in Brown Norway rats exposed to ovalbumin and concentrated air particulates.

The interaction between air particulates and genetic susceptibility has been implicated in the pathogenesis of asthma. The overall objective of this study was to determine the effects of inhalation exposure to environmentally relevant concentrated air particulates (CAPs) on the lungs of ovalbumin (ova) sensitized and challenged Brown Norway rats. Changes in gene expression were compared with lung tissue histopathology, morphometry, and biochemical and cellular parameters in bronchoalveolar lavage fluid (BALF). Ova challenge was responsible for the preponderance of gene expression changes, related largely to inflammation. CAPs exposure alone resulted in no significant gene expression changes, but CAPs and ova-exposed rodents exhibited an enhanced effect relative to ova alone with differentially expressed genes primarily related to inflammation and airway remodeling. Gene expression data was consistent with the biochemical and cellular analyses of the BALF, the pulmonary pathology, and morphometric changes when comparing the CAPs-ova group to the air-saline or CAPs-saline group. However, the gene expression data were more sensitive than the BALF cell type and number for assessing the effects of CAPs and ova versus the ova challenge alone. In addition, the gene expression results provided some additional insight into the TGF-beta-mediated molecular processes underlying these changes. The broad-based histopathology and functional genomic analyses demonstrate that exposure to CAPs exacerbates rodents with allergic inflammation induced by an allergen and suggests that asthmatics may be at increased risk for air pollution effects.

Effects of sequence on repeat expansion during DNA replication.

Small DNA repeat tracts are located throughout the human genome. The tracts are unstable, and expansions of certain repeat sequences cause neuromuscular disease. DNA expansions appear to be associated with lagging-strand DNA synthesis and DNA repair. At some sites of repeat expansion, e.g. the myotonic dystrophy type 2 (DM2) tetranucleotide repeat expansion site, more than one repeat tract with similar sequences lie side by side. Only one of the DM2 repeat tracts, however, is found to expand. Thus, DNA base sequence is a possible factor in repeat tract expansion. Here we determined the expansion potential, during DNA replication by human DNA polymerase beta, of several tetranucleotide repeat tracts in which the repeat units varied by one or more bases. The results show that subtle changes, such as switching T for C in a tetranucleotide repeat, can have dramatic consequences on the ability of the nascent-strand repeat tract to expand during DNA replication. We also determined the relative stabilities of self-annealed 100mer repeats by melting-curve analysis. The relative stabilities did not correlate with the relative potentials of the analogous repeats for expansion during DNA replication, suggesting that hairpin formation is not required for expansion during DNA replication.

Hairpin formation in Friedreich's ataxia triplet repeat expansion.

Triplet repeat tracts occur throughout the human genome. Expansions of a (GAA)(n)/(TTC)(n) repeat tract during its transmission from parent to child are tightly associated with the occurrence of Friedreich's ataxia. Evidence supports DNA slippage during DNA replication as the cause of the expansions. DNA slippage results in single-stranded expansion intermediates. Evidence has accumulated that predicts that hairpin structures protect from DNA repair the expansion intermediates of all of the disease-associated repeats except for those of Friedreich's ataxia. How the latter repeat expansions avoid repair remains a mystery because (GAA)(n) and (TTC)(n) repeats are reported not to self-anneal. To characterize the Friedreich's ataxia intermediates, we generated massive expansions of (GAA)(n) and (TTC)(n) during DNA replication in vitro using human polymerase beta and the Klenow fragment of Escherichia coli polymerase I. Electron microscopy, endonuclease cleavage, and DNA sequencing of the expansion products demonstrate, for the first time, the occurrence of large and growing (GAA)(n) and (TTC)(n) hairpins during DNA synthesis. The results provide unifying evidence that predicts that hairpin formation during DNA synthesis mediates all of the disease-associated, triplet repeat expansions.