Efficacy and tolerability of zinc acetate for treatment of chronic refractory cough: pilot randomised futility trial.

Background: Cough is the most reported symptom in the United States, with chronic refractory cough representing significant morbidity to patients. Zinc acetate may have beneficial effects in the cough reflex pathway. We sought to assess the safety and efficacy of zinc acetate in the management of chronic refractory cough. Study design and methods: This was a randomised, placebo-controlled, parallel-design pilot trial of individuals with chronic refractory cough. The effects of 6 weeks of zinc acetate versus placebo on quality of life and symptoms as measured by the Cough Quality-of-Life Questionnaire (CQLQ), Leicester Cough Questionnaire (LCQ), cough visual analogue score (C-VAS) and Global Assessment of Change in Cough (GACC) scores were evaluated. A futility analysis plan with a one-sided 80% confidence interval was used to compare treatment effect to published minimum clinically important differences (MCID) for each outcome. Results: 34 participants, 17 in each group, were enrolled and randomised. Participants were primarily white females with moderate-severe cough. Participants assigned to zinc acetate had a significant increase in serum zinc levels after 6 weeks, while those assigned to placebo did not. Both groups showed improvement in CQLQ, LCQ, C-VAS and GACC scores, but the treatment effects of zinc acetate versus placebo were small with confidence intervals that did not include the MCIDs. Interpretation: We observed no benefit of zinc therapy over placebo on cough symptoms or quality of life and conclude that larger trials of zinc for chronic cough are not warranted.

Losartan Effects on Emphysema Progression Randomized Clinical Trial: Rationale, Design, Recruitment, and Retention.

The Losartan Effects on Emphysema Progression (LEEP) trial was designed to test the hypothesis that losartan slows progression of emphysema in chronic obstructive pulmonary disease (COPD) patients (NCT00720226). It was conducted by the Pulmonary Trials Cooperative consortium, in collaboration with the American Lung Association Airways Clinical Research Centers network. We describe the design of the trial and challenges for recruitment and follow-up of participants. LEEP is a placebo-controlled, parallel randomized trial, allocation ratio of 1:1, with a planned sample size of 220. Primary eligibility criteria were mild emphysema based on high-resolution computed tomography (HRCT) scans with 5% to 35% voxels <-950 Hounsfield units (HU), airway obstruction based on spirometry, and not taking an angiotensin receptor blocker or angiotensin converting enzyme (ACE) inhibitor. Participants received either losartan or placebo for 48 weeks. A total of 2779 individuals were screened to enroll 220 eligible participants at 26 clinical sites, all located in the continental United States. Recruitment took 45% longer than planned (32 months versus 22 months), with an average accrual rate of 6.7 participants per month. Recruitment challenges included identification of eligible participants who were not already taking or who did not have an established clinical indication for an angiotensin receptor blocker or ACE inhibitor drug and recalls of contaminated lots of losartan by the Food and Drug Administration. A number of recruitment initiatives were launched in response. Recruitment was completed in February 2020, just prior to a nationwide shutdown of research activities due to the coronavirus disease 2019 (COVID-19) pandemic.

Association of mild cognitive impairment and characteristic of COPD and overall health status in a cohort study.

Introduction: We evaluated risk factors and demographic characteristics of associated with mild cognitive impairment (MCI) in patients with COPD. Methods: 220 individuals with COPD enrolled in a cohort study designed to evaluate anxiety conducted at 16 clinical centers. Cognitive impairment was assessed with the Montreal Cognitive Assessment (MoCA), a cutoff score of <26 defined as MCI. Data were collected including spirometry, 6-minute walk test, symptom burden by COPD Assessment Test and dyspnea by Modified Medical Research Council, anxiety measured by Anxiety Inventory of Respiratory Disease, Generalized Anxiety Disorder-7 and Hospital Anxiety Depression Scale, depression by Patient Health Questionnaire-9 and health status by Patient Reported Outcomes Measurement Information System and sleep quality by the Pittsburg Sleep Quality Index. Results: The median age was 65 years and 54% of participants were male. 119(54%) of participants had MCI as classified by MoCA. In multivariable logistic regression, higher odds ratios (OR) (95% confidence interval) for MCI (MoCA) <26 were associated with increased years of age, 1.06 (1.02 -1-09, p<0.003); African-American race, 3.68(1.67-8.11, p<0.001); persistent phlegm, 2 (1.12-3.57, p<0.01) and sleep disturbance, 1.04(1.01-1.08, p<0.01). Conclusions: COPD patients commonly screen positive for MCI. Characteristics associated with MCI included age, African-American race, sleep disturbance and persistent phlegm.

Test Performance Characteristics of the AIR, GAD-7, and HADS-Anxiety Screening Questionnaires for Anxiety in Chronic Obstructive Pulmonary Disease.

Rationale: Anxiety is a common comorbidity of chronic obstructive pulmonary disease (COPD) that is associated with higher morbidity and mortality. We evaluated three anxiety screening questionnaires: the Generalized Anxiety Disorder 7-Item Scale (GAD-7), the Hospital Anxiety and Depression Scale Anxiety subscale (HADS-A), and the Anxiety Inventory for Respiratory Disease (AIR).Objectives: To evaluate and compare the test performance characteristics of three anxiety screening questionnaires, using the Mini-International Neuropsychiatric Interview (MINI), version 7.0, as the "gold standard."Methods: Individuals with COPD were recruited at 16 centers. The MINI and questionnaires were administered by trained research coordinators at an in-person visit and readministered by telephone 2-4 weeks later. A composite score for the presence of any Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) anxiety disorder was computed, based on the MINI as the gold standard, compared with a participant screening positive on self-report measures for these analyses.Results: Two hundred and twenty eligible individuals with COPD were enrolled; 219 completed the study. Eleven percent were identified as having a DSM-V anxiety disorder, based on the MINI. Elevated anxiety symptoms based on questionnaires were 38% for the AIR, 30% for the GAD-7, and 20% for the HADS-A. Area under the receiver operating characteristic curve (AUC) was highest for the GAD-7 (0.78; 95% confidence interval [CI], 0.69-0.87), followed by the HADS-A (0.74; 95% CI, 0.64-0.84) and the AIR (0.66; 95% CI, 0.56-0.76). The AUC for the GAD-7 was significantly greater than for the AIR (P = 0.014). Sensitivity was not statistically different among the questionnaires: 77% for the GAD-7, 63% for the HADS-A, and 66% for the AIR. The HADS-A had the highest specificity, 85%, which was significantly higher than that of the GAD-7 (77%; P < 0.001) and the AIR (65%; P < 0.001); GAD-7 specificity was higher than AIR specificity (P < 0.001).Conclusions: Symptoms of anxiety among patients with COPD as identified by screening questionnaires were common and significantly higher than the prevalence of anxiety disorder meeting DSM-V criteria. The GAD-7, the HADS-A and the AIR questionnaires had fair to moderate psychometric properties as screening tools for anxiety in individuals with COPD, indicating the need for improved measures for this patient population.

A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism.

Autism is a childhood neuropsychiatric disorder that, despite exhibiting high heritability, has largely eluded efforts to identify specific genetic variants underlying its etiology. We performed a two-stage genetic study in which genome-wide linkage and family-based association mapping was followed up by association and replication studies in an independent sample. We identified a common polymorphism in contactin-associated protein-like 2 (CNTNAP2), a member of the neurexin superfamily, that is significantly associated with autism susceptibility. Importantly, the genetic variant displays a parent-of-origin and gender effect recapitulating the inheritance of autism.

Dynamic and redundant regulation of LRRK2 and LRRK1 expression.

BACKGROUND: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene account for a significant proportion of autosomal-dominant and some late-onset sporadic Parkinson's disease. Elucidation of LRRK2 protein function in health and disease provides an opportunity for deciphering molecular pathways important in neurodegeneration. In mammals, LRRK1 and LRRK2 protein comprise a unique family encoding a GTPase domain that controls intrinsic kinase activity. The expression profiles of the murine LRRK proteins have not been fully described and insufficiently characterized antibodies have produced conflicting results in the literature. RESULTS: Herein, we comprehensively evaluate twenty-one commercially available antibodies to the LRRK2 protein using mouse LRRK2 and human LRRK2 expression vectors, wild-type and LRRK2-null mouse brain lysates and human brain lysates. Eleven antibodies detect over-expressed human LRRK2 while four antibodies detect endogenous human LRRK2. In contrast, two antibodies recognize over-expressed mouse LRRK2 and one antibody detected endogenous mouse LRRK2. LRRK2 protein resides in both soluble and detergent soluble protein fractions. LRRK2 and the related LRRK1 genes encode low levels of expressed mRNA species corresponding to low levels of protein both during development and in adulthood with largely redundant expression profiles. CONCLUSION: Despite previously published results, commercially available antibodies generally fail to recognize endogenous mouse LRRK2 protein; however, several antibodies retain the ability to detect over-expressed mouse LRRK2 protein. Over half of the commercially available antibodies tested detect over-expressed human LRRK2 protein and some have sufficient specificity to detect endogenous LRRK2 in human brain. The mammalian LRRK proteins are developmentally regulated in several tissues and coordinated expression suggest possible redundancy in the function between LRRK1 and LRRK2.