Post Hoc Analysis of Lung Function Improvement and Patient-Reported Outcomes With Revefenacin in Adults With Moderate-to-Very Severe COPD and Comorbid Anxiety or Depression.

Background: Revefenacin, a once-daily, nebulized, long-acting muscarinic antagonist approved in the United States for the maintenance of chronic obstructive pulmonary disease (COPD), significantly improves lung function and quality of life versus placebo in patients with moderate-to-very severe COPD. Comorbid anxiety and/or depression may alter patients' symptom perception and response to bronchodilators. The impact of revefenacin in patients with COPD with comorbid anxiety and/or depression has not been previously investigated. Methods: This post hoc subgroup analysis examined data from two 12-week, randomized, phase 3 trials in patients with moderate-to-very severe COPD with the following self-reported subgroups: anxiety only (A), depression only (D), anxiety and depression (+A/+D), and neither anxiety nor depression (-A/-D). We assessed change from baseline in trough forced expiratory volume in 1 second (FEV1) at Day 85 and health status by the St George's Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT). Results: Of 812 patients, 90 (11%), 110 (14%), 141 (17%), and 471 (58%) had A, D, +A/+D, and -A/-D respectively. In revefenacin versus placebo, trough FEV1 significantly improved from baseline at Day 85 across all subgroups as well as the SGRQ and CAT scores in patients with A, +A/+D, and -A/-D. Revefenacin was well tolerated regardless of A/D status, with a minimal incidence of treatment-emergent antimuscarinic adverse events across subgroups. Conclusion: In this analysis, revefenacin versus placebo significantly improved health outcomes in patients with moderate-to-very severe COPD with A, +A/+D, and -A/-D, but not in patients with D. The safety profile of revefenacin was not affected by comorbid anxiety/depression status.

Guidance on Mitigating the Risk of Transmitting Respiratory Infections During Nebulization by the COPD Foundation Nebulizer Consortium.

BACKGROUND: Nebulizers are used commonly for inhaled drug delivery. Because they deliver medication through aerosol generation, clarification is needed on what constitutes safe aerosol delivery in infectious respiratory disease settings. The COVID-19 pandemic highlighted the importance of understanding the safety and potential risks of aerosol-generating procedures. However, evidence supporting the increased risk of disease transmission with nebulized treatments is inconclusive, and inconsistent guidelines and differing opinions have left uncertainty regarding their use. Many clinicians opt for alternative devices, but this practice could impact outcomes negatively, especially for patients who may not derive full treatment benefit from handheld inhalers. Therefore, it is prudent to develop strategies that can be used during nebulized treatment to minimize the emission of fugitive aerosols, these comprising bioaerosols exhaled by infected individuals and medical aerosols generated by the device that also may be contaminated. This is particularly relevant for patient care in the context of a highly transmissible virus. RESEARCH QUESTION: How can potential risks of infections during nebulization be mitigated? STUDY DESIGN AND METHODS: The COPD Foundation Nebulizer Consortium (CNC) was formed in 2020 to address uncertainties surrounding administration of nebulized medication. The CNC is an international, multidisciplinary collaboration of patient advocates, pulmonary physicians, critical care physicians, respiratory therapists, clinical scientists, and pharmacists from research centers, medical centers, professional societies, industry, and government agencies. The CNC developed this expert guidance to inform the safe use of nebulized therapies for patients and providers and to answer key questions surrounding medication delivery with nebulizers during pandemics or when exposure to common respiratory pathogens is anticipated. RESULTS: CNC members reviewed literature and guidelines regarding nebulization and developed two sets of guidance statements: one for the health care setting and one for the home environment. INTERPRETATION: Future studies need to explore the risk of disease transmission with fugitive aerosols associated with different nebulizer types in real patient care situations and to evaluate the effectiveness of mitigation strategies.

Point-of-care global coagulation assay parameters in normal dogs and dogs with primary immune-mediated hemolytic anemia.

OBJECTIVE: To compare viscoelastic parameters between healthy control dogs and dogs with primary immune-mediated hemolytic anemia (pIMHA) using a new, point-of-care viscoelastic coagulation monitor (VCM).a DESIGN: Retrospective study from 2017 to 2021. SETTING: Three regional private referral centers. ANIMALS: Eighteen client-owned dogs with pIMHA and 33 healthy control dogs. pIMHA dogs were defined based on established criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records of dogs with pIMHA and VCM performed at diagnosis from 2017 to 2021 and apparently healthy control dogs voluntarily enrolled in the blood donor program from 2017 to 2018 were reviewed. For the healthy control dogs, consent was obtained to perform VCM in addition to traditional screening. Compared to healthy control dogs, dogs with pIMHA had mean VCM parameters consistent with hypercoagulability, demonstrated by lower mean (SD) clot formation time (108 s [30] vs 233 s [55]; P < 0.0001), higher mean alpha angle (62 degrees [6] vs 52 degrees [6]; P < 0.0001), higher mean maximum clot formation (49 VCM units [11] vs 32 VCM units [5]; P < 0.0001), higher mean amplitude at 10 minutes (40 VCM units [11] vs 19 VCM units [3]; P < 0.0001), and higher mean amplitude at 20 minutes (47 VCM units [11] vs 25 VCM units [4]; P < 0.0001). pIMHA dogs also had significantly higher median (interquartile range) lysis index at 30 minutes (100% [100-100] vs 98% [90-100]; P < 0.0001). When compared to 3 established normal canine reference intervals, dogs with pIMHA had a significantly higher proportion of VCM variables (48%-57%) consistent with hypercoagulability, and a significant percentage of pIMHA dogs (78%-89%) had VCM tracings consistent with hypercoagulability overall, irrespective of the interval utilized for interpretation. CONCLUSIONS: This study demonstrates hypercoagulability in dogs with pIMHA when compared to healthy control dogs using VCM. Prospective evaluation is warranted to further characterize these findings as well as to evaluate their clinical impact.

Driving while navigating: On-road driving performance using GPS or printed instructions.

BACKGROUND.: Route navigation is a high-level skill and requires intact executive functioning to successfully find one's way while driving in unfamiliar environments. PURPOSE.: Driving performances were compared while navigating using electronic devices and printed directions on unfamiliar driving routes as well as in an interactive driving simulator. METHOD.: Twenty-four participants drove two on-road routes using GPS and printed directions, and navigated using printed directions in the simulator, using a point system to evaluate performance. The two unfamiliar routes, order of simulator and on-road driving, and use of GPS and printed directions were counterbalanced. Paired t test were used to compare both GPS versus printed directions and performance between on-road driving and the simulator. FINDINGS.: Participants' performance using GPS on the road was significantly better than with printed directions. There was no significant difference between performance in the simulator and on the road. IMPLICATIONS.: Using GPS may be an effective strategy for improving safety. Using a driving simulator may be an efficient means of evaluating the strategic level of driving, executive function, and readiness to drive.

Discovery of the Antitumor Effects of a Porphyrazine Diol (Pz 285) in MDA-MB-231 Breast Tumor Xenograft Models in Mice.

A series of porphyrazines (Pzs) with chiral bis-acetal moieties in the ß-pyrrole positions ((2R,3R)-2,3-dimethyl-2,3-dimethoxy-1,4-diox-2-ene) have been synthesized and screened as antitumor agents in MDA-MB-231 breast tumor cells in vitro. The lead Pz 285 was further tested in a mouse tumor xenograft model with Td-tomato-luc2 fluorescent breast tumor cells (MDA-MB-231 LM24 Her2+) that are highly metastatic to the lungs. Pz 285 shows marked antitumor effects in vivo, with treated mice exhibiting longer median survival that we attribute to smaller primary tumor regrowth after resection and less occurrence of metastasis when compared to vehicle control groups. Pz 285 is further compared to the clinically approved chemotherapeutic doxorubicin (Dox). This report lays the groundwork for development of an understudied class of compounds for classical chemotherapy.

Vaccine effectiveness against laboratory-confirmed influenza in infants: A matched case control study.

Influenza is a common and potentially serious infection in infants. Previous studies of influenza vaccine in this age group have reported widely varying estimates of vaccine effectiveness, and few have used laboratory confirmation of influenza diagnoses. We evaluated the effectiveness of 1 and 2 doses of the trivalent inactivated vaccine against laboratory-confirmed influenza in children aged 6 to 23 months within the Kaiser Permanente Northern California Medical Care Program for the 2003-2004, 2004-2005 and 2005-2006 influenza seasons. 1,648 children were included in the analyses, with an average of 4.5 controls matched to each of the 300 cases (213, 29 and 58 cases identified for each of the influenza seasons, respectively) based on birth month/year and zip code. Vaccination status was determined as of 14 days prior to the case patient's positive test result. Conditional logistic regression was used to calculate vaccine effectiveness for each season, adjusting for chronic medical conditions and other possible confounders. During the 2005-2006 influenza season, when predominant circulating virus strains and vaccine strains were well matched, vaccination was 76% [95% CI: 37-91%] effective against laboratory-confirmed infection. There was no statistically significant effect of vaccination, however, for the 2003-2004 or 2004-2005 seasons. Our results highlight the need for further study of influenza vaccine effectiveness in this age group.

Gender-dependent modulation of brain monoamines and anxiety-like behaviors in mice with genetic serotonin transporter and BDNF deficiencies.

1. Brain-derived neurotrophic factor (BDNF) supports serotonergic neuronal development and our recent study found that heterozygous mice lacking one BDNF gene allele interbred with male serotonin transporter (SERT) knockout mice had greater reductions in brain tissue serotonin concentrations, greater increases in anxiety-like behaviors and greater ACTH responses to stress than found in the SERT knockout mice alone. 2. We investigated here whether there might be gender differences in these consequences of combined SERT and BDNF deficiencies by extending the original studies to female mice, and also to an examination of the effects of ovariectomy and tamoxifen in these female mice, and of 21-day 17-beta estradiol implantation to male mice. 3. We found that unlike the male SERTxBDNF-deficient mice, female SERTxBDNF mice appeared protected by their gender in having significantly lesser reductions in serotonin concentrations in hypothalamus and other brain regions than males, relative to controls. Likewise, in the elevated plus maze, female SERTxBDNF-deficient mice demonstrated no increases in the anxiety-like behaviors previously found in males. 4. Furthermore, female SERTxBDNF mice did not manifest the approximately 40% reduction in the expression of TrkB receptors or the approximately 30% reductions in dopamine and its metabolites that male SERTxBDNF did. After estradiol implantation in male SERTxBDNF mice, hypothalamic serotonin was significantly increased compared to vehicle-implanted mice. These findings support the hypothesis that estrogen may enhance BDNF function via its TrkB receptor, leading to alterations in the serotonin circuits, which modulate anxiety-like behaviors. 5. This double-mutant mouse model contributes to the knowledge base that will help in understanding genexgenexgender interactions in studies of SERT and BDNF gene polymorphisms in human genetic diseases such as anxiety disorders and depression.

Obsessive-compulsive disorder symptom dimensions show specific relationships to psychiatric comorbidity.

The goals of this study were to examine relationships among symptom categories in obsessive-compulsive disorder (OCD), to establish OCD symptom dimensions by factor- and cluster-analytic analyses, and to explore associations between OCD symptom dimensions and comorbid neuropsychiatric conditions. A total of 317 OCD participants underwent a systematic diagnostic interview using the Structured Clinical Interview for DSM-IV. OCD symptoms assessed by the Yale-Brown Obsessive-Compulsive Scale Symptom Checklist (N=169) and by the Thoughts and Behaviors Inventory (N=275) were subjected to factor and cluster analyses. An identical four-factor solution emerged in two different data sets from overlapping samples, in agreement with most smaller factor-analytic studies employing the YBOCS checklist alone. The cluster analysis confirmed the four-factor solution and provided additional information on the similarity among OCD symptom categories at five different levels. OCD symptom dimensions showed specific relationships to comorbid psychiatric disorders: Factor I (aggressive, sexual, religious and somatic obsessions, and checking compulsions) was broadly associated with comorbid anxiety disorders and depression; Factor II (obsessions of symmetry, and repeating, counting and ordering/arranging compulsions) with bipolar disorders and panic disorder/agoraphobia; and Factor III (contamination obsessions and cleaning compulsions) with eating disorders. Factors I and II were associated with early onset OCD. This study encourages the use of cluster analyses as a supplementary method to factor analyses to establish psychiatric symptom dimensions. The frequent co-occurrence of OCD with other psychiatric disorders and the relatively specific association patterns between OCD symptom dimensions and comorbid disorders support the importance of OCD subtyping for treatment, genetic, and other research studies of this heterogeneous disorder.

Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice.

To study the neurochemical and behavioral effects of altered brain-derived neurotrophic factor (BDNF) expression on a brain serotonin system with diminished serotonin transport capability, a double-mutant mouse model was developed by interbreeding serotonin transporter (SERT) knockout mice with BDNF heterozygous knockout mice (BDNF +/-), producing SERT -/- x BDNF +/- (sb) mice. Prior evidence implicates serotonin and SERT in anxiety and stress responses. Some studies have shown that BDNF supports serotonergic neuronal development, leading to our hypothesis that reduced BDNF availability during development might exaggerate the consequences of absent SERT function. In the present study, brain serotonin and 5-hydroxyindol acetic acid concentrations in male sb mice were significantly reduced in the hippocampus and hypothalamus compared with wild-type control SB mice, BDNF-deficient Sb mice, and serotonin transporter knockout sB mice. The sb mice had significantly increased anxiety-like behaviors compared with SB, Sb, and sB mice as measured on the elevated plus maze test. These sb mice also had significantly greater increases in plasma adrenocorticotrophic hormone than mice with other genotypes after a stressful stimulus. Analysis of neuronal morphology showed that hypothalamic and hippocampal neurons exhibited 25-30% reductions in dendrites in sb mice compared with SB control mice. These findings support the hypothesis that genetic changes in BDNF expression interact with serotonin and other circuits that modulate anxiety and stress-related behaviors. Thus, this double-mutant mouse model should prove valuable in studying other gene x gene consequences for brain plasticity as well as in evaluating epistatic interactions of BDNF and serotonin transporter gene polymorphisms in neuropsychiatric disorders.