Citations

Abstract Introduction Meta-analytic studies support that insomnia is a risk factor for cognitive decline and dementia, but limited accounting of confounders reduces their validity. Further, it is unclear whether these associations are driven by specific insomnia phenotypes. In this study, we aimed to assess the relationship between insomnia and longitudinal global cognitive decline in community-dwelling older adults after considering self-reported sleep duration changes and other important characteristics. Methods From the Mayo Clinic Study of Aging (MCSA) cohort, we identified all (age>=50yo) cognitively unimpaired participants at baseline without comorbid neurological disease with at least two previous comprehensive neuropsychological evaluations. Participants with at least two occurrences of insomnia ICD diagnosis (by EMR and Rochester Epidemiological Project data) at least 30 days apart were classified as having insomnia, and those without any instance of diagnosis were considered negative for insomnia. Changes in sleep duration were assessed using the question #16 of BDI-2 and categorized in reduced sleep (yes/no). We fit mixed-effect regression models to assess whether insomnia was associated with standardized global cognitive scores, after adjusting for age, sex, education, APOEe4, composite cardiovascular and metabolic conditions scores, anxiety/depression, reduced sleep, OSA (ICD diagnosis), alcoholism (CAGE≥2), and pain (NSAIDs use). Number of cognitive assessments and time from baseline were included as both fixed and random effects. Multiple interactions (e.g. insomnia*reduced sleep) were included. A backward stepwise procedure maintaining the hierarchical principal for interactions was utilized to reach the most parsimonious models. Results 3063 participants (50.24% males, aged 70±9.73 at baseline) were included. Insomnia alone was not associated with a decrease in global cognition, but when combined with subjective reduction in sleep duration at baseline it was associated with a -0.19 (95% CI: -0.32, -0.07; interaction p=0.01) reduction in global cognitive scores. This was equivalent to approximately 3 additional years of age or 6 cardiometabolic comorbidities at baseline. The effect size was greater than those associated with baseline cognition for having any APOE e4 allele (-0.12) and alcoholism (-0.15). Conclusion Insomnia with reduced sleep duration phenotype is a potentially modifiable risk factor for cognitive decline in older adults. Further studies with objective sleep measures are necessary for objective confirmation. Support (if any) NIA/NIH

OBJECTIVES: We postulate that corticosteroid-related side effects in critically ill patients are similar across sepsis, acute respiratory distress syndrome (ARDS), and community-acquired pneumonia (CAP). By pooling data across all trials that have examined corticosteroids in these three acute conditions, we aim to examine the side effects of corticosteroid use in critical illness. DATA SOURCES: We performed a comprehensive search of MEDLINE, Embase, Centers for Disease Control and Prevention library of COVID research, CINAHL, and Cochrane center for trials. STUDY SELECTION: We included randomized controlled trials (RCTs) that compared corticosteroids to no corticosteroids or placebo in patients with sepsis, ARDS, and CAP. DATA EXTRACTION: We summarized data addressing the most described side effects of corticosteroid use in critical care: gastrointestinal bleeding, hyperglycemia, hypernatremia, superinfections/secondary infections, neuropsychiatric effects, and neuromuscular weakness. DATA SYNTHESIS: We included 47 RCTs ( n = 13,893 patients). Corticosteroids probably have no effect on gastrointestinal bleeding (relative risk [RR], 1.08; 95% CI, 0.87–1.34; absolute risk increase [ARI], 0.3%; moderate certainty) or secondary infections (RR, 0.97; 95% CI, 0.89–1.05; absolute risk reduction, 0.5%; moderate certainty) and may have no effect on neuromuscular weakness (RR, 1.22; 95% CI, 1.03–1.45; ARI, 1.4%; low certainty) or neuropsychiatric events (RR, 1.19; 95% CI, 0.82–1.74; ARI, 0.5%; low certainty). Conversely, they increase the risk of hyperglycemia (RR, 1.21; 95% CI, 1.11–1.31; ARI, 5.4%; high certainty) and probably increase the risk of hypernatremia (RR, 1.59; 95% CI, 1.29–1.96; ARI, 2.3%; moderate certainty). CONCLUSIONS: In ARDS, sepsis, and CAP, corticosteroids are associated with hyperglycemia and probably with hypernatremia but likely have no effect on gastrointestinal bleeding or secondary infections. More data examining effects of corticosteroids, particularly on neuropsychiatric outcomes and neuromuscular weakness, would clarify the safety of this class of drugs in critical illness.

This novel study deciphered the expression and function of protein phosphatase 2Aα (PP2Aα) in airway smooth muscle (ASM) during asthma and/or inflammation. We showed robust expression of PP2Aα in human ASM while its downregulation in asthmatic ASM. Similarly, we demonstrated reduced PP2Aα expression in ASM exposed to proinflammatory cytokines. PP2Aα activation inhibited bronchoconstriction of isolated mouse bronchi. In addition, we unveiled that PP2Aα activation inhibits the intracellular calcium release and myosin light chain phosphorylation in human ASM.

Abstract Airway remodeling is a cardinal feature of asthma, associated with increased airway smooth muscle (ASM) cell mass and upregulation of extracellular matrix deposition. Exaggerated ASM cell migration contributes to excessive ASM mass. Previously, we demonstrated the alleviating role of Kp (kisspeptin) receptor (KISS1R) activation by Kp-10 in mitogen (PDGF [platelet-derived growth factor])-induced human ASM cell proliferation in vitro and airway remodeling in vivo in a mouse model of asthma. Here, we examined the mechanisms by which KISS1R activation regulates mitogen-induced ASM cell migration. KISS1R activation using Kp-10 significantly inhibited PDGF-induced ASM cell migration, further confirmed using KISS1R shRNA. Furthermore, KISS1R activation modulated F/G actin dynamics and the expression of promigration proteins like CDC42 (cell division control protein 42) and cofilin. Mechanistically, we observed reduced ASM RhoA-GTPAse with KISS1R activation. The antimigratory effect of KISS1R was abolished by PKA (protein kinase A)-inhibitory peptide. Conversely, KISS1R activation significantly increased cAMP and phosphorylation of CREB (cAMP-response element binding protein) in PDGF-exposed ASM cells. Overall, these results highlight the alleviating properties of Kp-10 in the context of airway remodeling.

Background Mental health characteristics such as negative mood, fear avoidance, unhelpful thoughts regarding pain, and low self-efficacy are associated with symptom intensity and capability among patients with hip and knee osteoarthritis (OA). Knowledge gaps remain regarding the conceptual and statistical overlap of these constructs and which of these are most strongly associated with capability in people with OA. Further study of these underlying factors can inform us which mental health assessments to prioritize and how to incorporate them into whole-person, psychologically informed care. Questions/purposes (1) What are the distinct underlying factors that can be identified using statistical grouping of responses to a multidimensional mental health survey administered to patients with OA? (2) What are the associations between these distinct underlying factors and capability in knee OA (measured using the Knee Injury and Osteoarthritis Outcome Score, Joint Replacement [KOOS JR]) and hip OA (measured using Hip Disability and Osteoarthritis Outcome Score, Joint Replacement [HOOS JR]), accounting for sociodemographic and clinical factors? Methods We performed a retrospective cross-sectional analysis of adult patients who were referred to our program with a primary complaint of hip or knee pain secondary to OA between October 2017 and December 2020. Of the 2006 patients in the database, 38% (760) were excluded because they did not have a diagnosis of primary osteoarthritis, and 23% (292 of 1246) were excluded owing to missing data, leaving 954 patients available for analysis. Seventy-three percent (697) were women, with a mean age of 61 ± 10 years; 65% (623) of patients were White, and 52% (498) were insured under a commercial plan or via their employer. We analyzed demographic data, patient-reported outcome measures, and a multidimensional mental health survey (the 10-item Optimal Screening for Prediction of Referral and Outcome-Yellow Flag [OSPRO-YF] assessment tool), which are routinely collected for all patients at their baseline new-patient visit. To answer our first question about identifying underlying mental health factors, we performed an exploratory factor analysis of the OSPRO-YF score estimates. This technique helped identify statistically distinct underlying factors for the entire cohort based on extracting the maximum common variance among the variables of the OSPRO-YF. The exploratory factor analysis established how strongly different mental health characteristics were intercorrelated. A scree plot technique was then applied to reduce these factor groupings (based on Eigenvalues above 1.0) into a set of distinct factors. Predicted factor scores of these latent variables were generated and were subsequently used as explanatory variables in the multivariable analysis that identified variables associated with HOOS JR and KOOS JR scores. Results Two underlying mental health factors were identified using exploratory factor analysis and the scree plot; we labeled them “pain coping” and “mood.” For patients with knee OA, after accounting for confounders, worse mood and worse pain coping were associated with greater levels of incapability (KOOS JR) in separate models but when analyzed in a combined model, pain coping (regression coefficient -4.3 [95% confidence interval -5.4 to -3.2], partial R2 0.076; p < 0.001) had the strongest relationship, and mood was no longer associated. Similarly, for hip OA, pain coping (regression coefficient -5.4 [95% CI -7.8 to -3.1], partial R2 0.10; p < 0.001) had the strongest relationship, and mood was no longer associated. Conclusion This study simplifies the multitude of mental health assessments into two underlying factors: cognition (pain coping) and feelings (mood). When considered together, the association between capability and pain coping was dominant, signaling the importance of a mental health assessment in orthopaedic care to go beyond focusing on unhelpful feelings and mood (assessment of depression and anxiety) alone to include measures of pain coping, such as the Pain Catastrophizing Scale or Tampa Scale for Kinesiophobia, both of which have been used extensively in patients with musculoskeletal conditions. Level of Evidence Level III, prognostic study.

Rhythms in lung function and time-of-day-dependent exacerbation in disease symptoms have been noted dating back to the 5th century. Today, we recognize the 24-hour variation in normal lung function and how these fluctuations are associated with the circadian component of lung pathophysiology. Diseases of the airway such as allergic asthma, COPD, pulmonary fibrosis, pneumonia and sepsis, and lung cancer all have documented correlations with circadian rhythm and the peripheral molecular clock. Additionally, chronic exposure to particulate matter and other pollutants can induce alterations in clock genes/proteins, and disruption of the circadian system increases susceptibility to poor outcomes following insult to the airway. Investigations into targets of the molecular clock have shed light on chronotherapeutics that can be used to optimize therapeutic approaches in the clinic or leverage endogenous circadian networks to enhance efficacy of currently available treatments.

Alveolar type I (ATI) epithelial cells perform essential roles in maintaining lung function but have been challenging to study. We explored the signals that promote ATI fate in 3-D organoid cultures generated from either mixed distal human lung cells or purified alveolar type II (ATII) cells. This work fills an important void in our experimental repertoire for studying alveolar epithelial cells and identifies signals that promote human ATII to ATI cell differentiation.