Subphenotypes of self-reported symptoms and outcomes in long COVID: a prospective cohort study with latent class analysis.

OBJECTIVE: To characterise subphenotypes of self-reported symptoms and outcomes (SRSOs) in postacute sequelae of COVID-19 (PASC). DESIGN: Prospective, observational cohort study of subjects with PASC. SETTING: Academic tertiary centre from five clinical referral sources. PARTICIPANTS: Adults with COVID-19 ≥20 days before enrolment and presence of any new self-reported symptoms following COVID-19. EXPOSURES: We collected data on clinical variables and SRSOs via structured telephone interviews and performed standardised assessments with validated clinical numerical scales to capture psychological symptoms, neurocognitive functioning and cardiopulmonary function. We collected saliva and stool samples for quantification of SARS-CoV-2 RNA via quantitative PCR. OUTCOMES MEASURES: Description of PASC SRSOs burden and duration, derivation of distinct PASC subphenotypes via latent class analysis (LCA) and relationship with viral load. RESULTS: We analysed baseline data for 214 individuals with a study visit at a median of 197.5 days after COVID-19 diagnosis. Participants reported ever having a median of 9/16 symptoms (IQR 6-11) after acute COVID-19, with muscle-aches, dyspnoea and headache being the most common. Fatigue, cognitive impairment and dyspnoea were experienced for a longer time. Participants had a lower burden of active symptoms (median 3 (1-6)) than those ever experienced (p<0.001). Unsupervised LCA of symptoms revealed three clinically active PASC subphenotypes: a high burden constitutional symptoms (21.9%), a persistent loss/change of smell and taste (20.6%) and a minimal residual symptoms subphenotype (57.5%). Subphenotype assignments were strongly associated with self-assessments of global health, recovery and PASC impact on employment (p<0.001) as well as referral source for enrolment. Viral persistence (5.6% saliva and 1% stool samples positive) did not explain SRSOs or subphenotypes. CONCLUSIONS: We identified three distinct PASC subphenotypes. We highlight that although most symptoms progressively resolve, specific PASC subpopulations are impacted by either high burden of constitutional symptoms or persistent olfactory/gustatory dysfunction, requiring prospective identification and targeted preventive or therapeutic interventions.

Trajectories of Host-Response Subphenotypes in Patients With COVID-19 Across the Spectrum of Respiratory Support.

BACKGROUND: Hospitalized patients with severe COVID-19 follow heterogeneous clinical trajectories, requiring different levels of respiratory support and experiencing diverse clinical outcomes. Differences in host immune responses to SARS-CoV-2 infection may account for the heterogeneous clinical course, but we have limited data on the dynamic evolution of systemic biomarkers and related subphenotypes. Improved understanding of the dynamic transitions of host subphenotypes in COVID-19 may allow for improved patient selection for targeted therapies. RESEARCH QUESTION: We examined the trajectories of host-response profiles in severe COVID-19 and evaluated their prognostic impact on clinical outcomes. STUDY DESIGN AND METHODS: In this prospective observational study, we enrolled 323 inpatients with COVID-19 receiving different levels of baseline respiratory support: (1) low-flow oxygen (37%), (2) noninvasive ventilation (NIV) or high-flow oxygen (HFO; 29%), (3) invasive mechanical ventilation (27%), and (4) extracorporeal membrane oxygenation (7%). We collected plasma samples on enrollment and at days 5 and 10 to measure host-response biomarkers. We classified patients by inflammatory subphenotypes using two validated predictive models. We examined clinical, biomarker, and subphenotype trajectories and outcomes during hospitalization. RESULTS: IL-6, procalcitonin, and angiopoietin 2 persistently were elevated in patients receiving higher levels of respiratory support, whereas soluble receptor of advanced glycation end products (sRAGE) levels displayed the inverse pattern. Patients receiving NIV or HFO at baseline showed the most dynamic clinical trajectory, with 24% eventually requiring intubation and exhibiting worse 60-day mortality than patients receiving invasive mechanical ventilation at baseline (67% vs 35%; P < .0001). sRAGE levels predicted NIV failure and worse 60-day mortality for patients receiving NIV or HFO, whereas IL-6 levels were predictive in all patients regardless of level of support (P < .01). Patients classified to a hyperinflammatory subphenotype at baseline (< 10%) showed worse 60-day survival (P < .0001) and 50% of them remained classified as hyperinflammatory at 5 days after enrollment. INTERPRETATION: Longitudinal study of the systemic host response in COVID-19 revealed substantial and predictive interindividual variability influenced by baseline levels of respiratory support.

Impact of Advanced Practice Registered Nurses on Quality Measures: The Missouri Quality Initiative Experience.

PURPOSE: The purpose of this article is to review the impact of advanced practice registered nurses (APRNs) on the quality measure (QM) scores of the 16 participating nursing homes of the Missouri Quality Initiative (MOQI) intervention. The MOQI was one of 7 program sites in the US, with specific interventions unique to each site tested for the Centers for Medicaid and Medicare Services Innovations Center. While the goals of the MOQI for long-stay nursing home residents did not specifically include improvement of the QM scores, it was anticipated that improvement most likely would occur. Primary goals of the MOQI were to reduce the frequency of avoidable hospital admissions and readmissions; improve resident health outcomes; improve the process of transitioning between inpatient hospitals and nursing facilities; and reduce overall healthcare spending without restricting access to care or choice of providers. METHODS: A 2-group comparison analysis was conducted using statewide QMs; a matched comparison group was selected from facilities in the same counties as the intervention homes, similar baseline QM scores, similar size and ownership. MOQI nursing homes each had an APRN embedded full-time to improve care and help the facility achieve MOQI goals. Part of their clinical work with residents and staff was to focus on quality improvement strategies with potential to influence healthcare outcomes. Trajectories of QM scores for the MOQI intervention nursing homes and matched comparison group homes were tested with nonparametric tests to examine for change in the desired direction between the 2 groups from baseline to 36 months. A composite QM score for each facility was constructed, and baseline to 36-month average change scores were examined using nonparametric tests. Then, adjusting for baseline, a repeated measures analysis using analysis of covariance as conducted. RESULTS: Composite QM scores of the APRN intervention group were significantly better (P = .025) than the comparison group. The repeated measures analysis identified statistically significant group by time interaction (P = .012). Then group comparisons were made at each of the 6-month intervals and statistically significant differences were found at 24 months (P = .042) and 36 months (P = .002), and nearly significant at 30 months (P = .11). IMPLICATIONS: APRNs working full time in nursing homes can positively influence quality of care, and their impact can be measured on improving QMs. As more emphasis is placed on quality and outcomes for nursing home services, providers need to find successful strategies to improve their QMs. Results of these analyses reveal the positive impact on QM outcomes for the majority of the MOQI nursing homes, indicating budgeting for APRN services can be a successful strategy.

Call to action: APRNs in U.S. nursing homes to improve care and reduce costs.

BACKGROUND: Centers for Medicare and Medicaid Innovation Center sponsored the initiative to reduce avoidable hospitalizations among nursing facility residents. PURPOSE: Missouri Quality Initiative (MOQI) designed inter-professional model in nursing homes with advanced practice registered nurses (APRNs). METHOD: MOQI APRN model was implemented for 4 years in 16 nursing homes in a metro area of the Midwest. Hospitalizations were reduced (40% all-cause, 58% potentially avoidable), emergency room visits (54% all-cause, 65% potentially avoidable), Medicare expenditures for hospitalizations (34% all-cause, 45% potentially avoidable), and Medicare expenditures for emergency room visits (50% all-cause, 60% potentially avoidable) for long-stay nursing home residents. DISCUSSION: Success of the MOQI model reinforces decades of research demonstrating that care provided by APRNs is cost-effective, safe, and associated with positive health outcomes and patient satisfaction. CONCLUSION: Nursing homes can implement and benefit by hiring APRNs. However, changes in the Code of Federal Regulation (CFR 483.40) are necessary to improve patient access to care and encourage hiring APRNs in US nursing homes.

Diabetes self-management education improves medication utilization and retinopathy screening in the elderly.

AIMS: To evaluate the effect of diabetes education program attendance, which provides patients with diabetes self-management education, on prescriptions for cardiovascular risk reduction, prescriptions for diabetes treatments, and visits for retinopathy screening. METHODS: A population based cohort study of residents of Ontario, Canada with diagnosed diabetes aged ≥65 years was performed using administrative databases. Diabetes education program attendance was identified using a registry of visits to all diabetes education programs in the province in 2006. Using propensity score methods, 22,606 diabetes education program attendees were matched to an equal number of non-attendees. The proportions of patients with prescriptions filled and with ophthalmology/optometry visits were compared. RESULTS: Patients attending diabetes education programs had greater utilization of statins (70.6%) than non-attendees (69.4%, p<0.0001). Diabetes education program attendance was also associated with greater utilization of glucose lowering medications (83.7% vs. 82.0%, p<0.0001), antihypertensive medications (90.2% vs. 89.7%, p<0.0001), angiotensin converting enzyme inhibitors/angiotensin receptor blockers (79.8% vs. 78.9% p<0.0001), and glucose monitoring strips (82.2% vs. 65.6%, p<0.0001); and visits to ophthalmology/optometry (78.7% vs. 72.7%, p<0.0001). CONCLUSIONS: Diabetes self-management education at diabetes education programs is associated with better quality of care in the elderly in Ontario.

Overt immune dysfunction after Cushing's syndrome remission: a consecutive case series and review of the literature.

CONTEXT: Autoimmune diseases frequently improve during active Cushing's syndrome. Several studies have reported new onset or exacerbation of these conditions upon cortisol normalization. OBJECTIVE: Our objective was to investigate the incidence and clinical characteristics of patients with autoimmune or allergic diseases after Cushing's syndrome remission. METHODS: Consecutive cases of confirmed Cushing's syndrome were characterized. A review of the literature was conducted to identify previous descriptions of immune dysfunction upon remission and evidence of the hypothalamic-pituitary-adrenal axis influence on the immune system. RESULTS: Among 66 patients who achieved Cushing's syndrome remission, the incidence of immune dysfunction was 16.7%, where eight cases (72.7%) were noted for the first time and three (27.3%) were exacerbated. All had an ACTH-dependent cause. Glucocorticoids reduce proinflammatory cytokines and interact with other transcription factors affecting T cell and mast cell survival. CONCLUSION: Hypercortisolism induces a state of immunosuppression. After Cushing's syndrome remission, rebound immunity frequently results in overt conditions extending beyond thyroid dysfunction.

Differential regulation of cholesterol homeostasis in transgenic mice expressing human cholesterol ester transfer protein.

We investigated whether expression of cholesterol ester transfer protein (CETP) in mice alters the regulation of cholesterol metabolism. Transgenic mice expressing human CETP (CETP-TG) and nontransgenic littermates (non-TG) were fed either a monounsaturated fatty acid (MUFA) or a saturated fatty acid (SFA)-rich diet in the presence or absence of cholesterol. Mice fed with MUFA diet had higher CETP activity compared with SFA-fed mice. Addition of cholesterol to the MUFA diet decreased CETP activity, whereas addition of cholesterol to the SFA diet had no effect. Cholesterol 7alpha-hydroxylase (Cyp7a) activity was higher in CETP-TG mice compared with non-TG mice when fed a MUFA diet, whereas SFA fed CETP-TG mice showed lower Cyp7a activity as compared with non-TG. Microsomal triglyceride transfer protein (MTTP) activity was higher in CETP-TG mice compared with non-TG mice when fed a MUFA diet. HMG-CoA reductase activity was lower in CETP-TG mice compared with non-TG mice when fed a MUFA or a SFA diet. These data demonstrate that the regulation of Cyp7a, HMG-CoA reductase, and MTTP is altered in CETP-TG mice as compared with non-TG mice and these alterations are further modulated by the quality of dietary fats. These findings highlight the importance of CETP in regulating cholesterol homeostasis.

Lack of stimulation of cholesteryl ester transfer protein by cholesterol in the presence of a high-fat diet.

Cholesteryl ester transfer protein (CETP) is a key protein involved in the reverse cholesterol transport pathway. The regulation of CETP by dietary fats is not clearly understood. Transgenic mice expressing human CETP under the control of its natural flanking region were fed low- or high-fat diets enriched in monounsaturated fatty acids (MUFAs) or saturated fatty acids in the presence or absence of cholesterol. Addition of cholesterol to the low-fat MUFA diet increased CETP activity and mRNA expression, whereas addition of cholesterol to the high-fat MUFA diet led to a decrease in CETP activity and mRNA expression. In SW 872 cells, oleic acid and cholesterol stimulated CETP gene expression when given alone. However, addition of fatty acids along with cholesterol interfered with the stimulatory effect of cholesterol on CETP gene regulation. Cholesterol-mediated stimulation of CETP involves the transcription factor liver X receptor alpha (LXRalpha). High-fat MUFA diets inhibited the expression of LXRalpha, and addition of cholesterol to the high-fat MUFA diet did not rescue LXRalpha expression. Therefore, we present evidence for the first time that inhibition of LXRalpha expression by a high-fat MUFA diet leads to inhibition of CETP stimulation by cholesterol.