Using simulation modeling to inform intervention and implementation selection in a rapid stakeholder-engaged hybrid effectiveness-implementation randomized trial.

BACKGROUND: Implementation research generally assumes established evidence-based practices and prior piloting of implementation strategies, which may not be feasible during a public health emergency. We describe the use of a simulation model of the effectiveness of COVID-19 mitigation strategies to inform a stakeholder-engaged process of rapidly designing a tailored intervention and implementation strategy for individuals with serious mental illness (SMI) and intellectual/developmental disabilities (ID/DD) in group homes in a hybrid effectiveness-implementation randomized trial. METHODS: We used a validated dynamic microsimulation model of COVID-19 transmission and disease in late 2020/early 2021 to determine the most effective strategies to mitigate infections among Massachusetts group home staff and residents. Model inputs were informed by data from stakeholders, public records, and published literature. We assessed different prevention strategies, iterated over time with input from multidisciplinary stakeholders and pandemic evolution, including varying symptom screening, testing frequency, isolation, contact-time, use of personal protective equipment, and vaccination. Model outcomes included new infections in group home residents, new infections in group home staff, and resident hospital days. Sensitivity analyses were performed to account for parameter uncertainty. Results of the simulations informed a stakeholder-engaged process to select components of a tailored best practice intervention and implementation strategy. RESULTS: The largest projected decrease in infections was with initial vaccination, with minimal benefit for additional routine testing. The initial level of actual vaccination in the group homes was estimated to reduce resident infections by 72.4% and staff infections by 55.9% over the 90-day time horizon. Increasing resident and staff vaccination uptake to a target goal of 90% further decreased resident infections by 45.2% and staff infections by 51.3%. Subsequent simulated removal of masking led to a 6.5% increase in infections among residents and 3.2% among staff. The simulation model results were presented to multidisciplinary stakeholders and policymakers to inform the "Tailored Best Practice" package for the hybrid effectiveness-implementation trial. CONCLUSIONS: Vaccination and decreasing vaccine hesitancy among staff were predicted to have the greatest impact in mitigating COVID-19 risk in vulnerable populations of group home residents and staff. Simulation modeling was effective in rapidly informing the selection of the prevention and implementation strategy in a hybrid effectiveness-implementation trial. Future implementation may benefit from this approach when rapid deployment is necessary in the absence of data on tailored interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04726371.

The association between all-cause mortality and HIV acquisition risk groups in the United States, 2001-2014.

OBJECTIVE: To investigate associations between all-cause mortality and human immunodeficiency virus (HIV) acquisition risk groups among people without HIV in the United States. METHODS: We used data from 23,657 (NHANES) participants (2001-2014) and the Linked Mortality File to classify individuals without known HIV into HIV acquisition risk groups: people who ever injected drugs (ever-PWID); men who have sex with men (MSM); heterosexually active people at increased risk for HIV (HIH), using low income as a proxy for increased risk. We used Cox proportional hazards models to estimate adjusted and unadjusted all-cause mortality hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Compared with sex-specific heterosexually active people at average risk for HIV (HAH), the adjusted HR (95% CI) were: male ever-PWID 1.67 (1.14, 2.46), female ever-PWID 3.50 (2.04, 6.01), MSM 1.51 (1.00, 2.27), male HIH 1.68 (1.04, 2.06), female HIH 2.35 (1.87, 2.95), and male ever-PWID 1.67 (1.14, 2.46). CONCLUSIONS: Most people at increased risk for HIV in the US experience higher all-cause mortality than people at average risk. Strategies addressing social determinants that increase HIV risk should be incorporated into HIV prevention and other health promotion programs.

Pre-exposure Prophylaxis Persistence at a Diverse Sexual Health Clinic: Comparison of the pre-COVID-19 era to the COVID-19 era.

The COVID-19 pandemic interrupted health care delivery and exacerbated disparities. Many sexual health clinics transitioned to telemedicine, including for pre-exposure prophylaxis (PrEP). We conducted a retrospective cohort study of patients at an urban sexual health clinic to assess the likelihood and predictors of PrEP persistence in the year following PrEP initiation. We compared patients starting PrEP in the four months preceding the first COVID surge to those starting PrEP one year prior. We found lower PrEP persistence in the COVID cohort compared to the pre-COVID cohort (50.8% vs. 68.9%, respectively). In both cohorts, most care was provided through in-person visits and telemedicine was rare. In the pre-COVID cohort, older patients and those identifying as non-Hispanic White were more likely to persist on PrEP. In the COVID cohort, these disparities in PrEP persistence were not observed. Flexible models of care may facilitate equitable care engagement and re-engagement.

Development and validation of the age-associated dementia policy (AgeD-Pol) computer simulation model in the USA and Europe.

OBJECTIVE: To develop and validate a novel, microsimulation model that accounts for the prevalence and incidence of age-associated dementias (AAD), disease progression and associated mortality. DESIGN, DATA SOURCES AND OUTCOME MEASURES: We developed the AAD policy (AgeD-Pol) model, a microsimulation model to simulate the natural history, morbidity and mortality associated with AAD. We populated the model with age-stratified and sex-stratified data on AAD prevalence, AAD incidence and mortality among people with AAD. We first performed internal validation using data from the Adult Changes in Thought (ACT) cohort study. We then performed external validation of the model using data from the Framingham Heart Study, the Rotterdam Study and Kaiser Permanente Northern California (KPNC). We compared model-projected AAD cumulative incidence and mortality with published cohort data using mean absolute percentage error (MAPE) and root-mean-square error (RMSE). RESULTS: In internal validation, the AgeD-Pol model provided a good fit to the ACT cohort for cumulative AAD incidence, 10.4% (MAPE, 0.2%) and survival, 66.5% (MAPE, 8.8%), after 16 years of follow-up among those initially aged 65-69 years. In the external validations, the model-projected lifetime cumulative incidence of AAD was 30.5%-32.4% (females) and 16.7%-23.0% (males), using data from the Framingham and Rotterdam cohorts, and AAD cumulative incidence was 21.5% over 14 years using KPNC data. Model projections demonstrated a good fit to all three cohorts (MAPE, 0.9%-9.0%). Similarly, model-projected survival provided good fit to the Rotterdam (RMSE, 1.9-3.6 among those with and without AAD) and KPNC cohorts (RMSE, 7.6-18.0 among those with AAD). CONCLUSIONS: The AgeD-Pol model performed well when validated to published data for AAD cumulative incidence and mortality and provides a useful tool to project the AAD disease burden for health systems planning in the USA.

Tailoring glucocorticoids in patients with severe COVID-19: a narrative review.

OBJECTIVE: To discuss the pathogenesis of severe coronavirus disease 2019 (COVID-19) infection and the pharmacological effects of glucocorticoids (GCs) toward this infection. To review randomized controlled trials (RCTs) using GCs to treat patients with severe COVID-19, and investigate whether GC timing, dosage, or duration affect clinical outcomes. Finally. to discuss the use of biological markers, respiratory parameters, and radiological evidence to select patients for improved GC therapeutic precision. BACKGROUND: COVID-19 has become an unprecedented global challenge. As GCs have been used as key immunomodulators to treat inflammation-related diseases, they may play key roles in limiting disease progression by modulating immune responses, cytokine production, and endothelial function in patients with severe COVID-19, who often experience excessive cytokine production and endothelial and renin-angiotensin system (RAS) dysfunction. Current clinical trials have partially proven this efficacy, but GC timing, dosage, and duration vary greatly, with no unifying consensus, thereby creating confusion. METHODS: Publications through March 2021 were retrieved from the Web of Science and PubMed. Results from cited references in published articles were also included. CONCLUSIONS: GCs play key roles in treating severe COVID-19 infections. Pharmacologically, GCs could modulate immune cells, reduce cytokine and chemokine, and improve endothelial functions in patients with severe COVID-19. Benefits of GCs have been observed in multiple clinical trials, but the timing, dosage and duration vary across studies. Tapering as an option is not widely accepted. However, early initiation of treatment, a tailored dosage with appropriate tapering may be of particular importance, but evidence is inconclusive and more investigations are needed. Biological markers, respiratory parameters, and radiological evidence could also help select patients for specific tailored treatments.

Urban Sexual Health Clinic Patients With "Undetermined Risk" for HIV Are Less Likely to Receive Preexposure Prophylaxis.

BACKGROUND: New diagnoses of HIV increasingly occur among people who fall outside traditional transmission risk categories. This group remains poorly defined, and HIV prevention efforts for this group lag behind efforts for patients in other risk groups. METHODS: We conducted a retrospective review of patient visits at sexual health clinics in Boston, MA, over a 14-month period. Patients were classified into Centers for Disease Control and Prevention-defined HIV transmission risk categories. We compared frequencies of sexually transmitted infections (STIs), HIV, preexposure prophylaxis (PrEP) indications, and PrEP prescriptions. Predictors of HIV or STI among patients in the undetermined risk category were assessed with logistic regression. RESULTS: There were 4723 clinic visits during the study period. Patients in the undetermined risk group constituted the largest proportion (55.8%), followed by men who have sex with men (MSM; 42.7%). The proportion of visits by patients in the undetermined risk group with an indication for PrEP was low (28.0%) compared with MSM (91.3%) and MSM who also inject drugs (93.8%); however, the absolute number was high (737). Among patients with an indication for PrEP, those in the undetermined risk group were least likely to receive a prescription. Behavioral risk factors were poorly predictive of STI or HIV among patients in the undetermined risk group. CONCLUSIONS: Patients with undetermined risk for HIV constituted a large proportion of clinic visits and had a large volume of sexual health needs but rarely received PrEP when indicated. To end the HIV epidemic in the United States, prevention efforts must include people who fall outside traditional risk categories.

An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity.

Current models of SIRT1 enzymatic regulation primarily consider the effects of fluctuating levels of its co-substrate NAD+, which binds to the stably folded catalytic domain. By contrast, the roles of the sizeable disordered N- and C-terminal regions of SIRT1 are largely unexplored. Here we identify an insulin-responsive sensor in the SIRT1 N-terminal region (NTR), comprising an acidic cluster (AC) and a 3-helix bundle (3HB), controlling deacetylase activity. The allosteric assistor DBC1 removes a distal N-terminal shield from the 3-helix bundle, permitting PACS-2 to engage the acidic cluster and the transiently exposed helix 3 of the 3-helix bundle, disrupting its structure and inhibiting catalysis. The SIRT1 activator (STAC) SRT1720 binds and stabilizes the 3-helix bundle, protecting SIRT1 from inhibition by PACS-2. Identification of the SIRT1 insulin-responsive sensor and its engagement by the DBC1 and PACS-2 regulatory hub provides important insight into the roles of disordered regions in enzyme regulation and the mode by which STACs promote metabolic fitness.

Peptidoglycan Suppresses Phagocytic Activities and Apoptosis of Macrophages in Colonic Mucosa Tissues of Crohn's Disease Patients and In Vitro.

BACKGROUND Rac1 signaling plays a crucial role in controlling macrophage functions in CD. Peptidoglycan triggers several intracellular signaling pathways, including activation of Rac1, to regulate the function of macrophage. Suppressed Rac1 signaling in non-inflamed colonic mucosa of Crohn's disease patients has been shown to correlate with increased innate immunity. MATERIAL AND METHODS We examined the effect of peptidoglycan on Rac1 signaling in macrophages and mucosal tissue samples collected from 10 patients with active Crohn's disease and further investigated the effects of peptidoglycan on apoptosis and phagocytic activities of macrophages in vitro. RESULTS Macrophage infiltration and Rac1 signaling was increased in inflamed mucosal tissues of Crohn's disease patients. Immunoblotting assays revealed that peptidoglycan dose- and time-dependently increased the expression of Rac1-GTP, phosphorylated VAV1, and phosphorylated PAK1in RAW264.7 macrophages, which, however, was attenuated by 6-thioguanine. Peptidoglycan also dose-dependently inhibited phagocytic activities of human peripheral blood monocytic cells (PBMCs), which were partially abated by 6-thioguanine or NSC23766. Flow cytometry showed that peptidoglycan (3 µg/mL) decreased the proportion of apoptotic human PBMCs versus controls. The addition of 6-thioguanine or NSC3766 to peptidoglycan led to a sharper rise in the proportion of apoptotic human PBMCs than 6-thioguanine or NSC3766 alone. CONCLUSIONS Our findings suggest that Rac1 signaling is a common molecular target shared by peptidoglycan and immunosuppressive treatment in intestinal macrophages. Inhibiting Rac1 activation may be crucial for optimizing macrophage immunity for treatment of Crohn's disease.

Autoimmune Hepatitis-related Cirrhosis: Clinical Features and Effectiveness of Immunosuppressive Treatment in Chinese Patients.

BACKGROUND: The long-term outcomes of patients with autoimmune hepatitis (AIH) given the immunosuppressive treatment are considered to be preferable. However, little is known about the response of AIH patients with cirrhosis to immunosuppressive treatment. We assessed the effects of immunosuppressive therapy in Chinese AIH patients with cirrhosis from a tertiary hospital. METHODS: Patients with a clinical diagnosis of AIH January 2000 and December 2015 were retrospectively reviewed. Two-hundred and fourteen patients who were followed up and satisfied the simplified AIH criteria were included in the study. Among these patients, 87 presented with cirrhosis when initially diagnosed for AIH. Immunosuppressive treatments were employed in 57 AIH patients who did not present with cirrhosis and 39 patients who presented with cirrhosis. Initial responses to immunosuppressive treatment of patients with and without cirrhosis were analyzed. Independent risk factors were assessed for predicting the prognosis of patients. The t-test and Cox regression statistical analysis were used. RESULTS: In total, 96 AIH patients including 39 with cirrhosis and 57 without cirrhosis underwent immunosuppressive therapy. The overall complete remission after initial immunosuppressive treatment was achieved in 81/96 patients (84.4%), whereas 9/96 (9.4%) achieved incomplete response, and 6/96 (6.3%) occurred treatment failure. Compared to noncirrhotic patients, patients who presented with cirrhosis responded to treatment to a comparable extent regarding complete response (noncirrhosis 50/57 [87.7%] vs. cirrhosis 31/39 [79.5%], P = 0.275), incomplete remission (noncirrhosis 4/57 [7.0%] vs. cirrhosis 5/39 [12.8%], P = 0.338), and treatment failure (noncirrhosis 3/57 [5.3%] vs. cirrhosis 3/39 [7.7%], P = 0.629). Importantly, the remission rate was comparable (54/57 [94.7%] and 36/39 [92.3%], P = 0.629) for noncirrhotic and cirrhotic patients after immunosuppressive therapy. Compared to patients who maintained remission (n = 19) after drug withdrawal, patients who experienced relapse (n = 17) had significantly higher levels of serum immunoglobulin G at entry (15.0 ± 6.5 g/L vs. 22.3 ± 5.8 g/L, t = 2.814, P = 0.004). Moreover, cirrhosis at presentation significantly increased the risk of disease exacerbation (hazard ratio [HR]: 4.603; P = 0.002). The treatment of immunosuppressant (HR: 0.058; P = 0.005) and the level of aspartate aminotransferase at presentation (HR: 1.002; P = 0.017) also increased the risk of disease progression. CONCLUSIONS: The efficacy of initial immunosuppressive treatment in AIH patients with cirrhosis is comparable to that in those without cirrhosis. Cirrhotic patients not treated by immunosuppressants have poor long-term outcomes.