Multilevel joint model of longitudinal continuous and binary outcomes for hierarchically structured data.

Joint modeling has been a useful strategy for incorporating latent associations between different types of outcomes simultaneously, often focusing on a longitudinal continuous outcome characterized by an LME submodel and a terminal event subject to a Cox proportional hazard or parametric survival submodel. Applications to hierarchical longitudinal studies have been less frequent, particularly with respect to a binary process, which is commonly specified by a GLMM. Furthermore, many of the joint model developments have not allowed for investigations of nested effects, such as those arising from multicenter studies. To fill this gap, we propose a multilevel joint model that encompasses the LME submodel and GLMM through a Bayesian approach. Motivated by the need for timely detection of pulmonary exacerbation and characterization of irregularly observed lung function measurements in people living with cystic fibrosis (CF) receiving care across multiple centers, we apply the model to the data arising from US CF Foundation Patient Registry. In parallel, we examine the extent of bias induced by a non-hierarchical model. Our simulation study and application results show that incorporating the center effect along with individual stochastic variation over time within the LME submodel improves model estimation and prediction. Given that the center effect is evident in lung function observed in the CF population, accounting for center-specific power parameters by incorporating the symmetric power exponential power (spep) link function in the GLMM can facilitate more accurate conclusions in clinical studies.

Viral replication in human macrophages enhances an inflammatory cascade and interferon driven chronic COVID-19 in humanized mice.

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system1-20. Blocking either viral replication with Remdesivir21-23 or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.

Validation of a Spanish Version of the Prolapse and Incontinence Knowledge Questionnaire.

OBJECTIVE: The objective of this study was to validate a Spanish version of the Prolapse and Incontinence Knowledge Questionnaire (PIKQ). METHODS: Validation and reliability testing of the Spanish version of the PIKQ was conducted in 2 phases. In the first phase, a translation-back-translation method by 6 bilingual researchers was utilized to generate a final Spanish translation. In the second phase, bilingual women were randomized to complete the Spanish or English version first, followed by the alternate language. Agreement between individual items from English and Spanish versions was assessed by percent agreement and κ statistics. Intraclass correlation coefficients compared overall PIKQ scores and pelvic organ prolapse (POP) and urinary incontinence (UI) subscores. To establish test-retest reliability, we calculated Pearson correlation coefficients. In order to have a precision of 10% for 90% agreement, so that the lower 95% confidence interval would not be less than 80% agreement, 50 bilingual participants were required. RESULTS: Fifty-seven bilingual women were randomized and completed both versions of the PIKQ. Individual items showed 74%-97% agreement, good to excellent agreement (κ = 0.6-0.89) for 9 items and moderate agreement (κ = 0.4-0.59) for 14 items between English and Spanish PIKQ versions. Intraclass correlation coefficients of the overall score and POP and UI subscores showed excellent agreement (intraclass correlation coefficient = 0.81-0.91). Pearson correlation coefficients between initial and repeat Spanish scores were high: overall (r = 0.87) and for POP (r = 0.81) and UI subscores (r = 0.77). CONCLUSIONS: A valid and reliable Spanish version of the PIKQ has been developed to assess patient knowledge about UI and POP.

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.

Essentials in Minimally Invasive Gynecology Manual Skills Construct Validation Trial.

OBJECTIVE: To establish validity evidence for the Essentials in Minimally Invasive Gynecology laparoscopic and hysteroscopic simulation systems. METHODS: A prospective cohort study was IRB approved and conducted at 15 sites in the United States and Canada. The four participant cohorts based on training status were: 1) novice (postgraduate year [PGY]-1) residents, 2) mid-level (PGY-3) residents, 3) proficient (American Board of Obstetrics and Gynecology [ABOG]-certified specialists without subspecialty training); and 4) expert (ABOG-certified obstetrician-gynecologists who had completed a 2-year fellowship in minimally invasive gynecologic surgery). Qualified participants were oriented to both systems, followed by testing with five laparoscopic exercises (L-1, sleeve-peg transfer; L-2, pattern cut; L-3, extracorporeal tie; L-4, intracorporeal tie; L-5, running suture) and two hysteroscopic exercises (H-1, targeting; H-2, polyp removal). Measured outcomes included accuracy and exercise times, including incompletion rates. RESULTS: Of 227 participants, 77 were novice, 70 were mid-level, 33 were proficient, and 47 were experts. Exercise times, in seconds (±SD), for novice compared with mid-level participants for the seven exercises were as follows, and all were significant (P<.05): L-1, 256 (±59) vs 187 (±45); L-2, 274 (±38) vs 232 (±55); L-3, 344 (±101) vs 284 (±107); L-4, 481 (±126) vs 376 (±141); L-5, 494 (±106) vs 420 (±100); H-1, 176 (±56) vs 141 (±48); and H-2, 200 (±96) vs 150 (±37). Incompletion rates were highest in the novice cohort and lowest in the expert group. Exercise errors were significantly less and accuracy was greater in the expert group compared with all other groups. CONCLUSION: Validity evidence was established for the Essentials in Minimally Invasive Gynecology laparoscopic and hysteroscopic simulation systems by distinguishing PGY-1 from PGY-3 trainees and proficient from expert gynecologic surgeons.

Implementation of a chronic illness model for diabetes care in a family medicine residency program.

INTRODUCTION: While the Chronic Care Model (CCM) has been shown to improve the care of patients with chronic illnesses, primary care physicians have been unprepared in its use, and residencies have encountered challenges in introducing it into the academic environment. AIM: Our residency program has implemented a diabetes management program modeled on the CCM to evaluate its impact on health outcomes of diabetic patients and educational outcomes of residents. SETTING: University-affiliated, community-based family medicine residency program. PROGRAM DESCRIPTION: Six residents, two faculty clinicians, and clinic staff formed a diabetes management team. We redesigned the outpatient experience for diabetic patients by incorporating elements of the CCM: multidisciplinary team care through planned and group visits; creation of a diabetes registry; use of guidelines-based flow sheets; and incorporation of self-management goal-setting. Residents received extensive instruction in diabetes management, quality improvement, and patient self-management. PROGRAM EVALUATION: We achieved overall improvement in all metabolic and process measures for patients, with the percentage achieving HbA1c, LDL, and BP goals simultaneously increasing from 5.7% to 17.1%. Educational outcomes for residents, as measured by compliance with review of provider performance reports and self-management goal-setting with patients, also significantly improved. DISCUSSION: Through a learning collaborative experience, residency programs can successfully incorporate chronic care training for residents while addressing gaps in care for patients with diabetes.

Alkaline alpha-galactosidase degrades thylakoid membranes in the chloroplast during leaf senescence in rice.

Here, we studied the functional role of a chloroplast alkaline alpha-galactosidase (OsAkalphaGal) in the breakdown of thylakoid membranes during rice (Oryza sativa) leaf senescence. We assayed the enzyme activity of recombinant OsAkalphaGal with different natural substrates and examined the effect of ectopic OsAkalphaGal expression in rice plants. Recombinant OsAkalphaGal showed at least a two-fold greater substrate-binding affinity and a 10-fold greater turnover rate to galactolipid digalactosyl diacylglycerol than the raffinose family of oligosaccharides (verbascose, stachyose, raffinose) and melibiose. The OsAkalphaGal null mutant (osakalphagal) displayed a delayed leaf senescence phenotype. OsAkalphaGal complementation in osakalphagal recovered OsAkalphaGal expression and showed a senescence phenotype similar to that of wild-type plants. Transgenic plants overexpressing OsAkalphaGal (UbiP-OsAkalphaGal) exhibited retarded plant growth and development, and showed a pale-green phenotype coupled with a reduced chlorophyll content to 42% in newly unfolded leaves. UbiP-OsAkalphaGal leaves also showed a 29-fold increase in alkaline alpha-galactosidase activity compared with wild-type leaves. An ultrastructural study of Ubi-OsAkalphaGal chloroplasts in newly unfolded leaves revealed abnormal grana organization. Our findings strongly suggest that OsAkalphaGal is a thylakoid membrane-degrading enzyme involved in the degradation of digalactosyl diacylglycerol during rice leaf senescence.