FEV1 Variability Predicts Lung Transplant or Mortality in Cystic Fibrosis Patients in the US.

RATIONALE: Declines in percent predicted Forced Expiratory Volume in 1 Second (ppFEV1) are an important marker of clinical progression of Cystic Fibrosis (CF). OBJECTIVES: We examined ppFEV1 variability on a combined outcome of lung transplant or death. METHODS: We estimated the association between ppFEV1 variability and the combined outcome of lung transplant or death. We included children ages 8 years and above with CF and two prior years of ppFEV1 data before baseline between 2005 and 2021. We defined ppFEV1 increased variability as any relative increase or decrease of at least 10% in ppFEV1 from a two-year averaged baseline. A marginal structural Cox proportional hazards model was used. We examined a cumulative measure of ppFEV1 variability, defined as the cumulative proportion of visits with ppFEV1 variability at each visit. Kaplan-Meier survival curves were generated based upon quartiles of the cumulative distribution of ppFEV1 variability. MEASUREMENTS AND MAIN RESULTS: We included 9,706 CF patients in our cohort. Median age at cohort entry was 8.3 (IQR 8.2 - 8.4) years, 50% of patients were female, 94% white, and median baseline ppFEV1 was 94.4 (IQR 81.6 - 106.1). The unadjusted HR for increased ppFEV1 variability on lung transplant/mortality was 4.13 (95% CI 3.48 - 4.90) and the weighted HR was 1.49 (95% CI 1.19 - 1.86). Survival curves stratified by quartile of cumulative variability demonstrated an increased hazard of lung transplant/mortality as the proportion of cumulative ppFEV1 variability increased. CONCLUSIONS: We found a strong association between ppFEV1 variability and lung transplant or mortality in a cohort of people with CF in the US.

Impact of loss to follow-up on survival estimation for cystic fibrosis.

PURPOSE: Deaths among those lost to follow-up (LTFU) in the Cystic Fibrosis Foundation Patient Registry (CFFPR) are critically important to the epidemiology of cystic fibrosis (CF). Unreported deaths could impact estimates of survival if LTFU is associated with disease trajectory. METHODS: We characterized the LTFU population (1986-2017) from the CFFPR and identified deaths via linkage with the National Death Index (NDI). Median predicted survival age and conditional survival were estimated with and without additional deaths and person-time from the NDI. RESULTS: Of the 10,582 individuals LTFU in the CFFPR, 2,460 (23.2%) matched to an NDI death record. Individuals who died after LTFU with a CF diagnosis were 43% female, 91% White/non-Hispanic, 59% had advanced CF lung disease based on last CFFPR recorded forced expiratory volume in one second (FEV1) %predicted <40 and 18% were post-lung transplant. Median predicted survival age during the most recent period available, 2013-2017, increased from 44.3 years (95% CI: 43.2, 45.7) to 45.8 years (95% CI 44.5, 47.1) with the inclusion of NDI data. CONCLUSIONS: Inclusion of deaths and additional person-time among those LTFU changed the point estimate of median predicted survival for most time periods and increased the point estimate from 2009 onwards.

Disruption in Blood Pressure Control With the COVID-19 Pandemic: The PCORnet Blood Pressure Control Laboratory.

OBJECTIVE: To explore trends in blood pressure (BP) control before and during the COVID-19 pandemic. PATIENTS AND METHODS: Health systems participating in the National Patient-Centered Clinical Research Network (PCORnet) Blood Pressure Control Laboratory Surveillance System responded to data queries, producing 9 BP control metrics. Averages of the BP control metrics (weighted by numbers of observations in each health system) were calculated and compared between two 1-year measurement periods (January 1, 2019, through December 31, 2019, and January 1, 2020, through December 31, 2020). RESULTS: Among 1,770,547 hypertensive persons in 2019, BP control to <140/<90 mm Hg varied across 24 health systems (range, 46%-74%). Reduced BP control occurred in most health systems with onset of the COVID-19 pandemic; the weighted average BP control was 60.5% in 2019 and 53.3% in 2020. Reductions were also evident for BP control to <130/<80 mm Hg (29.9% in 2019 and 25.4% in 2020) and improvement in BP (reduction of 10 mm Hg in systolic BP or achievement of systolic BP <140 mm Hg; 29.7% in 2019 and 23.8% in 2020). Two BP control process metrics exhibited pandemic-associated disruption: repeat visit in 4 weeks after a visit with uncontrolled hypertension (36.7% in 2019 and 31.7% in 2020) and prescription of fixed-dose combination medications among those with 2 or more drug classes (24.6% in 2019 and 21.5% in 2020). CONCLUSION: BP control decreased substantially during the COVID-19 pandemic, with a corresponding reduction in follow-up health care visits among persons with uncontrolled hypertension. It is unclear whether the observed decline in BP control during the pandemic will contribute to future cardiovascular events.

Cystic fibrosis prevalence in the United States and participation in the Cystic Fibrosis Foundation Patient Registry in 2020.

BACKGROUND: The Cystic Fibrosis Foundation Patient Registry (CFFPR) collects data on individuals with cystic fibrosis (CF) in the United States (US). In 2012, the US CF population was estimated at 33,292 to 34,327 individuals, with 81-84% CFFPR participation. METHODS: In this study, we update these estimates via simulation to account for uncertainty in CF incidence by race or Hispanic ethnicity, initiation of CF newborn screening (NBS) programs by state, and updated cumulative survival for CF births 1968-2020. We defined registry participation as the proportion of individuals alive as of 2020 with any prior CFFPR participation as well as the proportion with contributing data in 2019 or 2020; we summarize CFFPR participation for those born prior to 1968. RESULTS: We estimated the 2020 prevalent CF population between 1968-2020 to be 38,804 (95% Uncertainty Interval (UI): 38,532 to 39,065) individuals, with 77% of the prevalent CF population contributing recent data. CFFPR participation differs by age (54% of those born in 1968) and exceeds >90% of the population born in 2009 or later. CONCLUSIONS: We demonstrate that the CFFPR remains a valid data source generalizable to the CF population. High participation among younger individuals may reflect the success of newborn screening programs and early referral to CF care. If engagement can be sustained, the percentage of individuals participating in the CFFPR will grow over time and there is an opportunity to identify factors associated with loss to follow up among older individuals to optimize the quality of the CFFPR data.

Automating Case Reporting of Chlamydia and Gonorrhea to Public Health Authorities in Oregon Clinics.

BACKGROUND: Optimizing sexually transmitted disease (STD) reporting to state public health authorities is important to reduce incidence and manage outbreaks of STDs. Electronic laboratory reporting (ELR) is the standard through which local clinics report STDs to state public health authority. Electronic case reporting (eCR) is an alternative approach which automates transmission of case reports to public health jurisdictions using electronic health record (EHR) data. METHODS: Working with 3 community health centers in Oregon between February 3, 2020 and May 15, 2020, we piloted an automated eCR approach for gonorrhea (GC) and chlamydia (CT) from these clinics to the Oregon Health Authority. We compared the eCR approach to the existing ELR approach to determine completeness of case reporting for GC/CT. RESULTS: A total of 365 eCRs from 206 unique patients were generated. Among 154 instances where the case detection logic was satisfied for CT, 37% (54 instances) were based on the presence of a diagnosis and 63% (97 instances) were based on laboratory data. Among 232 instances where logic was satisfied for GC, 44% (102 instances) reflected a diagnosis and 56% (130 instances) reflected laboratory results. Data completeness was uniformly equal or higher for eCRs versus ELRs. CONCLUSIONS: The eCR approach was successful in identifying CT and GC cases and provided a more complete set of information to assist public health authorities when compared with ELRs. Electronic case reporting has the potential to automate and relieve staff burden on an important reporting requirement for clinical providers.

Impact of the Early Phase of the COVID-19 Pandemic on US Healthcare Workers: Results from the HERO Registry.

BACKGROUND: The HERO registry was established to support research on the impact of the COVID-19 pandemic on US healthcare workers. OBJECTIVE: Describe the COVID-19 pandemic experiences of and effects on individuals participating in the HERO registry. DESIGN: Cross-sectional, self-administered registry enrollment survey conducted from April 10 to July 31, 2020. SETTING: Participants worked in hospitals (74.4%), outpatient clinics (7.4%), and other settings (18.2%) located throughout the nation. PARTICIPANTS: A total of 14,600 healthcare workers. MAIN MEASURES: COVID-19 exposure, viral and antibody testing, diagnosis of COVID-19, job burnout, and physical and emotional distress. KEY RESULTS: Mean age was 42.0 years, 76.4% were female, 78.9% were White, 33.2% were nurses, 18.4% were physicians, and 30.3% worked in settings at high risk for COVID-19 exposure (e.g., ICUs, EDs, COVID-19 units). Overall, 43.7% reported a COVID-19 exposure and 91.3% were exposed at work. Just 3.8% in both high- and low-risk settings experienced COVID-19 illness. In regression analyses controlling for demographics, professional role, and work setting, the risk of COVID-19 illness was higher for Black/African-Americans (aOR 2.32, 99% CI 1.45, 3.70, p < 0.01) and Hispanic/Latinos (aOR 2.19, 99% CI 1.55, 3.08, p < 0.01) compared with Whites. Overall, 41% responded that they were experiencing job burnout. Responding about the day before they completed the survey, 53% of participants reported feeling tired a lot of the day, 51% stress, 41% trouble sleeping, 38% worry, 21% sadness, 19% physical pain, and 15% anger. On average, healthcare workers reported experiencing 2.4 of these 7 distress feelings a lot of the day. CONCLUSIONS: Healthcare workers are at high risk for COVID-19 exposure, but rates of COVID-19 illness were low. The greater risk of COVID-19 infection among race/ethnicity minorities reported in the general population is also seen in healthcare workers. The HERO registry will continue to monitor changes in healthcare worker well-being during the pandemic. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04342806.

Informative censoring by health plan disenrollment among commercially insured adults.

PURPOSE: Health plan disenrollment occurs frequently in commercial insurance claims databases. If individuals who disenroll are different from those who remain enrolled, informative censoring may bias descriptive statistics as well as estimates of causal effect. We explored whether patterns of disenrollment varied by patient or health plan characteristics. METHODS: In a large cohort of commercially insured adults (2007-2013), we examined two primary outcomes: (a) within-year disenrollment between January 1 and December 30, which was considered to occur due to patient disenrollment from the health plan, and (b) end-of-year disenrollment on December 31, which was considered to occur due to either patient disenrollment from the health plan or withdrawal of the entire health plan from the commercial insurance database. In yearly cohorts, we identified factors independently associated with disenrollment by using log-binomial regression models to estimate risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Among 2 053 100 unique patient years, the annual proportion of within-year disenrollment remained steady across years (range, 13% to 14%) whereas the annual proportion of end-of-year disenrollment varied widely (range, 8% to 26%). Independent predictors of within-year disenrollment were related to health status, including age, comorbidities, frailty, hospitalization, emergency room visits, use of durable medical equipment, use of preventive care, and use of prescription medications. In contrast, independent predictors of end-of-year disenrollment were related to health plan characteristics including insurance plan type and geographic characteristics. CONCLUSIONS: Differential risk of disenrollment suggests that analytic approaches to address selection bias should be considered in studies using commercial insurance databases.

Cumulative Burden of Depression and All-Cause Mortality in Women Living With Human Immunodeficiency Virus.

Background: Research linking depression to mortality among people living with human immunodeficiency virus (PLWH) has largely focused on binary "always vs never" characterizations of depression. However, depression is chronic and is likely to have cumulative effects on mortality over time. Quantifying depression as a cumulative exposure may provide a better indication of the clinical benefit of enhanced depression treatment protocols delivered in HIV care settings. Methods: Women living with HIV (WLWH), naive to antiretroviral therapy, from the Women's Interagency HIV Study were followed from their first visit in or after 1998 for up to 10 semiannual visits (5 years). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. An area-under-the-curve approach was used to translate CES-D scores into a time-updated measure of cumulative days with depression (CDWD). We estimated the effect of CDWD on all-cause mortality using marginal structural Cox proportional hazards models. Results: Overall, 818 women contributed 3292 woman-years over a median of 4.8 years of follow-up, during which the median (interquartile range) CDWD was 366 (97-853). Ninety-four women died during follow-up (2.9 deaths/100 woman-years). A dose-response relationship was observed between CDWD and mortality. Each additional 365 days spent with depression increased mortality risk by 72% (hazard ratio, 1.72; 95% confidence interval, 1.34-2.20). Conclusions: In this sample of WLWH, increased CDWD elevated mortality rates in a dose-response fashion. More frequent monitoring and enhanced depression treatment protocols designed to reduce CDWD may interrupt the accumulation of mortality risk among WLWH.

Underutilization of Statins When Indicated in HIV-Seropositive and Seronegative Women.

Increased life expectancy of persons living with HIV infection receiving antiretroviral therapy heightens the importance of preventing and treating chronic comorbidities such as cardiovascular disease. While guidelines have increasingly advocated more aggressive use of statins for low-density lipoprotein (LDL) cholesterol reduction, it is unclear whether people with HIV, especially women, are receiving statins when indicated, and whether their HIV disease is a factor in access. We assessed the cumulative incidence of statin use after an indication in the Women's Interagency HIV Study (WIHS), from 2000 to 2014. Additionally, we used weighted proportional hazards regression to estimate the effect of HIV serostatus on the time to initiation of a statin after an indication. Cumulative incidence of statin use 5 years after an indication was low: 38% in HIV-seropositive women and 30% in HIV-seronegative women. Compared to HIV-seronegative women, the weighted hazard ratio for initiation of a statin for HIV-seropositive women over 5 years was 0.94 [95% confidence interval (CI) 0.62, 1.43]. Applying the American College of Cardiology and the American Heart Association (ACC/AHA) guidelines increased the proportion of HIV-seropositive women with a statin indication from 16% to 45%. Clinicians treating HIV-seropositive women should consider more aggressive management of the dyslipidemia often found in this population.

Mortality under plausible interventions on antiretroviral treatment and depression in HIV-infected women: an application of the parametric g-formula.

PURPOSE: Among HIV-infected persons, antiretroviral therapy (ART) and depression are strongly associated with mortality. We estimated reductions in 5-year mortality in Women's Interagency HIV Study participants under plausible hypothetical increases in ART initiation and reductions in depression (CES-D score≥16). METHODS: We followed 885 ART-naïve Women's Interagency HIV Study participants for 5 years from their first study visit after April 1998 to death or censoring. We used the parametric extended g-formula to estimate cumulative mortality under the natural course (NC) and alternative exposure distributions. RESULTS: Baseline prevalence of depression was 52% and 62% initiated ART by 5 years. Compared with mortality under NC (13.2%), immediate ART and elimination of 36% or 67% of depressive episodes were associated with risk differences (RDs) of -5.2% (95% CI: -7.7%, -2.6%) and -5.7 (95% CI: -8.7, -2.7). Compared with immediate ART and NC for depression, additionally eliminating 67% of the depressive episodes was associated with RD = -1.6 (95% CI: -3.9, 0.8). Compared with 5-year mortality under NC for ART and elimination of 67% of depression, also initiating ART immediately was associated with RD = -2.6 (95% CI: -5.0, -0.3). CONCLUSIONS: Increasing ART initiation and reducing depression were associated with moderate reductions in 5-year mortality among HIV-infected women.

Effects of Antiretroviral Therapy and Depressive Symptoms on All-Cause Mortality Among HIV-Infected Women.

Depression affects up to 30% of human immunodeficiency virus (HIV)-infected individuals. We estimated joint effects of antiretroviral therapy (ART) initiation and depressive symptoms on time to death using a joint marginal structural model and data from a cohort of HIV-infected women from the Women's Interagency HIV Study (conducted in the United States) from 1998-2011. Among 848 women contributing 6,721 years of follow-up, 194 participants died during follow-up, resulting in a crude mortality rate of 2.9 per 100 women-years. Cumulative mortality curves indicated greatest mortality for women who reported depressive symptoms and had not initiated ART. The hazard ratio for depressive symptoms was 3.38 (95% confidence interval (CI): 2.15, 5.33) and for ART was 0.47 (95% CI: 0.31, 0.70). Using a reference category of women without depressive symptoms who had initiated ART, the hazard ratio for women with depressive symptoms who had initiated ART was 3.60 (95% CI: 2.02, 6.43). For women without depressive symptoms who had not started ART, the hazard ratio was 2.36 (95% CI: 1.16, 4.81). Among women reporting depressive symptoms who had not started ART, the hazard ratio was 7.47 (95% CI: 3.91, 14.3). We found a protective effect of ART initiation on mortality, as well as a harmful effect of depressive symptoms, in a cohort of HIV-infected women.

Estimation of biomarker distributions using laboratory data collected during routine delivery of medical care.

PURPOSE: To examine the extent to which commonly ordered laboratory values obtained from large health care databases are representative of the distribution of laboratory values from the general population as reflected in the National Health and Nutrition Examination Survey. METHODS: Means of test values from commercial insurance laboratory data and National Health and Nutrition Examination Survey data were compared. Inverse probability of selection weighting was used to account for possible selection bias and to create comparability between the two data sources. RESULTS: The average values of most of the laboratory results from routine care were very close to their population means as estimated from NHANES. Tests that were more selectively ordered tended to differ. The inverse probability of selection weighting approach generally had a small effect on the estimated means but did improve estimation of some of the more selected tests. CONCLUSIONS: Commonly ordered laboratory tests appear to be representative of values from the underlying population. This suggests that trends and other patterns in biomarker levels in the population may be reasonably studied using data collected during the routine delivery of medical care.

The impact of radiosurgery fractionation and tumor radiobiology on the local control of brain metastases.

OBJECT: Experience with whole-brain radiation therapy for metastatic tumors in the brain has identified a subset of tumors that exhibit decreased local control with fractionated regimens and are thus termed radioresistant. With the advent of frameless radiosurgery, fractionated radiosurgery (2-5 fractions) is being used increasingly for metastatic tumors deemed too large or too close to crucial structures to be treated in a single session. The authors retrospectively reviewed metastatic brain tumors treated at 2 centers to analyze the dependency of local control rates on tumor radiobiology and dose fractionation. METHODS: The medical records of 214 patients from 2 institutions with radiation-naive metastatic tumors in the brain treated with radiosurgery given either as a single dose or in 2-5 fractions were analyzed retrospectively. The authors compared the local control rates of the radiosensitive with the radioresistant tumors after either single-fraction or fractionated radiosurgery. RESULTS: There was no difference in local tumor control rates in patients receiving single-fraction radiosurgery between radioresistant and radiosensitive tumors (p = 0.69). However, after fractionated radiosurgery, treatment for radioresistant tumors failed at a higher rate than for radiosensitive tumors with an OR of 5.37 (95% CI 3.83-6.91, p = 0.032). CONCLUSIONS: Single-fraction radiosurgery is equally effective in the treatment of radioresistant and radiosensitive metastatic tumors in the brain. However, fractionated stereotactic radiosurgery is less effective in radioresistant tumor subtypes. The authors recommend that radioresistant tumors be treated in a single fraction when possible and techniques for facilitating single-fraction treatment or dose escalation be considered for larger radioresistant lesions.

Modulation of the redox state of tubulin by the glutathione/glutaredoxin reductase system.

Alterations in the redox status of proteins have been implicated in the pathology of several neurodegenerative diseases. We report that peroxynitrite-induced disulfides in porcine brain tubulin are repaired by the glutaredoxin reductase system composed of glutathione reductase, human or Escherichia coli glutaredoxin, reduced glutathione, and NADPH. Reduction of disulfide bonds between the alpha- and beta-tubulin subunits by the glutathione reductase system was assessed by Western blot. Tubulin cysteine oxidation and reduction was quantitated by monitoring the incorporation of 5-iodoacetamido-fluorescein, a thiol-specific labeling reagent. Tubulin disulfide bond reduction by the glutaredoxin reductase system restored tubulin polymerization activity that was lost following peroxynitrite addition. In support of redox modulations of tubulin by glutathione, thiol-disulfide exchange between tubulin and oxidized glutathione was detected and quantitated by HPLC. In addition, glutathionylation of tubulin was detected by dot blot using an anti-GSH antibody.