Scoring donor lungs for graft failure risk: The Lung Donor Risk Index (LDRI).

Lung transplantation lags behind other solid organ transplants in donor lung utilization due, in part, to uncertainty regarding donor quality. We sought to develop an easy-to-use donor risk metric that, unlike existing metrics, accounts for a rich set of donor factors. Our study population consisted of n = 26 549 adult lung transplant recipients abstracted from the United Network for Organ Sharing Standard Transplant Analysis and Research file. We used Cox regression to model graft failure (GF; earliest of death or retransplant) risk based on donor and transplant factors, adjusting for recipient factors. We then derived and validated a Lung Donor Risk Index (LDRI) and developed a pertinent online application (https://shiny.pmacs.upenn.edu/LDRI_Calculator/). We found 12 donor/transplant factors that were independently predictive of GF: age, race, insulin-dependent diabetes, the difference between donor and recipient height, smoking, cocaine use, cytomegalovirus seropositivity, creatinine, human leukocyte antigen (HLA) mismatch, ischemia time, and donation after circulatory death. Validation showed the LDRI to have GF risk discrimination that was reasonable (C = 0.61) and higher than any of its predecessors. The LDRI is intended for use by transplant centers, organ procurement organizations, and regulatory agencies and to benefit patients in decision-making. Unlike its predecessors, the proposed LDRI could gain wide acceptance because of its granularity and similarity to the Kidney Donor Risk Index.

The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Cryoablation in lung transplantation: Its impact on pain, opioid use, and outcomes.

Objective: To assess the effect of intraoperative cryoablation on postoperative patient-reported pain, opioid use, and clinical outcomes in lung transplantation. Methods: We performed a single-center retrospective cohort study of adult lung transplant recipients from August 2017 to September 2018. We compared outcomes of patients who received intraoperative cryoablation of the intercostal nerves with those who did not. Primary outcomes were postoperative patient-reported pain scores and opioid use. Secondary outcomes included postoperative sedation and agitation levels and perioperative outcomes. Data were abstracted from patients' electronic health records. Results: Of the 102 patients transplanted, 45 received intraoperative cryoablation (intervention group) and 57 received the standard of care, which did not include intercostal or serratus blocks or immediate postoperative epidural placement (control group). The intervention group had significantly lower median and maximum postoperative pain scores at days 3 and 7 and significantly lower oral opioid use at days 3, 7, and 14 compared with the control group. Chronic opioid use at 3 and 6 months' posttransplant was lower in the intervention group. Differences in perioperative outcomes, including length of mechanical ventilation, sedation and agitation levels, and hospital stay, were not clinically meaningful. Survival at 30 days and 1 year was superior in the intervention compared with the control group. Conclusions: Findings suggest that use of intraoperative cryoablation is an effective approach for treating pain and reducing opioid use in patients who undergo lung transplant, but a randomized study across multiple institutions is needed to confirm these findings.

Body Mass Index and Cause-Specific Mortality after Lung Transplantation in the United States.

Rationale: Low and high body mass index (BMI) are associated with increased mortality after lung transplantation. Why extremes of BMI might increase risk of death is unknown. Objectives: To estimate the association of extremes of BMI with causes of death after transplantation. Methods: We performed a retrospective study of the United Network for Organ Sharing database, including 26,721 adults who underwent lung transplantation in the United States between May 4, 2005, and December 2, 2020. We mapped 76 reported causes of death into 16 distinct groups. We estimated cause-specific hazards for death from each cause using Cox models. Results: Relative to a subject with a BMI of 24 kg/m2, a subject with a BMI of 16 kg/m2 had 38% (hazard ratio [HR], 1.38; 95% confidence interval [95% CI], 0.99-1.90), 82% (HR, 1.82; 95% CI, 1.34-2.46), and 62% (HR, 1.62; 95% CI, 1.18-2.22) increased hazards of death from acute respiratory failure, chronic lung allograft dysfunction (CLAD), and infection, respectively, and a subject with a BMI of 36 kg/m2 had 44% (HR, 1.44; 95% CI, 0.97-2.12), 42% (HR, 1.42; 95% CI, 0.93-2.15), and 185% (HR, 2.85; 95% CI, 1.28-6.33) increased hazards of death from acute respiratory failure, CLAD, and primary graft dysfunction, respectively. Conclusions: Low BMI is associated with increased risk of death from infection, acute respiratory failure, and CLAD after lung transplantation, whereas high BMI is associated with increased risk of death from primary graft dysfunction, acute respiratory failure, and CLAD.

Text Message Reminders for the Second Dose of Influenza Vaccine for Children: An RCT.

BACKGROUND AND OBJECTIVES: Among children requiring 2 influenza doses in a given season, second dose receipt nearly halves the odds of influenza. Nationally, many children do not receive both needed doses. This study sought to compare the effectiveness of text message reminders with embedded interactive educational information versus usual care on receipt and timeliness of the second dose of influenza vaccine. METHODS: This trial took place over the 2017 to 2018 and 2018 to 2019 influenza seasons among 50 pediatric primary care offices across 24 states primarily from the American Academy of Pediatrics' Pediatric Research in Office Settings practice-based research network. Caregiver-child dyads of children 6 months to 8 years in need of a second influenza vaccination that season were individually randomized 1:1 into intervention versus usual care, stratified by age and language within each practice. Intervention caregivers received automated, personalized text messages, including educational information. Second dose receipt by April 30 (season end) and by day 42 (2 weeks after second dose due date) were assessed using Mantel Haenszel methods by practice and language. Analyses were intention to treat. RESULTS: Among 2086 dyads enrolled, most children were 6 to 23 months and half publicly insured. Intervention children were more likely to receive a second dose by season end (83.8% versus 80.9%; adjusted risk difference (ARD) 3.8%; 95% confidence interval [0.1 to 7.5]) and day 42 (62.4% versus 55.7%; ARD 8.3% [3.6 to 13.0]). CONCLUSIONS: In this large-scale trial of primary care pediatric practices across the United States, text message reminders were effective in promoting increased and timelier second dose influenza vaccine receipt.

Clinic navigation and home visits to improve asthma care in low income adults with poorly controlled asthma: Before and during the pandemic.

Asthma-related deaths, hospitalizations, and emergency visits are more numerous among low-income patients, yet management guidelines do not address this high-risk group's special needs. We recently demonstrated feasibility, acceptability, and preliminary evidence of effectiveness of two interventions to improve access to care, patient-provider communication, and asthma outcomes: 1) Clinic Intervention (CI): study staff facilitated patient preparations for office visits, attended visits, and afterwards confirmed patient understanding of physician recommendations, and 2) Home Visit (HV) by community health workers for care coordination and informing clinicians of home barriers to managing asthma. The current project, denominated "HAP3," combines these interventions for greater effectiveness, delivery of guideline-based asthma care, and asthma control for low-income patients recruited from 6 primary care and 3 asthma specialty practices. We assess whether patients of clinicians receiving guideline-relevant, real-time feedback on patient health and home status have better asthma outcomes. In a pragmatic factorial longitudinal trial, HAP3 enrolls 400 adults with uncontrolled asthma living in low-income urban neighborhoods. 100 participants will be randomized to each of four interventions: (1) CI, (2) CI with HVs, (3) CI and real-time feedback to asthma clinician of guideline-relevant elements of patients' current care, or (4) both (2) and (3). The outcomes are asthma control, quality of life, ED visits, hospitalizations, prednisone bursts, and intervention costs. The COVID-19 pandemic struck 6.5 months into recruitment. We describe study development, design, methodology, planned analysis, baseline findings and adaptions to achieve the original aims of improving patient-clinician communication and asthma outcomes despite the markedly changed pandemic environment.

A Guideline for Reporting Mediation Analyses of Randomized Trials and Observational Studies: The AGReMA Statement.

Importance: Mediation analyses of randomized trials and observational studies can generate evidence about the mechanisms by which interventions and exposures may influence health outcomes. Publications of mediation analyses are increasing, but the quality of their reporting is suboptimal. Objective: To develop international, consensus-based guidance for the reporting of mediation analyses of randomized trials and observational studies (A Guideline for Reporting Mediation Analyses; AGReMA). Design, Setting, and Participants: The AGReMA statement was developed using the Enhancing Quality and Transparency of Health Research (EQUATOR) methodological framework for developing reporting guidelines. The guideline development process included (1) an overview of systematic reviews to assess the need for a reporting guideline; (2) review of systematic reviews of relevant evidence on reporting mediation analyses; (3) conducting a Delphi survey with panel members that included methodologists, statisticians, clinical trialists, epidemiologists, psychologists, applied clinical researchers, clinicians, implementation scientists, evidence synthesis experts, representatives from the EQUATOR Network, and journal editors (n = 19; June-November 2019); (4) having a consensus meeting (n = 15; April 28-29, 2020); and (5) conducting a 4-week external review and pilot test that included methodologists and potential users of AGReMA (n = 21; November 2020). Results: A previously reported overview of 54 systematic reviews of mediation studies demonstrated the need for a reporting guideline. Thirty-three potential reporting items were identified from 3 systematic reviews of mediation studies. Over 3 rounds, the Delphi panelists ranked the importance of these items, provided 60 qualitative comments for item refinement and prioritization, and suggested new items for consideration. All items were reviewed during a 2-day consensus meeting and participants agreed on a 25-item AGReMA statement for studies in which mediation analyses are the primary focus and a 9-item short-form AGReMA statement for studies in which mediation analyses are a secondary focus. These checklists were externally reviewed and pilot tested by 21 expert methodologists and potential users, which led to minor adjustments and consolidation of the checklists. Conclusions and Relevance: The AGReMA statement provides recommendations for reporting primary and secondary mediation analyses of randomized trials and observational studies. Improved reporting of studies that use mediation analyses could facilitate peer review and help produce publications that are complete, accurate, transparent, and reproducible.

Comparative Effectiveness of Echinocandins vs Triazoles or Amphotericin B Formulations as Initial Directed Therapy for Invasive Candidiasis in Children and Adolescents.

BACKGROUND: Invasive candidiasis is the most common invasive fungal disease in children and adolescents, but there are limited pediatric-specific antifungal effectiveness data. We compared the effectiveness of echinocandins to triazoles or amphotericin B formulations (triazole/amphotericin B) as initial directed therapy for invasive candidiasis. METHODS: This multinational observational cohort study enrolled patients aged >120 days and <18 years with proven invasive candidiasis from January 1, 2014, to November 28, 2017, at 43 International Pediatric Fungal Network sites. Primary exposure was initial directed therapy administered at the time qualifying culture became positive for yeast. Exposure groups were categorized by receipt of an echinocandin vs receipt of triazole/amphotericin B. Primary outcome was global response at 14 days following invasive candidiasis onset, adjudicated by a centralized data review committee. Stratified Mantel-Haenszel analyses estimated risk difference between exposure groups. RESULTS: Seven-hundred and fifty invasive candidiasis episodes were identified. After exclusions, 541 participants (235 in the echinocandin group and 306 in the triazole/amphotericin B group) remained. Crude failure rates at 14 days for echinocandin and triazole/amphotericin B groups were 9.8% (95% confidence intervals [CI]: 6.0% to 13.6%) and 13.1% (95% CI: 9.3% to 16.8%), respectively. The adjusted 14-day risk difference between echinocandin and triazole/amphotericin B groups was -7.1% points (95% CI: -13.1% to -2.4%), favoring echinocandins. The risk difference was -0.4% (95% CI: -7.5% to 6.7%) at 30 days. CONCLUSIONS: In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days. These results may support echinocandins as initial directed therapy for invasive candidiasis in children and adolescents. CLINICAL TRIALS REGISTRATION: NCT01869829.

Intimate Partner Violence: Childhood Witnessing and Subsequent Experiences of College Undergraduates.

Previous work links witnessing adult violence in the home during childhood ("witnessing") and adolescent relationship violence, but studies are limited to recent experiences with one or two outcomes, missing the holistic viewpoint describing lifetime experiences across multiple types of violence. We measured associations between witnessing and victimization (being harmed by violence) and perpetration (causing harm by violence) among males and females for the three most common types of adolescent relationship violence (physical, sexual, and emotional), and we assessed whether students experienced multiple outcomes ("polyvictimization/ polyperpetration"). We also compared sex-specific differences to assess for additive effect modification. We used an anonymous, cross-sectional survey with 907 undergraduates attending randomly selected classes at three urban East Coast colleges. Multiple logistic regression and marginal standardization were used to estimate predicted probabilities for each outcome among witnesses and non-witnesses; additive interaction by sex was assessed using quantifiable measures. 214 (24%) students reported witnessing and 403 (44%) students experienced adolescent relationship violence, with 162 (17.9%) and 37 (4.1%) experiencing polyvictimization and polyperpetration, respectively. Witnesses had higher risk than non-witnesses for physical, sexual, and emotional victimization and perpetration. Notably, witnesses also had higher risk for polyvictimization and polyperpetration. Additive effect modification by sex was insignificant at 95% confidence bounds, but distinct patterns emerged for males and females. Except for sexual victimization, female witnesses were more likely than female non-witnesses to experience all forms of victimization, including polyvictimization; they also had higher risk for perpetration, particularly physical perpetration. In contrast, victimization outcomes did not differ for male witnesses, but male witnesses were more likely than male non-witnesses to perpetrate all forms of violence, including polyperpetration.

Survival Analysis of Treatment Efficacy in Comparative Coronavirus Disease 2019 Studies.

For survival analysis in comparative coronavirus disease 2019 trials, the routinely used hazard ratio may not provide a meaningful summary of the treatment effect. The mean survival time difference/ratio is an intuitive, assumption-free alternative. However, for short-term studies, landmark mortality rate differences/ratios are more clinically relevant and should be formally analyzed and reported.

Persistent Hypertension in Children and Adolescents: A 6-Year Cohort Study.

OBJECTIVES: To determine the natural history of pediatric hypertension. METHODS: We conducted a 72-month retrospective cohort study among 165 primary care sites. Blood pressure measurements from two consecutive 36 month periods were compared. RESULTS: Among 398 079 primary care pediatric patients ages 3 to 18, 89 347 had ≥3 blood pressure levels recorded during a 36-month period, and 43 825 children had ≥3 blood pressure levels for 2 consecutive 36-month periods. Among these 43 825 children, 4.3% (1881) met criteria for hypertension (3.5% [1515] stage 1, 0.8% [366] stage 2) and 4.9% (2144) met criteria for elevated blood pressure in the first 36 months. During the second 36 months, 50% (933) of hypertensive patients had no abnormal blood pressure levels, 22% (406) had elevated blood pressure levels or <3 hypertensive blood pressure levels, and 29% (542) had ≥3 hypertensive blood pressure levels. Of 2144 patients with elevated blood pressure in the first 36 months, 70% (1492) had no abnormal blood pressure levels, 18% (378) had persistent elevated blood pressure levels, and 13% (274) developed hypertension in the second 36-months. Among the 7775 patients with abnormal blood pressure levels in the first 36-months, only 52% (4025) had ≥3 blood pressure levels recorded during the second 36-months. CONCLUSIONS: In a primary care cohort, most children initially meeting criteria for hypertension or elevated blood pressure had subsequent normal blood pressure levels or did not receive recommended follow-up measurements. These results highlight the need for more nuanced initial blood pressure assessment and systems to promote follow-up of abnormal results.

Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis.

Diabetes has emerged as a major co-morbidity in cystic fibrosis (CF). The 75 g oral glucose tolerance test (OGTT) is used to screen for CF-related diabetes (CFRD) but is inconvenient, and adherence to screening is poor. The 50 g glucose challenge test (GCT) is shorter, performed non-fasting, and may serve to pre-screen the subset of individuals requiring confirmatory OGTT. We performed a pilot study in twenty-seven CF individuals across the glucose tolerance spectrum to test whether the GCT could identify subjects with abnormal glucose tolerance defined as 2-h OGTT glucose ≥7.8 mmol/L (2 h-AGT) or 1-h defined as 1-hr OGTT glucose ≥11.1 mmol/L (1 h-AGT). A GCT threshold of 8.1 mmol/L was 73% sensitive and 63% specific for 2hr-AGT and 80% sensitive and 65% specific for 1hr-AGT. Therefore, a screening GCT may reduce need for confirmatory OGTT for identifying AGT but a larger study is warranted to identify a robust cutoff for CFRD.

Association Between Mobile Telephone Interruptions and Medication Administration Errors in a Pediatric Intensive Care Unit.

Importance: Incoming text messages and calls on nurses' mobile telephones may interrupt medication administration, but whether such interruptions are associated with errors has not been established. Objective: To assess whether a temporal association exists between mobile telephone interruptions and subsequent errors by pediatric intensive care unit (PICU) nurses during medication administration. Design, Setting, and Participants: A retrospective cohort study was performed using telecommunications and electronic health record data from a PICU in a children's hospital. Data were collected from August 1, 2016, through September 30, 2017. Participants included 257 nurses and the 3308 patients to whom they administered medications. Exposures: Primary exposures were incoming telephone calls and text messages received on the institutional mobile telephone assigned to the nurse in the 10 minutes leading up to a medication administration attempt. Secondary exposures were the nurse's PICU experience, work shift (day vs night), nurse to patient ratio, and level of patient care required. Main Outcomes and Measures: Primary outcome, errors during medication administration, was a composite of reported medication administration errors and bar code medication administration error alerts generated when nurses attempted to give medications without active orders for the patient whose bar code they scanned. Results: Participants included 257 nurses, of whom 168 (65.4%) had 6 months or more of PICU experience; and 3308 patients, of whom 1839 (55.6%) were male, 1539 (46.5%) were white, and 2880 (87.1%) were non-Hispanic. The overall rate of errors during 238 540 medication administration attempts was 3.1% (95% CI, 3.0%-3.3%) when nurses were uninterrupted by incoming telephone calls and 3.7% (95% CI, 3.4%-4.0%) when they were interrupted by such calls. During day shift, the odds ratios (ORs) for error when interrupted by calls (compared with uninterrupted) were 1.02 (95% CI, 0.92-1.13; P = .73) among nurses with 6 months or more of PICU experience and 1.22 (95% CI, 1.00-1.47; P = .046) among nurses with less than 6 months of experience. During night shift, the ORs for error when interrupted by calls were 1.35 (95% CI, 1.16-1.57; P < .001) among nurses with 6 months or more of PICU experience and 1.53 (95% CI, 1.16-2.03; P = .003) among nurses with less than 6 months of experience. Nurses administering medications to 1 or more patients receiving mechanical ventilation and arterial catheterization while caring for at least 1 other patient had an increased risk of error (OR, 1.21; 95% CI, 1.03-1.42; P = .02). Incoming text messages were not associated with error (OR, 0.97; 95% CI, 0.92-1.02; P = .22). Conclusions and Relevance: This study's findings suggest that incoming telephone call interruptions may be temporally associated with medication administration errors among PICU nurses. Risk of error varied by shift, experience, nurse to patient ratio, and level of patient care required.

Patient Portal Usage and Outcomes Among Adult Patients with Uncontrolled Asthma.

BACKGROUND: Patient-clinician communication, essential for favorable asthma outcomes, increasingly relies on information technology including the electronic heath record-based patient portal. For patients with chronic disease living in low-income neighborhoods, the benefits of portal communication remain unclear. OBJECTIVE: To describe portal activities and association with 12-month outcomes among low-income patients with asthma formally trained in portal use. METHODS: In a longitudinal observational study within a randomized controlled trial, 301 adults with uncontrolled asthma were taught 7 portal tasks: reviewing upcoming appointments, scheduling appointments, reviewing medications, locating laboratory results, locating immunization records, requesting refills, and messaging. Half the patients were randomized to receive up to 4 home visits by community health workers. Patients' portal use by activities, rate of usage over time, frequency of appointments with asthma physicians, and asthma control and quality of life were assessed over time and estimated as of 12 months from randomization. RESULTS: Fewer than 60% of patients used the portal independently. Among users, more than half used less than 1 episode per calendar quarter. The most frequent activities were reading messages and viewing laboratory results and least sending messages and making appointments. Higher rates of portal use were not associated with keeping regular appointments during follow-up, better asthma control, or higher quality of life at 12-month postintervention. CONCLUSIONS: Patients with uncontrolled asthma used the portal irregularly if at all, despite in-person training. Usage was not associated with regular appointments or with clinical outcomes. Patient portals need modification to accommodate low-income patients with uncontrolled asthma.

Intergenerational effects of witnessing domestic violence: Health of the witnesses and their children.

Studies that explore intergenerational effects of witnessing domestic violence during childhood ("witnessing") are lacking. We examined effects of witnessing on general health status for adults who witnessed domestic violence during childhood and their children. Cross-sectional data from population-based phone interviews conducted in Philadelphia during 2012-2013 provided health information for 329 parents and children, and parent's witnessing exposure. We used propensity scores to predict parent's witnessing status using childhood confounders; response models included inverse probability of treatment weighting and population weights for standardization. Separate standardized multivariate logistic regression models provided average treatment effects and 95% CIs for associations between childhood witnessing and below average health for: 1) adults who witnessed and 2) their children. Sensitivity analyses guided interpretation. Standardized models showed no differences in average treatment effects for below average adult health for witnesses vs. non-witnesses [0.04 (-0.12, 0.19)]. Conversely, children whose parents witnessed had considerably higher probability of having below average health than children whose parents did not witness [0.15 (0.02, 0.28)]. An unmeasured confounder would need 3.0-fold associations with both exposure and outcome to completely remove observed effects, indicating a moderate relationship. However, the lower confidence bound could cross 1.0 in the presence of a weaker unmeasured confounder having 1.2-fold associations with both exposure and outcome, while controlling for our same measured confounders. Witnessing during childhood did not affect adult health in our population, but we found moderate evidence supporting harmful intergenerational effects of witnessing on health, with parent's witnessing exposure affecting their child's health.

Inhaler Technique in Low-Income, Inner-City Adults with Uncontrolled Asthma.

BACKGROUND: Poor inhaler technique has been shown to be associated with less asthma control and increased health care utilization. Little is known about the impact of inhaler technique on the most vulnerable patients. OBJECTIVE: This study examined inhaler technique in low-income, inner-city adults with uncontrolled asthma. METHODS: Inhaler technique data and other patient characteristics were evaluated in adults drawn from 2 studies conducted at the University of Pennsylvania. Subjects were from low-income Philadelphia neighborhoods and had uncontrolled asthma. Baseline characteristics were collected. Inhaler technique was rated by research coordinators who were trained with written materials. RESULTS: In 584 adults, 56% of metered dose inhaler users and 64% of dry powder inhaler users had adequate visually assessed inhaler technique. Inhaler technique did not vary by reading comprehension or numeracy levels. CONCLUSIONS: In this group of patients with uncontrolled asthma, visually assessed inhaler technique was adequate in more than one-half. Although incorrect inhaler technique is generally common and must be routinely addressed, this study suggests that other factors that lead to poor control must be identified.