Connectivity Profile for Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson Disease.

OBJECTIVE: This study was undertaken to describe relationships between electrode localization and motor outcomes from the subthalamic nucleus (STN) deep brain stimulation (DBS) in early stage Parkinson disease (PD) pilot clinical trial. METHODS: To determine anatomical and network correlates associated with motor outcomes for subjects randomized to early DBS (n = 14), voxelwise sweet spot mapping and structural connectivity analyses were carried out using outcomes of motor progression (Unified Parkinson Disease Rating Scale Part III [UPDRS-III] 7-day OFF scores [∆baseline➔24 months, MedOFF/StimOFF]) and symptomatic motor improvement (UPDRS-III ON scores [%∆baseline➔24 months, MedON/StimON]). RESULTS: Sweet spot mapping revealed a location associated with slower motor progression in the dorsolateral STN (anterior/posterior commissure coordinates: 11.07 ± 0.82mm lateral, 1.83 ± 0.61mm posterior, 3.53 ± 0.38mm inferior to the midcommissural point; Montreal Neurological Institute coordinates: +11.25, -13.56, -7.44mm). Modulating fiber tracts from supplementary motor area (SMA) and primary motor cortex (M1) to the STN correlated with slower motor progression across STN DBS subjects, whereas fiber tracts originating from pre-SMA and cerebellum were negatively associated with motor progression. Robustness of the fiber tract model was demonstrated in leave-one-patient-out (R = 0.56, p = 0.02), 5-fold (R = 0.50, p = 0.03), and 10-fold (R = 0.53, p = 0.03) cross-validation paradigms. The sweet spot and fiber tracts associated with motor progression revealed strong similarities to symptomatic motor improvement sweet spot and connectivity in this early stage PD cohort. INTERPRETATION: These results suggest that stimulating the dorsolateral region of the STN receiving input from M1 and SMA (but not pre-SMA) is associated with slower motor progression across subjects receiving STN DBS in early stage PD. This finding is hypothesis-generating and must be prospectively tested in a larger study. ANN NEUROL 2023;94:271-284.

Patient Safety Outcomes under Flexible and Standard Resident Duty-Hour Rules.

BACKGROUND: Concern persists that extended shifts in medical residency programs may adversely affect patient safety. METHODS: We conducted a cluster-randomized noninferiority trial in 63 internal-medicine residency programs during the 2015-2016 academic year. Programs underwent randomization to a group with standard duty hours, as adopted by the Accreditation Council for Graduate Medical Education (ACGME) in July 2011, or to a group with more flexible duty-hour rules that did not specify limits on shift length or mandatory time off between shifts. The primary outcome for each program was the change in unadjusted 30-day mortality from the pretrial year to the trial year, as ascertained from Medicare claims. We hypothesized that the change in 30-day mortality in the flexible programs would not be worse than the change in the standard programs (difference-in-difference analysis) by more than 1 percentage point (noninferiority margin). Secondary outcomes were changes in five other patient safety measures and risk-adjusted outcomes for all measures. RESULTS: The change in 30-day mortality (primary outcome) among the patients in the flexible programs (12.5% in the trial year vs. 12.6% in the pretrial year) was noninferior to that in the standard programs (12.2% in the trial year vs. 12.7% in the pretrial year). The test for noninferiority was significant (P = 0.03), with an estimate of the upper limit of the one-sided 95% confidence interval (0.93%) for a between-group difference in the change in mortality that was less than the prespecified noninferiority margin of 1 percentage point. Differences in changes between the flexible programs and the standard programs in the unadjusted rate of readmission at 7 days, patient safety indicators, and Medicare payments were also below 1 percentage point; the noninferiority criterion was not met for 30-day readmissions or prolonged length of hospital stay. Risk-adjusted measures generally showed similar findings. CONCLUSIONS: Allowing program directors flexibility in adjusting duty-hour schedules for trainees did not adversely affect 30-day mortality or several other measured outcomes of patient safety. (Funded by the National Heart, Lung, and Blood Institute and Accreditation Council for Graduate Medical Education; iCOMPARE ClinicalTrials.gov number, NCT02274818.).

Sleep and Alertness in a Duty-Hour Flexibility Trial in Internal Medicine.

BACKGROUND: A purpose of duty-hour regulations is to reduce sleep deprivation in medical trainees, but their effects on sleep, sleepiness, and alertness are largely unknown. METHODS: We randomly assigned 63 internal-medicine residency programs in the United States to follow either standard 2011 duty-hour policies or flexible policies that maintained an 80-hour workweek without limits on shift length or mandatory time off between shifts. Sleep duration and morning sleepiness and alertness were compared between the two groups by means of a noninferiority design, with outcome measures including sleep duration measured with actigraphy, the Karolinska Sleepiness Scale (with scores ranging from 1 [extremely alert] to 9 [extremely sleepy, fighting sleep]), and a brief computerized Psychomotor Vigilance Test (PVT-B), with long response times (lapses) indicating reduced alertness. RESULTS: Data were obtained over a period of 14 days for 205 interns at six flexible programs and 193 interns at six standard programs. The average sleep time per 24 hours was 6.85 hours (95% confidence interval [CI], 6.61 to 7.10) among those in flexible programs and 7.03 hours (95% CI, 6.78 to 7.27) among those in standard programs. Sleep duration in flexible programs was noninferior to that in standard programs (between-group difference, -0.17 hours per 24 hours; one-sided lower limit of the 95% confidence interval, -0.45 hours; noninferiority margin, -0.5 hours; P = 0.02 for noninferiority), as was the score on the Karolinska Sleepiness Scale (between-group difference, 0.12 points; one-sided upper limit of the 95% confidence interval, 0.31 points; noninferiority margin, 1 point; P<0.001). Noninferiority was not established for alertness according to the PVT-B (between-group difference, -0.3 lapses; one-sided upper limit of the 95% confidence interval, 1.6 lapses; noninferiority margin, 1 lapse; P = 0.10). CONCLUSIONS: This noninferiority trial showed no more chronic sleep loss or sleepiness across trial days among interns in flexible programs than among those in standard programs. Noninferiority of the flexible group for alertness was not established. (Funded by the National Heart, Lung, and Blood Institute and American Council for Graduate Medical Education; ClinicalTrials.gov number, NCT02274818.).

The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults : A Response-Adaptive, Randomized Clinical Trial.

BACKGROUND: Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences. OBJECTIVE: To compare the effects of 4 doses of vitamin D3 supplements on falls. DESIGN: 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333). SETTING: 2 community-based research units. PARTICIPANTS: 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L. INTERVENTION: 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D3 doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose. MEASUREMENTS: Time to first fall or death over 2 years (primary outcome). RESULTS: During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d; n = 308) and those randomly assigned to receive 200 IU/d (n = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15]; P = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46]). LIMITATIONS: The control group received 200 IU of vitamin D3 per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached. CONCLUSION: In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D3 supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D3 doses of 1000 IU/d or higher. PRIMARY FUNDING SOURCE: National Institute on Aging.

Education Outcomes in a Duty-Hour Flexibility Trial in Internal Medicine.

BACKGROUND: Concern persists that inflexible duty-hour rules in medical residency programs may adversely affect the training of physicians. METHODS: We randomly assigned 63 internal medicine residency programs in the United States to be governed by standard duty-hour policies of the 2011 Accreditation Council for Graduate Medical Education (ACGME) or by more flexible policies that did not specify limits on shift length or mandatory time off between shifts. Measures of educational experience included observations of the activities of interns (first-year residents), surveys of trainees (both interns and residents) and faculty, and intern examination scores. RESULTS: There were no significant between-group differences in the mean percentages of time that interns spent in direct patient care and education nor in trainees' perceptions of an appropriate balance between clinical demands and education (primary outcome for trainee satisfaction with education; response rate, 91%) or in the assessments by program directors and faculty of whether trainees' workload exceeded their capacity (primary outcome for faculty satisfaction with education; response rate, 90%). Another survey of interns (response rate, 49%) revealed that those in flexible programs were more likely to report dissatisfaction with multiple aspects of training, including educational quality (odds ratio, 1.67; 95% confidence interval [CI], 1.02 to 2.73) and overall well-being (odds ratio, 2.47; 95% CI, 1.67 to 3.65). In contrast, directors of flexible programs were less likely to report dissatisfaction with multiple educational processes, including time for bedside teaching (response rate, 98%; odds ratio, 0.13; 95% CI, 0.03 to 0.49). Average scores (percent correct answers) on in-training examinations were 68.9% in flexible programs and 69.4% in standard programs; the difference did not meet the noninferiority margin of 2 percentage points (difference, -0.43; 95% CI, -2.38 to 1.52; P=0.06 for noninferiority). od Institute and the ACGME; iCOMPARE ClinicalTrials.gov number, NCT02274818 .). CONCLUSIONS: There was no significant difference in the proportion of time that medical interns spent on direct patient care and education between programs with standard duty-hour policies and programs with more flexible policies. Interns in flexible programs were less satisfied with their educational experience than were their peers in standard programs, but program directors were more satisfied. (Funded by the National Heart, Lung, and Blo

A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation.

BACKGROUND: Long-term treatment with supplemental oxygen has unknown efficacy in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation. METHODS: We originally designed the trial to test whether long-term treatment with supplemental oxygen would result in a longer time to death than no use of supplemental oxygen among patients who had stable COPD with moderate resting desaturation (oxyhemoglobin saturation as measured by pulse oximetry [Spo2], 89 to 93%). After 7 months and the randomization of 34 patients, the trial was redesigned to also include patients who had stable COPD with moderate exercise-induced desaturation (during the 6-minute walk test, Spo2 ≥80% for ≥5 minutes and <90% for ≥10 seconds) and to incorporate the time to the first hospitalization for any cause into the new composite primary outcome. Patients were randomly assigned, in a 1:1 ratio, to receive long-term supplemental oxygen (supplemental-oxygen group) or no long-term supplemental oxygen (no-supplemental-oxygen group). In the supplemental-oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep. The trial-group assignment was not masked. RESULTS: A total of 738 patients at 42 centers were followed for 1 to 6 years. In a time-to-event analysis, we found no significant difference between the supplemental-oxygen group and the no-supplemental-oxygen group in the time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P=0.52), nor in the rates of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19), and COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17). We found no consistent between-group differences in measures of quality of life, lung function, and the distance walked in 6 minutes. CONCLUSIONS: In patients with stable COPD and resting or exercise-induced moderate desaturation, the prescription of long-term supplemental oxygen did not result in a longer time to death or first hospitalization than no long-term supplemental oxygen, nor did it provide sustained benefit with regard to any of the other measured outcomes. (Funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services; LOTT ClinicalTrials.gov number, NCT00692198 .).

External Validation and Recalculation of the CODEX Index in COPD Patients. A 3CIAplus Cohort Study.

The CODEX index was developed and validated in patients hospitalized for COPD exacerbation to predict the risk of death and readmission within one year after discharge. Our study aimed to validate the CODEX index in a large external population of COPD patients with variable durations of follow-up. Additionally, we aimed to recalculate the thresholds of the CODEX index using the cutoffs of variables previously suggested in the 3CIA study (mCODEX). Individual data on 2,755 patients included in the COPD Cohorts Collaborative International Assessment Plus (3CIA+) were explored. A further two cohorts (ESMI AND EGARPOC-2) were added. To validate the CODEX index, the relationship between mortality and the CODEX index was assessed using cumulative/dynamic ROC curves at different follow-up periods, ranging from 3 months up to 10 years. Calibration was performed using univariate and multivariate Cox proportional hazard models and Hosmer-Lemeshow test. A total of 3,321 (87.8% males) patients were included with a mean ± SD age of 66.9 ± 10.5 years, and a median follow-up of 1,064 days (IQR 25-75% 426-1643), totaling 11,190 person-years. The CODEX index was statistically associated with mortality in the short- (≤3 months), medium- (≤1 year) and long-term (10 years), with an area under the curve of 0.72, 0.70 and 0.76, respectively. The mCODEX index performed better in the medium-term (<1 year) than the original CODEX, and similarly in the long-term. In conclusion, CODEX and mCODEX index are good predictors of mortality in patients with COPD, regardless of disease severity or duration of follow-up.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma.

RATIONALE: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease. OBJECTIVES: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma. METHODS: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays. MEASUREMENTS AND MAIN RESULTS: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10-9; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene. CONCLUSIONS: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).

Effect of inhaled glucocorticoids in childhood on adult height.

BACKGROUND: The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height. METHODS: We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 µg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry. RESULTS: Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P=0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P=0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P=0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants. CONCLUSIONS: The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.).

The transitioning from trials to extended follow-up studies.

BACKGROUND: Investigators may elect to extend follow-up of participants enrolled in a randomized clinical trial after the trial comes to its planned end. The additional follow-up may be initiated to learn about longer term effects of treatments, including adverse events, costs related to treatment, or for reasons unrelated to treatment such as to observe the natural course of the disease using the established cohort from the trial. PURPOSE: We examine transitioning from trials to extended follow-up studies when the goal of additional follow-up is to observe longer term treatment effects. METHODS: We conducted a literature search in selected journals from 2000 to 2012 to identify trials that extended follow-up for the purpose of studying longer term treatment effects and extracted information on the operational and logistical issues in the transition. We also draw experience from three trials coordinated by the Johns Hopkins Coordinating Centers that made transitions to extended follow-up: the Alzheimer's Disease Anti-inflammatory Prevention Trial, Multicenter Uveitis Steroid Treatment trial, and Childhood Asthma Management Program. RESULTS: Transitions are not uncommon in multicenter clinical trials, even in trials that continued to the planned end of the trial. Transitioning usually necessitates new participant consents. If study infrastructure is not maintained during the transition, participants will be lost and re-establishing the staff and facilities will be costly. Merging data from the trial and follow-up study can be complicated by changes in data collection measures and schedules. LIMITATIONS: Our discussion and recommendations are limited to issues that we have experienced in transitions from trials to follow-up studies. DISCUSSION: We discuss issues such as maintaining funding, institutional review board and consent requirements, contacting participants, and combining data from the trial and follow-up phases. We conclude with a list of recommendations to facilitate transitions from a trial to an extended follow-up study.

Weight gain after lung reduction surgery is related to improved lung function and ventilatory efficiency.

RATIONALE: Lung volume reduction surgery (LVRS) is associated with weight gain in some patients, but the group that gains weight after LVRS and the mechanisms underlying this phenomenon have not been well characterized. OBJECTIVES: To describe the weight change profiles of LVRS patients enrolled in the National Emphysema Treatment Trial (NETT) and to correlate alterations in lung physiological parameters with changes in weight. METHODS: We divided 1,077 non-high-risk patients in the NETT into groups according to baseline body mass index (BMI): underweight (<21 kg/m(2)), normal weight (21-25 kg/m(2)), overweight (25-30 kg/m(2)), and obese (>30 kg/m(2)). We compared BMI groups and LVRS and medical groups within each BMI stratum with respect to baseline characteristics and percent change in BMI (%ΔBMI) from baseline. We examined patients with (ΔBMI ≥ 5%) and without (ΔBMI < 5%) significant weight gain at 6 months and assessed changes in lung function and ventilatory efficiency (Ve/Vco(2)). MEASUREMENTS AND MAIN RESULTS: The percent change in BMI was greater in the LVRS arm than in the medical arm in the underweight and normal weight groups at all follow-up time points, and at 12 and 24 months in the overweight group. In the LVRS group, patients with ΔBMI ≥ 5% at 6 months had greater improvements in FEV(1) (11.53 ± 9.31 vs. 6.58 ± 8.68%; P < 0.0001), FVC (17.51 ± 15.20 vs. 7.55 ± 14.88%; P < 0.0001), residual volume (-66.20 ± 40.26 vs. -47.06 ± 39.87%; P < 0.0001), 6-minute walk distance (38.70 ± 69.57 vs. 7.57 ± 73.37 m; P < 0.0001), maximal expiratory pressures (12.73 ± 49.08 vs. 3.54 ± 32.22; P = 0.0205), and Ve/Vco(2) (-1.58 ± 6.20 vs. 0.22 ± 8.20; P = 0.0306) at 6 months than patients with ΔBMI < 5% at 6 months. CONCLUSIONS: LVRS leads to weight gain in nonobese patients, which is associated with improvement in lung function, exercise capacity, respiratory muscle strength, and ventilatory efficiency. These physiological changes may be partially responsible for weight gain in patients who undergo LVRS.

Severe chronic bronchitis in advanced emphysema increases mortality and hospitalizations.

BACKGROUND: Chronic bronchitis in COPD has been associated with an increased exacerbation rate, more hospitalizations, and an accelerated decline in lung function. The clinical characteristics of patients with advanced emphysema and chronic bronchitis have not been well described. METHODS: Patients randomized to medical therapy in the National Emphysema Treatment Trial were grouped based on their reports of cough and phlegm on the St. George's Respiratory Questionnaire(SGRQ) at baseline: chronic bronchitis(CB+) and no chronic bronchitis(CB-). The patients were similarly categorized into severe chronic bronchitis(SCB+) or no severe chronic bronchitis (SCB-) based on the above definition plus report of chest trouble. Kaplan-Meier survival analysis was used to determine the relationships between chronic bronchitis and severe chronic bronchitis and survival and time to hospitalization. Lung function and SGRQ scores over time were compared between groups. RESULTS: The CB+(N = 234; 38%) and CB- groups(N = 376; 62%) had similar survival (median 60.8 versus 65.7 months, p = 0.19) and time to hospitalization (median 26.9 versus 24.9 months, p = 0.84). The SCB+ group(N = 74; 12%) had worse survival (median 47.7 versus 65.7 months, p = 0.02) and shorter time to hospitalization (median 18.5 versus 26.7 months, p = 0.02) than the SCB- group (N = 536; 88%). Mortality and hospitalization rates were not increased when chest trouble was analyzed by itself. The CB+ and CB-groups had similar lung function and SGRQ scores over time. The SCB+ and SCB-groups had similar lung function over time, but the SCB+ group had significantly worse SGRQ scores. CONCLUSIONS: Severe chronic bronchitis is associated with worse survival, shorter time to hospitalization, and worse health-related quality of life.

The National Emphysema Treatment Trial (NETT) Part II: Lessons learned about lung volume reduction surgery.

Substantial information regarding the role of lung volume reduction surgery (LVRS) in severe emphysema emanates from the National Emphysema Treatment Trial (NETT). The NETT was not a crossover trial and therefore was able to examine the effects of optimal medical management and LVRS on short- and long-term survival,as well as lung function, exercise performance, and quality of life.The NETT generated multiple insights into the preoperative, perioperative,and postoperative management of patients undergoing thoracotomy; described pain control techniques that were safe and effective; and emphasized the need to address nonpulmonary issues to optimize surgical outcomes. After the NETT, newer investigation has focused on bronchoscopic endobronchial interventions and other techniques less invasive than LVRS to achieve lung reduction.In this review, we summarize what we currently know about the role of LVRS in the treatment of severe emphysema as a result of insights gained from the NETT and provide a brief review of the newer techniques of lung volume reduction.

The National Emphysema Treatment Trial (NETT): Part I: Lessons learned about emphysema.

The National Emphysema Treatment Trial (NETT) was a multicenter prospective randomized controlled trial that compared optimal medical treatment, including pulmonary rehabilitation, with optimal medical treatment plus lung volume reduction surgery (LVRS). It was the largest and most complete collection of patient demographic, clinical, physiological, and radiographic data ever compiled in severe emphysema. NETT investigated the effects of optimal medical management and LVRS on short- and long-term survival, as well as lung function, exercise performance, and quality of life. NETT also provided much information regarding the evaluation and prognosis of severe emphysema; specifically the important negative influences that hyperinflation and small airway disease have on survival. NETT emphasized the importance of addressing nonpulmonary issues such as nutrition, cardiac disease, anxiety, and depression in emphysema. NETT demonstrated that physiological, genomic, and radiographic phenotype can predict patient survival as well as response to treatment. Because the major purpose of NETT was to compare bilateral LVRS with optimal medical treatment in emphysema, patients enrolled into NETT were comprehensively characterized and selected to have a specific window of airflow obstruction and hyperinflation and to lack significant comorbidities. The NETT patient population's restrictive features offer distinct advantages (well-characterized predominant emphysematous phenotype) and disadvantages (lack of comorbidities and significant chronic bronchitis) that must be considered when interpreting the implications of these results. Herein, we provide a summary of the major NETT findings that provide insight into the evaluation and medical treatment of emphysema.

The Relationship of Falls With Achieved 25-Hydroxyvitamin D Levels From Vitamin D Supplementation: The STURDY Trial.

Context: The Study to Understand Fall Reduction and Vitamin D in You (STURDY), a randomized trial enrolling older adults with low 25-hydroxyvitamin D [25(OH)D], demonstrated vitamin D supplementation ≥ 1000 IU/day did not prevent falls compared with 200 IU/day, with doses ≥ 2000 IU/day potentially showing safety concerns. Objective: To examine associations of achieved and change in 25(OH)D concentrations after 3 months of vitamin D supplementation with fall risk. Design: Observational analysis of trial data. Setting: General community. Participants: A total of 637 adults aged ≥ 70 with baseline 25(OH)D concentrations 10 to 29 ng/mL and elevated fall risk. Three-month on-treatment absolute 25(OH)D; absolute and relative changes from baseline. Main Outcome Measures: Incident first fall (primary) and first consequential fall (injury or sought medical care) up to 24 months. Cox models were adjusted for sociodemographics, season, Short Physical Performance Battery, and body mass index. Results: At baseline, mean (SD) age was 77.1 (5.4) years and 25(OH)D was 22.1 (5.1) ng/mL; 43.0% were women and 21.5% non-White. A total of 395 participants experienced ≥ 1 fall; 294 experienced ≥ 1 consequential fall. There was no association between absolute achieved 25(OH)D and incident first fall (30-39 vs < 30 ng/mL hazard ratio [HR], 0.93; 95% CI, 0.74-1.16; ≥40 vs < 30 ng/mL HR, 1.09; 95% CI, 0.82-1.46; adjusted overall P = 0.67), nor absolute or relative change in 25(OH)D. For incident consequential first fall, the HR (95% CI) comparing absolute 25(OH)D ≥ 40 vs < 30 ng/mL was 1.38 (0.99-1.90). Conclusion: Achieved 25(OH)D concentration after supplementation was not associated with reduction in falls. Risk of consequential falls may be increased with achieved concentrations ≥ 40 ng/mL. Trial Registration: ClinicalTrials.gov: NCT02166333.

Effects of Vitamin D on Physical Function: Results From the STURDY Trial.

BACKGROUND: Studies of the relationship between vitamin D and physical functioning have had inconsistent results. METHODS: Physical functioning measures were collected for up to 2 years during a 2-stage, Bayesian, response-adaptive, randomized trial of 4 doses of vitamin D3 supplementation (200 [control], 1 000, 2 000, and 4 000 IU/day) to prevent falls. Two community-based research units enrolled adults aged ≥70 years, with elevated fall risk and serum 25-hydroxyvitamin D level of 10-29 ng/mL. The Pooled Higher Doses (PHD) group (≥1 000 IU/day, n = 349) was compared to the control group (n = 339) on changes in Short Physical Performance Battery (SPPB) score and its component tests, Timed Up-and-Go (TUG) test, 6-minute walk distance, and grip strength. RESULTS: The trial enrolled 688 participants. Mean age was 77.2 years, 56.4% were male, 79.7% White, and 18.2% Black. While the PHD and control groups both lost function over time on most outcomes, the 2 groups did not show differential change overall on any outcome. Incidence of transitioning to poor functioning on gait speed, SPPB score, or TUG test did not differ by dose group. CONCLUSION: In older persons with low serum 25-hydroxyvitamin D level and elevated fall risk, high-dose vitamin D supplementation, ≥1 000 IU/day, did not improve measures of physical function compared to 200 IU/day. CLINICAL TRIAL REGISTRATION: NCT02166333.

Physiologic correlates of sleep quality in severe emphysema.

BACKGROUND: Sleep quality is poor in severe emphysema. We hypothesized that in addition to nocturnal oxygen desaturation, the severity of airflow obstruction and degree of thoracic hyperinflation are responsible. METHODS: Twenty-five patients (14 males, 64 ± 6 [ ± SD] yrs, BMI 24.7 ± 4.2 kg/m(2)) with severe emphysema (FEV(1) = 28 ± 8% predicted, TLC = 125 ± 14% predicted) were studied. Measurements included spirometry, lung volumes, arterial blood gas, length of the diaphragm's zone of apposition (LZAP) and a polysomnogram. RESULTS: Total sleep time (TST) was 227 ± 93 minutes with a sleep efficiency (SE) of 56 ± 21%. The mean SaO(2), lowest SaO(2), and% TST with a SaO(2) < 90% were 90 ± 5%, 83 ± 8% and 29 ± 40%, respectively. TST correlated with FEV(1)% (r = 0.5, p = 0.02), FVC% (r = 0.4, p = 0.03) and LZAP (r = 0.5, p = 0.01). SE correlated with FEV(1)% (r = 0.5, p = 0.02) and LZAP (r = 0.5, p = 0.01), but not with FVC% (r = 0.4, p = 0.07). Additionally, TST and SE correlated negatively with residual volume% (r = -0.4, p = 0.046, and r = -0.4, p = 0.03, respectively). There was no correlation between TST and SE and measures of nocturnal oxygenation. Multiple linear regression was used to predict TST, with 50% (r(2) = 0.49) explained by a combination of LZAP (27%), mean SaO(2) (23%), and the lowest SaO(2) (< 1%). To predict SE, 44% (r(2) = 0.43) was explained by a combination of LZAP (29%), mean SaO(2) (14%), and the lowest SaO(2) (1%). CONCLUSION: Although parameters of respiratory function and mechanics correlate with sleep quality, both nocturnal oxygenation and measurements of respiratory function/mechanics predict sleep quality in severe emphysema.

The effects of vitamin D supplementation on types of falls.

BACKGROUND/OBJECTIVES: To assess whether vitamin D supplementation prevents specific fall subtypes and sequelae (e.g., fracture). DESIGN: Secondary analyses of STURDY (Study to Understand Fall Reduction and Vitamin D in You)-a response-adaptive, randomized clinical trial. SETTING: Two community-based research units. PARTICIPANTS: Six hundred and eighty-eight participants ≥70 years old with elevated fall risk and baseline serum 25-hydroxyvitamin D levels of 10-29 ng/ml. INTERVENTION: 200 IU/day (control), 1000 IU/day, 2000 IU/day, or 4000 IU/day of vitamin D3. MEASUREMENTS: Outcomes included repeat falls and falls that were consequential, were injurious, resulted in emergency care, resulted in fracture, and occurred either indoors or outdoors. RESULTS: After adjustment for multiple comparisons, the risk of fall-related fracture was greater in the pooled higher doses (≥1000 IU/day) group compared with the control (hazard ratio [HR] = 2.66; 95% confidence interval [CI]:1.18-6.00). Although not statistically significant after multiple comparisons adjustment, time to first outdoor fall appeared to differ between the four dose groups (unadjusted p for overall difference = 0.013; adjusted p = 0.222), with risk of a first-time outdoor fall 39% lower in the 1000 IU/day group (HR = 0.61; 95% CI: 0.38-0.97; unadjusted p = 0.036; adjusted p = 0.222) and 40% lower in the 2000 IU/day group (HR = 0.60; 95%CI 0.38-0.97; p = 0.037; adjusted p = 0.222), each versus control. CONCLUSION: Vitamin D supplementation doses ≥1000 IU/day might have differential effects on fall risk based on fall location and fracture risk, with the most robust finding that vitamin D doses between 1000 and 4000 IU/day might increase the risk of first time falls with fractures. Replication is warranted, given the possibility of type 1 error.

Survival benefit of lung transplantation compared with medical management and pulmonary rehabilitation for patients with end-stage COPD.

BACKGROUND: COPD patients account for a large proportion of lung transplants; lung transplantation survival benefit for COPD patients is not well established. METHODS: We identified 4521 COPD patients in the United Network for Organ Sharing (UNOS) dataset transplanted from May 2005 to August 2016, and 604 patients assigned to receive pulmonary rehabilitation and medical management in the National Emphysema Treatment Trial (NETT). After trimming the populations for NETT eligibility criteria and data completeness, 1337 UNOS and 596 NETT patients remained. Kaplan-Meier estimates of transplant-free survival from transplantation for UNOS, and NETT randomisation, were compared between propensity score-matched UNOS (n=401) and NETT (n=262) patients. RESULTS: In propensity-matched analyses, transplanted patients had better survival compared to medically managed patients in NETT (p=0.003). Stratifying on 6 min walk distance (6 MWD) and FEV1, UNOS patients with 6 MWD <1000 ft (∼300 m) or FEV1 <20% of predicted had better survival than NETT counterparts (median survival 5.0 years UNOS versus 3.4 years NETT; log-rank p<0.0001), while UNOS patients with 6 MWD ≥1000 ft (∼300 m) and FEV1 ≥20% had similar survival to NETT counterparts (median survival, 5.4 years UNOS versus 4.9 years NETT; log-rank p=0.73), interaction p=0.01. CONCLUSIONS: Overall survival is better for matched lung transplant patients compared with medical management alone. Patients who derive maximum benefit are those with 6 MWD <1000 ft (∼300 m) or FEV1 <20% of predicted, compared with pulmonary rehabilitation and medical management.

Association of Guideline-Recommended COPD Inhaler Regimens With Mortality, Respiratory Exacerbations, and Quality of Life: A Secondary Analysis of the Long-Term Oxygen Treatment Trial.

BACKGROUND: Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear. RESEARCH QUESTION: Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes? STUDY DESIGN AND METHODS: We conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site. RESULTS: The trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66). INTERPRETATION: Among patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.