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Background: Childhood vitamin A deficiency leads to increased morbidity and mortality. Human milk is the only source of vitamin A for exclusively breastfed infants. Dried Moringa oleifera leaf powder (moringa) is a good food source of provitamin A and other carotenoids. Its effect during lactation on human milk vitamin A and carotenoid content is unclear. Objectives: Our objective was to investigate the effect of maternal moringa consumption on human milk retinol and carotenoid concentrations and maternal and infant vitamin A status. Methods: We conducted a 3-month pilot single-blinded cluster-randomized controlled trial in breastfeeding mother-infant pairs (n = 50) in Kenya. Mothers received corn porridge with (20 g/d) or without moringa with complete breast expressions and maternal and infant serum collected at enrollment (infant

BACKGROUND: In the United States, there are over seven million stroke survivors, with many facing gait impairments due to foot drop. This restricts their community ambulation and hinders functional independence, leading to several long-term health complications. Despite the best available physical therapy, gait function is incompletely recovered, and this occurs mainly during the acute phase post-stroke. Therapeutic options are limited currently. Novel therapies based on neurobiological principles have the potential to lead to long-term functional improvements. The Brain-Computer Interface (BCI) controlled Functional Electrical Stimulation (FES) system is one such strategy. It is based on Hebbian principles and has shown promise in early feasibility studies. The current study describes the BCI-FES clinical trial, which examines the safety and efficacy of this system, compared to conventional physical therapy (PT), to improve gait velocity for those with chronic gait impairment post-stroke. The trial also aims to find other secondary factors that may impact or accompany these improvements and establish the potential of Hebbian-based rehabilitation therapies. METHODS: This Phase II clinical trial is a two-arm, randomized, controlled, longitudinal study with 66 stroke participants in the chronic (> 6 months) stage of gait impairment. The participants undergo either BCI-FES paired with PT or dose-matched PT sessions (three times weekly for four weeks). The primary outcome is gait velocity (10-meter walk test), and secondary outcomes include gait endurance, range of motion, strength, sensation, quality of life, and neurophysiological biomarkers. These measures are acquired longitudinally. DISCUSSION: BCI-FES holds promise for gait velocity improvements in stroke patients. This clinical trial will evaluate the safety and efficacy of BCI-FES therapy when compared to dose-matched conventional therapy. The success of this trial will inform the potential utility of a Phase III efficacy trial. TRIAL REGISTRATION: The trial was registered as BCI-FES Therapy for Stroke Rehabilitation on February 19, 2020, at clinicaltrials.gov with the identifier NCT04279067.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p

IntroductionTo determine whether percutaneous tibial nerve stimulation (PTNS) is superior to sham stimulation for the treatment of fecal incontinence (FI) in women refractory to first-line treatments.MethodsWomen aged 18 years or older with ≥3 months of moderate-to-severe FI that persisted after a 4-week run-in phase were randomized 2:1 (PTNS:sham stimulation) to 12 weekly 30-minute sessions in this multicenter, single-masked, controlled superiority trial. The primary outcome was change from baseline FI severity measured by St. Mark score after 12 weeks of treatment (range 0-24; minimal important difference, 3-5 points). The secondary outcomes included electronic bowel diary events and quality of life. The groups were compared using an adjusted general linear mixed model.ResultsOf 199 women who entered the run-in period, 166 (of 170 eligible) were randomized, (111 in PTNS group and 55 in sham group); the mean (SD) age was 63.6 (11.6) years; baseline St. Mark score was 17.4 (2.7); and recording was 6.6 (5.5) FI episodes per week. There was no difference in improvement from baseline in St. Mark scores in the PTNS group when compared with the sham group (-5.3 vs -3.9 points, adjusted difference [95% confidence interval] -1.3 [-2.8 to 0.2]). The groups did not differ in reduction in weekly FI episodes (-2.1 vs -1.9 episodes, adjusted difference [95% confidence interval] -0.26 [-1.85 to 1.33]). Condition-specific quality of life measures did not indicate a benefit of PTNS over sham stimulation. Serious adverse events occurred in 4% of each group.DiscussionAlthough symptom reduction after 12 weeks of PTNS met a threshold of clinical importance, it did not differ from sham stimulation. These data do not support the use of PTNS as conducted for the treatment of FI in women.

Human milk oligosaccharides (HMOs) support the development of a healthy gut microbiome and the growth of infants. We aimed to determine the association of different HMOs with severe acute malnutrition (SAM) among Bangladeshi young infants. This study was nested within a single-blind, randomized, pilot clinical trial (NCT0366657). A total of 45 breastmilk samples from mothers of

BackgroundEarly administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19.MethodsIn this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause.ResultsA total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, -6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups.ConclusionsThe administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767.).

Background & aimsIncreased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce excess liver fat and directly inhibit inflammatory and fibrogenic pathways. We assessed the safety and efficacy of TVB-2640 in patients with nonalcoholic steatohepatitis in the United States.Methods3V2640-CLIN-005 (FASCINATE-1) was a randomized, placebo-controlled, single-blind study at 10 US sites. Adults with ≥8% liver fat, assessed by magnetic resonance imaging proton density fat fraction, and evidence of liver fibrosis by magnetic resonance elastography ≥2.5 kPa or liver biopsy were eligible. Ninety-nine patients were randomized to receive placebo or 25 mg or 50 mg of TVB-2640 (orally, once-daily for 12 weeks). The primary end points of this study were safety and relative change in liver fat after treatment.ResultsLiver fat increased in the placebo cohort by 4.5% relative to baseline; in contrast TVB-2640 reduced liver fat by 9.6% in the 25-mg cohort (n = 30; least squares mean: -15.5%; 95% confidence interval, -31.3 to -0.23; P = .053), and 28.1% in the 50-mg cohort (n = 28; least squares mean: -28.0%; 95% confidence interval, -44.5 to -11.6; P = .001). Eleven percent of patients in the placebo group achieved a ≥30% relative reduction of liver fat compared to 23% in the 25-mg group, and 61% in the 50-mg group (P < .001). Secondary analyses showed improvements of metabolic, pro-inflammatory and fibrotic markers. TVB-2640 was well tolerated; adverse events were mostly mild and balanced among the groups.ConclusionsTVB-2640 significantly reduced liver fat and improved biochemical, inflammatory, and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in patients with nonalcoholic steatohepatitis. ClinicalTrials.gov, Number NCT03938246.

BACKGROUNDThe aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention.METHODSIndividuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3-12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing.RESULTSTwenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses (P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological (P = 0.04) and clinical (P = 0.01) responses.CONCLUSIONTo our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent.TRIAL REGISTRATIONNCT02581137FUNDINGNIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870.

BackgroundIndividualized hemodynamic management during surgery relies on accurate titration of vasopressors and fluids. In this context, computer systems have been developed to assist anesthesia providers in delivering these interventions. This study tested the hypothesis that computer-assisted individualized hemodynamic management could reduce intraoperative hypotension in patients undergoing intermediate- to high-risk surgery.MethodsThis single-center, parallel, two-arm, prospective randomized controlled single blinded superiority study included 38 patients undergoing abdominal or orthopedic surgery. All included patients had a radial arterial catheter inserted after anesthesia induction and connected to an uncalibrated pulse contour monitoring device. In the manually adjusted goal-directed therapy group (N = 19), the individualized hemodynamic management consisted of manual titration of norepinephrine infusion to maintain mean arterial pressure within 10% of the patient's baseline value, and mini-fluid challenges to maximize the stroke volume index. In the computer-assisted group (N = 19), the same approach was applied using a closed-loop system for norepinephrine adjustments and a decision-support system for the infusion of mini-fluid challenges (100 ml). The primary outcome was intraoperative hypotension defined as the percentage of intraoperative case time patients spent with a mean arterial pressure of less than 90% of the patient's baseline value, measured during the preoperative screening. Secondary outcome was the incidence of minor postoperative complications.ResultsAll patients were included in the analysis. Intraoperative hypotension was 1.2% [0.4 to 2.0%] (median [25th to 75th] percentiles) in the computer-assisted group compared to 21.5% [14.5 to 31.8%] in the manually adjusted goal-directed therapy group (difference, -21.1 [95% CI, -15.9 to -27.6%]; P < 0.001). The incidence of minor postoperative complications was not different between groups (42 vs. 58%; P = 0.330). Mean stroke volume index and cardiac index were both significantly higher in the computer-assisted group than in the manually adjusted goal-directed therapy group (P < 0.001).ConclusionsIn patients having intermediate- to high-risk surgery, computer-assisted individualized hemodynamic management significantly reduces intraoperative hypotension compared to a manually controlled goal-directed approach.Editor’s perspective

In a large health system, we evaluated the effectiveness of electronic health record patient portal reminders in increasing pediatric influenza vaccination rates. We conducted an intention-to-treat randomized clinical trial of 22 046 children from 6 months to

BackgroundEarly childhood development (ECD) programmes can help address early disadvantages for the 43% of children younger than 5 years in low-income and middle-income countries who have compromised development. We aimed to test the effectiveness of two group-based delivery models for an integrated ECD responsive stimulation and nutrition education intervention using Kenya's network of community health volunteers.MethodsWe implemented a multi-arm, cluster-randomised community effectiveness trial in three rural subcounties across 60 villages (clusters) in western Kenya. Eligible participants were mothers or female primary caregivers aged 15 years or older with children aged 6-24 months at enrolment. If married or in established relationships, fathers or male caregivers aged 18 years or older were also eligible. Villages were randomly assigned (1:1:1) to one of three groups: group-only delivery with 16 fortnightly sessions; mixed delivery combining 12 group sessions with four home visits; and a comparison group. Villages in the intervention groups were randomly assigned (1:1) to invite or not invite fathers and male caregivers to participate. Households were surveyed at baseline and immediately post-intervention. Assessors were masked. Primary outcomes were child cognitive and language development (score on the Bayley Scales of Infant Development third edition), socioemotional development (score on the Wolke scale), and parental stimulation (Home Observation for Measurement of the Environment inventory). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03548558.FindingsBetween Oct 1 and Nov 12, 2018, 1152 mother-child dyads were enrolled and randomly assigned (n=376 group-only intervention, n=400 mixed-delivery intervention, n=376 comparison group). At the 11-month endline survey (Aug 5-Oct 31, 2019), 1070 households were assessed for the primary outcomes (n=346 group only, n=373 mixed delivery, n=351 comparison). Children in group-only villages had higher cognitive (effect size 0·52 SD [95% CI 0·21-0·83]), receptive language (0·42 SD [0·08-0·77]), and socioemotional scores (0·23 SD [0·03-0·44]) than children in comparison villages at endline. Children in mixed-delivery villages had higher cognitive (0·34 SD [0·05-0·62]) and socioemotional scores (0·22 SD [0·05-0·38]) than children in comparison villages; there was no difference in language scores. Parental stimulation also improved for group-only (0·80 SD [0·49-1·11]) and mixed-delivery villages (0·77 SD [0·49-1·05]) compared with the villages in the comparison group. Including fathers in the intervention had no measurable effect on any of the primary outcomes.InterpretationParenting interventions delivered by trained community health volunteers in mother-child groups can effectively promote child development in low-resource settings and have great potential for scalability.FundingEunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.

BackgroundThe responsibility and stress of being a family caregiver are associated with reduced physical and mental health.PurposeTo examine whether a 24-week aerobic exercise program improves multiple aspects of psychological functioning in family caregivers.MethodsFamily caregivers of patients with Alzheimer's disease and other dementias (n = 68) were recruited and randomized into either an aerobic exercise group (n = 34) or a waitlist control group (n = 34). The exercise group was assigned a 24-week aerobic training program that incrementally increased the intensity, duration, and frequency of the exercise program until 150 min of moderate to vigorous activity were completed per week by the ninth week. Twelve measures of psychological functioning were administered at baseline and compared with responses completed following the intervention.ResultsMultilevel modeling revealed significant decreases in caregiver burden (β = -4.60, 95% confidence interval [CI] = [-8.82, -0.38], RLMM2 = 0.11) and depression (β = -2.59, 95% CI = [-4.79, -0.38], RLMM2 = 0.13), as well as increases in mastery (β = 1.78, 95% CI = [0.09, 3.46], RLMM2 = .04) in the exercise intervention group compared to the control group.ConclusionFamily caregivers report high levels of depression and caregiver burden. Engagement in a 24-week exercise intervention can ameliorate the perceived burden of caregiving, symptoms of depression, and their sense of mastery.

PurposeThe objectives of this study were to evaluate the feasibility and efficacy of fractional CO2 laser therapy in gynecologic cancer survivors.MethodsThis was a pilot, multi-institutional randomized sham-controlled trial of women with gynecologic cancers with dyspareunia and/or vaginal dryness. Participants were randomized to fractional CO2 laser treatment or sham laser treatment. The primary aim was to estimate the proportion of patients who had improvement in symptoms based on the Vaginal Assessment Scale (VAS). Secondary aims included changes in sexual function assessed using the Female Sexual Functioning Index (FSFI) and urinary symptoms assessed using the the Urinary Distress Inventory (UDI-6).ResultsEighteen women participated in the study, ten in the treatment arm and eight in the sham arm. The majority of participants had stage I (n = 11, 61.1 %) or II (n = 3, 16.7 %) endometrial cancer with adenocarcinoma histology (n = 9, 50 %). In total, 15 (83.3 %) of the participants completed all treatments and follow-up visit. There was no difference in the change in the median VAS score from baseline to follow-up. However, there was an improvement in change in the median total FSFI score with treatment compared with sham (Δ 6.5 vs -0.3, p = 0.02). The change in the median UDI-6 score was lower in the treatment arm (Δ -14.6 vs -2.1, p = 0.17), but this was not statistically significant. There were no reported serious adverse events.ConclusionsFractional CO2 laser therapy is feasible in gynecologic cancer survivors, with preliminary evidence of safety. In addition, there was preliminary evidence of improvement in sexual function compared with sham treatment. Clinicaltrial.gov Identifier: NCT03372720 (OSU-17261; NCI-2017-02051).

ObjectivesWe aimed to compare the efficacy of 2 commonly used contemporary vaginal estrogen administrations versus placebo for the prevention of urinary tract infection (UTI) in postmenopausal women with a clinical diagnosis of recurrent UTI (rUTI).MethodsThis was an investigator-initiated, multicenter, single-blind, randomized, placebo-controlled trial of vaginal estrogen (delivered via ring or cream) compared with placebo. Postmenopausal women with documented rUTI were randomized to receive either vaginal estrogen (via ring or cream) or placebo cream in a 1:1:1 fashion. The primary outcome was occurrence of UTI at 6 months. After 6 months, open-label use of ring or active cream was offered to all participants for an additional 6 months. Because of slower than expected recruitment, sample size calculations and block randomization schema were revised to combine estrogen groups (ring or cream) for statistical comparisons to placebo cream in a 1:1 fashion.ResultsThirty-five women were randomized with 9 dropouts (1 ring, 2 cream, and 6 placebo) prior to the 6 months. Intention-to-treat analysis (assuming dropouts as failures) revealed fewer women treated with vaginal estrogen had a UTI within 6 months versus placebo (11/18 vs 16/17, respectively; P = 0.041). Per-protocol analysis revealed fewer subjects treated with vaginal estrogen had a UTI at 6 months (8/15 vs 10/11, respectively; P = 0.036).ConclusionsCommonly prescribed forms of vaginal estrogen with contemporary dosing schedules prevent UTIs in postmenopausal women with an active diagnosis of rUTI.

BackgroundThe number of people living with stroke has increased demand for rehabilitation. A potential solution is telerehabilitation for health care delivery to promote self-management. One such approach is the Augmented Community Telerehabilitation Intervention (ACTIV). This structured 6-month program uses limited face-to-face sessions, telephone contact, and text messages to augment stroke rehabilitation.ObjectiveTo investigate whether ACTIV improved physical function compared with usual care.MethodsThis 2-arm, parallel randomized controlled trial was conducted in 4 New Zealand centers. Inclusion criteria were patients with first-ever stroke, age >20 years, and discharged home. A blinded assessor completed outcome measurement in participants' homes at baseline, postintervention, and 6 months postintervention. Stratified block randomization occurred after baseline assessment, with participants allocated to ACTIV or usual care control.ResultsA total of 95 people were recruited (ACTIV: n = 47; control: n = 48). Postintervention intention-to-treat analysis found a nonsignificant difference between the groups in scores (4·51; P = .07) for physical function (measured by the physical subcomponent of the Stroke Impact Scale). The planned per-protocol analysis (ACTIV: n = 43; control: n = 48) found a significant difference in physical function between the groups (5·28; P = .04). Improvements in physical function were not maintained at the 12-month follow-up.ConclusionsACTIV was not effective in improving physical function in the ACTIV group compared with the usual care group. The per-protocol analysis raises the possibility that for those who receive more than 50% of the intervention, ACTIV may be effective in preventing deterioration or even improving physical function in people with stroke, in the period immediately following discharge from hospital.

Electrophysiological studies show that nicotine enhances neural responses to characteristic frequency stimuli. Previous behavioral studies partially corroborate these findings in young adults, showing that nicotine selectively enhances auditory processing in difficult listening conditions. The present work extended previous work to include both young and older adults and assessed the nicotine effect on sound frequency and intensity discrimination. Hypotheses were that nicotine improves auditory performance and that the degree of improvement is inversely proportional to baseline performance. Young (19-23 years old) normal-hearing nonsmokers and elderly (61-80) nonsmokers with normal hearing between 500 and 2000 Hz received nicotine gum (6 mg) or placebo gum in a single-blind, randomized crossover design. Participants performed three experiments (frequency discrimination, frequency modulation identification, and intensity discrimination) before and after treatment. The perceptual differences were analyzed between pre- and post-treatment, as well as between post-treatment nicotine and placebo conditions as a function of pre-treatment baseline performance. Compared to pre-treatment performance, nicotine significantly improved frequency discrimination. Compared to placebo, nicotine significantly improved performance for intensity discrimination, and the improvement was more pronounced in the elderly with lower baseline performance. Nicotine had no effect on frequency modulation identification. Nicotine effects are task-dependent, reflecting possible interplays of subjects, tasks and neural mechanisms.

ObjectiveThe goal of this study was to investigate the effect of progranulin insufficiency on extracellular vesicles (EVs), a heterogeneous population of vesicles that may contribute to progression of neurodegenerative disease. Loss-of-function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD), and brains from GRN carriers with FTD (FTD-GRN) exhibit signs of lysosomal dysfunction. Lysosomal dysfunction may induce compensatory increases in secretion of exosomes, EVs secreted from the endolysosomal system, so we hypothesized that progranulin insufficiency would increase EV levels in the brain.MethodsWe analyzed levels and protein contents of brain EVs from Grn-/- mice, which model the lysosomal abnormalities of FTD-GRN patients. We then measured brain EVs in FTD-GRN patients. To assess the relationship of EVs with symptomatic disease, we measured plasma EVs in presymptomatic and symptomatic GRN mutation carriers.ResultsGrn-/- mice had elevated brain EV levels and altered EV protein contents relative to wild-type mice. These changes were age-dependent, occurring only after the emergence of pathology in Grn-/- mice. FTD-GRN patients (n = 13) had elevated brain EV levels relative to controls (n = 5). Symptomatic (n = 12), but not presymptomatic (n = 7), GRN carriers had elevated plasma EV levels relative to controls (n = 8).InterpretationThese data show that symptomatic FTD-GRN patients have elevated levels of brain and plasma EVs, and that this effect is modeled in the brain of Grn-/- mice after the onset of pathology. This increase in EVs could influence FTD disease progression, and provides further support for EVs as potential FTD biomarkers.

ObjectiveTo examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG).MethodsThis study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups.ResultsPatients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone.ConclusionsThymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone.Clinicaltrialsgov identifierNCT00294658.Classification of evidenceThis study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

To determine whether concurrent posttraumatic stress disorder (PTSD) should affect whether to augment or switch medications when major depressive disorder (MDD) has not responded to a prior antidepressant trial. Patients at 35 Veterans Health Administration medical centers from December 2012 to May 2015 with nonpsychotic MDD (N = 1,522) and a suboptimal response to adequate antidepressant treatment were randomly assigned to 3 "next step" treatments: switching to bupropion, augmenting the current antidepressant with bupropion, and augmenting with the antipsychotic aripiprazole. Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C₁₆) determined remission and response by 12 weeks and relapse after remission. Survival analyses compared treatment effects in patients with concurrent PTSD diagnosed with the Mini-International Neuropsychiatric Interview (n = 717, 47.1%) and those without PTSD (n = 805, 52.9%). Patients diagnosed with PTSD showed more severe depressive symptoms at baseline and were less likely to achieve either remission or response by 12 weeks. Augmentation with aripiprazole was associated with greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (relative risk [RR] = 1.26; 95% CI, 1.01-1.59) as well as in patients without PTSD (RR = 1.29; 95% CI, 1.05-1.97) (78.9% response with aripiprazole augmentation vs 66.9% with switching to bupropion). Treatment comparisons with the group receiving augmentation with bupropion were not significant. There was no significant interaction between treatment group and PTSD on remission (P = .70), response (P = .98), or relapse (P = .15). Although PTSD was associated with poorer overall outcomes, the presence of concurrent PTSD among Veterans in this trial did not affect the comparative effectiveness of medications on response, remission, or relapse after initial remission. ClinicalTrials.gov identifier: NCT01421342.

RATIONALE: Electrophysiological studies show that systemic nicotine narrows frequency receptive fields and increases gain in neural responses to characteristic frequency stimuli. We postulated that nicotine enhances related auditory processing in humans. OBJECTIVES: The main hypothesis was that nicotine improves auditory performance. A secondary hypothesis was that the degree of nicotine-induced improvement depends on the individuals baseline performance. METHODS: Young (18-27 years old), normal-hearing nonsmokers received nicotine (Nicorette gum, 6mg) or placebo gum in a single-blind, randomized, crossover design. Subjects performed four experiments involving tone-in-noise detection, temporal gap detection, spectral ripple discrimination, and selective auditory attention before and after treatment. The perceptual differences between posttreatment nicotine and placebo conditions were measured and analyzed as a function of the pre-treatment baseline performance. RESULTS: Nicotine significantly improved performance in the more difficult tasks of tone-in-noise detection and selective attention (effect size = - 0.3) but had no effect on relatively easier tasks of temporal gap detection and spectral ripple discrimination. The two tasks showing significant nicotine effects further showed no baseline-dependent improvement. CONCLUSIONS: Nicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation.

Background and objectivePatients with chronic respiratory failure are increasingly managed with domiciliary non-invasive ventilation (NIV). There may be limited ability to provide NIV titration for these complex patients, and ventilatory requirements and upper airway support needs may change over time. Therefore, an automatically adjusting expiratory positive airway pressure (AutoEPAP) algorithm may offer advantages over manually adjusted EPAP for treating these patients. This study compared 4% oxygen desaturation index (ODI4%) values during the use of an AutoEPAP algorithm versus manual EPAP titration with the intelligent volume-assured pressure support (iVAPS) algorithm.MethodsThis prospective, single-blind, randomized, crossover study was conducted at six US sites. Patients with chronic respiratory failure (neuromuscular disease, chronic obstructive pulmonary disease, obesity hypoventilation and other aetiologies) and an apnoea-hypopnoea index of >5/h who were already established NIV users underwent a single night of NIV with the iVAPS manual EPAP and iVAPS AutoEPAP in the sleep laboratory in random order.ResultsA total of 38 patients constituted the study population. Mean ODI4% was statistically non-inferior with AutoEPAP versus manual EPAP (P < 0.0001). There was no difference in the effect on ODI4% across respiratory failure subgroups. Ventilation parameters and gas exchange were similar with either NIV mode, indicating equally effective treatment of respiratory failure. Sleep parameters were improved during AutoEPAP versus manual EPAP.ConclusionA single night of NIV using the iVAPS with AutoEPAP algorithm was non-inferior to a single night of iVAPS with manual EPAP titration in patients with respiratory failure.Clinical trial registrationNCT02683772 at clinicaltrials.gov.

BackgroundVisible light (400 to 700 nm) is common in our environment, comprising 44% of total solar radiation and a large component of environmental light exposure. The effects of visible light on skin remain undefined. The red light portion of the visible spectrum (600 to 700 nm) may be used to treat skin diseases as a monotherapeutic modality or in combination with other agents. Light-emitting diode-red light (LED-RL) phototherapy may represent an important advance in light-based treatment modalities because it is non-invasive, inexpensive, portable, and easily combinable with other therapies. We previously determined the maximum tolerated dose (MTD) of high-fluence LED-RL (HF-LED-RL) in skin of color individuals to be 320 J/cm2. To the best of our knowledge, no clinical trials have been performed to determine the safety of higher doses of HF-LED-RL in Caucasian non-Hispanic individuals. The aim of this study is to investigate the safety of HF-LED-RL at doses of 480 and 640 J/cm2 in healthy Caucasian non-Hispanic individuals.MethodsThis is a single-blind, dose-escalation, randomized, controlled, phase I trial titled Safety Trial Assessing Red-light on Skin (STARS) 2. Healthy subjects will be randomly assigned to groups of five (three subjects randomly assigned to HF-LED-RL phototherapy and two subjects randomly assigned to mock therapy). Subjects in group 1 will receive HF-LED-RL or mock irradiation at the starting dose of 480 J/cm2, and the dose will be escalated in the subsequent group (group 2) to 640 J/cm2. The MTD is defined as the dose level below the dose at which two or more subjects (>20% of the cohort) experience a dose-limiting toxicity (DLT). After either the MTD is established or the study endpoint of 640 J/cm2 is achieved, additional HF-LED-RL phototherapy subjects and mock therapy subjects will be enrolled at that fluence (group 3) for a total number of up to 60 subjects. Each subject will receive a total of nine irradiation sessions, three times per week for three consecutive weeks.DiscussionThis follow-up study aims to provide important knowledge about safety and cutaneous effects of HF-LED-RL phototherapy of 480 and 640 J/cm2 in Caucasian non-Hispanic subjects. The importance of this clinical trial is that it may establish new treatment paradigms and a safety profile for LED-RL based on race and ethnicity.Trial registrationClinicalTrials.gov Identifier: NCT03433222 . Registered on February 1, 2018 - Retrospectively registered. Protocol date and version: January 12, 2018; version 1.

BackgroundUp to 75% of inpatients with mental disorders smoke, and their life expectancy is decreased by up to 25 years compared to the general population. Hospitalized patients without monitoring after discharge quickly return to prehospitalization levels of tobacco use. The aim of the 061 QuitMental study is to assess the effectiveness of a multicomponent and motivational telephone-based intervention to stop smoking through a quitline addressed to smokers discharged from mental health hospital wards.MethodsA pragmatic randomized controlled trial, single blinded, will include 2:1 allocation to the intervention group (IG) and the control group (CG). The IG will receive telephone assistance to quit smoking (including psychological and psychoeducational support, and pharmacological treatment advice if required) proactively for 12 months, and the CG will receive only brief advice after discharge. The sample size, calculated with an expected difference of 15 points on smoking abstinence between groups (IG, 20% and CG, 5%), α = 0.05, β = 0.10, and 20% loss, will be 334 participants (IG) and 176 participants (CG). Participants are adult smokers discharged from psychiatric units of five acute hospitals. Measurements include dependent variables (self-reported 7-day point prevalence smoking abstinence (carbon monoxide verified), duration of abstinence, number of quit attempts, motivation, and self-efficacy to quit) and independent variables (age, sex, and psychiatric diagnoses). In data analysis, IG and CG data will be compared at 48 h and 1, 6, and 12 months post discharge. Multivariate logistic regression (odds ratio; 95% confidence interval) of dependent variables adjusted for potential confounding variables will be performed. The number needed to treat to achieve one abstinence outcome will be calculated. We will compare the abstinence rate of enrolled patients between groups.DiscussionThis trial evaluates an innovative format of a quitline for smokers with severe mental disorders regardless of their motivation to quit. If effective, the pragmatic nature of the study will permit transfer to routine clinical practice in the National Health System.Trial registrationClinicalTrials.gov, NCT03230955 . Registered on 24 July 2017.

ImportanceFew health systems have adopted effective dementia care management programs. The Care Ecosystem is a model for delivering care from centralized hubs across broad geographic areas to caregivers and persons with dementia (PWDs) independently of their health system affiliations.ObjectiveTo determine whether the Care Ecosystem is effective in improving outcomes important to PWDs, their caregivers, and payers beyond those achieved with usual care.Design, setting, and participantsA single-blind, randomized clinical trial with a pragmatic design was conducted among PWDs and their caregivers. Each PWD-caregiver dyad was enrolled for 12 months between March 20, 2015, and February 28, 2017. Data were collected until March 5, 2018. Study interventions and assessments were administered over the telephone and internet by clinical and research teams in San Francisco, California, and Omaha, Nebraska. Of 2585 referred or volunteer PWD-caregiver dyads in California, Iowa, or Nebraska, 780 met eligibility criteria and were enrolled. A total of 512 PWD-caregiver dyads were randomized to receive care through the Care Ecosystem and 268 dyads to receive usual care. All eligible PWDs had a dementia diagnosis; were enrolled or eligible for enrollment in Medicare or Medicaid; and spoke English, Spanish, or Cantonese. Analyses were intention-to-treat.InterventionTelephone-based collaborative dementia care was delivered by a trained care team navigator, who provided education, support and care coordination with a team of dementia specialists (advanced practice nurse, social worker, and pharmacist).Main outcomes and measuresPrimary outcome measure: Quality of Life in Alzheimer's Disease based on caregiver's rating of 13 aspects of PWD's well-being (including physical health, energy level, mood, living situation, memory, relationships, and finances) on a 4-point scale (poor to excellent). Secondary outcomes: frequencies of PWDs' use of emergency department, hospitalization, and ambulance services; caregiver depression (score on 9-Item Patient Health Questionnaire; higher scores indicate more severe depression); and caregiver burden (score on 12-Item Zarit Burden Interview; higher scores indicate more severe caregiver burden).ResultsThe 780 PWDs (56.3% female; mean [SD] age, 78.1 [9.9] years) and 780 caregivers (70.9% female; mean [SD] age, 64.7 [12.0] years) lived in California (n = 452), Nebraska (n = 284), or Iowa (n = 44). Of 780 dyads, 655 were still active at 12 months, and 571 completed the 12-month survey. Compared with usual care, the Care Ecosystem improved PWD quality of life (B, 0.53; 95% CI, 0.25-1.30; P = .04), reduced emergency department visits (B, -0.14; 95% CI, -0.29 to -0.01; P = .04), and decreased caregiver depression (B, -1.14; 95% CI, -2.15 to -0.13; P = .03) and caregiver burden (B, -1.90; 95% CI, -3.89 to -0.08; P = .046).Conclusions and relevanceEffective care management for dementia can be delivered from centralized hubs to supplement usual care and mitigate the growing societal and economic burdens of dementia.Trial registrationClinicalTrials.gov identifier: NCT02213458.

Most data analyses rely on models. To complement statistical models, psychologists have developed cognitive models, which translate observed variables into psychologically interesting constructs. Response time models, in particular, assume that response time and accuracy are the observed expression of latent variables including 1) ease of processing, 2) response caution, 3) response bias, and 4) non-decision time. Inferences about these psychological factors, hinge upon the validity of the models' parameters. Here, we use a blinded, collaborative approach to assess the validity of such model-based inferences. Seventeen teams of researchers analyzed the same 14 data sets. In each of these two-condition data sets, we manipulated properties of participants' behavior in a two-alternative forced choice task. The contributing teams were blind to the manipulations, and had to infer what aspect of behavior was changed using their method of choice. The contributors chose to employ a variety of models, estimation methods, and inference procedures. Our results show that, although conclusions were similar across different methods, these "modeler's degrees of freedom" did affect their inferences. Interestingly, many of the simpler approaches yielded as robust and accurate inferences as the more complex methods. We recommend that, in general, cognitive models become a typical analysis tool for response time data. In particular, we argue that the simpler models and procedures are sufficient for standard experimental designs. We finish by outlining situations in which more complicated models and methods may be necessary, and discuss potential pitfalls when interpreting the output from response time models.

ObjectiveThe main objective of this study was to evaluate the accuracy of emergency physician-performed point-of-care ultrasound (POCUS) for the diagnosis of small-bowel obstruction (SBO) compared to computed tomography (CT).MethodsWe performed a prospective, multicenter, observational study examining a convenience sample of adult patients with potential SBO presenting to the emergency department (ED) between July 2014 and May 2017. Each POCUS was interpreted at the bedside by the performing emergency physician and retrospectively by an expert reviewer. Test characteristics were calculated for POCUS, blinded expert interpretation, and specific POCUS parameters.ResultsA total of 217 subjects were included in the primary analysis with an overall SBO prevalence of 42.9%. For the diagnosis of SBO, POCUS demonstrated an overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 0.88 (95% confidence interval [CI] = 0.80 to 0.94), 0.54 (95% CI = 0.45 to 0.63), 1.92 (95% CI = 1.56 to 2.35), and 0.22 (95% CI = 0.12 to 0.39), respectively. Expert review yielded a similar sensitivity (0.89 [95% CI = 0.81 to 0.95]) with a significantly higher specificity (0.82 [95% CI = 0.74 to 0.88]). The more sensitive sonographic parameters for both POC sonographers and expert reviewers were small-bowel dilation ≥ 25 mm (0.87 [95% CI = 0.79 to 0.93], 0.87 [95% CI = 0.79 to 0.93]) and abnormal peristalsis (0.82 [95% CI = 0.72 to 0.89], 0.85 [95% CI = 0.76 to 0.87]). The more specific parameters for both groups were transition point (0.82 [95% CI = 0.74 to 0.89], 0.98 [95% CI = 0.94 to 1.00]), intraperitoneal free fluid (0.82 [95% CI = 0.74 to 0.89], 0.93 [95% CI = 0.87 to 0.97]), and bowel wall edema (0.76 [95% CI = 0.67 to 0.83], 0.93 [95% CI = 0.87 to 0.97]).ConclusionPOCUS is moderately sensitive for SBO, although less specific, when performed by a diverse group of emergency physicians across multiple EDs. Interpretation of acquired POCUS images is significantly more accurate when performed by physicians with prior emergency ultrasound fellowship training and familiarity with the sonographic appearance of SBO.

BackgroundUse of oral live-attenuated polio vaccines (OPV), and injected inactivated polio vaccines (IPV) has almost achieved global eradication of wild polio viruses. To address the goals of achieving and maintaining global eradication and minimising the risk of outbreaks of vaccine-derived polioviruses, we tested novel monovalent oral type-2 poliovirus (OPV2) vaccine candidates that are genetically more stable than existing OPVs, with a lower risk of reversion to neurovirulence. Our study represents the first in-human testing of these two novel OPV2 candidates. We aimed to evaluate the safety and immunogenicity of these vaccines, the presence and extent of faecal shedding, and the neurovirulence of shed virus.MethodsIn this double-blind, single-centre phase 1 trial, we isolated participants in a purpose-built containment facility at the University of Antwerp Hospital (Antwerp, Belgium), to minimise the risk of environmental release of the novel OPV2 candidates. Participants, who were recruited by local advertising, were adults (aged 18-50 years) in good health who had previously been vaccinated with IPV, and who would not have any contact with immunosuppressed or unvaccinated people for the duration of faecal shedding at the end of the study. The first participant randomly chose an envelope containing the name of a vaccine candidate, and this determined their allocation; the next 14 participants to be enrolled in the study were sequentially allocated to this group and received the same vaccine. The subsequent 15 participants enrolled after this group were allocated to receive the other vaccine. Participants and the study staff were masked to vaccine groups until the end of the study period. Participants each received a single dose of one vaccine candidate (candidate 1, S2/cre5/S15domV/rec1/hifi3; or candidate 2, S2/S15domV/CpG40), and they were monitored for adverse events, immune responses, and faecal shedding of the vaccine virus for 28 days. Shed virus isolates were tested for the genetic stability of attenuation. The primary outcomes were the incidence and type of serious and severe adverse events, the proportion of participants showing viral shedding in their stools, the time to cessation of viral shedding, the cell culture infective dose of shed virus in virus-positive stools, and a combined index of the prevalence, duration, and quantity of viral shedding in all participants. This study is registered with EudraCT, number 2017-000908-21 and ClinicalTrials.gov, number NCT03430349.FindingsBetween May 22 and Aug 22, 2017, 48 volunteers were screened, of whom 15 (31%) volunteers were excluded for reasons relating to the inclusion or exclusion criteria, three (6%) volunteers were not treated because of restrictions to the number of participants in each group, and 30 (63%) volunteers were sequentially allocated to groups (15 participants per group). Both novel OPV2 candidates were immunogenic and increased the median blood titre of serum neutralising antibodies; all participants were seroprotected after vaccination. Both candidates had acceptable tolerability, and no serious adverse events occurred during the study. However, severe events were reported in six (40%) participants receiving candidate 1 (eight events) and nine (60%) participants receiving candidate 2 (12 events); most of these events were increased blood creatinine phosphokinase but were not accompanied by clinical signs or symptoms. Vaccine virus was detected in the stools of 15 (100%) participants receiving vaccine candidate 1 and 13 (87%) participants receiving vaccine candidate 2. Vaccine poliovirus shedding stopped at a median of 23 days (IQR 15-36) after candidate 1 administration and 12 days (1-23) after candidate 2 administration. Total shedding, described by the estimated median shedding index (50% cell culture infective dose/g), was observed to be greater with candidate 1 than candidate 2 across all participants (2·8 [95% CI 1·8-3·5] vs 1·0 [0·7-1·6]). Reversion to neurovirulence, assessed as paralysis of transgenic mice, was low in isolates from those vaccinated with both candidates, and sequencing of shed virus indicated that there was no loss of attenuation in domain V of the 5'-untranslated region, the primary site of reversion in Sabin OPV.InterpretationWe found that the novel OPV2 candidates were safe and immunogenic in IPV-immunised adults, and our data support the further development of these vaccines to potentially be used for maintaining global eradication of neurovirulent type-2 polioviruses.FundingBill & Melinda Gates Foundation.

ObjectivesIntracranial pressure over 20 mm Hg is associated with poor neurologic prognosis, but measuring intracranial pressure directly requires an invasive procedure. Dilation of the optic nerve sheath on axial ultrasound of the eye has been correlated with elevated intracranial pressure, but optimal cutoffs have been inconsistent possibly related to the measurement technique. A coronal technique has been studied on healthy volunteers but not on patients with high intracranial pressure. We compared two measurement techniques (axial and coronal) in patients with suspected high intracranial pressure due to trauma, bleeding, tumor, or infection.DesignProspective blinded observational study.SettingTwo tertiary referral center ICUs.PatientsTwenty adults admitted to the ICU at risk for increased intracranial pressure expected to receive invasive intracranial monitoring.InterventionsUltrasound measurements of the optic nerve sheath in axial and coronal views either averaged between eyes or the highest in either eye.Measurements and main resultsCoronal measurements showed less variability between each eye than axial measurements (mean difference 0.5 mm vs 1 mm; p = 0.03) and were associated with high intracranial pressure at first measurement and over 24 hours (area under the receiver operating characteristic range 0.7-0.8). Mean and highest axial measurements showed improved association with first (area under the receiver operating characteristic 0.87-0.94) and highest intracranial pressure measurement (area under the receiver operating characteristic 0.89-0.96) within 24 hours. A cutoff of highest axial measurement in either eye greater than 6.2 mm or mean axial measurement between eyes of 5.6 mm had a sensitivity of 100% in predicting high intracranial pressure over the following 24 hours.ConclusionsThe highest axial measurement of optic nerve sheath diameter in either eye is the most predictive of patients with high intracranial pressure in our population. This comparison of measurement techniques has not previously been described and should be further explored to set test cutoffs for ultrasound of the optic nerve sheath diameter.

PurposeTo test the effects of an encapsulated cell-based delivery of a neuroprotective agent, ciliary neurotrophic factor (CNTF), on progression of macular telangiectasia type 2, a neurodegenerative disease with no proven effective therapy.DesignRandomized sham-controlled clinical trial.ParticipantsNinety-nine study eyes of 67 eligible participants were enrolled.MethodsSingle-masked randomized clinical trial of 24 months' duration conducted from May 2014 through April 2017 in 11 clinical centers of retinal specialists in the United States and Australia. Participants were randomized 1:1 to surgical implantation of intravitreal sustained delivery of human CNTF versus a sham procedure.Main outcome measuresThe primary outcome was the difference in the area of neurodegeneration as measured in the area of the ellipsoid zone disruption (or photoreceptor loss) measured on spectral-domain (SD) OCT images at 24 months from baseline between the treated and untreated groups. Secondary outcomes included comparison of visual function changes between treatment groups.ResultsAmong the 67 participants who were randomized (mean age, 62±8.9 years; 41 women [61%]; 58 white persons [86%]), 65 (97%) completed the study. Two participants (3 study eyes) died and 3 participants (4 eyes) were found ineligible. The eyes receiving sham treatment had 31% greater progression of neurodegeneration than the CNTF-treated eyes. The difference in mean area of photoreceptor loss was 0.05±0.03 mm2 (P = 0.04) at 24 months. Retinal sensitivity changes, measured using microperimetry, were correlated highly with the changes in the area of photoreceptor loss (r = 0.86; P < 0.0001). The mean retinal sensitivity loss of the sham group was 45% greater than that of the treated group (decrease, 15.81±8.93 dB; P = 0.07). Reading speed deteriorated in the sham group (-13.9 words per minute) with no loss in the treated group (P = 0.02). Serious adverse ocular effects were found in 2 of 51 persons (4%) in the sham group and 2 of 48 persons (4%) in the treated group.ConclusionsIn participants with macular telangiectasia type 2, a surgical implant that released CNTF into the vitreous cavity, compared with a sham procedure, slowed the progression of retinal degeneration. Further research is needed to assess longer-term clinical outcomes and safety.

BackgroundThe notion of obesity as an addictive process is controversial. However, studies show that between 5.9 and 30.7% of adolescents with obesity report food or eating addiction. Few weight management interventions have tested techniques based on addiction medicine principles.MethodsThis multi-center randomized control trial (RCT) is designed to test the effectiveness of a mobile health (mHealth) weight-loss intervention based on addiction principles, such as withdrawal and tolerance, in a sample of 180 adolescents (ages 14-18) recruited from four pediatric weight management clinics in Southern California. Akin to a Multiphase Optimization Strategy (MOST) design evaluating multicomponent behavioral interventions, we will compare the combination of an app + phone coaching (App+Coach) to app alone (App) and in-clinic multi-disciplinary (Clinic) intervention arms. The primary outcome is mean change in zBMI and %BMIp95 over 18 months. We hypothesize that youth who receive App+Coach will have a greater reduction in body weight over the 18-month study period at a lower cost than standard of care models. Secondary outcomes include adherence to treatment regimen, intervention satisfaction, effect of the intervention on metabolic factors and activity level. We will also explore potential moderators of intervention effectiveness such as addictive eating habits, self-regulation and executive functioning.ConclusionsNew and creative approaches are needed to address pediatric obesity. If successful, this RCT may provide an innovative and cost-effective mHealth approach, based on addiction methods, for weight loss among adolescents with overweight and obesity.

ObjectiveTo compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given.Study designA total of 202 neonates of

Veterans seeking care in VA medical facilities have high rates of chronic pain, which often co-occur with mental health and substance use disorders, including prescription opioid misuse. The overall goal of the Optimizing Pain Treatment Interventions (OPTI) study was to pilot a 12-week Collaborative Care intervention to improve opioid safety, chronic pain disability, and use of non-pharmacological pain management strategies in veterans in VA primary care. Between November 2014 and January 2017, 100 veteran patients with chronic pain and high-risk prescription opioid use (e.g., high-dose therapy, early refills, etc.) were enrolled and completed an initial one-hour study visit with a primary care provider (PCP) within 4 weeks of enrollment. Study PCPs were guided by a web-based opioid management decision support program and templated notes in the VA electronic medical record. After assessment and education, study PCPs used Shared Decision-Making to formulate a Pain Care Plan aligned with a participant's personal values and goals. After the initial visit, patients randomized to Collaborative Care received one Motivational Interviewing (MI) session with a Care Manager followed by 3 Care Manager-delivered brief telephone MI sessions at 6, 8, and 12 weeks to reinforce Pain Care Plans; patients randomized to an Attention Control condition met with a Care Manager briefly, followed by 3 brief scripted telephone psychoeducation sessions at 6, 8, and 12 weeks. Masked evaluators assessed outcomes at baseline, end of intervention (12 weeks), and after eight weeks of no contact (20 weeks). We present study rationale, detailed methods, preliminary results and lessons learned.

Although effective in controlling malaria, indoor residual spraying results in elevated exposure to insecticides such as dichlorodiphenyltrichloroethane (DDT) and pyrethroids. These chemicals cross the placenta, but no studies have examined their associations with birth outcomes in populations residing in indoor residual spraying areas. We investigated this question in the Venda Health Examination of Mothers, Babies and Their Environment (VHEMBE), a birth cohort study of 751 South African children born between 2012 and 2013. We measured maternal peripartum serum DDT and urine pyrethroid metabolite concentrations and collected data on birth weight, length, head circumference, and duration of gestation. We analyzed the data using marginal structural models with inverse-probability-of-treatment weights, generalized propensity scores, and standard conditional linear regression. Using all 3 analytical methods, p,p'-DDT, o,p'-DDT, and to a lesser extent p,p'-dichlorodiphenyldichloroethylene were related to elevated birth weight, birth length, and head circumference among girls. Changes in gestational duration did not mediate this relationship, suggesting that these exposures accelerate fetal growth, which is consistent with the known estrogenic properties of o,p'-DDT and p,p'-DDT. No associations with pyrethroid metabolites were found. Results suggest that prenatal exposure to DDT is related to elevated birth size. Further studies are needed to elucidate the implications of these findings.

This article describes the protocol for the Systematic Multi-domain Alzheimer's Risk Reduction Trial (SMARRT), a single-blind randomized pilot trial to test a personalized, pragmatic, multi-domain Alzheimer's disease (AD) risk reduction intervention in a US integrated healthcare delivery system. Study participants will be 200 higher-risk older adults (age 70-89 years with subjective cognitive complaints, low normal performance on cognitive screen, and ≥ two modifiable risk factors targeted by our intervention) who will be recruited from selected primary care clinics of Kaiser Permanente Washington, oversampling people with non-white race or Hispanic ethnicity. Study participants will be randomly assigned to a two-year Alzheimer's risk reduction intervention (SMARRT) or a Health Education (HE) control. Randomization will be stratified by clinic, race/ethnicity (non-Hispanic white versus non-white or Hispanic), and age (70-79, 80-89). Participants randomized to the SMARRT group will work with a behavioral coach and nurse to develop a personalized plan related to their risk factors (poorly controlled hypertension, diabetes with evidence of hyper or hypoglycemia, depressive symptoms, poor sleep quality, contraindicated medications, physical inactivity, low cognitive stimulation, social isolation, poor diet, smoking). Participants in the HE control group will be mailed general health education information about these risk factors for AD. The primary outcome is two-year cognitive change on a cognitive test composite score. Secondary outcomes include: 1) improvement in targeted risk factors, 2) individual cognitive domain composite scores, 3) physical performance, 4) functional ability, 5) quality of life, and 6) incidence of mild cognitive impairment, AD, and dementia. Primary and secondary outcomes will be assessed in both groups at baseline and 6, 12, 18, and 24 months.

ObjectiveThe aim of the study was to examine whether anxiety and depressive symptoms are associated with an adverse cardiac autonomic profile among midlife women with hot flashes.MethodsAnxiety and depressive symptoms were evaluated by validated self-administered questionnaires among peri- and postmenopausal women in a randomized trial of slow-paced respiration for hot flashes. Pre-ejection period (PEP), a marker of sympathetic activation, and respiratory sinus arrhythmia (RSA), a marker of parasympathetic activation, were measured at baseline and 12 weeks using impedance cardiography and electocardiography. Multivariable repeated measures linear regression models examined associations between anxiety and depression symptoms and autonomic markers, corrected for multiple comparisons with Benjamini-Hochberg procedure, and adjusted for age and body mass index.ResultsAmong the 121 participants, greater state anxiety was associated with shorter PEP, reflecting higher sympathetic activity (β = -0.24, P = 0.02). Greater trait anxiety and cognitive anxiety were associated with lower RSA, reflecting decreased parasympathetic activity (β = -0.03, P

BackgroundAlthough Dialectical Behaviour Therapy (DBT) is an evidence-based psychosocial treatment for borderline personality disorder (BPD), the demand for it exceeds available resources. The commonly researched 12-month version of DBT is lengthy; this can pose a barrier to its adoption in many health care settings. Further, there are no data on the optimal length of psychotherapy for BPD. The aim of this study is to examine the clinical and cost-effectiveness of 6 versus 12 months of DBT for chronically suicidal individuals with BPD. A second aim of this study is to determine which patients are as likely to benefit from shorter treatment as from longer treatment.Methods/designPowered for non-inferiority testing, this two-site single-blind trial involves the random assignment of 240 patients diagnosed with BPD to 6 or 12 months of standard DBT. The primary outcome is the frequency of suicidal or non-suicidal self-injurious episodes. Secondary outcomes include healthcare utilization, psychiatric and emotional symptoms, general and social functioning, and health status. Cost-effectiveness outcomes will include the cost of providing each treatment as well as health care and societal costs (e.g., missed work days and lost productivity). Assessments are scheduled at pretreatment and at 3-month intervals until 24 months.DiscussionThis is the first study to directly examine the dose-effect of psychotherapy for chronically suicidal individuals diagnosed with BPD. Examining both clinical and cost effectiveness in 6 versus 12 months of DBT will produce answers to the question of how much treatment is good enough. Information from this study will help to guide decisions about the allocation of scarce treatment resources and recommendations about the benefits of briefer treatment.Trial registrationNCT02387736 . Registered February 20, 2015.

ObjectiveThe aim of the study was to examine whether anxiety and depressive symptoms are associated with an adverse cardiac autonomic profile among midlife women with hot flashes.MethodsAnxiety and depressive symptoms were evaluated by validated self-administered questionnaires among peri- and postmenopausal women in a randomized trial of slow-paced respiration for hot flashes. Pre-ejection period (PEP), a marker of sympathetic activation, and respiratory sinus arrhythmia (RSA), a marker of parasympathetic activation, were measured at baseline and 12 weeks using impedance cardiography and electocardiography. Multivariable repeated measures linear regression models examined associations between anxiety and depression symptoms and autonomic markers, corrected for multiple comparisons with Benjamini-Hochberg procedure, and adjusted for age and body mass index.ResultsAmong the 121 participants, greater state anxiety was associated with shorter PEP, reflecting higher sympathetic activity (β = -0.24, P = 0.02). Greater trait anxiety and cognitive anxiety were associated with lower RSA, reflecting decreased parasympathetic activity (β = -0.03, P

BackgroundBreast cancer survivors rank fatigue (e.g., decreased vitality) as their number one concern affecting quality of life. Excess adiposity is associated with decreased vitality in breast cancer survivors, yet weight loss intervention trials report inconsistent effects on this parameter.MethodsThis is a secondary analysis of the Exercise and Nutrition to Enhance Recovery and Good Health for You trial, in which 692 overweight or obese breast cancer survivors ≤5 years from diagnosis, initiated weight loss interventions, and completed assessments semi-annually for 2 years. Assessments included the Godin Leisure-Time Exercise Questionnaire and the SF-36 MOS vitality subscale as an inverse measure of fatigue. Multilevel structural equation models estimated the direct effects of physical activity on vitality and indirect effects through body mass index (BMI) changes.ResultsWithin-person findings show that at assessments with greater physical activity, BMI was significantly lower (B = -0.07, p < 0.001) and vitality was higher (B = 0.22, p < 0.001). However, there was no direct relationship between lower BMI and higher vitality (B = -0.11, p = 0.262) after controlling for the relationship of physical activity with BMI and physical activity with vitality. The between-person indirect effect of physical activity change through BMI change to vitality was significant (B = 0.03, p < 0.001). Participants whose physical activity was above the mean (B = 0.37, p < 0.001) and whose BMI was below the mean (B = -1.05, p < 0.001) were more likely to report greater vitality.ConclusionImprovements in vitality are primarily associated with increases in physical activity rather than BMI changes in this trial. Vitality was lower among survivors with higher BMI, although within-individual changes in BMI had no effect on vitality. Physical activity and weight loss share mechanistic links to vitality with physical activity potentially increasing (e.g., in an additive or synergistic manner) the effect of BMI reduction on vitality.

Alcohol use is common, imposes a staggering burden on public health, and often resists treatment. The central extended amygdala (EAc)-including the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce)-plays a key role in prominent neuroscientific models of alcohol drinking, but the relevance of these regions to acute alcohol consumption in humans remains poorly understood. Using a single-blind, randomized-groups design, multiband fMRI data were acquired from 49 social drinkers while they performed a well-established emotional faces paradigm after consuming either alcohol or placebo. Relative to placebo, alcohol significantly dampened reactivity to emotional faces in the BST. To rigorously assess potential regional differences in activation, data were extracted from unbiased, anatomically predefined regions of interest. Analyses revealed similar levels of dampening in the BST and Ce. In short, alcohol transiently reduces reactivity to emotional faces and it does so similarly across the two major divisions of the human EAc. These observations reinforce the translational relevance of addiction models derived from preclinical work in rodents and provide new insights into the neural systems most relevant to the consumption of alcohol and to the initial development of alcohol abuse in humans.

A possible precision-medicine approach to treating obstructive sleep apnoea (OSA) involves targeting ventilatory instability (elevated loop gain) using supplemental inspired oxygen in selected patients. Here we test whether elevated loop gain and three key endophenotypic traits (collapsibility, compensation and arousability), quantified using clinical polysomnography, can predict the effect of supplemental oxygen on OSA severity.36 patients (apnoea-hypopnoea index (AHI) >20 events·h-1) completed two overnight polysomnographic studies (single-blinded randomised-controlled crossover) on supplemental oxygen (40% inspired) versus sham (air). OSA traits were quantified from the air-night polysomnography. Responders were defined by a ≥50% reduction in AHI (supine non-rapid eye movement). Secondary outcomes included blood pressure and self-reported sleep quality.Nine of 36 patients (25%) responded to supplemental oxygen (ΔAHI=72±5%). Elevated loop gain was not a significant univariate predictor of responder/non-responder status (primary analysis). In post hoc analysis, a logistic regression model based on elevated loop gain and other traits (better collapsibility and compensation; cross-validated) had 83% accuracy (89% before cross-validation); predicted responders exhibited an improvement in OSA severity (ΔAHI 59±6% versus 12±7% in predicted non-responders, p=0.0001) plus lowered morning blood pressure and "better" self-reported sleep.Patients whose OSA responds to supplemental oxygen can be identified by measuring their endophenotypic traits using diagnostic polysomnography.

Primary care-based approaches to address concurrent obesity and cardiovascular disease risk factors (CVDRFs) that begin with a high intensity intervention that is subsequently decreased (i.e., stepped-down) if weight loss is achieved have not been rigorously examined. Our study is a 20-month, single-blind randomized controlled trial at five primary care clinics in San Diego, CA, in 2013, where 262 obese adults (aged 25-70 years; 32.1% male; 59.2% white) with at least one CVDRF were enrolled into planned care for obesity and risk reduction (PCORR) using a stepped-down approach or enhanced usual care (EUC). All patients received physician recommendations for weight loss and CVDRFs. EUC patients (n = 132) received an individual session with a health educator every 4 months. PCORR patients (n = 130) received individual and group sessions (in-person, mail, telephone, and email) in three steps, characterized by less contact if success was achieved. At 20 months, 40.7%, 23.8%, and 15.4% of PCORR patients were in steps 1, 2, and 3, respectively (25.2% were lost to follow-up). PCORR resulted in a between-group difference in reduction in body weight of 6.1% [95% CI, 5.3 to 6.9] compared to EUC 2.8% [95% CI, 2.0 to 3.6] p = 0.007, with a greater reduction in BMI (35.2 [95% CI, 34.4 to 35.9] to 33.7 [95% CI, 32.9 to 34.5] kg/m2) than EUC (36.0 [95% CI, 35.3 to 36.8] to 35.1 [95% CI, 34.3 to 35.9] kg/m2), as indicated by a significant treatment by time interaction (p = 0.009). PCORR resulted in greater weight loss over 20 months than EUC.Trial registrationClinicalTrials.gov, NCT01134029.

Background Despite epidemiologic evidence for increased cardiovascular morbidity and mortality associated with both high dietary and serum phosphate in humans with normal renal function, no controlled phosphate intervention studies of systemic hemodynamics have been reported. Higher serum 25(OH) vitamin D levels are associated with better cardiovascular outcomes, but vitamin D increases intestinal phosphate absorption.Methods We conducted a prospective outpatient study with blinded assessment in 20 young adults with normal renal function randomized to high phosphate (regular diet plus 1 mmol/kg body wt per day of Na as neutral sodium phosphate) or low phosphate (regular diet plus lanthanum, 750 mg thrice/day, plus 0.7 mmol/kg body wt per day of Na as NaCl) for 11 weeks. After 6 weeks, all subjects received vitamin D3 (600,000 U) by intramuscular injection. Outcome parameters were 24-hour ambulatory systolic and diastolic BP (SBP and DBP), pulse rate (PR), biomarkers, and measures of endothelial and arterial function.Results Compared with the low-phosphate diet group, the high-phosphate diet group had a significant increase in mean±SEM fasting plasma phosphate concentration (0.23±0.11 mmol/L); 24-hour SBP and DBP (+4.1; 95% confidence interval [95% CI], 2.1 to 6.1; and +3.2; 95% CI, 1.2 to 5.2 mm Hg, respectively); mean 24-hour PR (+4.0; 95% CI, 2.0 to 6.0 beats/min); and urinary metanephrine and normetanephrine excretion (54; 95% CI, 50 to 70; and 122; 95% CI, 85 to 159 µg/24 hr, respectively). Vitamin D had no effect on any of these parameters. Neither high- nor low-phosphate diet nor vitamin D affected endothelial function or arterial elasticity.Conclusions Increased phosphate intake (controlled for sodium) significantly increases SBP, DBP, and PR in humans with normal renal function, in part, by increasing sympathoadrenergic activity.

ObjectiveTo evaluate whether the progression of individual motor features was influenced by early deep brain stimulation (DBS), a post hoc analysis of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) score (after a 7-day washout) was conducted from the 2-year DBS in early Parkinson disease (PD) pilot trial dataset.MethodsThe prospective pilot trial enrolled patients with PD aged 50-75 years, treated with PD medications for 6 months-4 years, and no history of dyskinesia or other motor fluctuations, who were randomized to receive optimal drug therapy (ODT) or DBS plus ODT (DBS + ODT). At baseline and 6, 12, 18, and 24 months, all patients stopped all PD therapy for 1 week (medication and stimulation, if applicable). UPDRS-III "off" item scores were compared between the ODT and DBS + ODT groups (n = 28); items with significant between-group differences were analyzed further.ResultsUPDRS-III "off" rest tremor score change from baseline to 24 months was worse in patients receiving ODT vs DBS + ODT (p = 0.002). Rest tremor slopes from baseline to 24 months favored DBS + ODT both "off" and "on" therapy (p < 0.001, p = 0.003, respectively). More ODT patients developed new rest tremor in previously unaffected limbs than those receiving DBS + ODT (p = 0.001).ConclusionsThese results suggest the possibility that DBS in early PD may slow rest tremor progression. Future investigation in a larger cohort is needed, and these findings will be tested in the Food and Drug Administration-approved, phase III, pivotal, multicenter clinical trial evaluating DBS in early PD.Classification of evidenceThis study provides Class II evidence that for patients with early PD, DBS may slow the progression of rest tremor.

World Health Organization recommends exclusive breastfeeding for infants for the first 6 months of life, followed by introduction of nutritious complementary foods alongside breastfeeding. Breast milk remains a significant source of nourishment in the second half of infancy and beyond; however, it is not clear whether more breast milk is always better. The present study was designed to determine the association between amount of breast milk intake at 9-10 months of age and infant growth and development by 12-18 months of age. The study was nested in a randomized controlled trial conducted in Malawi. Regression analysis was used to determine associations between breast milk intake and growth and development. Mean (SD) breast milk intake at 9-10 months of age was 752 (244) g/day. Mean (SD) length-for-age z-score at 12 months and change in length-for-age z-score between 12 and 18 months were -1.69 (1.0) and -0.17 (0.6), respectively. At 18 months, mean (SD) expressive vocabulary score was 32 (24) words and median (interquartile range) skills successfully performed for fine, gross, and overall motor skills were 21 (19-22), 18 (16-19), and 38 (26-40), respectively. Breast milk intake (g/day) was not associated with either growth or development. Proportion of total energy intake from breast milk was negatively associated with fine motor (β = -0.18, p = .015) but not other developmental scores in models adjusted for potential confounders. Among Malawian infants, neither breast milk intake nor percent of total energy intake from breast milk at 9-10 months was positively associated with subsequent growth between 12 and 18 months, or development at 18 months.

BACKGROUND:Based on the assumption that relatively large volumes of local anesthetic optimize an adductor canal block (ACB), we theorized that an ACB administered as repeated boluses would improve analgesia without compromising mobility, compared with a continuous infusion. METHODS:We performed a randomized, blinded, controlled study, including patients scheduled for total knee arthroplasty with spinal anesthesia. Patients received 0.2% ropivacaine via a catheter in the adductor canal administered as either repeated intermittent boluses (21 mL/3 h) or continuous infusion (7 mL/h). The primary outcome was total (postoperative day [POD], 0-2) opioid consumption (mg), administered as patient-controlled analgesia. Pain, ambulation, and quadriceps muscle strength were secondary outcomes. RESULTS:We randomized 110 patients, of whom 107 were analyzed. Total opioid consumption (POD, 0-2) was a median (range) of 23 mg (0-139) in the bolus group and 26 mg (3-120) in the infusion group (estimated median difference, 4 mg; 95% confidence interval [CI], -13 to 5; P = .29). Linear mixed-model analyses revealed no difference in pain during knee flexion (mean difference, 2.6 mm; 95% CI, -2.9 to 8.0) or at rest (mean difference, 1.7 mm; 95% CI, -1.5 to 4.9). Patients in the bolus group had improved quadriceps sparing on POD 2 (median difference, 7.4%; 95% CI, 0.5%-15.5%). However, this difference was not present on POD 1 or reflected in the ambulation tests (P > .05). CONCLUSIONS:Changing the mode of administration for an ACB from continuous infusion to repeated intermittent boluses did not decrease opioid consumption, pain, nor mobility.

This study involved a randomized, controlled, single-blind 12-month treatment study of a comprehensive nutritional and dietary intervention. Participants were 67 children and adults with autism spectrum disorder (ASD) ages 3-58 years from Arizona and 50 non-sibling neurotypical controls of similar age and gender. Treatment began with a special vitamin/mineral supplement, and additional treatments were added sequentially, including essential fatty acids, Epsom salt baths, carnitine, digestive enzymes, and a healthy gluten-free, casein-free, soy-free (HGCSF) diet. There was a significant improvement in nonverbal intellectual ability in the treatment group compared to the non-treatment group (+6.7 ± 11 IQ points vs. -0.6 ± 11 IQ points, p = 0.009) based on a blinded clinical assessment. Based on semi-blinded assessment, the treatment group, compared to the non-treatment group, had significantly greater improvement in autism symptoms and developmental age. The treatment group had significantly greater increases in EPA, DHA, carnitine, and vitamins A, B2, B5, B6, B12, folic acid, and Coenzyme Q10. The positive results of this study suggest that a comprehensive nutritional and dietary intervention is effective at improving nutritional status, non-verbal IQ, autism symptoms, and other symptoms in most individuals with ASD. Parents reported that the vitamin/mineral supplements, essential fatty acids, and HGCSF diet were the most beneficial.

BackgroundPrevious reports from the Management of Myelomeningocele Study demonstrated that prenatal repair of myelomeningocele reduces hindbrain herniation and the need for cerebrospinal fluid shunting, and improves motor function in children with myelomeningocele. The trial was stopped for efficacy after 183 patients were randomized, but 30-month outcomes were only available at the time of initial publication in 134 mother-child dyads. Data from the complete cohort for the 30-month outcomes are presented here. Maternal and 12-month neurodevelopmental outcomes for the full cohort were reported previously.ObjectiveThe purpose of this study is to report the 30-month outcomes for the full cohort of patients randomized to either prenatal or postnatal repair of myelomeningocele in the original Management of Myelomeningocele Study.Study designEligible women were randomly assigned to undergo standard postnatal repair or prenatal repair

IntroductionAlthough traditional patient-centered medical homes (PCMHs) are effective for patients with complex needs, it is unclear whether homeless-tailored PCMHs work better for homeless veterans. We examined the impact of enrollment in a Veterans Health Administration (VHA) homeless-tailored PCMH on health services use, cost, and satisfaction compared with enrollment in a traditional, nontailored PCMH.MethodsWe conducted a prospective, multicenter, quasi-experimental, single-blinded study at 2 VHA medical centers to assess health services use, cost, and satisfaction during 12 months among 2 groups of homeless veterans: 1) veterans receiving VHA homeless-tailored primary care (Homeless-Patient Aligned Care Team [H-PACT]) and 2) veterans receiving traditional primary care services (PACT). A cohort of 266 homeless veterans enrolled from June 2012 through January 2014.ResultsCompared with PACT patients, H-PACT patients had more social work visits (4.6 vs 2.7 visits) and fewer emergency department (ED) visits for ambulatory care-sensitive conditions (0 vs 0.2 visits); a significantly smaller percentage of veterans in H-PACT were hospitalized (23.1% vs 35.4%) or had mental health-related ED visits (34.1% vs 47.6%). We found significant differences in primary care provider-specific visits (H-PACT, 5.1 vs PACT, 3.6 visits), mental health care visits (H-PACT, 8.8 vs PACT, 13.4 visits), 30-day prescription drug fills (H-PACT, 40.5 vs PACT, 58.8 fills), and use of group therapy (H-PACT, 40.1% vs PACT, 53.7%). Annual costs per patient were significantly higher in the PACT group than the H-PACT group ($37,415 vs $28,036). In logistic regression model of acute care use, assignment to the H-PACT model was protective as was rating health "good" or better.ConclusionHomeless veterans enrolled in the population-tailored primary care approach used less acute care and costs were lower. Tailored-care models have implications for care coordination in the US Department of Veterans Affairs VA and community health systems.