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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

BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.

BACKGROUND: The clinical burden of Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other post-infectious fatiguing illnesses (PIFI) is increasing. There is a critical need to advance understanding of the effectiveness and sustainability of innovative approaches to clinical care of patients having these conditions. METHODS: We aim to assess the effectiveness of a Long COVID and Fatiguing Illness Recovery Program (LC&FIRP) in a two-arm, single-blind, pragmatic, quality improvement, professional cluster, randomized controlled trial in which 20 consenting clinicians across primary care clinics in a Federally Qualified Health Center system in San Diego, CA, will be randomized at a ratio of 1:1 to either participate in (1) weekly multi-disciplinary team-based case consultation and peer-to-peer sharing of emerging best practices (i.e., teleECHO (Extension for Community Healthcare Outcomes)) with monthly interactive webinars and quarterly short courses or (2) monthly interactive webinars and quarterly short courses alone (a control group); 856 patients will be assigned to participating clinicians (42 patients per clinician). Patient outcomes will be evaluated according to the study arm of their respective clinicians. Quantitative and qualitative outcomes will be measured at 3- and 6-months post-baseline for clinicians and every 3-months post assignment to a participating clinician for patients. The primary patient outcome is change in physical function measured using the Patient-Reported Outcomes Measurement Information System (PROMIS)-29. Analyses of differences in outcomes at both the patient and clinician levels will include a linear mixed model to compare change in outcomes from baseline to each post-baseline assessment between the randomized study arms. A concurrent prospective cohort study will compare the LC&FIRP patient population to the population enrolled in a university health system. Longitudinal data analysis approaches will allow us to examine differences in outcomes between cohorts. DISCUSSION: We hypothesize that weekly teleECHO sessions with monthly interactive webinars and quarterly short courses will significantly improve clinician- and patient-level outcomes compared to the control group. This study will provide much needed evidence on the effectiveness of a technology-enabled multi-disciplinary team-based care model for the management of Long COVID, ME/CFS, and other PIFI within a federally qualified health center. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05167227 . Registered on December 22, 2021.

BackgroundPain is frequent after cardiac surgery and source of multiple complications that can impair postoperative recovery. Regional anesthesia seems to be an interesting technique to reduce the pain in this context, but its effectiveness in improving recovery has been poorly studied so far. The objective of this study is to compare the effectiveness of two of the most studied chest wall blocks in cardiac surgery, i.e., the superficial and the deep parasternal intercostal plane blocks (SPIP and DPIP respectively), in addition to standard care, versus the standard care without regional anesthesia, on the quality of postoperative recovery (QoR) after cardiac surgery with sternotomy.MethodsThis is a single-center, single-blind, controlled, randomized trial with a 1:1:1 ratio. Patients (n = 254) undergoing cardiac surgery with sternotomy will be randomized into three groups: a control group with standard care and no regional anesthesia, a SPIP group with standard care and a SPIP, and a DPIP with standard care and a DPIP. All groups will receive the usual analgesic protocol. The primary endpoint is the value of the QoR evaluated by the QoR-15 at 24 h after the surgery.DiscussionThis study will be the first powered trial to compare the SPIP and the DPIP on global postoperative recovery after cardiac surgery with sternotomy.Trial registrationClinicalTrials.gov NCT05345639. Registered on April 26, 2022.

Artificial intelligence (AI) has been developed for echocardiography1-3, although it has not yet been tested with blinding and randomization. Here we designed a blinded, randomized non-inferiority clinical trial (ClinicalTrials.gov ID: NCT05140642; no outside funding) of AI versus sonographer initial assessment of left ventricular ejection fraction (LVEF) to evaluate the impact of AI in the interpretation workflow. The primary end point was the change in the LVEF between initial AI or sonographer assessment and final cardiologist assessment, evaluated by the proportion of studies with substantial change (more than 5% change). From 3,769 echocardiographic studies screened, 274 studies were excluded owing to poor image quality. The proportion of studies substantially changed was 16.8% in the AI group and 27.2% in the sonographer group (difference of -10.4%, 95% confidence interval: -13.2% to -7.7%, P

BackgroundEvidence-based interventions to protect against cognitive decline among older adults at risk for Alzheimer's disease and related dementias (ADRD) are urgently needed. Rehabilitation approaches to support memory and behavioral/lifestyle interventions are recognized as promising strategies for preserving or improving cognitive health, although few previous interventions have combined both approaches. This paper describes the protocol of the Brain Boosters intervention, which synergistically combines training in compensatory and healthy lifestyle behaviors and supports implementation and tracking of new behaviors with a digital application.MethodsThe study utilizes a single-site, single-blinded, randomized controlled design to compare a structured lifestyle and compensatory aid intervention to an education-only self-guided intervention. We plan to enroll 225 community-dwelling adults (25% from underrepresented groups) aged 65 + who endorse subjective cognitive decline (SCD) and low baseline levels of healthy lifestyle behaviors. Both interventions will be administered in group format, consisting of 15 two-hour classes that occur weekly for ten weeks and taper to bi-monthly and monthly, for an intervention duration of 6 months. Participants in both interventions will receive education about a variety of memory support strategies and healthy lifestyle behaviors, focusing on physical and cognitive activity and stress management. The structured intervention will also receive support in adopting new behaviors and tracking set goals aided by the Electronic Memory and Management Aid (EMMA) digital application. Primary outcomes include global cognition (composite of memory, attention, and executive function tests) and everyday function (Everyday Cognition Questionnaire). Data will be collected at baseline and outcome visits, at approximately 6, 12, and 18 months. Qualitative interviews, self-report surveys (e.g., indicators of self-determination, health literacy) and EMMA data metrics will also be used to identify what components of the intervention are most effective and for whom they work.DiscussionSuccessful project completion will provide valuable information about how individuals with SCD respond to a compensation and preventative lifestyle intervention assisted by a digital application, including an understanding of factors that may impact outcomes, treatment uptake, and adherence. The work will also inform development, scaling, and personalization of future interventions that can delay disability in individuals at risk for ADRD.Trial registrationClinicalTrials.gov. (NCT05027789, posted 8/30/2021).

BackgroundUpper extremity (UE) stroke rehabilitation requires patients to perform exercises at home, yet patients show limited benefit from paper-based home exercise programs.ObjectiveTo compare the effectiveness of 2 home exercise programs for reducing UE impairment: a paper-based approach and a sensorized exercise system that incorporates recommended design features for home rehabilitation technology.MethodsIn this single-blind, randomized controlled trial, 27 participants in the subacute phase of stroke were assigned to the sensorized exercise (n = 14) or conventional therapy group (n = 13), though 2 participants in the conventional therapy group were lost to follow-up. Participants were instructed to perform self-guided movement training at home for at least 3 hours/week for 3 consecutive weeks. The sensorized exercise group used FitMi, a computer game with 2 puck-like sensors that encourages movement intensity and auto-progresses users through 40 exercises. The conventional group used a paper book of exercises. The primary outcome measure was the change in Upper Extremity Fugl-Meyer (UEFM) score from baseline to follow-up. Secondary measures included the Modified Ashworth Scale for spasticity (MAS) and the Visual Analog Pain (VAP) scale.ResultsParticipants who used FitMi improved by an average of 8.0 ± 4.6 points on the UEFM scale compared to 3.0 ± 6.1 points for the conventional participants, a significant difference (t-test, P = .029). FitMi participants exhibited no significant changes in UE MAS or VAP scores.ConclusionsA sensor-based exercise system incorporating a suite of recommended design features significantly and safely reduced UE impairment compared to a paper-based, home exercise program.Trial registrationClinicalTrials.gov Identifier: NCT03503617.

IntroductionMost people living with dementia want to remain living in their own homes, and are supported to do so by family carers and homecare workers. There are concerns that homecare is often unable to meet the needs of this client group, with limited evidence regarding effective interventions to improve it for people living with dementia. We have developed a training and support programme for homecare workers (NIDUS-Professional) to be delivered alongside support sessions for people living with dementia and their family carers (NIDUS-Family). We aim to assess (1) its acceptability among homecare workers and employing agencies, and (2) the feasibility of homecare workers, people living with dementia and their family carers completing the outcomes of intervention in a future randomised controlled trial.Methods and analysisThis is a cluster-randomised (2:1) single-blind, multisite feasibility trial. We aim to recruit 60-90 homecare workers, 30-60 clients living with dementia and their family carers through 6-9 English homecare agencies. In the intervention arm, homecare staff will be offered six group sessions on video call over three months, followed by monthly group sessions over the subsequent three-month period. Outcome measures will be collected at baseline and at six months.Ethics and disseminationThe study received ethical approval on 7 January 2020 from the Camden & King's Cross Research Ethics Committee. Study reference: 19/LO/1667. Findings will be disseminated through a peer-reviewed journal, conference presentation and blog to research and clinical audiences; we will attend forums to present findings to participating homecare agencies and their clients.Trial registration numberISRCTN15757555.

BackgroundHealth systems are increasingly interested in collaborative dementia care. Implementation challenges include the limited dementia specialist workforce, time pressures of high-volume care, increasing use of telemedicine, and inadequate reimbursement. The Care Ecosystem is a telephone-based collaborative dementia care model designed to augment existing healthcare services and be amenable to scale. Here we present the latest evidence for the Care Ecosystem, including the effects among subpopulations at risk for health disparities (rural and Hispanic/Latino), and facilitators from the early phase of Care Ecosystem implementation at 6 diverse health systems.MethodEffectiveness was evaluated in a single-blind, randomized clinical trial (N = 804). Persons with dementia (PWD)-caregiver dyads were randomized to receive 12 months of the intervention (N = 527) or usual care (N = 277). Outcomes were measured via telephone surveys at 6 and 12 months after randomization and medical record review. Subgroup analyses were performed for the 124 dyads who identified as Hispanic/Latino, and the 66 who lived in rural Nebraska or Iowa. The intervention was primarily delivered by an unlicensed, trained care team navigator, who provided education, support and care coordination with supervision and help from a dementia specialist team (advanced practice nurse, social worker, and pharmacist). Implementation facilitators were evaluated through observation and qualitative interviews with clinical teams at 6 health systems implementing the model.ResultsThe PWD-caregiver dyads lived in California (n = 476), Nebraska (n = 286), or Iowa (n = 42). Compared with usual care, the Care Ecosystem improved PWD quality of life, reduced emergency department visits, reduced the use of potentially inappropriate medications, and decreased caregiver depression and caregiver burden. Effect sizes were similar or greater in Hispanic/Latino and rural subgroups on most outcomes. Facilitators of Care Ecosystem implementation included open-access implementation tools (online training, care protocols), the adaptability of the care model, the care team navigator role, and remote care delivery.ConclusionEffective dementia care can be delivered by care team navigators via telephone to mitigate the burdens of dementia, including for underserved PWD living in rural areas or who identify as Hispanic/Latino. Implementation is a challenge although features of the care model appear to facilitate adoption.

BackgroundLarge-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years.MethodsA multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods.DiscussionIf effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns.Trial registrationISRCTN17325135 . Registration date 27 November 2019.

Pain is inversely associated with cognitive function in older adults, but the effects of pain on cognitive decline are not fully clear. This study examined the associations of baseline pain, pain persistence, and incident pain with changes in cognition across 10 years in a sample of healthy community-dwelling older adults (n = 688; Mage = 74, SD = 6.05) from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial. While ACTIVE was a four-arm single-blind cognitive training randomized controlled trial, the present study includes only participants from the no-contact control group. Pain was examined using the Medical Outcomes Survey SF-36-Item (MOS SF-36) and cognitive tests examined simple processing speed, complex processing speed, divided and selective attention, memory, reasoning, and cognitive status. Multilevel models tested the associations of baseline pain, incident pain, and pain persistence on cognitive function and cognitive decline, adjusted for baseline age, time (years after follow-up), race, gender, education, marital status, and depressive symptoms at baseline and over time. Thirty-one percent reported pain at baseline which was related to worse baseline memory and accelerated decline in processing speed. Forty-two percent of older adults reported incident pain had accelerated decline in complex processing speed, divided attention, memory, reasoning, and cognitive status. On average, older adults reported a mean of two waves of pain persistence related to accelerated decline in memory. In sum, pain is common in community-dwelling older adults and is related to accelerated cognitive decline, especially when the incident. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Psychiatry stands to benefit from brief non-pharmacological treatments that effectively reduce depressive symptoms. To address this need, we conducted a single-blind randomized clinical trial assessing how a 6-day immersive psychosocial training program, followed by 10-min daily psychosocial exercises for 30 days, improves depressive symptoms. Forty-five adults were block-randomized by depression score to two arms: (a) the immersive psychosocial training program and 10-min daily exercise group (36 days total; total n = 23; depressed at baseline n = 14); or (b) a gratitude journaling control group (36 days total; total n = 22; depressed at baseline n = 13). The self-report PHQ-9 was used to assess depression levels in both groups at three time points: baseline, study week one, and study week six. Depression severity improved over time, with a significantly greater reduction in the psychosocial training program group (-82.7%) vs. the control group (-23%), p = 0.02 for baseline vs. week six. The effect size for this reduction in depression symptoms was large for the intervention group (d = -1.3; 95% CI, -2.07, -0.45; p

ContextIt has been suggested that a gluten-free and casein-free (GFCF) diet may alleviate the symptoms of autism spectrum disorder (ASD) and facilitate neurodevelopment of children with ASD. Studies to date have been inconclusive.ObjectiveThis study aimed to evaluate (through quantitative meta-analysis) the efficacy and safety of a GFCF diet for children with ASD. To our knowledge, this is the first time such an analysis has been carried out.Data sourcesEight electronic databases were searched, from the establishment of each database up to March 27, 2020: PubMed, Web of Science, Embase (Ovid), PsycINFO (Ovid), Cochrane Library, CNKI, Wanfang, and VIP databases.Data extractionTwo authors independently performed the data extraction and risk-of-bias assessment.Data analysisA quantitative meta-analysis was performed with standard procedures by using Stata SE 15 software. Within the total of 8 studies, with 297 participants, 5 studies reported significant reductions in stereotypical behaviors [standard mean difference (SMD) = -0.41, 95% confidence interval (CI): -0.68 to -0.15], and 3 studies reported improvements in cognition (SMD = -0.46, 95% CI: -0.91 to -0.01) following GFCF dietary intervention . No statistically significant changes were observed in other symptomatic categories (all P > 0.05).ConclusionThe current meta-analysis showed that a GFCF diet can reduce stereotypical behaviors and improve the cognition of children with ASD. Though most of the included studies were single-blind, the benefits of a GFCF diet that have been indicated are promising. Additional studies on a larger scale are warranted.Systematic review registrationPROSPERO registration no. CRD42020177619.

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.

BackgroundNVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b-3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America.MethodsWe conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction-confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed.ResultsOf the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted - 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P

Study designRandomized, controlled single-blind cross over study. This study was registered on ClinicalTrials.gov (NCT02473614).ObjectivesExamine usership patterns and feasibility of MusicGlove for at home hand rehabilitation therapy following chronic spinal cord injury.SettingHomes of participants.MethodsTen participants with chronic spinal cord injury completed two baseline assessments of hand function. After a stable baseline was determined all participants were randomized into two groups: Experimental and Control. Each group was given a recommended therapy dosage. Following this participants switched interventions.ResultsOn average participants had higher levels of compliance (6.1 ± 3.5 h.), and completed more grips (15,760 ± 9,590 grips) compared to participants in previous stroke studies using the same device. Participants modulated game parameters in a manner consistent with optimal challenge principles from motor learning theory. Participants in the experimental group increased their prehension ability (1 ± 1.4 MusicGlove, 0.2 ± 0.5 Control) and performance (1.4 ± 2.2 MusicGlove, 0.4 ± 0.55 Control) on the Graded and Redefined Assessment of Strength, Sensibility, and Prehension subtests. Increases in performance on the Box and Blocks Test also favored the experimental group compared to the conventional group at the end of therapy (4.2 ± 5.9, -1.0 ± 3.4 respectively).ConclusionsMusicGlove is a feasible option for hand therapy in the home-setting for individuals with chronic SCI. Participants completed nearly twice as many gripping movements compared to individuals from the sub-acute and chronic stroke populations, and a number far greater than the number of movements typically achieved during traditional rehabilitation.

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.).

BackgroundAt interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported.MethodsWe enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021.ResultsThe trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified.ConclusionsThe mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

ObjectiveMany patients with subacute stroke rely on the nonparetic arm and leg to propel manual wheelchairs. We designed a bimanual, lever-driven wheelchair (LARA) to promote overground mobility and hemiparetic arm exercise. This study measured the feasibility of using LARA to increase arm movement, achieve mobility, and improve arm motor recovery (clinicaltrials.gov/ct2/show/NCT02830893).DesignRandomized, assessor-blind, controlled trial.SettingTwo inpatient rehabilitation facilities.SubjectsNineteen patients with subacute stroke (1 week to 2 months post-stroke) received 30 minutes extra arm movement practice daily, while admitted to inpatient rehabilitation (n = 10) or before enrollment in outpatient therapy (n = 9).InterventionsPatients were randomized to train with the LARA wheelchair (n = 11) or conventional exercises with a rehabilitation therapist (n = 8).Main measuresNumber of arm movements per training session; overground speed; Upper Extremity Fugl-Meyer score at three-month follow-up.ResultsParticipants who trained with LARA completed 254 (median) arm movements with the paretic arm each session. For three participants, LARA enabled wheelchair mobility at practical indoor speeds (0.15-0.30 m/s). Fugl-Meyer score increased 19 ± 13 points for patients who trained with LARA compared to 14 ± 7 points with conventional exercises (P = 0.32). Secondary measures including shoulder pain and increased tone did not differ between groups. Mixed model analysis found significant interaction between LARA training and treatment duration (P = 0.037), informing power analysis for future investigation.ConclusionsPractising arm movement with a lever-driven wheelchair is a feasible method for increasing arm movement early after stroke. It enabled wheelchair mobility for a subset of patients and shows potential for improving arm motor recovery.

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.

Introduction: Although smoking prevalence has recently declined, the smoking prevalence in China remains high. Extensive research has demonstrated ways that social media can assist in quitting smoking. WeChat is the most commonly used social media platform in China but has not been used for smoking cessation. A process evaluation of a novel WeChat-based smoking cessation intervention was conducted to measure its efficacy of content delivery, participant satisfaction, engagement, and likelihood of recommendation to others. Methods: A three-week, three-arm, single-blind randomized control trial was established. WeChat was used to recruit 403 participants and to deliver intervention messages and process evaluation surveys to them. Recruitment advertisements were posted on an official WeChat account and were forwarded to WeChat Moments. Intervention messages were delivered once a day during weekdays, using the WeChat broadcasting messages function, with two messages being sent each time. Process evaluation surveys were organized using Wenjuanwang and were delivered via WeChat. Process assessments were conducted every Friday to assess intervention message receipt, satisfaction level, engagement level, and recommendation to others. The receipt of intervention messages was measured by a self-reported question indicating which messages were read each week. Satisfaction was measured by a five-item Likert scale survey. Engagement was measured by a one-item Likert scale survey. Recommendation to others was measured by one self-reported question. Results: Participants read an average of 4.76 (out of 10), 5.80 (out of 10), and 4.25 (out of 6) messages at week 1, week 2, and week 3, respectively. The second messages were less likely to be read compared to the first messages (52.3% vs. 61.6%, respectively). Moreover, within each single week, the number of participants who read the intervention messages gradually decreases over time. Picture-based intervention messages tended to be less likely to be read than video-based intervention messages. Total program satisfaction scores ranged between 5 and 25, and the overall scores for satisfaction for each week were 21.55, 22.27, and 22.76, respectively. No significant differences were found in all the satisfaction indicators between groups. More than 60% of participants reported being either highly engaged or somewhat engaged each week. In addition, most participants (93.0% at week 1, 95.8% at week 2, and 96.2% at week 3) reported that they were willing to recommend our program to others. Discussion: A WeChat-based smoking cessation intervention for Chinese smokers was implemented and evaluated. For future studies, one should consider sending messages of a higher importance as the first message of a given day. Smokers had a higher rate of reading intervention messages at the beginning part of each week, during which, relatively important messages should be prioritized. One might also consider alternating the topics and formats of the messages for a better engagement of the users in future studies.

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.

Perioperative pain management is an important consideration in early recovery and patient satisfaction following laparoscopic donor nephrectomy. Transmuscular quadratus lumborum block has been described to reduce pain and opioid usage following several abdominal surgeries. In this prospective single-blind randomized controlled trial, we compared 52 patients who adhered to our institutional donor nephrectomy Early Recovery After Surgery pathway, which includes a laparoscopic-guided transversus abdominus plane block, to 40 patients who additionally received a transmuscular quadratus lumborum block with liposomal bupivacaine. Compared to control patients, those who received the block spent longer in the operating room prior to the surgical start (65.4 vs. 51.6 min, P

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.

BackgroundDelays in diagnosis and treatment of tuberculosis (TB) remain common in high-burden countries. To improve case detection, substantial investments have been made to scale-up Xpert MTB/RIF (Xpert), a cartridge-based nucleic acid amplification test that can detect TB within 2 hours, as a replacement for sputum smear microscopy. However, the optimal strategy for implementation of Xpert testing remains unclear.MethodsThe Xpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) trial uses an ultra-pragmatic, hybrid type II effectiveness-implementation design to assess the effectiveness and implementation of a streamlined strategy for delivery of Xpert testing in real-world settings. Twenty health centers with TB microscopy units were selected to participate in the trial, with ten health centers randomized to the intervention strategy (onsite molecular testing using GeneXpert Edge, process redesign to facilitate same-day TB diagnosis and treatment, and performance feedback) or routine care (onsite sputum smear microscopy plus referral of sputum samples to Xpert testing sites). The primary outcome is the number of patients with microbiologically confirmed TB who were initiated on treatment within 14 days of presentation to the health center, which reflects successful completion of the TB diagnostic evaluation process. Secondary outcomes include health outcomes (6-month vital status), as well as measures of the reach, adoption, and implementation of the intervention strategy.DiscussionThe design elements and implementation approach for the XPEL-TB trial were intentionally selected to minimize disruptions to routine care procedures, with the goal of limiting their influence on key primary and secondary outcomes. Trial findings may result in increased support and funding for rapid, onsite molecular testing as the standard-of-care for all patients being evaluated for TB.Trial registrationUS National Institutes of Health's ClinicalTrials.gov, NCT03044158. Registered 06 February 2017. Pan African Clinical Trials Registry, PACTR201610001763265. Registered 03 September 2016.

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.

BACKGROUND: Lower-limb amputation (LLA) due to non-traumatic vascular etiology is linked to extremely low physical activity and high disability. OBJECTIVE: To test the feasibility of a biobehavioral intervention designed to promote physical activity. DESIGN: A randomized, single-blind feasibility trial with a crossover design. SETTING: Veterans Administration Medical Center. PARTICIPANTS: Military veterans (age: 65.7 [7.8] years; mean [standard deviation]) with nontraumatic lower-limb amputation (LLA), randomized to two groups: GROUP1 (n = 16) and GROUP2 (n = 15). Both groups had similar baseline amputation characteristics (level of amputation and time since amputation). INTERVENTIONS: Twelve weekly, 30-minute telehealth sessions of physical activity behavior-change intervention, with GROUP1 participating in weeks 1-12 and GROUP2 in weeks 13-24. GROUP1 noncontact phase in weeks 13-24 and GROUP2 attention control telehealth phase in weeks 1-12. MAIN OUTCOME MEASURES: Feasibility (participant retention, dose goal attainment, intervention acceptability [Intrinsic Motivation Inventory [IMI] Interest and Enjoyment scale], safety) and signal of efficacy (free-living physical activity [accelerometer-based average daily step count], Late Life Function and Disability Index - Disability Scale [LLFDI-DS]). RESULTS: Participant retention rate was high (90%), with three participants lost to follow-up during the intervention period. Dose goal attainment was low, with only 10% of participants achieving an a priori walking dose goal. Intervention was rated as acceptable, with mean IMI Interest and Enjoyment score (5.8) statistically higher than the null value of 5.0 (P = .002). There were no between-group differences in adverse event rates (falls: P = .19, lower extremity wounds: P = .60). There was no signal of efficacy for change in average daily step count (d = -0.15) or LLFDI-DS (d = -0.22 and 0.17 for frequency and limitations scales, respectively). CONCLUSIONS: Telehealth delivered biobehavioral intervention resulted in acceptable participant retention, low dose goal attainment, high participant acceptability, and low safety risk, while having no signal of efficacy (physical activity, disability) for people with nontraumatic LLA.

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p

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.

IntroductionTotal knee arthroplasty (TKA) reduces joint symptoms, but habitual movement compensations persist years after surgery. Preliminary research on movement training interventions have signaled initial efficacy for remediating movement compensations and restoring knee joint loading symmetry during dynamic functional tasks after TKA. The purpose of this clinical trial is to determine if physical rehabilitation that includes movement training restores healthy movement patterns after TKA and reduces the risk of osteoarthritis (OA) progression in the contralateral knee.Methods/design150 participants will be enrolled into this randomized controlled trial. Participants will be randomly allocated to one of two dose-equivalent treatment groups: standard rehabilitation plus movement training (MOVE) or standard rehabilitation without movement training (CONTROL). Movement training will promote between-limb symmetry and surgical knee loading during activity-based exercises. Movement training strategies will include real-time biofeedback using in-shoe pressure sensors and verbal, visual, and tactile cues from the physical therapist. The primary outcome will be change in peak knee extension moment in the surgical knee during walking, from before surgery to six months after surgery. Secondary outcomes will include lower extremity movement symmetry during functional tasks, physical function, quadriceps strength, range of motion, satisfaction, adherence, contralateral knee OA progression, and incidence of contralateral TKA.DiscussionThis study will provide insights into the efficacy of movement training after unilateral TKA, along with mechanisms for optimizing long-term physical function and minimizing negative sequelae of compensatory movement patterns.

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.

Therapeutic applications of light emitting diode-red light (LED-RL) are expanding, yet data on its clinical effects are lacking. Our goal was to evaluate the safety of high fluence LED-RL (≥160 J/cm2 ). In two phase I, single-blind, dose escalation, randomized controlled trials, healthy subjects received LED-RL or mock irradiation to the forearm thrice weekly for 3 weeks at fluences of 160-640 J/cm2 for all skin types (STARS 1, n = 60) and at 480-640 J/cm2 for non-Hispanic Caucasians (STARS 2, n = 55). The primary outcome was the incidence of adverse events (AEs). The maximum tolerated dose was the highest fluence that did not elicit predefined AEs. Dose-limiting AEs, including blistering and prolonged erythema, occurred at 480 J/cm2 in STARS 1 (n = 1) and 640 J/cm2 in STARS 2 (n = 2). AEs of transient erythema and hyperpigmentation were mild. No serious AEs occurred. We determined that LED-RL is safe up to 320 J/cm2 for skin of color and 480 J/cm2 for non-Hispanic Caucasian individuals. LED-RL may exert differential cutaneous effects depending on race and ethnicity, with darker skin being more photosensitive. These findings may guide future studies to evaluate the efficacy of LED-RL for the treatment of various diseases.

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.

BackgroundSkin fibrosis is a significant global health problem that affects over 100 million people annually and has a profoundly negative impact on quality of life. Characterized by excessive fibroblast proliferation and collagen deposition, skin fibrosis underlies a wide spectrum of dermatologic conditions ranging from pathologic scars secondary to injury (e.g., burns, surgery, trauma) to immune-mediated diseases. Effective anti-scarring therapeutics remain an unmet need, underscoring the importance of developing novel approaches to treat and prevent skin fibrosis. Our in vitro data show that light emitting diode-red light (LED-RL) can modulate key cellular and molecular processes involved in skin fibrosis. In two phase I clinical trials (STARS 1 and STARS 2), we demonstrated the safety and tolerability of LED-RL at fluences of 160 J/cm2 up to 480 J/cm2 on normal human skin.Methods/designCURES (Cutaneous Understanding of Red-light Efficacy on Scarring) is a dose-ranging, randomized, parallel group, split-face, single-blind, mock-controlled phase II study to evaluate the efficacy of LED-RL to limit post-surgical skin fibrosis in subjects undergoing elective mini-facelift surgery. Thirty subjects will be randomly allocated to three treatment groups to receive LED-RL phototherapy or temperature-matched mock irradiation (control) to either periauricular incision site at fluences of 160 J/cm2, 320 J/cm2, or 480 J/cm2. Starting one week post-surgery (postoperative days 4-8), treatments will be administered three times weekly for three consecutive weeks, followed by efficacy assessments at 30 days, 3 months, and 6 months. The primary endpoint is the difference in scar pliability between LED-RL-treated and control sites as determined by skin elasticity and induration measurements. Secondary outcomes include clinical and photographic evaluations of scars, 3D skin imaging analysis, histological and molecular analyses, and adverse events.DiscussionLED-RL is a therapeutic modality of increasing importance in dermatology, and has the potential to limit skin fibrosis clinically by decreasing dermal fibroblast activity and collagen production. The administration of LED-RL phototherapy in the early postoperative period may optimize wound healing and prevent excessive scarring. The results from this study may change the current treatment paradigm for fibrotic skin diseases and help to pioneer LED-RL as a safe, non-invasive, cost-effective, portable, at-home therapy for scars.Trial registrationClinicalTrials.gov, NCT03795116 . Registered on 20 December 2018.

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.