A Series of Personalized Virtual Light Therapy Interventions for Fatigue: Feasibility Randomized Crossover Trial for N-of-1 Treatment.

BACKGROUND: Fatigue is one of the most common symptoms treated in primary care and can lead to deficits in mental health and functioning. Light therapy can be an effective treatment for symptoms of fatigue; however, the feasibility, scalability, and individual-level heterogeneity of light therapy for fatigue are unknown. OBJECTIVE: This study aimed to evaluate the feasibility, acceptability, and effectiveness of a series of personalized (N-of-1) interventions for the virtual delivery of bright light (BL) therapy and dim light (DL) therapy versus usual care (UC) treatment for fatigue in 60 participants. METHODS: Participants completed satisfaction surveys comprising the System Usability Scale (SUS) and items assessing satisfaction with the components of the personalized trial. Symptoms of fatigue were measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) daily, PROMIS weekly, and ecological momentary assessment (EMA) questionnaires delivered 3 times daily. Comparisons of fatigue between the BL, DL, and UC treatment periods were conducted using generalized linear mixed model analyses between participants and generalized least squares analyses within individual participants. RESULTS: Participants rated the usability of the personalized trial as acceptable (average SUS score=78.9, SD 15.6), and 92% (49/53) of those who completed satisfaction surveys stated that they would recommend the trial to others. The levels of fatigue symptoms measured using the PROMIS daily fatigue measure were lower or improved in the BL (B=-1.63, 95% CI -2.63 to -0.63) and DL (B=-1.44, 95% CI -2.50 to -0.38) periods relative to UC. The treatment effects of BL and DL on the PROMIS daily measure varied among participants. Similar findings were demonstrated for the PROMIS weekly and EMA measures of fatigue symptoms. CONCLUSIONS: The participant scores on the SUS and satisfaction surveys suggest that personalized N-of-1 trials of light therapy for fatigue symptoms are both feasible and acceptable. Both interventions produced significant (P<.05) reductions in participant-reported PROMIS and EMA fatigue symptoms relative to UC. However, the heterogeneity of these treatment effects across participants indicated that the effect of light therapy was not uniform. This heterogeneity along with high ratings of usability and satisfaction support the use of personalized N-of-1 research designs in evaluating the effect of light therapy on fatigue for each patient. Furthermore, the results of this trial provide additional support for the use of a series of personalized N-of-1 research trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04707846; https://clinicaltrials.gov/ct2/show/NCT04707846.

A Series of Remote Melatonin Supplement Interventions for Poor Sleep: Protocol for a Feasibility Pilot Study for a Series of Personalized (N-of-1) Trials.

BACKGROUND: Poor sleep, defined as short-duration or poor-quality sleep, is a frequently reported condition with many deleterious effects including poorer cognitive functioning, increased accidents, and poorer health. Melatonin has been shown to be an efficacious treatment to manage symptoms of poor sleep. However, the treatment effects of melatonin on sleep can vary greatly between participants. Personalized, or N-of-1, trial designs represent a method for identifying the best treatment for individual participants. Although using N-of-1 trials of melatonin to treat poor sleep is possible, the feasibility, acceptability, and effectiveness of N-of-1 trials using melatonin are unknown. Using the National Institutes of Health Stage Model for Behavioral Intervention Development, a stage IB (intervention refinement, modification, and adaptation and pilot testing) design appeared to be needed to address these feasibility questions. OBJECTIVE: This trial series evaluates the feasibility, acceptability, and effectiveness of a series of personalized interventions for remote delivery of melatonin dose (3 and 0.5 mg) versus placebo supplements for self-reported poor sleep among 60 participants. The goal of this study is to provide valuable information about implementing remote N-of-1 randomized controlled trials to improve poor sleep. METHODS: Participants will complete a 2-week baseline followed by six 2-week alternating intervention periods of 3 mg of melatonin, 0.5 mg of melatonin, and placebo. Participants will be randomly assigned to 2 intervention orders. The feasibility and acceptability of the personalized trial approach will be determined with participants' ratings of usability and satisfaction with the remote, personalized intervention delivery system. The effectiveness of the intervention will be measured using participants' self-reported sleep quality and duration and Fitbit tracker-measured sleep duration and efficiency. Additional measures will include ecological momentary assessment measures of fatigue, stress, pain, mood, concentration, and confidence as well as measures of participant adherence to the intervention, use of the Fitbit tracker, and survey data collection. RESULTS: As of the submission of this protocol, recruitment for this National Institutes of Health stage IB personalized trial series is approximately 78.3% complete (47/60). We expect recruitment and data collection to be finalized by June 2023. CONCLUSIONS: Evaluating the feasibility, acceptability, and effectiveness of a series of personalized interventions of melatonin will address the longer term aim of this program of research-is integrating N-of-1 trials useful patient care? The personalized trial series results will be published in a peer-reviewed journal and will follow the CONSORT (Consolidated Standards of Reporting Trials) extension for N-of-1 trials (CENT 2015) reporting guidelines. This trial series was approved by the Northwell Health institutional review board. TRIAL REGISTRATION: ClinicalTrials.gov NCT05349188; https://www.clinicaltrials.gov/study/NCT05349188. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45313.

Series of virtual light therapy interventions for fatigue: a feasibility pilot study protocol for a series of personalised (N-of-1) trials.

INTRODUCTION: Fatigue is one of the most commonly recorded patient symptoms that can result in deficits in aspects of psychomotor functioning, cognition, work performance and mood. Research shows that bright light and dim light therapy may be an efficacious way to reduce symptoms of fatigue. Still, the feasibility, scalability, individual treatment effects and adverse event heterogeneity of these treatments are unknown. METHODS AND ANALYSIS: The current study evaluates the feasibility, acceptability and effectiveness of a series of personalised (N-of-1) interventions for virtual delivery of bright light therapy and dim light therapy versus usual care treatment for fatigue in 60 participants. We hypothesise that this study will provide valuable information about implementing virtual, N-of-1 randomised controlled trials (RCTs) for fatigue. It will also offer results about determining participants' ratings of usability and satisfaction with the virtual, personalised intervention delivery system; evaluating participants' improvement of fatigue symptoms; and, in the long term, identify ways to integrate N-of-1 light therapy trials into patient care. ETHICS AND DISSEMINATION: This trial was approved by the Northwell Health Institutional Review Board. The trial results will be published in a peer-reviewed journal. All publications resulting from this series of personalised trials will follow the Consolidated Standards of Reporting Trials extension for N-of-1 trials CENT 2015 reporting guidelines. REGISTRATION DETAILS: This trial is registered in www. CLINICALTRIALS: gov (number NCT04707846). TRIAL REGISTRATION NUMBER: NCT04707846.

Personal preferences for Personalised Trials among patients with chronic diseases: an empirical Bayesian analysis of a conjoint survey.

OBJECTIVE: To describe individual patient preferences for Personalised Trials and to identify factors and conditions associated with patient preferences. DESIGN: Each participant was presented with 18 conjoint questions via an online survey. Each question provided two choices of Personalised Trials that were defined by up to eight attributes, including treatment types, clinician involvement, study logistics and trial burden on a patient. SETTING: Online survey of adults with at least two common chronic conditions in the USA. PARTICIPANTS: A nationally representative sample of 501 individuals were recruited from the Chronic Illness Panel by Harris Poll Online. Participants were recruited from several sources, including emails, social media and telephone recruitment of the target population. MAIN OUTCOME MEASURES: The choice of Personalised Trial design that the participant preferred with each conjoint question. RESULTS: There was large variability in participants' preferences for the design of Personalised Trials. On average, they preferred certain attributes, such as a short time commitment and no cost. Notably, a population-level analysis correctly predicted 62% of the conjoint responses. An empirical Bayesian analysis of the conjoint data, which supported the estimation of individual-level preferences, improved the accuracy to 86%. Based on estimates of individual-level preferences, patients with chronic pain preferred a long study duration (p≤0.001). Asthma patients were less averse to participation burden in terms of data-collection frequency than patients with other conditions (p=0.002). Patients with hypertension were more cost-sensitive (p<0.001). CONCLUSION: These analyses provide a framework for elucidating individual-level preferences when implementing novel patient-centred interventions. The data showed that patient preference in Personalised Trials is highly variable, suggesting that individual differences must be accounted for when marketing Personalised Trials. These results have implications for advancing precise interventions in Personalised Trials by indicating when rigorous scientific principles, such as frequent monitoring, is feasible in a substantial subset of patients.

Interventions to Prevent Perinatal Depression: US Preventive Services Task Force Recommendation Statement.

Importance: Perinatal depression, which is the occurrence of a depressive disorder during pregnancy or following childbirth, affects as many as 1 in 7 women and is one of the most common complications of pregnancy and the postpartum period. It is well established that perinatal depression can result in adverse short- and long-term effects on both the woman and child. Objective: To issue a new US Preventive Services Task Force (USPSTF) recommendation on interventions to prevent perinatal depression. Evidence Review: The USPSTF reviewed the evidence on the benefits and harms of preventive interventions for perinatal depression in pregnant or postpartum women or their children. The USPSTF reviewed contextual information on the accuracy of tools used to identify women at increased risk of perinatal depression and the most effective timing for preventive interventions. Interventions reviewed included counseling, health system interventions, physical activity, education, supportive interventions, and other behavioral interventions, such as infant sleep training and expressive writing. Pharmacological approaches included the use of nortriptyline, sertraline, and omega-3 fatty acids. Findings: The USPSTF found convincing evidence that counseling interventions, such as cognitive behavioral therapy and interpersonal therapy, are effective in preventing perinatal depression. Women with a history of depression, current depressive symptoms, or certain socioeconomic risk factors (eg, low income or young or single parenthood) would benefit from counseling interventions and could be considered at increased risk. The USPSTF found adequate evidence to bound the potential harms of counseling interventions as no greater than small, based on the nature of the intervention and the low likelihood of serious harms. The USPSTF found inadequate evidence to assess the benefits and harms of other noncounseling interventions. The USPSTF concludes with moderate certainty that providing or referring pregnant or postpartum women at increased risk to counseling interventions has a moderate net benefit in preventing perinatal depression. Conclusions and Recommendation: The USPSTF recommends that clinicians provide or refer pregnant and postpartum persons who are at increased risk of perinatal depression to counseling interventions. (B recommendation).

Clinical Usefulness of Bright White Light Therapy for Depressive Symptoms in Cancer Survivors: Results from a Series of Personalized (N-of-1) Trials.

Purpose: Little is known about the effectiveness of bright white light therapy (BWL) for depressive symptoms in cancer survivors, many of whom prefer non-pharmacological treatments. The purpose of this study was to compare the effectiveness of BWL versus dim red light therapy (DRL) on depressive symptoms within individual cancer survivors using personalized (N-of-1) trials. Methods: Cancer survivors with at least mild depressive symptoms were randomized to one of two treatment sequences consisting of counterbalanced crossover comparisons of three-weeks of lightbox-delivered BWL (intervention) or DRL (sham) for 30 min each morning across 12 weeks. A smartphone application guided cancer survivors through the treatment sequence and facilitated data collection. Cancer survivors tracked end-of-day depressive symptoms (primary outcome) and fatigue using visual analog scales. Within-patient effects of BWL were assessed using an autoregressive model with adjustment for linear time trends. Results: Eight of nine cancer survivors completed the 12-week protocol. Two survivors reported significantly (i.e., p < 0.05) lower depressive symptoms (-1.3 ± 0.5 and -1.30 ± 0.9 points on a 10-point scale), five reported no difference in depressive symptoms, and one reported higher depressive symptoms (+1.7 ± 0.6 points) with BWL versus DRL. Eight of nine cancer survivors recommended personalized trials of BWL to others. Conclusions: There were heterogeneous effects of three-week BWL on self-reported depressive symptoms among cancer survivors, with some finding a benefit but others finding no benefit or even harm. Implications for Cancer Survivors: Personalized trials can help cancer survivors learn if BWL is helpful for improving their depressive symptoms.

Interventions to Prevent Falls in Community-Dwelling Older Adults: US Preventive Services Task Force Recommendation Statement.

Importance: Falls are the leading cause of injury-related morbidity and mortality among older adults in the United States. In 2014, 28.7% of community-dwelling adults 65 years or older reported falling, resulting in 29 million falls (37.5% of which needed medical treatment or restricted activity for a day or longer) and an estimated 33 000 deaths in 2015. Objective: To update the 2012 US Preventive Services Task Force (USPSTF) recommendation on the prevention of falls in community-dwelling older adults. Evidence Review: The USPSTF reviewed the evidence on the effectiveness and harms of primary care-relevant interventions to prevent falls and fall-related morbidity and mortality in community-dwelling older adults 65 years or older who are not known to have osteoporosis or vitamin D deficiency. Findings: The USPSTF found adequate evidence that exercise interventions have a moderate benefit in preventing falls in older adults at increased risk for falls and that multifactorial interventions have a small benefit. The USPSTF found adequate evidence that vitamin D supplementation has no benefit in preventing falls in older adults. The USPSTF found adequate evidence to bound the harms of exercise and multifactorial interventions as no greater than small. The USPSTF found adequate evidence that the overall harms of vitamin D supplementation are small to moderate. Conclusions and Recommendation: The USPSTF recommends exercise interventions to prevent falls in community-dwelling adults 65 years or older who are at increased risk for falls. (B recommendation) The USPSTF recommends that clinicians selectively offer multifactorial interventions to prevent falls in community-dwelling adults 65 years or older who are at increased risk for falls. Existing evidence indicates that the overall net benefit of routinely offering multifactorial interventions to prevent falls is small. When determining whether this service is appropriate for an individual, patients and clinicians should consider the balance of benefits and harms based on the circumstances of prior falls, presence of comorbid medical conditions, and the patient's values and preferences. (C recommendation) The USPSTF recommends against vitamin D supplementation to prevent falls in community-dwelling adults 65 years or older. (D recommendation) These recommendations apply to community-dwelling adults who are not known to have osteoporosis or vitamin D deficiency.

Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: US Preventive Services Task Force Recommendation Statement.

Importance: Because of the aging population, osteoporotic fractures are an increasingly important cause of morbidity and mortality in the United States. Approximately 2 million osteoporotic fractures occurred in the United States in 2005, and annual incidence is projected to increase to more than 3 million fractures by 2025. Within 1 year of experiencing a hip fracture, many patients are unable to walk independently, more than half require assistance with activities of daily living, and 20% to 30% of patients will die. Objective: To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on vitamin D supplementation, with or without calcium, to prevent fractures. Evidence Review: The USPSTF reviewed the evidence on vitamin D, calcium, and combined supplementation for the primary prevention of fractures in community-dwelling adults (defined as not living in a nursing home or other institutional care setting). The review excluded studies conducted in populations with a known disorder related to bone metabolism (eg, osteoporosis or vitamin D deficiency), taking medications known to be associated with osteoporosis (eg, long-term steroids), or with a previous fracture. Findings: The USPSTF found inadequate evidence to estimate the benefits of vitamin D, calcium, or combined supplementation to prevent fractures in community-dwelling men and premenopausal women. The USPSTF found adequate evidence that daily supplementation with 400 IU or less of vitamin D and 1000 mg or less of calcium has no benefit for the primary prevention of fractures in community-dwelling, postmenopausal women. The USPSTF found inadequate evidence to estimate the benefits of doses greater than 400 IU of vitamin D or greater than 1000 mg of calcium to prevent fractures in community-dwelling postmenopausal women. The USPSTF found adequate evidence that supplementation with vitamin D and calcium increases the incidence of kidney stones. Conclusions and Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of vitamin D and calcium supplementation, alone or combined, for the primary prevention of fractures in community-dwelling, asymptomatic men and premenopausal women. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with doses greater than 400 IU of vitamin D and greater than 1000 mg of calcium for the primary prevention of fractures in community-dwelling, postmenopausal women. (I statement) The USPSTF recommends against daily supplementation with 400 IU or less of vitamin D and 1000 mg or less of calcium for the primary prevention of fractures in community-dwelling, postmenopausal women. (D recommendation) These recommendations do not apply to persons with a history of osteoporotic fractures, increased risk for falls, or a diagnosis of osteoporosis or vitamin D deficiency.

Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement.

Importance: Neural tube defects are among the most common major congenital anomalies in the United States and may lead to a range of disabilities or death. Daily folic acid supplementation in the periconceptional period can prevent neural tube defects. However, most women do not receive the recommended daily intake of folate from diet alone. Objective: To update the 2009 US Preventive Services Task Force (USPSTF) recommendation on folic acid supplementation in women of childbearing age. Evidence Review: In 2009, the USPSTF reviewed the effectiveness of folic acid supplementation in women of childbearing age for the prevention of neural tube defects in infants. The current review assessed new evidence on the benefits and harms of folic acid supplementation. Findings: The USPSTF assessed the balance of the benefits and harms of folic acid supplementation in women of childbearing age and determined that the net benefit is substantial. Evidence is adequate that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. Therefore, the USPSTF reaffirms its 2009 recommendation. Conclusions and Recommendation: The USPSTF recommends that all women who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 µg) of folic acid. (A recommendation).

A Biobehavioral Framework to Address the Emerging Challenge of Multimorbidity.

Multimorbidity, the co-occurrence of multiple physical or psychological illnesses, is prevalent particularly among older adults. The number of Americans with multiple chronic diseases is projected to increase from 57 million in 2000 to 81 million in 2020. However, behavioral medicine and health psychology, while focusing on the co-occurrence of psychological/psychiatric disorders with primary medical morbidities, have historically tended to ignore the co-occurrence of primary medical comorbidities, such as diabetes and cancer, and their biopsychosocial implications. This approach may hinder our ecologically valid understanding of the etiology, prevention, and treatment for individual patients with multimorbidity. In this selective review, we propose a heuristic behavioral framework for the etiology of multimorbidity. More acknowledgment and systematic research on multiple, co-existing disorders in behavioral medicine are consistent with the biopsychosocial model's emphasis on treating the "whole person," which means not considering any single illness, its symptoms, risk factors, or mechanisms, in isolation. As systems analytics, big data, machine learning, and mixed-model trajectory analyses, among others, come online and become more widely available, we may be able to tackle multimorbidity more holistically, efficiently, and satisfactorily.

Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this study was to review the effects of vitamin D supplementation on depressive symptoms in randomized controlled trials. Although low vitamin D levels have been observationally associated with depressive symptoms, the effect of vitamin D supplementation as an antidepressant remains uncertain. METHODS: MEDLINE, CINAHL, AMED, PsycINFO, Scopus, The Cochrane Library, and references of included reports (through May 2013) were searched. Two independent reviewers identified and extracted data from randomized trials that compared the effect of vitamin D supplementation on depressive symptoms to a control condition. Two additional reviewers assessed study quality using The Cochrane Risk of Bias Tool. Seven trials (3191 participants) were included. RESULTS: Vitamin D supplementation had no overall effect on depressive symptoms (standardized mean difference [SMD], 0.14; 95% confidence interval [CI], -0.33 to 0.05, p = .16), although considerable heterogeneity was observed. Subgroup analysis showed that vitamin D supplementation for participants with clinically significant depressive symptoms or depressive disorder had a moderate, statistically significant effect (2 studies: SMD, -0.60; 95% CI, -1.19 to -0.01; p = .046), but a small, nonsignificant effect for those without clinically significant depression (5 studies: SMD, -0.04; 95% CI, -0.20 to 0.12; p = .61). Most trials had unclear or high risk of bias. Studies varied in the amount, frequency, duration, and mode of delivery of vitamin D supplementation. CONCLUSIONS: Vitamin D supplementation may be effective for reducing depressive symptoms in patients with clinically significant depression; however, further high-quality research is needed.