Hikikomori, pathological social withdrawal, is becoming a crucial mental health issue in Japan and worldwide. We have developed a 3-day family intervention program for hikikomori sufferers based on Mental Health First Aid (MHFA) and Community Reinforcement and Family Training (CRAFT). This study aims to confirm the effectiveness of the 3-day program by a randomized controlled trial.SD, 7.8), and 14 to the Program group . This study was discontinued due to the COVID-19 pandemic; the recruitment rate was 36.3% of our target sample size of 80.This study was registered on the UMIN Clinical Trials Registry (UMIN000037289). Fifteen parents were assigned to the treat as usual (TAU) group  in the Program group and one participant (7.7%) in the TAU group reported actual behavioral changes .We could not draw general conclusions on the effectiveness of the program due to the study discontinuation. Nevertheless, this study indicates the necessity for revision of the program to improve family members’ confidence in engaging with hikikomori sufferers, with safer approaching by families. Pathological social withdrawal  is a condition avoiding social participation and staying at home almost every day for 6 months or longer . Hikikom1). The study was a single-center, open-label, randomized trial, and allocation results were open to both participants and program providers. Participants were family members living with hikikomori sufferers. Participants were assigned in a 1:1 ratio to the standard intervention (family support) plus 3-day program (Program group) or the standard intervention only (TAU group) according to the randomization procedure described in Randomization.This study was registered on the UMIN Clinical Trials Registry (UMIN-CTR)  living with hikikomori sufferers (2) participant receiving standard hikikomori family support  (3) age 20 years or older (4) hikikomori duration of their hikikomori sufferer was at least 6 months. The exclusion criteria were as follows; (1) participants have learned MHFA program previously, (2) hikikomori sufferers had continuously used the support institutions within the past 6 months, (3) difficulty in reading or writing Japanese, (4) difficulty in attending the program continuously due to a serious physical or psychiatric symptoms, (5) daily violence from the hikikomori sufferers, (6) the intervention is likely to cause danger to the participants or their family due to severe aggression of hikikomori sufferers, (7) the intervention is likely to cause hikikomori sufferers’ suicidal ideation or self-harming behavior.Standard intervention (TAU) in this study is defined as continuous consultation or advice provided to a family member in person or by telephone at a hikikomori support institution such as mental health welfare center, hikikomori community support center, family association, youth support station, non-profit organization, community health center, medical institution, consultation center, social welfare council, or school.Candidates were recruited through hikikomori support institutions including Kyushu University Hospital and related medical institutions, Fukuoka City Mental Health and Welfare Center, Fukuoka Hikikomori Community Support Center, hikikomori family associations, and public health centers in Fukuoka city. Candidates who applied to the study were contacted by phone to confirm eligibility and exclusion criteria. Recruitment began in June 2019; however, the study was discontinued in December 2020 due to COVID-19 pandemic in Japan.Assignment was performed by the co-author (JK), a biostatistician in the Center for Clinical and Translational Research, Kyushu University. Randomization was assured because of his complete independence of program providers. Participants were assigned to the Program group or the TAU group immediately after the baseline interview to ascertain eligibility criteria and informed consent. Assignment included a 2 × 2 stratification with family avoidance by hikikomori sufferers and hikikomori duration (≥ 24 months/< 24 months) as allocation factors. The study was an open-label randomized trial, and allocation was open to both participants and program providers.For the Program group, a program consisted of three sessions (3-day program) was implemented after informed consent. During the program, participants continued the standard intervention. The program was group family classes conducted fortnightly and each session was 180 min. Programs were conducted over a five-course period from June 2019 through March 2021, with group sizes ranging from 3 to 8 participants. All programs were conducted by a MHFA trainer psychiatrist TAK and two MHFA instructors, clinical psychologists (HK and HU). No follow-up sessions were held after the program; evaluations were conducted by mailed questionnaires.via mailed questionnaires at the same time as the Program group. As an ethical view, participants in the TAU group were allowed to attend the program after completion of all evaluations if they wished.Participants in the TAU group continued the standard intervention and were only evaluated No evaluation or intervention was directly conducted for their hikikomori sufferers  in either group.The 3-day program was designed to provide family members of behavioral skills using scenario role-playing as well as lectures so that they can make appropriate approaches in response to hikikomori sufferers.The program was a partially revised version of which we developed based on MHFA and CRAFT . The numSelf-administered questionnaires were implemented at four time points: within 1 month of the program , immediately after the program (T2), 2 months after the program (T3), and 6 months after the program (T4) for the Program group. For TAU group, questionnaires were administered at the same time as the Program group. All the questionnaires were mailed to the participants, and participants were asked to return them. We have collected the information on the participants (parents) themselves and their evaluation of hikikomori sufferers (child), as shown below.We measured the perceived skills of approaching to hikikomori sufferers based on the five-steps of the MHFA, as evaluated in our previous studies , 7. We pWe measured the confidence associated with MHFA, stigma toward mental health problems, depressive symptoms and stress responses among participants, and problematic and adaptive behaviors in hikikomori sufferers. These measures were identical to our previous studies , 7.For confidence, the original 6-item scale was administered . Based oFor stigma, the Japanese version of the 12-item Link’s Devaluation-Discrimination Scale was administered . RespondParticipants’ depressive symptoms were assessed using the Japanese version of the Patient Health Questionnaire (PHQ-9) , 15. ThiThe Stress Response Scale-18 (SRS-18) was used to assess participants’ psychological stress responses . This scThe Hikikomori Behavior Checklist (HBCL) was used to assess the problematic behaviors of hikikomori sufferers . This scThe Adaptive Behaviors Scale for Hikikomori (ABS-H) was used for hikikomori sufferers’ adaptive behaviors . This scIn addition, we conducted the Family Attitude Scale (FAS) to measure participants’ negative attitudes toward hikikomori sufferers . The FASBesides these self-administered questionnaires, participants were asked to report actual behavioral changes such as social participation and adverse events including self-harm and aggressive behaviors among hikikomori sufferers. In the present study, two couples participated in each group; we incorporated maternal report because mothers tend to spend more time with hikikomori sufferers in many hikikomori cases.Based on the results of previous pilot studies , 7, the In this study, statistical analysis was performed with reference to previous RCTs reporting the efficacy of MHFA , 21. DatFor social participation, other behavioral changes, and adverse events among hikikomori sufferers, odds ratios were calculated in each time point based on parental reports.p < 0.05.All the analyses were performed using R version 4.1.3 , with a SD, 8.56) and 15 to the TAU group . Fourteen participants were assigned to the Program group .This is the first pilot RCT study to examine the effectiveness of family intervention program for hikikomori. The program seems to have some merits for family members of hikikomori on families’ skill improvement and behavioral changes among the hikikomori sufferers. However, this study was aborted due to the COVID-19, thus we could not draw general conclusions on the effectiveness of the program. Nevertheless, we believe that some important findings were observed in this study. Interestingly, the present study suggested that confidence decreased in both groups. This implies that standard family support (TAU) as well as the present program would decrease confidence of family members approaching hikikomori sufferers. Decrease in confidence in the Program group would be attributed to the increase in revised program content as a result of the addition of active listening and small-step approaches. This might have caused the participants to learn more skills and to feel difficulty, resulting in decreased confidence. In addition, although no serious violence or self-harm was reported in this study, hikikomori sufferers would have shown mental health issues such as depressed mood. It is possible that hasty approaches by family to such hikikomori sufferers may have led to a decreased confidence for not succeeding in affecting behavioral changes of hikikomori sufferers. Increase in avoidance of conversation was suggested among Program group at T4 (6 months later), which may be the result of undesirable family approaches. Monthly follow-up session was conducted in the previous studies; follow-ups after program would be important to evaluate the family’s engagement and to establish skill acquisition. Decreased confidence in the TAU group might be related to different factors as to the Program group. The TAU group showed improved mental health, possibly suggesting that families may be remaining psychologically stable while avoiding confronting hikikomori sufferers. In other words, the family members turn a blind eye and the behavioral changes in hikikomori sufferers would not occur, resulting in the decreased confidence among families. As families’ confidence declines, they might get more reluctant to be in touch with the hikikomori sufferers, leading to prolonged hikikomori. In addition, changes in both problematic and adaptive behaviors were observed in the Program group, suggesting that behavior changes may be more likely to occur by this program. Based on previous studies, we believe that encouraging family to get involved in their hikikomori sufferers is meaningful . In addiTherefore, we should revise this intervention program by improving family members’ confidence in engaging with hikikomori sufferers, with safer approaching by families to their hikikomori sufferers. Hikikomori sufferers and their families show diversity; considering their individuality may lead to a safer approach . AssessiSeveral limitations can be assumed for this study. As noted above, this study recruited only 36.25% of the target sample size, which would have limited its statistical power. Therefore, we have discussed with cautious and proposed future directions. In the future, the study design must be revised to allow for adequate recruitment of participants using online systems even in COVID-19 pandemic (The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Ethics Committee of Kyushu University Hospital. The patients/participants provided their written informed consent to participate in this study.HK, HU, SK, TK, TN, and TAK conceived and designed the study. JK performed sample size estimation and conducted assignment of participants. MS, SN, KS, MT, KK, DF, NH, YS, KO, and TK contributed to modifying the program and provided program materials. HK, HU, YH, and TAK recruited the participants and collected data. HK, HU, and TAK implemented the program and analyzed the collected data. HK and TAK wrote the first draft of the manuscript. DF, HU, JK, KS, KK, KO, MT, MS, NH, SK, SN, TN, TK, and YH commented on the manuscript. All authors carefully read the manuscript and approved the final version for submission.


The use of botanical drugs is integral to healthcare practices of indigenous populations. From there stems–combined with a growing interest in and popularity of using botanical medicines and supplements in everyday healthcare and wellbeing–the steady increase in demand for readily available herbal products that are efficacious, safe and of high quality . BotanicMethods of extraction, concentration, purification, and isolation have been an integral part of botanical medicine since its onset. Along with the increase of knowledge and understanding of the phytochemical and phytopharmaceutical properties of botanical ingredients, they have developed from simple infusions, decoctions and macerations into complex processes involving multiple steps and solvents. Indeed, with a better understanding of the characteristics of single actives or matrices thereof, suitable processing methods such as extraction and fractionation utilizing appropriate solvent systems have gained upmost importance.Herein also lies the danger for emergence of a disjunct between the interests of academia, industry, healthcare regulators and the consumer: academia must be careful not to conduct research for research’s sake and create output that–while novel and groundbreaking–is challenging to incorporate into products or communicate to the consumer. Study of effects or compounds outside the realm of traditional uses or to address severe disease states may serve as an example here, as it puts the onus of translating results of preclinical research and conducting clinical research sufficient both in quantity and quality to meet the requirements of healthcare regulations on  manufacturers, not to forget building sustainable supply chains, which can easily become economically unobtainable or simply not practical, especially if the resulting product would be of a narrow therapeutic spectrum. This statement, however, should not be misconstrued as dismissive of cutting-edge research of compounds, their effects, and their purification, isolation and even synthetization, but rather serve as a reminder, just as much to industry, that innovation needs to include collaboration from an early stage onward in order to create botanical products that address and meet market demands .The composition of herbal extracts, fractions, or isolates, as well as their bioavailability, very much depend on the processing methods applied. Conversely, the suitability of an extract for the desired dosage form and finished product, such as hygroscopicity, heat stability, and thus, e.g., the need for excipients, must be taken into account when creating and investigating botanical ingredients for commercial applications.https://www.frontiersin.org/articles/10.3389/fphar.2022.963160/full)• Elucidation of novel activities through fractionation of traditional medicines (https://www.frontiersin.org/articles/10.3389/fphar.2022.980066/full)• Tools to examine functional properties of compounds obtained from plant extracts • Processing methods impacting extract properties (https://www.frontiersin.org/articles/10.3389/fphar.2022.1013340/full)• Extract properties determining suitability for dosage forms • Analytical methods for the determination of authenticity of botanical extracts in finished products (https://www.frontiersin.org/articles/10.3389/fphar.2022.981978/full)• Labeling of botanical extracts in finished products from a regulatory perspective  speaks to the pigmentation effect of Epimedium brevicornum Maxim. ethanolic extract and identifies epimedin B as an effective melanogenic compound. Authors of (https://www.frontiersin.org/articles/10.3389/fphar.2022.980066/full) have explored the versatility of yeast (Saccharomyces cerevisiae) in assessing the antioxidant and anti-aging capacities of flavonoids extracted from plant material. Authors of (https://www.frontiersin.org/articles/10.3389/fphar.2022.1007746/full) and (https://www.frontiersin.org/articles/10.3389/fphar.2022.1003209/full), investigated how harvesting, processing, drying and other processing steps affect properties and composition of extracts made from ginkgo (Ginkgo biloba L.) and chamomile (Matricaria chamomilla L.), respectively. Authors of (https://www.frontiersin.org/articles/10.3389/fphar.2022.1013340/full) discuss the impact of botanical extracts’ compounds and physical properties on their suitability of use in herbal tea formulation. The focus of (https://www.frontiersin.org/articles/10.3389/fphar.2022.925298/full) and (https://www.frontiersin.org/articles/10.3389/fphar.2022.931203/full) lies on the application of analytical methods, such as HPTLC and FTIR spectroscopy in quality assessment and the identification of adulterants in finished herbal products. Last, but not least (https://www.frontiersin.org/articles/10.3389/fphar.2022.981978/full) discusses the challenges of labelling botanical extracts as to appropriately inform manufacturers and consumers of their quality while adhering to regulatory requirements.Specifically (It is hoped that the collection of publications presented in this Research Topic will stimulate further research and collaboration between academia, industry, and regulators with the goal of developing and incorporating botanical extracts that are suitable for use, and safe and efficacious ingredients in a wide variety of botanical products.


Home-delivered, medically supportive meals may improve food security status, HIV viral suppression, and immune health for low-income PLHIV in rural settings.Food insecurity disproportionately affects rural communities and people living with HIV (PLHIV). The Food Access Pilot Project (FAPP) was a California state-funded program that provided home-delivered, medically supportive meals via online meal vendors to food-insecure PLHIV in three rural counties. We performed longitudinal, retrospective analyses of FAPP participant data  over 36 months from a Ryan White client management database. Pre-post analyses demonstrated increased prevalence of food security and CD4 ≥ 500 between baseline and 12 months. Population-averaged trends using generalized estimating equations adjusted for participant demographics demonstrated increased odds of viral suppression and CD4 ≥ 500, and increased CD4 count (cells/mm Amongst people living with HIV (PLHIV), food insecurity—a state of limited access to nutritionally adequate food—is a well-documented driver of poor health outcomes, including lower viral load suppression and CD4 counts , 2, decrAmong people with HIV, diabetes and/or other chronic health conditions, programs providing medically supportive food—meals and groceries that meet basic nutritional needs and follow medical guidelines for disease prevention and management—have recently been shown to improve food security, mental health outcomes and chronic disease management , 15. MedThus far, many medically supportive food interventions have been implemented by large, non-profit organizations based in or near urban areas. Several prominent groups include Community Servings in Boston, Massachusetts, the Metropolitan Area Neighborhood Nutrition Alliance (MANNA) in Philadelphia, Pennsylvania, and Project Open Hand in San Francisco, California. In comparison, there is a relative paucity of medically supportive food interventions that address food insecurity in rural areas or that serve rural PLHIV, indicating the need for expanded approaches to provide nutrition services to PLHIV in rural communities.The Food Access Pilot Project (FAPP) was a California state-funded program administered by The Health Trust, a non-profit organization based in the San Francisco Bay Area. It aimed to improve the health and nutrition of PLHIV in three rural CA counties  by home-delivering individualized, medically supportive meals and pantry boxes via online vendors, while also connecting clients with telephone-based support from a registered dietitian (RD). As part of an external evaluation of this program, we assessed for changes in food security and HIV health outcomes, including viral load and CD4 count, amongst FAPP clients over the course of program participation. Based on prior published research, we hypothesized that FAPP participation would be associated with improvement in food security status and HIV clinical outcomes.We performed retrospective, longitudinal analyses of FAPP participant data from a Ryan White client management database, including food insecurity status and HIV clinical health outcomes, before and after program enrollment.The FAPP program was funded and initiated by the California State Office of AIDS (CDPH/OA) in response to concerns that food insecurity was a pressing area of need for PLHIV throughout the state—and particularly, in rural counties. For this pilot program, the CDPH/OA identified counties that lacked robust food bank utilization but had reliable case management services integrated with the AIDS Regional Information and Evaluation System (ARIES) (see Data Source below). While the goal of the FAPP program is to expand to all areas with need, these criteria allowed for the identification of pilot counties that had both a strong need for food support as well as a working infrastructure for patient referral and outcomes assessment. This led to the inclusion of Humboldt, Napa, and San Joaquin counties. Humboldt is over 300 miles north of the San Francisco Bay Area near the Oregon border and is the most rural of the three counties; Napa is in the greater Bay Area and is home to many lower-income communities despite its famous wineries; and San Joaquin is located within the agricultural Central Valley, which is predominantly rural but contains urban centers (e.g. Stockton).To be eligible for FAPP program enrollment, clients were required to be eligible for and enrolled in Ryan White , have a positive screen for food insecurity based on a two-item screener , and livThe FAPP program was implemented remotely by The Health Trust, a non-profit organization based in the San Francisco Bay Area, whose mission is to build health equity in Silicon Valley. It provides funding, direct services, and advocacy to improve health through food, housing, and chronic disease prevention and management.As part of the FAPP program, clients could receive either home-delivered prepared meals or meal kits on a weekly basis, which were intended to provide approximately 30% of clients’ daily nutritional needs. Those who expressed further need could receive an additional monthly pantry box with non-perishable grocery items. All meals, meal kits, and pantry boxes were purchased by Health Trust staff for FAPP clients through online commercial meal vendors , and all vendors were vetted to ensure the quality and nutritional value of the food support and their ability to deliver to rural areas. Health Trust staff involved with day-to-day management of the FAPP program included a program coordinator and a RD.Beginning in January 2017, local case managers in Humboldt, Napa, and San Joaquin counties referred food-insecure, Ryan White eligible HIV patients on a rolling basis to Health Trust staff for enrollment into the FAPP program. The Health Trust RD then contacted each new client via telephone to discuss their health needs, medical comorbidities, and food preferences in order to select the optimal format and contents of the food that would be provided. For example, clients with limited kitchen access or physical limitations hindering food preparation were able to choose the prepared meals option, while those who preferred to cook their own meals could choose to receive meal kits. Throughout the program, the RD provided nutritional counseling and support as needed, and clients were able to switch between meals and meal kits if they wished. Health Trust staff also routinely checked in with clients to offer support and address any issues with food delivery or program participation.All meals, meal kits and pantry boxes were provided at no cost to program participants, and meal deliveries continued until a recipient chose to withdraw or could not be contacted by program staff or county case managers. Due to rolling enrollment, the duration of program enrollment amongst clients ranged from several months to several years.With approval from the CDPH/OA, which funded both the FAPP program and the subsequent program evaluation, The Health Trust provided the evaluation team with de-identified data from ARIES, a statewide HIV/AIDS client management database funded and overseen by the CDPH/OA. ARIES tracks and supports the coordination of care provided by Ryan White-funded service providers for PLHIV covered by the Ryan White HIV/AIDS Care Act. When PLHIV access Ryan White clinical care or ancillary services, data from these encounters  are entered into ARIES and viewable to other Ryan White providers. All HIV health outcomes in ARIES used for this analysis involved lab data resulting from healthcare visits conducted as part of usual HIV care received by the client, i.e. not for research purposes or related to the FAPP program. During the program, Health Trust staff also entered data on client demographics and food insecurity into ARIES for internal assessment purposes. The evaluation team received de-identified ARIES data for FAPP participants on health and program variables dated from January 2017 through March 2019.Given that HIV outcomes data in ARIES came from healthcare encounters and not research assessments, HIV viral load and CD4 count data were not available at pre-set or prescribed intervals in relation to the FAPP program. Instead, they were distributed unevenly, with gaps of various intervals between consecutive tests. Given this dispersed data structure, as well as rolling enrollment into the FAPP program, we created an analytic dataset by first processing each client’s data relative to their own enrollment date. ARIES data was available for the greatest number of clients during a 36-month window from 24 months prior to enrollment to 12 months after, with significant drop-off in data availability outside of this time frame , per CDC definitions , which s3 (CD4 ≥ 500), a standard clinical marker of healthy immune function [We determined whether individuals had a CD4 count greater than or equal to 500 cells/mmfunction , 24. We First, we assessed paired outcomes at baseline and 12 months amongst clients with data available at both time points . Baseline values were identified as the outcome closest to enrollment prior to enrollment within a 6-month window. The 12-month values were the outcomes recorded closest to 12 months, between 6 to 12 months of enrollment. If a participant did not have an outcome value in both of these time ranges, they were excluded from the paired analysis. We used McNemar’s test to assess changes in the proportion of clients achieving food security, viral suppression, undetectable viral load and CD4 ≥ 500. A pre-post difference was statistically significant at α = 0.05 using the Exact McNemar’s significance probability.Given the small sample sizes available for the paired pre-post analysis described above, we then used generalized estimating equations to estimate population-averaged trends in viral suppression, undetectable viral load, CD4 ≥ 500, and continuous CD4 count at 6-month intervals between baseline and the first 12 months of program enrollment, spanning 18 months total (“program trends”). Logistic regression with GEE was used to assess dichotomous outcomes and linear regression with GEE was used to assess the continuous outcome, with the time interval as the primary explanatory variable. All models were adjusted for age, gender, race/ethnicity and county to address potential confounding by demographic or geographic differences, and used robust standard errors. A sensitivity analysis was conducted including “time on ART” as an additional covariate. This variable was not included in the main analysis given that about one-third of participants were missing data on their duration of ART.Finally, we took advantage of the existence of the longitudinal pre-program data 24 months prior to enrollment up until 6 months prior to enrollment , in order to assess population-averaged trends in clinical outcomes in the period immediately prior to the baseline (“pre-program trends”). The purpose of this analysis was to address the possibility that any program trends in viral load or CD4 count we observed could be the result of pre-existing trends.Stata 16  was used for all analyses. The UCSF IRB designated this program evaluation utilizing de-identified secondary data as a quality improvement initiative rather than human subjects research, and so did not exercise direct oversight of the evaluation. The release of the de-identified secondary data was approved by CDPH/OA, and the evaluation team practiced rigorous procedures to protect the confidentiality of participant data. As part of FAPP program enrollment, all participants provided written consent to have their ARIES data shared for evaluation purposes.We analyzed the demographics and health characteristics of 191 FAPP participants enrolled between January 2017 and March 2019 , viral load (n = 45) and CD4 count (n = 33) at baseline and 12 months. On average, participants from San Joaquin county were less likely to have paired data compared to those from Humboldt and Napa. There were no significant differences in terms of age, gender, and race between those with paired data and those without.At baseline, all FAPP clients screened positively for food insecurity, i.e. none were food secure. After 12 months, the proportion of clients reporting food security increased significantly from 0% to 62.1% (p < 0.001) (Table Amongst clients with data at baseline and 12 months (n = 45), we observed an increase in the proportion of individuals with viral suppression  and undetectable viral load  at 12 months, though these results were not statistically significant (Table Amongst clients with data at baseline and 12 months (n = 33), we observed an increase in the proportion of individuals with CD4 ≥ 500   and 460 person-time observations  for CD4 count.For every 6 months of FAPP enrollment, there were 91.2% increased odds  of viral suppression Table . There w3 (p = 0.010) for every 6 months of enrollment. Prior to enrollment, there was an increase in CD4 count of 16.5 cells/mm3 which was not statistically significant (p = 0.138).For every 6 months of FAPP enrollment, there were 42.8% increased odds  of CD4 ≥ 500  in order to participate . In the The FAPP model has several key features, including the use of online meal vendors, involvement of a registered dietitian, and integration of local case management infrastructure, which speak to both the potential benefits and drawbacks of this program model for rural—and urban—underserved areas. A program report detailing results from semi-structured interviews with FAPP stakeholders  suggeste. However, direct RD involvement tends to also raise the cost of food programs and may not be strictly necessary for all activities; finding alternatives may help to make the program more sustainable. Finally, the program model leveraged the expertise and existing relationships of county case managers with their clients, which were critical for program recruitment and client retention. Counties without strong case-management programs—which may also have a higher need for programs like the FAPP—may not be able to equally participate in and benefit from this type of program model. While our results indicate that the FAPP is promising, key practical considerations need to be addressed for programs utilizing similar models to sustainably improve the health for PLHIV in rural areas on a wider scale.Program stakeholders previously reported that centralized RD support was among the FAPP program benefits . The RD,The results of this study should be interpreted in light of several limitations. First, this study did not include a control group, and thus we cannot rule out that the improvements we observed in viral load and CD4 count may be due to external factors rather than participation in the program itself. For instance, we cannot rule out the possibility that these results were related to ongoing, statewide efforts to decrease HIV transmissions and eliminate HIV-related deaths, or local efforts to improve HIV care in the three counties. Nonetheless, it is still plausible that these positive health outcomes are in part related to FAPP participation, as our data suggests almost no statistically significant pre-program trends, and previous qualitative interviews with stakeholders suggested perceived changes in client health outcomes. Next, our analysis was limited by a high degree of missing viral load and CD4 count data in the ARIES database—approximately 20% of clients had paired data available for the pre-post analysis, and 80% for the population-averaged trends analysis. There may be many reasons for these missing data, including patients missing care appointments, incomplete or delayed reporting of clinical data by providers, or participants visiting non-Ryan White-funded providers whose data are not reported to ARIES. It is possible that patterns of missing data could be related to patterns of change in viral load and CD4 count (e.g. if clients with more missing data were unable to access care due to more severe illness), which could bias the results away from the null. Finally, this study may not be generalizable to other rural counties within or outside of California, as the counties chosen for this program were required to have robust case management services in order to facilitate client recruitment, to minimize loss to follow-up, and for logistical coordination. This may not be the case for all counties and could potentially pose barriers to implementation.This evaluation offers insight into the feasibility and potential impact of a food support intervention designed specifically to serve a rural population with HIV. FAPP participation was associated with improvement in food security status, HIV viral suppression and immune health, suggesting a promising role for home-delivered, medically supportive meals for PLHIV in rural counties. These findings should be tested using more rigorous study designs including a control group to assess program impact. The FAPP model utilizes several innovative features to overcome rural barriers to food delivery and may offer important insight to inform the design and implementation of medically supportive food programs for vulnerable populations—both urban and rural—moving forward.


ARID1A mutational status is considered to hold prognostic significance in a range of solid malignancies, yet in endometriosis‐related ovarian carcinomas there has been a lack of clarity of its prognostic role. Moreover, the relationship between ARID1A status and immune infiltrate is also poorly understood. In a recent issue of The Journal of Pathology, a large comprehensive study by Heinze, Nazeran et al addressed these areas by reviewing 1,623 endometriosis‐associated ovarian carcinomas and correlating ARID1A status using standardised immunohistochemistry to infer mutation status, with comprehensive clinicopathological features, mismatch repair status and CD8+ tumour infiltrating lymphocytes. The study definitively showed that ARID1A status does not provide any independent prognostic value in endometriosis‐associated ovarian carcinomas. ARID1A loss was, however, shown to be associated with mismatch repair deficiency and increased CD8+ tumour infiltrating lymphocytes in endometrioid ovarian carcinoma, which may be relevant for future studies. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.The ARID1A tumour suppressor protein is a component of the SWI/SNF chromatin remodelling complex, which is mutated in approximately 20% of all human cancers.  ARID1A mutations in endometriosis‐associated ovarian cancers (EAOCs), which include endometrioid ovarian carcinoma (ENOC) and clear cell ovarian carcinoma (CCOC), has led researchers to attempt to understand its significance with respect to clinical outcomes and the tumour immune microenvironment. Thus far there has been a lack of clarity on its prognostic role in ovarian carcinomas, with previous reports showing conflicting or lack of association between ARID1A status and clinical outcome. Studies using genetically engineered mouse models have shown that ARID1A deficiency leads to increases in tumour infiltrating lymphocytes (TILs), immune checkpoint activation and subsequent sensitisation to PD‐L1 checkpoint blockade, due to a proposed loss of interaction with the mismatch repair (MMR) protein MSH2 [+ TILs in CCOC, although these studies have been limited by small sample size. To address these areas, Heinze, Nazeran et al [ARID1A mutational status as measured by protein loss using immunohistochemistry (IHC) with clinical information, MMR status and CD8+ TILs.The high prevalence of ARID1A loss of function mutations in gynaecological cancers [n = 111) and high‐grade serous ovarian cancer cases . Importantly, the authors showed that ARID1A loss is not an independent prognostic factor for either ENOC or CCOC when assessing a variety of survival metrics, including overall survival, progression‐free survival and disease‐specific survival. They confirmed, however, the importance of prognostic factors, such as the presence of residual disease and stage, with residual disease and higher stage being associated with poorer outcomes.ARID1A IHC has previously been shown to be a robust biomarker for detecting  cancers . Heinze + TILs within the tumour epithelium (933 ENOC and 480 CCOC), with ARID1A loss being associated with statistically significant higher CD8+ TILs in ENOC but not in CCOC, although a trend to higher CD8+ TILs was seen. A modest yet statistically significant overall survival benefit was observed in ENOC patients with high CD8+ TILs scores. No such trend was observed in CCOC. CD8+ TILs were significantly associated with MMR deficiency (MMRd) in ENOC and CCOC tumours, with an overall rate of MMRd of 13% of ENOC tumours and 5% of CCOC tumours. A significant association between ARID1A loss and MMRd was noted, present in 22% of all ENOC, highlighting that ARID1A loss is probably confounded by MMRd, given MMRd results in a high mutational burden in an otherwise genomically quiet tumour type.A smaller cohort of tumours was assessed for CD8We would like to commend the authors on this impressive large‐scale international effort highlighting that ARID1A IHC is a reproducible and reliable test for loss of function mutational status, which can be used in mainstream pathology laboratories. Moreover, the authors provide clarity and definitive evidence of the lack of prognostic significance of ARID1A in EAOC. However, these results do not discount the importance of developing therapeutic strategies to target tumours with loss of ARID1A and the clinical relevance of investigating the possible predictive value of ARID1A for immune‐modulatory therapies, given the overall poor clinical outcome in these disease types. One approach utilising synthetic‐lethal approaches for targeting ARID1A‐deficient cancers with the ATR inhibitor ceralasertib with or without the  PARP (poly ADP ribose polymerase) inhibitor olaparib is being assessed in the ATARI phase II international proof‐of‐concept clinical trial. In this trial, ARID1A IHC is being used upfront to stratify patients with ovarian and endometrial clear cell carcinoma, together with other rare gynaecological tumours, into the two treatment arms depending on their ARID1A status.In this current study, the authors used tissue microarrays as a practical method for obtaining an initial insight into the pathology of each sample. One limitation is that a tissue microarray may fail to accurately capture subclonal staining patterns and intra‐tumoural heterogeneity. In addition, the logistics of sequencing large numbers of patient samples to assess tumour mutational burden and to determine POLE (DNA polymerase ε) status was not possible. Future studies incorporating these elements and serial patient samples would allow a deeper assessment with respect to modern molecular prognostic subtypes of ENOC, tumour evolution and responses to treatment.+ TILs in ENOC and intra‐tumoural CD8+ immune cells suggestive of a possible role for immunotherapy. Low response rates have been demonstrated in initial clinical trials in relapsed ovarian cancer. However, CCOC has shown improved response rates compared with other epithelial ovarian cancers, including the highest response rate of 15.8% to pembrolizumab in the phase II KEYNOTE‐100 trial, compared with 8.5% in unselected ovarian cancer. NINJA, a randomised phase III trial in platinum‐resistant ovarian cancer patients, assessed nivolumab compared with chemotherapy, showing no statistically significant survival benefit, but a numerically longer overall survival in CCOC patients  in the stroma relative to tumour. The spatial location of these immune subpopulations has also been shown to hold clinical significance in a range of solid malignancies, such as colorectal, breast and lung cancer [+ cells, and this interaction results in a reduction in motility of CD8+ cells in the tumour microenvironment, ‘trapping’ them in the stroma and contributing to a T‐cell excluded tumour phenotype associated with worse outcome [ARID1A‐mutated tumours. Khalique et al [+/CD4+ regulatory T‐cells) in the stroma relative to tumours of patients with improved outcomes, suggesting that the ‘tumour‐exclusion’ of these cells is important in maintaining an effective anti‐tumour immune response. It would be useful to validate these spatial findings in larger cohorts, such as that of Heinze, Nazeran et al [Although the authors scored CD88+ cells . Recentls [et al  quantifig cancer , 6, 7, 8 outcome . This inue et al  also fouan et al .et al [+‐specific signatures. Khalique et al [et al [Recent studies have additionally used gene expression profiling to identify prognostic gene expression signatures in CCOCs. Tan et al  identifiue et al  also idel [et al  would prThis large current study highlights the importance of maintaining clinical databases , with international registry collaborations enabling a robust and powerful dataset with which one can draw definitive conclusions. ARID1A has been shown not to be an independent prognostic biomarker and is confounded by MMRd in EAOC. Ongoing research is needed to determine its clinical relevance in additional ethnic populations in a rapidly evolving landscape of treatment options and to take these findings into consideration when interpreting the results of trials where known biomarkers of response include MMRd.All authors were involved in writing and approving the final version of the manuscript.


Despite the high burden of frailty among cardiac rehabilitation (CR) participants, it is unclear which frailty-related deficits are related to program completion.Data from a single-centre exercise- and education-based CR program were included. A frailty index (FI) based on 25 health deficits was constructed. Logistic regression was used to estimate the odds of CR completion based on the presence of individual FI items. The odds of completion for cumulative deficits related to biomarkers, body composition, quality of life, as well as a composite of traditional and non-traditional cardiovascular risk factor domains were examined.A total of 3,756 individuals were included in analyses. Eight of 25 FI variables were positively associated with program completion while 8 others were negatively associated with completion. The variable with the strongest positive association was the food frequency questionnaire score , whereas the deficit with strongest negative association was a decline in health over the last year . An increased number of cardiovascular deficits were associated with an increased odds of CR completion ). A higher number of traditional CR deficits were predictive of CR completion ), but non-traditional measures predicted non-completion ).A greater number of non-traditional cardiovascular deficits was associated with non-completion. These data should be used to implement intervention to patients who are most vulnerable to drop out to maximize retention.The online version contains supplementary material available at 10.1186/s12877-022-03624-0. The efficacy of exercise-based cardiac rehabilitation (CR) for reducing complications related to cardiovascular disease has been consistently demonstrated –4. A recPatients entering CR are now older and more likely to be burdened with other health problems not necessarily related to their referring diagnosis . FrailtyPatients were eligible for CR if they experienced an acute cardiovascular event, including coronary artery disease, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft or valve surgery, heart failure or a combination of other diagnoses with few referrals . Patients were excluded if they had a critical illness  requiring other treatments or another condition that would preclude them from participating in the program, such as severe stroke. Patients were also excluded if a frailty index (FI) could not be calculated. A total of 4,004 patients enrolled in a 12-week exercise and education-based CR program between 2005–2015 were eligible for the current study .Routinely collected CR data from the nurse practitioner, dietician, and physiotherapist staff were used in this study. Clinical data were subsequently entered into a research database by a research assistant that were used for the present study. Participant characteristics included admission demographics consisting of age in years, sex , smoking status , marital status , education , employment , beta-blocker and lipid lowering medication use, and referring diagnosis (see above list for eligibility into CR).Frailty was measured with a 25-item FI at admission using a guidelines-based approach and previously used in the CR cohort . The folThe CR program was a phase two traditional center- and group-based 12-week behaviour change intervention, with sessions focused on education (1 session/week) and exercise (up to 2 sessions/week), each lasting approximately 60 min. Exercise sessions were structured as follows: a 10-min warm-up, 40 min of aerobic training, and 10 min of resistance training. The goals of the program were to reduce CVD risk factors by incorporating exercise, improving diet, and optimizing medical management. Patients were given an exercise prescription for both group-based sessions and for their home-based program. These prescriptions were individually tailored to the patient .The 12-week CR program provided patients with a multidisciplinary healthcare team, consisting of a CR program lead, nurse practitioner, nurses, physiotherapist, and dietician, guided by the cardiac medical director . Upon adp-value (0.15) [Demographic variables are presented as frequency (percent) or mean (standard deviation) for categorical and continuous variables, respectively. Demographics, and program completion across levels of frailty were compared using logistic regression. Individual variables contributing to the FI were entered into multivariable models controlling for age, sex, education, marital status, employment, smoking status, and referring diagnosis. Based on individual deficits, odds ratios for program completion and 95% confidence intervals were estimated. All variables were standardized such that the odds ratios presented represent a 10% change in each of the individual FI deficits. The cumulative effect of deficits in domains related to cardiovascular health, body composition, and quality of life categories were also investigated for eligible participants  . Effect This study was an analysis of data collected as part of a CR program. Nova Scotia Health Authority privacy policies were followed during the conduction of the study. Thus, the risk for harming individual patients was minimal. No known privacy breaches occurred during this study.A total of 4,004 individuals were eligible, and 3,756 had sufficient information to allow for the calculation of an FI at baseline. The distribution of demographic variables and baseline frailty levels stratified by CR completion are displayed in Table The ORs for completion of CR for each of the variables contributing to the FI are displayed in Fig. Further analyses aimed to identify whether a greater number of cumulative health deficits from the cardiovascular, body composition, and quality of life domains were associated with CR non-completion Fig. . An incrp < 0.001). In the non-traditional cardiovascular health domain, individuals with 8 and 9 + health deficits had significantly decreased odds of completion compared to those with no deficits  and 0.62  respectively) , and body composition variables . Further, patients who identified a negative change in their health (according to the SF-36) in the last year were less likely to complete CR. Higher scores on quality of life measured by the SF-36 , as well as fat free mass, and the food frequency questionnaire were associated with an increased odds of CR completion. A 10% increase in the food frequency questionnaire score was associated with the greatest odds of CR completion. One potential reason for this could be that those individuals who were more concerned eating a healthy diet were also most concerned with their physical health, therefore resulting in a higher odds of CR completion. These findings demonstrate that while traditionally measured factors such as biomarkers and body composition have an impact on the likelihood of completing an exercise-based CR program, so do non-traditional measures which estimate quality of life. A total of 7 unique quality of life variables were associated with CR completion. That is, a patient’s self-reported quality of life is an important aspect to focus on when identifying individuals who are at risk of drop out from CR. Quality of life-related deficits could be addressed by the addition of mental health interventions for these patients with the aim of having positive impacts on self-image, as well as physical fitness. Overall, the current investigation identifies health deficits that should be focused on by program administrators to ensure maximum retention in CR programs. In the future, patients with deficits identified by this research should be focused upon for maximal program retention.Even though we have demonstrated that older age was associated with greater CR completion rates, frailty is an independent risk factor for failure to finish the program . Here, wLower odds of completion were observed for individuals with a greater number of accumulated body composition deficits, and non-traditional cardiovascular disease deficits. This means that for each additional deficit accumulated in these domains, the likelihood of completion decreases. This finding suggests that these variables, which are not traditionally considered in the context of cardiovascular disease, have an impact on CR completion. Additionally, individuals with eight or more non-traditional cardiovascular risk factors had significantly decreased odds of completion. To our knowledge, this is the first paper to undertake this investigation. These findings highlight the importance of considering non-traditional  variables when prioritizing individuals for interventions that improve retention in CR. These non-traditional variables were mostly related to quality of life as measured by the SF-36, meaning that patients with lower self-reported quality of life are more vulnerable to program dropout. Again, this emphasizes the importance of treating disease holistically and keeping this in mind when delivering CR programs. Increased focus on quality of life could translate into increased rates of CR completion, therefore, decreasing risk of further frailty and/or complications related to CVD. This phenomenon could be investigated in the future by incorporating interventions aimed specifically at improving mental health – such as psychological counselling, or meditation – into CR; therefore increasing the number of health domains targeted by the program. Further, the effectiveness of these interventions could then be examined using a quasi-experimental study design comparing completion before and after the inclusion of these interventions.When interaction analyses were conducted, we concluded that participant factors had little impact on the associations between FI deficits and CR completion. That is, the relationships between FI contributors and CR completion were not modified by any of the demographic or participant factors that were investigated. This suggests that consideration of frailty deficits is important to maximize CR retention despite participant demographic factors. Additionally, similar strategies for retention can be applied to all participants based on their FI deficits, irrespective of their sex, referring diagnosis, or other demographic variables.Based on the individual health deficit associations, participants with worse clinical indicators, body habitus, and recent health decline were less likely to complete CR. Many potential factors could contribute to these findings, such as physicians using negative language in consultations with patients, or patients having poorer perception of their health overall based on their physical characteristics. These are examples of factors that could de-motivate patients and alter their likelihood of CR completion. On the other hand, patients with higher quality of life ratings in several categories, and those with higher fat free mass were more likely to complete the program; thus, increased quality of life could positively reinforce and motivate individuals to improve their quality of life.p-values for the individual variable analysis (Supplemental Table SThere are limitations to be considered with the present study. Regarding selection bias, individuals who did not have sufficient information to calculate an FI could have differed significantly from the remainder of the population, therefore influencing our results. However, these individuals did not differ significantly based on demographic variables, and represented a small minority of the overall sample. A second limitation includes the method by which the accumulation of deficits analysis was completed. If patients had missing values for any of the constituent variables, the maximum number of deficits that could have been identified would be one less than the total number of deficits available. However, all participants considered had enough valid variables to construct a representative FI based on guideline recommendations, which should mean that the risk of bias in this case is low. It is also important to consider that participants in this study reside in a large urban center, which may impact the generalizability of these results. This study also does not capture other reasons why people dropped out of CR; for example, younger people may be less likely to complete CR due to work or family commitments. The current study could also have issues related to multiple comparisons; however, false discovery rate testing did not detect any significant changes in Despite these limitations, our investigation advances the knowledge on how frailty contributes to completing CR. This information may be useful for program directors regarding which participants should be targeted with specific interventions for retention. That is, if administrators are aware of the most relevant frailty-related deficits, they can work to retain individuals who would otherwise be likely to drop out of the program. To identify these participants, data would have to be entered at program initiation, with a code written that could identify patients with the deficits discussed in this paper. Program administrators could then target individuals with the highest risk of drop out at program intake, based on their current deficits – both traditional and non-traditional – by offering them additional sessions or learning materials relevant to their current situation. Following this, a matched quasi-experimental study could be undertaken to compare completion rates before and after the addition of this new intervention, with the goal of identifying whether or not it was efficacious.This study adds to our knowledge of the importance of understanding frailty deficits with respect to CR completion, demonstrating the association of 16 individual frailty contributors with CR completion. Indeed, we identify specific frailty deficits which should be considered for targeted interventions in the future to retain the maximum number of participants in this CR program.Additional file 1: Table S1. Breakdown of category composition for accumulation of deficits analyses. Table S2. Frailty index variables and their respective cut-off values used at cardiac rehabilitation admission and completion. Table S3. Investigation of potential interactions between frailty index contributors and age, sex, referring diagnosis, and baseline frailty level. Table S4. False discovery rate adjusted p-values for individual frailty deficits.


Gerofit, a facility-based program transitioned to GTH, a completely virtual structured exercise program, at the onset of the pandemic and previously demonstrated that Veterans already engaged sustained performance with this transition . This study investigated whether gains in performance are achieved and sustained in Veterans who participated in GTH only, as it is unknown if virtual programs are as robust as facility-based programs. Measures of performance  and self-reported function (SF-36 + 1.8 points) will be assessed from baseline to 3,6, and 12 months. Pooled results from 14 sites have been accumulated and change scores, age and gender-based percentile changes and clinically meaningful thresholds will be presented. This knowledge can have implications to support programs for older adults aging in place.


However, to date, few adolescent dating violence (ADV) prevention programs have been developed for and evaluated with youth exposed to IPV. An exception is Moms and Teens for Safe Dates (MTSD), an evidence-based ADV prevention program for mothers or maternal caregivers (mothers) exposed to IPV and their teenagers. The MTSD program comprises a series of booklets that families complete together in a home that includes activities to promote positive family communication and healthy teenager relationships. We developed a web-adapted version of the MTSD program—entitled action plan for engaging with the program—that may increase program uptake and completion.This protocol is for a research study that has the following three main objectives: to assess the acceptability of eMTSD; to identify the feasibility of the research process, including program adherence and participant recruitment and assessment; and to explore the acceptability, feasibility, and preliminary efficacy of 2 features—text reminders and the creation of an adherence support groups (n=25 dyads per group): text reminders and action planning, text reminders only, action planning only, and no adherence supports. All participants will complete brief web-based assessments at enrollment after each module is completed, after the full program is completed, and 90 days after enrollment. Program adherence will be tracked using website use metrics.Approximately 100 mothers and their teenagers will be invited to complete eMTSD, which includes six 30-minute web-based modules over a 6-week period. Mothers will be recruited through community organizations and social media advertising and will be eligible to participate if they have at least 1 teenager aged 12 to 16 years living with them, have experienced IPV after the teenager was born, are not currently living with an abusive partner, and have access to an internet-enabled device. Using a factorial design, enrolled dyads will be randomized to the following four The data collected will be synthesized to assess the acceptability of the program and the feasibility of the study procedures. An exploratory analysis will examine the impact of adherence support on program completion levels. In November 2021, ethical approval was received and recruitment was initiated. Data collection is expected to continue until December 2022.The web-based delivery of a family-based healthy relationship program for teenagers exposed to IPV may offer a convenient, low-cost, and engaging approach to preventing ADV. The findings from this study are expected to guide future research.DERR1-10.2196/35487 You are a superstar! To stay on track, make a plan to complete Module 1 with [teen’s name] by [goal day]! Module 1 will help you and your teen talk about healthy relationships. Need technical support? We want to help! Text back ‘Y’ or call XXX-XXX-XXXX”Motivation reminder for a mother that has not logged in“Dear [mom’s name], we re-sent the login information for the Moms & Teens program to your email. This fun, convenient, and free research-based program has been shown to benefit moms and teens. Make a plan now to login this week to complete the Getting Started module and begin the program with [teen’s name] so that you can get back on track to finish the program by [goal day]. If you need technical support to login to the program text back ‘Y’ or call XXX-XXX-XXXX!”Once the recommended six week program completion period is complete, all participants who have not finished the program will be notified via email and text and asked to complete the program before the two week grace period ends.action plan in the form of implementation intentions that “spell out the where, when, and how of goal striving in advance.” Research supports this strategy, with a meta-analysis finding that implementation intentions have a moderate to large positive effect on goal attainment [action planning form administered through the REDCap  web application. The action planning form asks participants to (1) make an individual goal for when they would like to finish the program, (2) create a plan for where and when they will complete the program modules with their teenagers, and (3) complete 3 if-then statements to identify the potential barriers to completion that may arise and how they will overcome them. Mothers will be instructed that they can print or save the form to refer to if they desire.Gollwitzer  proposedtainment . Drawingfeasibility will be assessed both in reference to the research processes and to the eMTSD program; that is, feasibility outcomes provide information that enables us to assess the questions of can this study be done and can this program be done. Specifically, we define feasibility as the extent to which (1) the study is successfully conducted with respect to recruitment, randomization, delivery of adherence support, retention, and assessment, and (2) the eMTSD program can be successfully conducted by mothers and teenagers [In this study, eenagers ,25. TextRecruitment rateNumber of dyads recruited per monthEnrollment ratePercentage of eligible dyads who enroll in the studyRandomizationPercentage of enrolled dyads correctly randomizedRetention ratePercentage of enrolled dyads who complete the follow-up surveyAdherence supportsPercentage of SMS text messages eligible to be delivered and which are sentPercentage of mothers eligible for action planning who complete a planData collectionPercentage of missing data within surveysTime taken to complete surveysProgram uptake and adherencePercentage of participants who log in at least oncePercentage of participants who start the program with their teenagerPercentage of modules completed or pages viewedPercentage of enrolled participants who complete the programAdherence index, comprising the sum of the number of completed modules, number of unique visits to the site, and maximum time between visits Time taken to complete program modulesParticipant report of facilitators of and barriers to engaging with the program, including technical problems accessing or using the websiteIn this study, acceptability will be assessed in reference to the eMTSD program, as well as with respect to adherence support factors (SMS text message reminders and action planning). Drawing from the Theoretical Framework of Acceptability (TFA), we define acceptability as the extent to which mothers and teenagers consider eMTSD to be appropriate based on their cognitive and emotional responses to the intervention ,28. The Data sources for assessing feasibility and acceptability outcomes described further in the following sections include (1) web analytics , which capture data needed to assess program adherence; (2) module completion surveys, which are embedded in the web-based program and assess program acceptability; (3) program completion surveys, administered through REDCap, which assess program acceptability and barriers to completion among all participants enrolled in the study; (4) baseline and 90-day follow-up surveys, also administered through REDCap, which access constructs in the program conceptual model ; and (5)Website use data will include the number of program log-ins, pages viewed, visit times, and modules completed. In addition, the participants will be offered the opportunity to rate the selected videos and activities from 1 to 5 stars. Altogether, ratings and website use data will inform our understanding of the acceptability of videos and activities and allow for the assessment of program engagement and adherence.Brief (1- to 2-minute) module completion surveys will be embedded in the web-based program. These surveys will appear at the end of each module and solicit mother and teenager feedback on module acceptability and any technical problems encountered. Mothers and teenagers will be asked to complete separate surveys before proceeding to the next module.Both mothers and teenagers will be asked to complete the program completion surveys, which will be administered through REDCap. The links to the surveys will be emailed to the mothers after completion of the final module. Surveys will assess program acceptability indicators , as wellBaseline and follow-up surveys, administered to mothers and teenagers through REDCap at enrollment and 90 days following enrollment, will assess the demographic characteristics of participants, including both the mother’s and teenager’s past exposure to IPV (baseline only), as well as cognitions, skills, and behaviors targeted by the eMTSD program. The collection of these data will allow us to describe study participants; gauge survey length and completion rates; assess psychometric properties of key measures; and explore pre-post changes in the cognition, skills, and behaviors targeted by the program . A study tracking database will capture data on staff contacts with potential participants, telephone eligibility screens, participant enrollment, program log-in, survey completion reminders, and incentive disbursements. These data will be used to explore the effectiveness of different recruitment strategies for identifying individuals who meet the study inclusion criteria by recruitment source and participant characteristics.t tests and chi-square tests) will be used to examine associations between demographic and background characteristics of mother and teenager participants  and (1) recruitment source , (2) program adherence, (3) program acceptability, and (4) study retention. These analyses will help identify potential sources of bias and characterize program feasibility and acceptability as a function of participants’ demographic characteristics.Descriptive statistics will be used to summarize the demographic characteristics of the study population and feasibility and acceptability indicators for the sample. Bivariate statistical procedures . Paired t tests and McNemar test will be used to examine trends in pre-post changes in cognition, skills, and behaviors targeted for change by the program  based on the expectation of being in the green zone (acceptable outcome). Using this approach, an adequate sample size is that which gives high power (≥80%) to reject being in the red zone if the green zone holds true.We used the approach described by Lewis et al  to deterul) and green zone lower limit (Gll) for these outcomes are (1) the proportion of those eligible from those who enroll (Rul=0.60 and Gll=0.75), (2) the proportion of those who agree or strongly agree that the program is acceptable across all indicators >0.60 (Rul=0.55 and Gll=0.75), (3) the proportion of those enrolled who initiated the use of the program with their teenager >0.50 (Rul=0.50 and Gll=0.65), and (4) the proportion of those enrolled who completed the program >0.30 (Rul=0.30 and Gll=0.50). The null hypothesis test, for which the sample size is calculated, is that the true outcome is not greater than Rul.Three focal feasibility and acceptability outcomes were selected to determine the sample size: (1) enrollment rate, (2) overall program acceptability, (3) teenager program initiations, and (4) program completion rates. The point estimates that will be considered the red zone upper limit . Mothers who screen as eligible will be provided with information about the study and will provide electronic consent for their and their teenager’s participation. Teenagers will also complete the electronic assent form. Surveys will include referral information for support in addressing mental health and violence prevention and treatment for all participants. All project data will be deidentified before analysis and securely stored in encrypted files on servers that adhere to the University of North Carolina at Chapel Hill policy on the storage and transmission of sensitive data.This feasibility and acceptability study began recruitment in November 2021, and the study results will be available in 2023.We anticipate that this feasibility and acceptability study will determine whether the eMTSD program merits rigorous testing in future hybrid effectiveness-implementation trials. Such a trial may be designed to examine program effects on ADV outcomes and the impacts of delivery mode (web-based vs booklet) and implementation support  on D&I outcomes. Furthermore, we expect that the results of this study will inform our understanding of optimal recruitment strategies and identify potential changes to the delivery and content of the program and implementation support that would improve acceptability and feasibility.MTSD is one of the few violence prevention programs that has been developed and tested with youth exposed to IPV, and to the best of our knowledge, is the only program that targets risk and protective factors at both the family and individual levels . The feaThe limitations of this study include the use of a convenience sample, which may preclude our ability to generalize findings to the population as a whole and explore differences in findings across subgroups . In addition, survey data rely on self-reporting and are, thus, potentially susceptible to social desirability response bias. The strengths of the study include the use of a multipronged recruitment strategy, which will allow us to explore the effectiveness of different recruitment sources and the testing of different implementation strategies (action planning and text reminders) that may increase program adherence.If eMTSD is acceptable and effective in preventing ADV, it is hoped that the program may be promoted by organizations serving survivors of IPV and their families. Given the dearth of programs designed specifically for youth exposed to IPV, eMTSD may address a critical gap in ADV prevention efforts and decrease the likelihood of abusive dating and intimate partnerships during adolescence and adulthood, as well as the adverse health and social impacts of ADV and IPV.


Exposure to disasters in early life may induce lifetime health risk, but investigation on earthquake exposure and DM in later life is still limited. The aim of the current study is to evaluate the association between exposure to the Tangshan Earthquake in early life and diabetes mellitus (DM) incidence in adulthood, and explore the modification of lifestyles on DM development.Participants who were free of DM at baseline from the Kailuan Study were included in this study. All participants were divided into fetal-exposed, infant-exposed, early childhood-exposed and nonexposed group. The effect of earthquake exposure on DM and modification of lifestyles were examined by multivariable-adjusted Cox proportional hazard model.The exposed group had a higher risk of DM than nonexposed group, especially in infant-exposed and early childhood-exposed group, with hazard ratio (HR) of 1.62  and 1.46 , respectively. After stratifying by lifestyles, a significant modification was observed in alcohol consumption.Exposing to earthquake in early life could increase DM incidence in later life, and alcohol consumption might modify the effect of earthquake exposure on DM development. More attention should be paid on the preventions of DM among adults who exposed to earthquake in their early life. Diabetes mellitus (DM) is a common kind of metabolic disease globally with an estimation of 425 million afflicted individuals in 2017. The global prevalence of DM is increasing and expected to reach to 522 million by 2030  study in Tangshan, China , 13. In In this study, we included participants who participated in at least one survey from 2006 to 2017 and were born in the destructive zone of the Tangshan earthquake between July 28th, 1974 and May 4th, 1979. And the birth location of participants was collected based on the information of identification card. Inclusion criteria for birth dates was based on the Tangshan earthquake date  and gestation period of 280 days. According to the date of the Tangshan earthquake and birth date of each participant, participants born between May 4th, 1977 and May 4th, 1979 were not exposed to the earthquake, who were defined as nonexposed group, and participants born between July 28th, 1974 and May 4th, 1977 were exposed to earthquake in gestation or early life, who were defined as exposed group. Meanwhile, exposed group were further divided into fetal-exposed group with participants born between July 28th, 1976 and May 4th, 1977, infant-exposed group with participants born between July 28th, 1975 and July 28th, 1976, and early childhood-exposed group with participants born between July 28th, 1974 and July 28th, 1975. The criteria for excluded were as follow: (1) participants who were not born in the destructive zone of the Tangshan earthquake; (2) participants without location of birth; (3) participants with DM at the baseline survey. Ultimately, a total of 7,568 eligible participants were included in this study. More details of the included and excluded individuals are shown in The Tangshan earthquake was a natural disaster resulting from a magnitude 7.6 earthquake that hit the region around Tangshan, Hebei, China on July 28th, 1976. It is a kind of severe natural catastrophic event that can cause adverse physiological and mental responses. In this study, earthquake exposure was defined based on the date of the Tangshan earthquake and birth date of each participant. Earthquake severity was measured by seismic intensity according to the New Chinese Seismic Intensity Scale in 1957, which varied from I (not felt) to XI (disastrous), and the destructive zone was comprised of area where the intensity was between destructive and disastrous (V–XI) . All parThe demographic characteristics , lifestyles  and medical history of participants were collected face-to-face by trained staff using a standard questionnaire, which had been described in previous research , the earCurrent smokers were defined as individuals who have smoked at least one cigarette per day over the last 6 months. Past smokers were defined as individuals who have quit smoking before or during the baseline survey. Meanwhile, current drinkers were defined as individuals who have drunk at least once a month over the past year, and past drinkers were defined as individuals who have quit drinking before or during the baseline survey. The sedentary behavior was defined as poor, intermediate or ideal with a relative sedentary time of ≥8, 4–7 and <4 h/day, respectively. For individuals who had physical activity 1–2 times per week and lasted for more than 20 min per time were defined as intermediate physical activity. The diet status of individuals was defined as poor, intermediate and ideal based on salt intake of ≥10, 6–9 and <6 g/day, respectively .2 (m2). Biochemical evaluation used the same fasting blood sample taken in the morning. Concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were measured at Kailuan General Hospital and 10 affiliated hospitals using an autoanalyzer .DM was defined as either a self-reported physician diagnosis, or taking antidiabetic medication, or fasting blood glucose (FBG) ≥7.0 mmol/L in physical examination . Self-reχ ± s) or median values with interquartile range (IQR) were used for continuous variables. Number and percentage (%) were used to describe categorical variables. Kolmogorov–Smirnov tests were performed for checking data normality. Pearson χ2 test for categorical variables and Student t test or Mann-Whitney U test for continuous variables were used to compare the characteristics of the participants across baseline groups. The follow-up period was defined from the baseline survey to the onset of DM or the last visit on December 31th, 2017.For baseline characteristics of the study participants, mean ± standard deviation (2), high education level (below high school or high school or above), income level , earthquake bereavement  and healthy lifestyle score . Model 3 included Model 2 and additionally adjusted for systolic blood pressure (SBP) (continuous variables), diastolic blood pressure (DBP) (continuous variables), TG (continuous variables), HDL (continuous variables), and LDL (continuous variables).The comparison of the DM incidence with earthquake exposure was calculated by multivariate cox regression model, and hazard ratios (HR) with 95% CI were also calculated, with nonexposed individuals as the reference category. Except for all exposure and outcome variables, the missing covariates were imputed by multiple imputation methods . Model 1P for interaction was calculated based on the number of exposure groups (nonexposed and exposed) and the number of subgroups for each modificator in subgroup analysis. The sensitivity analysis was performed to examine the effect of earthquake bereavement. We analyzed the 2014 and 2016 bereavement questionnaires , and further compared the risk of DM with stratification of non-bereaved and bereaved earthquake survivors, with the nonexposed group as the reference. Furthermore, we compared the risk of incident DM with stratification of earthquake exposure  with the nonexposed group as the reference category. As the incidence of DM and other factors is not linearly increase with age, and the age difference between born during the earthquake and post-earthquake may introduce substantial bias in analysis. Many previous studies have employed the age-balance method to minimize the bias between earthquake (exposed group) and post-earthquake births (nonexposed group)  –20, whicP < 0.05 was considered as statistically significant.All analyses were conducted using SAS , and a two-tailed n = 1,449), were not born in earthquake destructive zone (n = 309) and had DM at the baseline (n = 194), 7,568 participants were included in this study (P < 0.05). The distributions of high education level and earthquake bereavement were significantly different in two groups (P < 0.05) In addition, the baseline characteristics were almost comparable between participants included and those excluded due to missing birth places information, except that participants without birth places information had a lower proportion of males . Compared with the nonexposed participants, the exposed participants had increased risks of DM in adulthood with HR of 1.47  after multivariable adjustment in Model 3. Furthermore, in the age-balance analysis, the group combined of pre-earthquake and post-earthquake births was set as reference group, the increased risk of DM in exposed group remained statistically significant  (As shown in 5–1.48)] .P-interaction = 0.23). However, a positive modification effect was found in an individual lifestyle factor, alcohol consumption (P-interaction < 0.05), and the HR of drinkers and non-drinkers were 1.82  and 1.14 , respectively. Sensitivity analysis showed that the incidence density of DM was 10.44/1,000 person-years and 11.35/1,000 person-year for the non-bereaved and bereaved survivors, respectively  and 1.46  after multivariable adjustment in Model 3 .To the best of our knowledge, this is the first study investigated associations between earthquake exposure in early life and risk of DM in adulthood in Asian populations. Moreover, it is also the first report about the effect of earthquake bereavement and the interaction of lifestyles and earthquake on the incidence of DM in adulthood. Our findings indicated that participants in the Tangshan earthquake exposed group were inclined to develop DM in adulthood. No interaction effect was observed between earthquake exposure and healthy lifestyle score, but an individual lifestyle factor, alcohol consumption was found that had positive modification effect on DM development. Meanwhile, compared with nonexposed participants, the bereaved survivors had increased risks of DM in adulthood, and the infant and early childhood period were specific susceptible earthquake exposure windows of DM development.Supported by the DOHaD hypothesis, previous studies have linked exposure to disaster events in early life to metabolic disorders in adulthood. Lumey et al. showed that fetuses and children exposed to the Ukraine famine of 1932–33 was associated with an increased risk of DM in adulthood, with an odds ratio (OR) of 1.47 (95% CI 1.37–1.58) and 1.26 (95% CI 1.14–1.39) in extreme famine regions and severe famine regions . As for P for trend <0.001), which indicated that more effective and sustainable mental health services were needed for bereaved survivors.Previous epidemiological and experimental studies have found that lifestyles may have impact on the risk of DM. Based on the China Cardiometabolic Disease and Cancer Cohort, Lu et al. found a significant interaction between ideal cardiovascular health metrics (ICVHMs) and famine exposure in early life on the risk of DM . KautzkyAmount studies have emphasized that the early life is a vulnerable period of development. Zhang et al. used the data from the Chronic Disease Survey and observed an increased risk of hyperglycemia in early childhood famine exposure cohort compared to the unexposed cohort with an OR of 1.46  . AnotherThe mechanisms underlying the observed association between earthquake exposure in early life and DM in adulthood is difficult to determine and should be explored further. Evidence suggests that physiological stress response due to exposure to adversity in early life may be associated with concomitant activations of stress-related biological pathways , 32, 33.The strengths of the current study include the large community-based cohort in northern China covered data on medical examinations, histories of disease, lifestyle factors, which could adjust potential confounding factors at individual level. In addition, the ages of eligible participants exposed to the Tangshan earthquake have been limited from fetal to 2 years old, which minimized the impact of aging on elevated risks of DM outcomes. However, there were several limitations to our study. First, in Kailuan study, the diagnosis of DM was based on a single measurement of FBG rather than oral glucose tolerance testing or the measurement of HbA1c, and therefore, the incidence of DM might have been underestimated. Second, our study did not distinguish between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). According to the Clinical Guideline for Prevention and Treatment of T2DM in China, T2DM represents 95% of all cases of DM. Third, all participants were employees and retirees of the Kailuan Group, and 82.07% of participants were males, and we did not further stratify the analysis by gender. In addition, the territoriality of our northern occupational population is a restriction, the generalizability of the results is relatively limited. Finally, we acknowledged that the age differences would introduce bias in the development of DM. We have tried to minimize the impact of age differences as possible by using the age-balance method, which was commonly used in previous studies. However, the limitations of combining age group were still exist.In conclusion, the cohort study among Chinese populations suggests that exposure to earthquake in early life associated with DM in adulthood, and alcohol consumption and bereavement were all have impact on the incidence of DM. Furthermore, the significant association was observed in infant and early childhood-exposed group, which indicated that the infant and early childhood periods might be the sensitive windows of exposure period. These findings provide evidence on the adverse experiences in early life linked to DM in adults and emphasize the importance of enhancing health practice and sustainable mental health services among earthquake survivors to prevent early-stage chronic metabolic disorders.