Mobile health strategies for smoking cessation  have been shown to be effective in helping smokers quit. However, further research is needed to better understand user experiences with these platforms.This qualitative study aims to explore the experiences of real-world users of a publicly available smoking cessation program (SmokefreeTXT).Semistructured phone interviews were conducted with 36 SmokefreeTXT users between March and July 2014. Of these 36 participants, 50% (18/36) of participants completed the SmokefreeTXT program , and 50% (18/36) did not complete the program . Interview questions focused on smoking behaviors, quitting history, opinions on the program’s content and structure, answering assessment questions, using keywords, reasons for opting out, and perceived usefulness of the program for quitting smoking. A thematic content analysis was conducted, with a focus on themes to increase program engagement and optimization.The findings highlighted features of the program that participants found beneficial, as well as some elements that showed opportunities for improvement to boost program retention and successful cessation. Specifically, most participants found the SmokefreeTXT program to be convenient and supportive of cessation; however, some found the messages to be repetitive and reported a desire for more flexibility based on their readiness to quit and cessation progress. We also found that program completion did not necessarily indicate successful smoking cessation and that program opt out, which might be interpreted as a less positive outcome, may occur because of successful cessation. Finally, several participants reported using SmokefreeTXT together with other evidence-based cessation methods or non–evidence-based strategies.Qualitative interviews with real-world SmokefreeTXT users showed high program acceptability, engagement with program features, and perceived utility for smoking cessation. Our findings directly informed several program updates, such as adding an adaptive quit date feature and offering supplemental information on live support services for users who prefer human interaction during the cessation process. The study has implications for other digital tobacco cessation interventions and highlights important topics that warrant future research, such as the relationship between program engagement  and successful cessation. Although cigarette smoking rates have declined over time, smoking remains the leading preventable cause of death in the United States . In 2019Despite the demonstrated efficacy of SMS text message–based smoking cessation programs in quantitative evaluations, qualitative studies of user experiences with SMS text message cessation programs are scarce -15. The To address these gaps, we explore the experiences of real-world users of a publicly available smoking cessation program (SmokefreeTXT). Specifically, we conducted qualitative interviews with real-world users  of the National Cancer Institute’s (NCI) publicly available SmokefreeTXT program to understand perceptions about program structure and content, engagement with specific program features, and perceived utility of the program for smoking cessation. We also investigate potential differences in program experience between users who completed the SmokefreeTXT program and those who opted out of the program before completion.SmokefreeTXT is a free, publicly available, fully automated SMS text message–based smoking cessation program introduced in 2011 by the NCI . The proSmokefreeTXT comprises 6 to 8 weeks of SMS text messages that provide cessation motivation, tips on preparing to quit, advice on managing cravings, quit smoking facts, and recognition of cessation milestones. SmokefreeTXT also refers program users to Smokefree web resources for more detailed smoking cessation information, as well as to the National Network of Tobacco Cessation Quitlines and the NCI Cancer Information Service. Individuals can enroll in SmokefreeTXT through the Smokefree website or by texting a keyword to a short code QUIT to 47848). At the time of enrollment, users are prompted to set a quit date within 2 weeks of enrollment. Depending on when users set their quit date, they can receive up to 2 weeks of preparation messages leading up to that date. Starting on the quit date, the 6-week intervention comprises 1 to 5 SMS text messages each day, including behavioral intervention and social support messages that target smoking cessation goals  message during a particular time of day, it would help then...I would stop and think about the things that were going on around me at that time, and then based on what I replied to the message and what my craving level was...I could say...these are the things that are making me crave.program completer, male, ex-smokerHowever, many participants reported barriers in responding to assessments, including not having time to respond, not recalling the messages, or feeling guilty for having smoked or relapsed:I’m smoking, and yet, it thinks that I’ve been quit for five days. Don’t tell. So, I’m not responding to it, but that’s because I know I slipped up. But at the same time, I still want the messages to come through.program completer, female, smokerAmong program noncompleters, more than half reported opting out because they were not successful in quitting smoking. A few participants expressed guilt about continuing to use the program while they were still smoking:Why did I opt out? Well, I started smoking again...It just would make me feel like I was lying, you know? Even if I typed in “slip,” when I throw back a pack and a half a day, that’s not a slip. That’s a habit again.program noncompleter, male, smokerSome noncompleters reported opting out as they had successfully quit smoking, and one of these participants reported opting out as the messages were becoming a trigger to smoke after he had quit.Some noncompleters reported that they opted out as a result of the volume and content of the SMS text messages. Some reported that the number of texts received per day contributed to opt out, either reporting that the number of texts per day was too high or that the decrease in messages over time was a factor in opting out:They kind of slowed down the texts, and...it kind of made me feel that I didn’t need it anymore...The messages weren’t as strong.program noncompleter, female, ex-smokerSome noncompleters also reported that they opted out because the messages on their own were not enough of a motivator to quit:I’d read the text...and then soon as I would close it out light a cigarette within two minutes...I don’t think it did a trigger...It just didn’t do anything to prevent it...it didn’t really help me to say, “okay, I’m not going to.”program noncompleter, male, smokerAlong with smoking status and SMS text message–related factors that contributed to opt out, a few participants reported that they had technical issues with their mobile phones that contributed to opt out. One of the participants reported that he no longer needed the program because he had enough social support at the time.Several participants reported that they were still smoking at the time they enrolled in SmokefreeTXT, whereas fewer said they had started their quit attempt before enrollment. Several participants reported that they joined SmokefreeTXT during one of the multiple quit attempts, and some reported that they were enrolled in the program multiple times, re-enrolling in the program after completion or opt out:...I was like, you know, I really want to quit. So I thought like maybe this [SmokefreeTXT] will work. And I tried it the first time and I quit for a while and...I had to restart it because I started smoking again. And then I was like I quit for a while and then like things just got crazy and I started smoking and then I was like “I’m going to text the [SmokefreeTXT] number again and it’s going to be the last time I do it.”program completer, female, ex-smokerhelpful and reporting that it made them feel more confident about quitting. Several participants who were smoking at the time of the study reported that, although they did not fully quit while enrolled in the program, the program helped them quit temporarily or reduce their smoking (fewer cigarettes per day and smoking less frequently).Approximately half of the participants reported that they felt that SmokefreeTXT had a positive impact on their quitting process, calling the program Half of the participants reported that although SmokefreeTXT was a useful component of their quit plan, they also relied on other strategies. Notably, several participants reported using strategies that were not evidence-based, such as switching to smokeless tobacco or using hypnosis rather than evidence-based methods such as over-the-counter nicotine replacement therapy (NRT) or prescription cessation medications. Although there are no reports on the implications for SmokefreeTXT on the effectiveness of or adherence to NRT, a couple of participants reported they were motivated to use NRT while they were enrolled in the SmokefreeTXT program, and a few participants reported that they would like SmokefreeTXT to facilitate access to NRT, such as by providing coupons. Several participants also reported using other mHealth cessation resources while enrolled in SmokefreeTXT, such as cessation smartphone apps and social media focused on cessation support . Some participants who reported using cessation smartphone apps reported that they would like features of cessation apps to be incorporated into SmokefreeTXT, including tracking money saved by not smoking and smoking milestones (number of days since quitting).Interviews with SmokefreeTXT users showed high program acceptability, engagement with program features, and perceived utility for smoking cessation. Participants provided feedback on program content and functionality, which informed changes to the program. Moreover, the findings provide insights into the complex relationship between program engagement and cessation, which warrants future research.This qualitative study adds to the limited body of literature that assesses user experiences of smoking cessation SMS text messaging programs. A unique component of this study is its focus on the experiences and perceptions of real-world users of the publicly available SmokefreeTXT smoking cessation SMS text messaging program, which, to our knowledge, has not been explored by other studies of cessation SMS text messaging programs -16. The As has been found in prior qualitative studies, participants reported that SmokefreeTXT was easier to use than other live support services that require a more significant time commitment ,14. TheyIn terms of program structure, many participants reported that they would like the ability to customize message timing, program duration, and quit date settings, which has been reported in previous studies ,16. Thisslips may not feel relevant if a user had relapsed). Therefore, as quitting smoking is rarely a linear process, it is important to consider other metrics of program success in addition to abstinence [Although participants liked that the keyword feature allowed them to receive on-demand support and that the smoking assessment questions provided accountability, in some instances, participants reported that assessments triggered feelings of guilt if they had relapsed, which mirrors previous research . In addistinence . For exastinence ,15. PartTo our knowledge, this is one of the first qualitative studies of cessation text program users that has explored the factors influencing program opt out. Two existing studies compared the experiences of users who either quit smoking or did not quit smoking while using a cessation SMS text messaging program ,15. As pThese findings also suggest that strategies to re-engage users that opt out should not be a one-size-fits-all approach. Although smoking relapse and cessation were the primary drivers of opt out, a few participants cited the number of messages as a reason for opting out, and others reported opting out as they did not find the messages sufficiently motivating to help them quit smoking. This reinforces the need to consider the message volume and tone when developing an automated program ,14. Opt Finally, although most participants reported that SmokefreeTXT was a useful component of a quit plan, approximately half relied on other cessation strategies as a complement to SmokefreeTXT. Notably, many of the strategies used by study participants were not evidence-based, and some participants reported supplementing their use of SmokefreeTXT by switching from cigarettes to other tobacco products, exposing them to further health risks associated with tobacco use. Therefore, it is important to consider how SMS text message programs can be used to encourage participants to both find evidence-based support  and work synergistically with these other supports.ready if they would like to keep the quit date they set or not ready to postpone the start of their quit attempt and set a new date.The results of this study have informed several optimizations to the program. For example, SmokefreeTXT has added messages that provide supplemental information on live support services and has optimized the SMS text message library to ensure that SMS text messages are more varied and less repetitive. Since conducting this study, the SmokefreeTXT program has also been changed to allow users to have a more flexible quit date at the start of the program. Users can set a quit date in the past if they begin their quit attempt before starting the SmokefreeTXT program, and users are also sent a message the day before their scheduled quit date and asked to text success of users who opt out or remain in the program.Although we conducted qualitative interviews with users of the SmokefreeTXT program, several findings may also be applicable to the development and optimization of other cessation SMS text messaging programs. First, it may be important to allow users to customize the number of SMS text messages that they receive in the program. Cessation SMS text messaging programs may also be used with other cessation strategies; thus, it may be beneficial for SMS text message content to include messages about evidence-based cessation strategies. Relatedly, live support  is a cessation resource that can be recommended within SMS text message programs to benefit users who prefer human interaction as a component of their cessation process. Finally, program retention versus opt out may have limitations in the ability to predict the cessation This study had several limitations. First, we conducted in-depth interviews with a small convenience sample of SmokefreeTXT users who were mostly young, White, and had at least some college education. Thus, the results may not be generalizable to a wider population of smokers in the United States. Most current users of SmokefreeTXT are White , which demonstrates the need to consider how the program can better reach other demographic groups. In 2016, the SmokefreeTXT program began collecting race and ethnicity data as part of program opt in to track the demographics of the program over time, and future research recruitment efforts may be informed by these data.SmokefreeTXT users who agreed to participate in the study may have been highly motivated to provide feedback on the program, whether positive or negative, which may have influenced the results. In addition, smoking status was not biochemically verified and relied on the self-reports of the users during the interviews. It is possible that some users stated that they had quit smoking to be more socially acceptable to the interviewer.This study was conducted in 2014; since then, both mobile phone technology and the SmokefreeTXT program have evolved. However, although there have been changes to message content and quit date flexibility over time, the overarching structure and features of the SmokefreeTXT program  have remained consistent. Furthermore, the results still provide unique data from users who were not part of an intervention trial, and the SmokefreeTXT program continues to be widely used. Thus, the results can still provide actionable information for those developing new or adapting established cessation SMS text messaging interventions. Given the increasing importance of mHealth as an avenue for cessation, data from this study are still relevant today. In addition, some of the findings presented here may have new relevance as improvements to technology enable some of the recommended optimizations, such as the integration of SMS text messages with other digital resources; for example, quitlines or chat applications.success through program opt out versus retention, and the importance of recommending evidence-based cessation resources (including live support via quitlines for users who prefer human interaction during the cessation process) to be used with smoking cessation text programs.Qualitative interviews with real-world SmokefreeTXT users showed high program acceptability, engagement with program features, and perceived utility for smoking cessation. Our findings demonstrate the importance of allowing customization to the frequency of SMS text messages within cessation text programs, the limitations of measuring cessation


Juvenile idiopathic inflammatory myositis (JIIM) is a multisystem inflammatory disease that impacts the muscles, skin, and blood vessels. Gray-scale power Doppler ultrasound is a technique that can be used to assist the diagnosis of JIIM and myositis in general. We report a case of an atypical symptomatic JIIM myositis flare that shows increased muscle echogenicity without the corresponding increase (complete absence) of Doppler flow. Juvenile idiopathic inflammatory myositis (JIIM) is a multisystem inflammatory disease that impacts the muscles, skin, and blood vessels . Major sA 17-year-old male presented with a two-year history of skin rashes over his hand and lower extremities weakness. Physical examination revealed Gottron changes on his right third metacarpophalangeal joint and proximal interphalangeal joints, right fourth proximal interphalangeal joints, and left fifth metacarpophalangeal joint and proximal interphalangeal joints. A patch of dry skin with mild erythema was discovered on the left ankle and on the anterior aspect of the lower leg. Laboratory workup showed elevated muscle enzymes, including elevated aspartate aminotransferase (186 IU/L), alanine aminotransferase (341 IU/L), aldolase (17.8 U/L), LDH 350 U/L), and CK . Based on modified Bohan and Peter criteria, he was diagnosed with dermatomyositis [0 U/L, anTypically, increased muscle echogenicity in inflammatory processes coincides with mild to moderate increases in Doppler flow unless a pathological process, such as compartment syndrome, is occurring . In thisThe lack of discrimination of myositis is important to both the research community and the practicing clinician. Consensus on the utility of gray-scale power Doppler ultrasound in the workup of JIIM and other inflammatory myopathies remains limited but evolving. Early clinical studies indicated that power Doppler ultrasound, in conjunction with gray-scale ultrasound, could reasonably be used in the diagnosis of myositis-related diseases, such as JIIM. . SpecifiBased on the symptomatology and MRI findings, our patient was experiencing a JIIM flare; however, the power Doppler ultrasound findings were more suggestive of compartment syndrome, a pathological condition that we know was not present in this patient. Our case provides an example of how ultrasound images with Doppler can be misleading in JIIM and may not fully detect a flareup. More research is needed to understand the diagnostic potential of gray-scale ultrasound with power Doppler as well as its relative sensitivity and specificity in the diagnosis of JIIM and other related diseases.


Gastrointestinal (GI) strictures are difficult to treat in a variety of disease processes. Currently, there are no Food and Drug Administration (FDA) approved drugs for fibrosis in the GI tract. One of the limitations to developing anti-fibrotic drugs has been the lack of a reproducible, relatively inexpensive, large animal model of fibrosis-driven luminal stricture. This study aimed to evaluate the feasibility of creating a model of luminal GI tract strictures. Argon plasma coagulation (APC) was applied circumferentially in porcine esophagi in vivo. Follow-up endoscopy (EGD) was performed at day 14 after the APC procedure. We noted high grade, benign esophageal strictures (n = 8). All 8 strictures resembled luminal GI fibrotic strictures in humans. These strictures were characterized, and then successfully dilated. A repeat EGD was performed at day 28 after the APC procedure and found evidence of recurrent, high grade, fibrotic, strictures at all 8 locations in all pigs. Pigs were sacrificed and gross and histologic analyses performed. Histologic examination showed extensive fibrosis, with significant collagen deposition in the lamina propria and submucosa, as well as extensive inflammatory infiltrates within the strictures. In conclusion, we report a porcine model of luminal GI fibrotic stricture that has the potential to assist with developing novel anti-fibrotic therapies as well as endoscopic techniques to address recurring fibrotic strictures in humans. Current endoscopic management of GI strictures include bougie or balloon dilation, stent placement, intra-stricture steroid injections, and needle-knife stricturotomy8. Unfortunately, most strictures recur, requiring frequent and in some cases life-long endoscopic procedures. In many patients, despite aggressive frequent dilation, salvage surgical resection or stricturoplasty is necessary, often associated with considerable morbidity and mortality9.A fibrotic stricture can occur at several locations in the GI tract, such as the esophagus 10. For example, in Crohn’s disease, the prevailing view has traditionally been that fibrosis could be effectively treated or prevented by treating the inflammation. However, the past 20 years of clinical experience treating Crohn’s patients with potent anti-inflammatory biologics  has revealed little to no impact on the progression of fibrostenosing complications in Crohn’s patients11. One of the limitations to advancing anti-fibrotics to date has been the lack of a large animal model of fibrosis-driven luminal stricture. There is an immediate need to develop such a model to advance the development of novel therapies using standard commercially available endoscopic equipment. Due to its ease of access, straightforward anatomical configuration, and absence of the need for specialized preparation, the esophagus is a logical location for such a model. Pigs are the ideal species for the creation of a large animal model given that their GI anatomy closely resembles that of humans, also because of their accessibility and cost, and the endoscopists’ familiarity.Some of the unifying features of GI luminal strictures across disease processes are (1) extracellular collagen deposition and fibrosis, and (2) our current inability to prevent recurrence after endoscopic/surgical treatment13. The two approaches, however, are technically complex, time consuming, and are often marred by a high rate of complications16. Other methods such as endoscopic radiofrequency ablation (RFA), it is technically quite simple, however the stricture created are short and not durable17. Another method of cap ligation followed by mucosal inversion and snare resection was effective at creating esophageal stricture, require a double channel endoscope19. Therefore, there is a necessity to explore a simple, safe and reproducible approach to create pre-clinical models to promote the development of therapies.Endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) have been used to create large animal esophageal stricture models in the past21. Compared with ESD, APC is less technically demanding, less time-consuming, and has a superior safety profile. The aim of this study was to create a large animal model of luminal GI strictures that can demonstrate a strong fibrotic component, as well as tendency to recur after endoscopic treatment.Argon plasma coagulation (APC) is a non-contact thermal method commonly used to treat gastrointestinal bleeding as well as to de-bulk tumors in cases where surgery is not recommendedAPC was successfully performed at a total of 8 different locations in the esophagi of 3 pigs  such as fever, pain, bleeding, or perforation. All pigs were able to tolerate a liquid diet on day 1 and a regular/solid diet thereafter. The amount of solid food intake was unrestricted when provided.All pigs underwent endoscopic follow-up and balloon dilation at day 14 Fig. . StrictuIn the first 4–7 days after the first follow-up endoscopy with stricture dilation, two pigs exhibited systemic symptoms. Pig number 2 developed progressive solid food intolerance characterized by vomiting and regurgitation, which started at day 18 (4 days after stricture dilation). Diet was downgraded to liquids. The pig survived until day 28 on liquid diet. Pig number 3 developed progressive weight loss, but no vomiting or regurgitation. This pig was successfully maintained on regular diet. Pig number 1 had no symptoms of luminal obstruction and also did not experience weight loss (Supplementary Table The third and last endoscopy was performed 14 days after the second EGD with stricture dilation (day 28 from index EGD with APC ablation). It was noted that all strictures re-stenosed and that the degree of stenosis was worse at all sites in all 3 pigs. The average lumen diameter was 1.9 mm, despite successful balloon dilation to 9 mm at day 14  strictures represent an abnormal narrowing of the GI lumen. These are commonly seen in clinical practice and pose a therapeutic challenge. There are multiple etiologies for strictures, such as chronic inflammation in CD and UC34. The development of new endoscopic accessories and therapeutic agents is hindered by the lack of a suitable large animal model of GI strictures. An ideal model should be a large animal, relatively inexpensive, technically feasible, and safe. In addition, an ideal model of luminal GI stricture should demonstrate a dense fibrotic reaction and stricture re-formation after balloon dilation (similar to human fibrotic GI strictures). ESD has been used to create swine esophageal strictures for in vivo pre-clinical studies36. In this study, we report a novel technique using APC to create an in-vivo pig esophageal stricture model for therapeutic studies. Compared to ESD, APC is technically easier, is less time consuming and requires significantly less expertise. Therefore, we suggest that the method described by us is ideal for the purpose of a large animal model of fibrotic luminal GI strictures.A multitude of approaches have been suggested to prevent stricture formation or progression, however, a definitive preventative therapy does not yet existIn this study, we created 8 strictures in a total of 3 pigs using APC. In follow-up endoscopies at days 14 and 28, we successfully demonstrated persistence of 8 out of 8 APC-induced strictures. CRE balloon dilation was also feasible in all but one stricture (due to intense fibrosis and high grade stricture). No major complications from stricture creation was noted. We also demonstrated that all strictures recurred and worsened within two weeks post dilation. It is important to note that this model of swine stricture recurrence reflects our clinical experience in patients. Fluoroscopy confirmed the presence and re-formation of all strictures. Additionally, histologic examination showed fibrosis of the lamina propria and submucosa at the strictured sites.Luminal GI strictures with a strong fibrotic component can reliably be modeled in swine using APC. The protocol outlined here resulted in fibrotic strictures that are relevant to human diseases, including peptic esophageal strictures, post-surgical anastomotic strictures and some of the inflammatory bowel disease-related strictures. The presence of inflammation at site of strictures mirrors a similar scenario seen in strictures in IBD (CD and UC). Mirroring typical behavior of human luminal GI strictures, the created strictures demonstrated a strong and recurrent fibrotic component refractory to endoscopic dilation. The demonstration of induction of fibrosis, inflammation associated with the strictures, and particularly natural recurrence of strictures in this model after endoscopic dilation, render this novel swine model of GI strictures unique. The technique we used was feasible, effective, safe, reproducible, and relatively inexpensive. The swine model of luminal GI fibrotic stricture reported in this study is the first of its kind and has the potential to assist in developing novel anti-fibrotic therapies, as well as creating endoscopic and surgical techniques to address these fibrotic recurring strictures in humans.Sus scrofa domestica, female, 35–40 kg) were purchased  and housed in the Johns Hopkins large animal facility. Pigs were fed with a commercial porcine diet , and water was provided ad libitum. After arrival, pigs were acclimated for 1 week ahead of procedure as described37. This study was performed under the approval of the Johns Hopkins University Animal Care and Use Committee (ACUC). All procedures were conducted in compliance with the Guide for the Care and Use of Laboratory Animals, as well as the Animal Welfare Act, applicable Animal Welfare Regulations at an AAALAC-accredited facility40. Furthermore, the study was carried out in compliance with the Animal Research: Reporting of in Vivo experiments (ARRIVE) guidelines41.Three heathy Yorkshire pigs , and electrocardiogram (ECG) were monitored by a veterinary technician anesthetist throughout the procedures and were recorded each 15 min. Pigs were placed in a supine position for endoscopy. Following the endoscopy, pigs were returned to the animal facility after they recovered from sedation.Pigs were fasted overnight. Pigs were sedated with intramuscular injection of a cocktail made of 1 mg/kg Telazol reconstituted with 25 mg/kg Ketamine and 2.5 mg/kg xylazine-(TKX). Pigs were transferred to the procedure room, intubated with a 7.5 French endotracheal tube and general anesthesia was maintained with 0.4–0.6% Isoflurane gas . 0.9% Sodium Chloride was administered via an intravenous line in a marginal ear vein. Heart rate, respiratory rate, blood pressure, temperature, end-tidal COAll procedures were performed using a forward-viewing single channel upper gastrointestinal endoscope and a video scope system . The endoscope was inserted through the mouth to the esophagus and stomach. An initial complete endoscopic examination of the esophageal and gastric mucosa was performed to ensure there were no pre-existing lesions. APC was carried out with an electrosurgical device system, an APC generator (VIO 300D) and an APC2-unit . The electrical setting was pulsed APC, effect 2, 30–40 Watts. The argon flow was set at 0.8 L/min. APC was applied in a circumferential manner using a straight fire forward catheter, creating a 3 cm longitudinal area of mucosal devitalization (Supplementary Table Post-procedure protocol included a liquid diet on day one (Ensure—3 cans three times per day), progressed to regular diet afterwards. Vital signs were monitored and recorded 3 times on post-operative day one, and then once daily. Post-operative pain was managed with carprofen (Rimadyl) as needed at 5–10 mg/kg via subcutaneous injection. In addition, potential complications such as bleeding and perforation were assessed by monitoring stool and urine outputs, oral intake, and reluctance to move.The first follow-up EGD was performed at day 14 post APC-induced mucosal ablation  wire-guided Esophageal/Pyloric/Colonic balloon dilatation catheter  over a 0.035 inch guidewire and an Alliance II Integrated Inflation/Lithotripsy device were used to perform stricture dilatation. Esophageal strictures with luminal narrowing greater than 50% were managed with endoscopic balloon dilation. The strictures were progressively dilated from 7 to 9 mm using a 6–8 and an 8–10 mm dilation balloon. If there was resistance to dilation noted during the procedure, then the largest diameter achieved was recorded. At day 28 from index EGD, a second follow-up EGD was performed to re-assess the strictures , Masson's trichrome, and Sirius Red staining were used to identify fibrosis. The stricture fibrosis scoring were assessed by a GI pathologist of Johns Hopkins Hospital.Supplementary Information.


Participants also preferred program content that was recommended for them by experts  and programs with fewer sessions . Program benefits did not predict fathers’ choice of program. Prior use of a parenting program, level of education, perceived role of parenting for adolescent mental health, and being part of a dual-working family were associated with preferences. Application of these findings may improve paternal enrolment in web-based preventive parenting programs.Few fathers enrol in web-based preventive parenting programs for adolescent mental health, despite the evidence of the benefits associated with their participation. To inform the development of father-inclusive programs, this study used a discrete choice experiment (DCE) design to determine (a) the relative influence of number of sessions, program benefits, program participants, and user control over program content on fathers’ preferences for web-based preventive parenting programs; and (b) whether selected father characteristics were associated with their preferences. One hundred and seventy-one fathers completed the DCE survey, which comprised 25 choices between hypothetical programs. Programs that included the participant’s adolescent child ( Mental health problems are one of the leading causes of disability and disadvantage for adolescents worldwide ,2. EstimIn the interest of reducing associated social, economic and health costs, evidence-based interventions have been developed to address factors that affect an adolescent’s risk of mental health problems. Meta-analytic reviews have shown that various parenting behaviors, such as harsh parenting and monitoring, are important risk or protective factors for adolescent mental health ,10,11. TDespite the promise of preventive parenting programs, poor parental engagement presents a significant barrier to effectively disseminating these interventions at the scale required to effect population-level benefits for adolescent mental health. Uptake of parenting programs is often as low as 20–30% of target populations ,17, and This is particularly concerning given evidence of fathers’ unique and important role in the aetiology and prevention of adolescent mental health conditions ,27. AlthDCEs are a methodology which allow researchers to determine the relative strength of predictors of consumer choices using stated preference data. Participants are presented with a series of choices between alternative products, which are systematically varied on specified attributes . It is assumed that individuals make decisions based on the principle of utility maximisation. In other words, when faced with a choice between products, individuals will typically select the alternative which affords them the greatest value or benefit. This value or utility is assumed to derive from the constituent characteristics (‘attributes’) of a product or type of healthcare service. Therefore, utility can be divided into systematic (derived from explainable attributes and covariates) and random components . Discrete choice models thus describe changes in the likelihood a consumer selects a particular product or type of healthcare service, corresponding to manipulation of their properties (or attribute levels) and covariates. DCEs have been increasingly utilized in health economics to address key policy issues, as they can provide insight into consumer preferences to improve adherence to public health programs, and can be used to quantify trade-offs consumers and other agents in the health sector are willing to make between different aspects of programs .In the current study, we examined the influence of selected program attributes on fathers’ preferences for web-based preventive parenting programs using a DCE design. Design of DCEs requires the development of attribute sets which are salient, plausible, and capable of being traded , and incNumber of sessions describes the amount of time required to complete a program in full, operationalized as the number of sessions (or modules) in the program. Cunningham et al.  found thProgram benefits refer to improvements in parenting or the parent-child relationship that can be anticipated as a result of program participation. Salari and Filus  found thProgram participants describe members of the family who participate in the program. Fabiano et al.  found thUser control over program content refers to the extent to which the user has agency over the content that is included in an individualized program. A range of studies have highlighted fathers’ desire for flexibility and personalisation of program content to enhance their interest in participating in parenting interventions ,39. The number of sessions, program benefits, program participants, and user control over program content on their preferred web-based parenting program; and (b) whether selected father characteristics were associated with their preferences. We hypothesized that fathers would be more likely to prefer programs with fewer sessions, and that programs where fathers could choose program topics would be preferred over those where program topics were based on expert recommendation. We also hypothesized that program participants and program benefits would influence fathers’ preferences for web-based parenting programs, but as these attributes were exploratory, we did not form directional hypotheses.Understanding fathers’ preferences for web-based parenting programs can inform the development of father-inclusive parenting programs. Increasing paternal uptake of web-based parenting programs for adolescent mental health can potentially address parenting factors amongst fathers and consequently improve adolescent mental health outcomes. Therefore, the aims of this study were to use a DCE design to explore in a sample of fathers of adolescents aged 12–18 years, (a) the relative influence of This study utilized a cross-sectional survey design. For the DCE, a full factorial design that included three attributes with three levels and one attribute with two levels was selected. In contrast with ‘efficient’ or ‘optimal main effect’ designs, full factorial designs give an equal probability of seeing every possible choice set. Given the known challenges inherent in recruiting fathers into research studies , we choshttp://www.prolific.ac (last accessed on 12 May 2021)) is an online research recruitment platform that allows researchers to identify individuals who are interested in participating in online research studies, whilst Qualtrics Panels ) is a recruitment service that partners with online panel providers to identify research samples. Crowdsourcing platforms have been found to be an efficient source of recruitment for large samples of fathers, that can yield high quality and reliable data [Participants were recruited through both community sampling and the use of paid survey panels identified through Prolific Academic and Qualtrics Panels. Prolific Academic (ble data .n = 49) by advertising through emailing lists of community organisations, and on social media sites such as Facebook, Twitter, Reddit and Instagram. Fathers were also recruited via word of mouth and snowballing. Advertisements described the project as a study of fathers’ preferences for online parenting programs for adolescent mental health. Eligible community members were invited to complete the survey by accessing an included link.Convenience sampling was used to recruit participants to the community subsample (n = 51) were then invited to respond to a 15-min survey. Of those eligible, 43 fathers completed the survey.Participants on the Prolific Academic platform who had responded to pre-screening demographic questions that they were male, resided in Australia, and were a parent, were invited to respond to a brief screening questionnaire which asked the age of their children. One hundred and forty-one individuals responded to this screening questionnaire. Those whose response indicated they had at least one child between the ages of 12 and 18 years . These revealed that with an α error probability of 0.05, a minimum of 970 observations  was needed to obtain statistical power for main effects analyses at the 0.80 level recommended by Cohen [Calculation of minimum sample size requires researchers to determine initial beliefs about parameter values . Due to by Cohen .Participants were 171 fathers of at least one adolescent child. To be eligible for this study, participants had to (a) identify as male, (b) be a caregiver to at least one adolescent aged 12–18 years, (c) reside in Australia, and (d) have sufficient English language proficiency to respond to a 15-min online survey. Demographic characteristics of the sample are detailed in 2 = 20.53, p = 0.01), education , and father lifetime mental health diagnosis . A higher proportion of fathers recruited from Prolific Academic were tertiary educated and had partners that were employed full time. Fathers recruited from the community were more likely to report a lifetime mental health diagnosis.Almost half of the combined sample (49.7%) rated their knowledge of adolescent mental health as ‘good’ or ‘excellent’. When asked about their confidence in their parenting for adolescent mental health, 31.0% of the sample indicated they were ‘moderately confident’ or ‘extremely confident’, and 56.1% were ‘moderately confident’ or ‘extremely confident’ using the internet to identify resources and information on different topics. After responding to demographic questions and choice sets, 91.2% indicated they would be interested in using an online program designed to help parents develop skills and knowledge to reduce their adolescent’s risk of mental health difficulties like those described in the survey, if given the choice. Chi-square tests showed differences across subsamples only in partner employment  comprised three levels which included recognizing and understanding issues with their adolescent’s mental health, preventing or assisting with issues with their adolescent’s mental health, or building a positive relationship with their adolescent. The attribute program participants  had three levels which included fathers only, me and my parenting partner, and me and my adolescent. Finally, the attribute user control over program content had two levels, which included the user choosing program topics based on their preferences, and the user being allocated program topics based on expert recommendation. The DCE was presented in the format shown in The survey requested participants to repeatedly choose between pairs of hypothetical web-based parenting programs. Each hypothetical program consisted of four attributes, with descriptors of various alternatives (known as levels) for each attribute. The attribute Example choice set. Participants were asked to indicate which option they would select if given the choice between the two programs.In this study we combined literature reviews and qualitative research to inform attribute generation. Consistent with recommendations by Louviere et al.  and RyanN(N − 1)/2) ‘choice sets’ which each comprised two hypothetical parenting programs for comparison. A random subset of 25 choice sets was drawn for each individual survey. The number of choices sets was selected based on acceptable respondent burden, identified through survey piloting and consultation with the research team. The left/right orientation of parenting program options were randomized within choice sets when presented on screen (top/bottom for surveys that were completed using a smartphone).All attributes and levels were randomized in a full-factorial design, producing 54 unique parenting program options. These were combined in all possible pairings to construct 1431 .Summary statistics were produced for demographic variables, and inferences regarding the influence of program attributes on choice of program were analysed using cumulative link models to predict choices, using attribute levels as predictors. To address subsidiary research questions about whether father characteristics are associated with their preferences for program attributes, we included predetermined variables of interest as predictors in this model: whether fathers reported prior use of a parenting program, were tertiary educated, reported a past or current mental health diagnosis in themselves or their adolescent, or were part of a dual-working family. Prior use of a parenting program, tertiary education, past or current mental health diagnosis for fathers and their adolescent, and being part of a dual working family were computed as binary variables. Dual working families were defined as those in which both the participant and their partner were engaged in part- or full-time work. Confidence in parenting for adolescent mental health was treated as a continuous predictor and measured using a 5-point Likert scale ranging from ‘Not at all confident’ to ‘Extremely confident’. We also examined whether fathers’ perceived role of parenting for adolescent mental health issues  and confidence in parenting for adolescent mental health interacted with their preferences.Prior to main analyses, data was screened for missing values, left/right selection bias, and non-differentiation of choices. Three cases with <80% of data were deemed unsuitable for analysis and excluded, as were 33 cases with evidence of non-differentiation of choices. number of sessions and program participants. Fathers who were more likely to prefer to complete the program with their partner were less likely to prefer programs with fewer sessions . No other significant interactions were found between attribute levels. The Akaike information criterion index (AIC) for the model which accounted for this interaction was marginally better than the AIC for the main-effects-only cumulative link model (5768.49 vs. 5777.28), and the AIC for the most complex model (5814.35). Hence here we report the model that includes only the interaction between numbers of sessions and program participants (see As there were many different levels of possible complexity in the model (corresponding to including more and higher-level interaction effects), we initially reviewed the most complex model with all two-, three-, and four- way interactions and identified a significant interaction effect between program participants. Fathers were more likely to prefer a program that they could complete with their adolescent  or parenting partner , than a program that was designed for fathers only. Fathers’ choices were also influenced by the user control over program content. Fathers were more likely to prefer a program where program topics were allocated based on expert recommendation , than a program where users choose program topics based on their own preferences. Number of sessions also influenced fathers’ choices . Fathers were more likely to prefer a program with 4 sessions to a program with 8 sessions. They also preferred programs with 1 session to a program with 8 sessions.Fathers’ choices were most strongly influenced by program benefits did not have a statistically significant effect on fathers’ choices . In contrast, program participants did not differ by whether they were in a dual-working family, the presence of a past or current mental health diagnosis in themselves or their adolescent child, or confidence in parenting for adolescent mental health. However, compared to those who had previously used a parenting program, fathers who had not previously used a parenting program had a stronger preference for a program they could complete with their partner, over a program designed for fathers only . Additionally, compared to those with a tertiary qualification, non-tertiary educated fathers had a less strong preference for a program designed for them to complete with their adolescent over a program designed for fathers only . Fathers who believed the role of parenting for adolescent mental health was shared equally by them and their parenting partner had a stronger preference for a program they could complete with their partner  or adolescent child  than those who believed it was mostly theirs or their partner’s role.We tested exploratory associations between selected demographic variables and program attributes by sequentially entering interaction terms between program attributes and each demographic variable of interest, and deleting those where no association was found. We report a final model with those associations here .Fathers’ preferences for program benefits and user control over program content did not differ by any of the selected participant characteristics.Finally, fathers’ preferences for number of sessions, program benefits, program participants, and user control over program content. We also sought to investigate whether these preferences were associated with fathers’ prior use of a parenting program, education, history of mental health diagnosis in themselves or their adolescent, employment, perceived role of parenting for adolescent mental health issues, and confidence in parenting for adolescent mental health.This study explored whether fathers’ preferences for web-based parenting programs for adolescent mental health were influenced by We found that fathers’ preferences for web-based parenting programs were most strongly influenced by the family members the program is designed to involve. Specifically, fathers were more likely to prefer a program that they could complete with their adolescent child or parenting partner over one that was designed for fathers only. This finding suggests that father-inclusive approaches to program development which target fathers alone may have less broad appeal than strategies that seek to incentivise fathers’ participation alongside their parenting partner or adolescent child. Evidence regarding fathers’ preferences for father-only parenting programs is inconsistent in the existing literature. Although some studies have found that fathers report a preference for father-only group parenting programs ,24, survFathers’ preferences for inclusion of their child in parenting interventions has been given limited attention in the extant literature. However, this finding does support the strong importance placed by fathers on using parenting programs for building positive relationships with their child . FathersFathers were also more likely to prefer a program in which content was predetermined for them by subject matter experts over a program where users could select content based on their own preferences. This did not differ according to the selected father characteristics tested in our model. Contrary to what was hypothesized, this suggests that control over content selection may be less of a priority to fathers than confidence in the expert knowledge underpinning program topics. In prior research, fathers have rated ‘demonstrated effectiveness’ as most influential on their decision to participate in a parenting program among a range of program features , and havRegarding number of sessions, we found that fathers were most likely to prefer a program with four sessions compared to a program with one or eight sessions, with eight sessions being their least preferred option. Fathers in dual-working families and fathers whose adolescent child has had a past or current mental health diagnosis reported a less strong preference for four sessions or one session over eight sessions. However, fathers’ preferences did not differ according to prior use of parenting programs, presence of past or current mental health diagnosis in themselves, perceived role of parenting for adolescent mental health issues, or confidence in parenting for adolescent mental health. Higher adherence—observed program usage, proportionate to the amount intended to be therapeutic by program developers—to parenting programs is commonly associated with improved outcomes ,67, whicFinally, benefits conferred by participating in a program did not have a statistically significant effect on fathers’ preferences. Perceived benefits have been shown to positively predict parenting program attendance , but theAlthough external validity for DCEs is generally high, with stated preferences often corresponding well to real-life choices , it is pOur study utilized a relatively small sample in comparison to other DCEs of parenting interventions ,43,45 anThis is one of few early studies to provide an in-depth examination of engagement factors for parenting programs amongst fathers of adolescents, and to our knowledge is the first to utilise a DCE methodology to explore fathers’ preferences for features of web-based preventive parenting programs. Fathers in this study preferred programs that they could complete alongside their parenting partner or adolescent child, that were delivered across fewer sessions, and where program content was selected for them based on expert recommendation. Benefits conferred on fathers through program use did not have a statistically significant effect on their choices when weighed against the other program characteristics. Program developers should take fathers’ preferences for aspects of program delivery into account when designing web-based parenting programs for adolescent mental health or modifying them to increase father-inclusiveness. Improving father engagement by increasing the appeal of web-based parenting programs has the potential to improve parenting and adolescent mental health outcomes at a population level.


Phakopsora pachyrhizi, an obligate biotrophic fungal pathogen, is the most devastating soybean production disease worldwide. Currently, timely fungicide application is the only means to control ASR in the field. We investigated cellulose nanofiber (CNF) application on ASR disease management. CNF-treated leaves showed reduced lesion number after P. pachyrhizi inoculation compared to control leaves, indicating that covering soybean leaves with CNF confers P. pachyrhizi resistance. We also demonstrated that formation of P. pachyrhizi appressoria, and also gene expression related to these formations, such as chitin synthases (CHSs), were significantly suppressed in CNF-treated soybean leaves compared to control leaves. Moreover, contact angle measurement revealed that CNF converts soybean leaf surface properties from hydrophobic to hydrophilic. These results suggest that CNF can change soybean leaf surface hydrophobicity, conferring resistance against P. pachyrhizi, based on the reduced expression of CHSs, as well as reduced formation of pre-infection structures. This is the first study to investigate CNF application to control field disease.Asian soybean rust (ASR) caused by  Phakopsora pachyrhizi, an obligate biotrophic fungal pathogen, is the most devastating soybean production disease worldwide, with an estimated crop yield loss of up to 90%. ASR has impacted the South American economy in recent years. P. pachyrhizi host range is broad and can infect diverse leguminous plant leaves in the field  in the mesophyll cells 24–48 h after infection  caused by he field . The infhe field , P. pachnfection . Five tooduction . UrediniP. pachyrhizi, including chemical control by fungicide application, growing ASR resistant soybean cultivars, and employing cultivation practices. Synthetic fungicides are the primary ASR disease control method. However, fungicide use can cause many problems such as environmental impacts  from pigeon pea (Cajanus cajan) showed full resistance against P. pachyrhizi. Conversely, identifying resistance traits from non-host plant species has become an intelligent approach. Medicago truncatula Tnt1 mutant lines and identified an inhibitor of rust germ tube differentiation 1 (irg1) mutant with reduced formation of pre-infection structures, including germ-tubes and appressoria. They demonstrated that the loss of abaxial epicuticular wax accumulation resulting in reduced surface hydrophobicity inhibited formation of pre-infection structures on the irg1 mutant  were germinated in a growth chamber at 25/20°C with 16-h-light/8-h-dark cycle (100–150 μmol m–2 s–1) for 3–4 weeks.Susceptible soybean cultivar seeds (P. pachyrhizi T1–2 (5 spores/ml using a hand sprayer for uniform spore deposition. The inoculated plants were maintained in a chamber for 24 h with 90–95% humidity at 23°C in the dark. The plants were then transferred to a growth chamber (22/20°C with 16-h-light/8-h-dark cycle) and incubated further to allow symptom development. To quantify ASR lesion number on CNF-treated plants, soybean leaves were spray-inoculated with P. pachyrhizi. At 10 days after inoculation, photographs were taken, and lesions were counted to calculate the lesion number per cm2. Lesions were counted from 54 random fields on three independent leaves.An isolate of the ASR pathogen izi T1–2  was main®) was supplied through the courtesy of Chuetsu Pulp & Paper . CNF suspension was adjusted to a concentration of 0.1% (v/v) in water including 0.02% Tween 20 before treatment. Both adaxial and abaxial sides of soybean leaves were spray-treated with 0.1% CNF till runoff and then the treated soybean plants were dried at room temperature for 3–4 h before inoculation. Scopoletin  was pre-solved as 500 mM stock solutions in dimethyl sulfoxide  and diluted to 500 μM in P. pachyrhizi spore suspensions.Cellulose nanofiber  staining and photographed. The germ-tubes forming differentiated appressoria were counted as appressoria. The differentiated germ-tubes without appressoria that grew on the leaf surface were also counted from at least 100 urediniosopres on three independent leaves.To quantify the formation of pre-infection structures including germ-tubes and appressoria on control, CNF-, and scopletin-treated plants, soybean leaves were spray-inoculated with P. pachyrhizi spores (2 × 105/ml). Six hours after inoculation, pre-infection structures were observed with a Nikon ECLIPSE 80i phase contrast microscope. The germ-tubes forming differentiated appressoria were counted as appressoria. The differentiated germ-tubes without appressoria that grew on the leaf surface were also counted from at least 500 urediniosopres on three independent leaves.The formation of pre-infection structures on borosilicate glass slides and polyethylene tape with or without CNF treatment was quantified after dropping The surface hydrophobicity on the CNF-treated leaves, borosilicate glass slides, and polyethylene tapes were investigated based on contact angle measurement using an automatic contact angle meter DM-31 . The contact angle was measured by dropping 2 μl of water from a syringe attached to the DM-31 automatic contact angle meter. The contact angle was measured on the adaxial and abaxial leaf surfaces, and polyethylene tapes with or without 0.1% CNF treatments. The contact angle was analyzed using the multi-functional integrated analysis software FAMAS (Kyowa Interface Science).green fluorecent protein (GFP), and chitin synthase (CHS) were synthesized using the in vitro Transcription T7 Kit . Briefly, we designed three primer sets to amplify P. pachyrhizi CHS5-1 fragments  of ragments . After Rphoresis  and quanP. pachyrhizi 1 × 105 spores/ml. The inoculated leaves were immediately fixed, and total RNA was extracted from the leaf areas and purified using RNAiso Plus (TaKaRa). To investigate the SIGS efficacy, expression levels of CHSs were quantified after dropping 1 × 105/ml of P. pachyrhizi spores containing 10 ng/ml dsRNA on polyethylene tape. Six hours after inoculation, total RNA was purified using RNAiso Plus. To investigate the gene expression profiles of P. pachyrhizi CHSs during infection, 4-week-old soybean leaves were spray-inoculated with P. pachyrhizi 1 × 105 spores/ml and incubated in darkness overnight, and then transferred to a growth chamber (22/20°C with a 16-h-light/8-h-dark cycle). At 2, 4, 6, 12, and 24 h after inoculation, total RNA was extracted from the inoculated leaf areas and purified using RNAiso Plus. For gene expression profiles of P. pachyrhizi CHSs and soybean defense-related genes, 4-week-old soybean leaves covered with or without 0.1% CNF were spray-inoculated with P. pachyrhizi 1 × 105 spores/ml and incubated in darkness overnight, and then transferred to a growth chamber (22/20°C with a 16-h-light/8-h-dark cycle). At 6, 12, and 24 h after inoculation, total RNA was extracted from the inoculated leaf areas and purified using RNAiso Plus according to the manufacture’s protocol.For urediniospores attachment assay, 4-week-old soybean leaves covered with or without 0.1% CNF were spray-inoculated with P. pachyrhizi ubiquitin 5 (PpUBQ5) and soybean ubiquitin 3 (GmUBQ3) were used to compare urediniospores attachment on soybean leaves. P. pachyrhizi elongation factor 1α (PpEF1α) and PpUBQ5 were used to normalize P. pachyrhizi gene expression. Soybean GmEF1α and GmUBQ3 were used as internal controls to normalize soybean gene expression.Two micrograms of total RNA were treated with gDNA Remover  to eliminate genomic DNA, and the DNase-treated RNA was reverse transcribed using the ReverTra Ace qPCR RT Master Mix (TOYOBO). The cDNA (1:10) was then used for quantitative RT-PCR using the primers shown in P. pachyrhizi and observed lesion formation including uredinia at 10 days after inoculation. CNF-treated leaves showed reduced lesion area compared to control leaves  and isoflavone reductase (IFR), all defense marker PR genes and defense-related genes were clearly induced within 6 h of P. pachyrhizi inoculation, and these transcripts reached high levels at 12 h  production and defense-related gene expression. Furthermore, chitin nanofiber treatment can reduce the occurrence of Fusarium wilt disease in tomato plants , in conjunction with analysis of P. pachyrhizi cell wall properties on CNF-treated leaves, will be necessary to understand CHSs molecular function during formation of pre-infection structures.Cellulose nanofiber-treatments suppressed ructures , 5. CHSsructures . Treitscoperties . These rP. pachyrhizi, one of the most important soybean diseases (We demonstrated that CNF-treatments suppressed ASR caused by diseases  associatdiseases . BecauseP. pachyrhizi CHSs functioned successfully in reducing pre-infection structures formation on hydrophobic polyethylene surfaces (P. pachyrhizi genes encoding an acetyl-CoA acyltransferase, a 40S ribosomal protein S16, and glycine cleavage system H protein reduced pustule numbers over 70%. SIGS against filamentous fungi threating agronomically important crops has also been studied, including head blight caused by Fusarium graminearum and gray mold caused by Botrytis cinerea (F. graminearum cytochrome P450 genes, which are required for fungal ergosterol biosynthesis, successfully inhibited fungal growth in barley. Although further precise studies for SIGS targeting P. pachyrhizi virulence genes will be needed, SIGS is a powerful tool to develop sustainable disease management strategies.Our results demonstrated that SIGS targeting surfaces . SIGS issurfaces . Hu et a cinerea . Koch etP. pachyrhizi inoculation, and reached high levels at 12 h (P. pachyrhizi inoculation (PR genes and defense-related genes were significantly less at 6 h in CNF-treated soybean leaves compared to control leaves (PR genes and defense-related genes in CNF-treated leaves is the result of the decreased penetration rate associated with reduced appressoria formation. However, since the transcripts of defense marker PR genes and defense-related genes were suppressed even though P. pachyrhizi infection was not completely prevented in CNF-treated soybean leaves, further investigation of CNF effects on plant defense responses will be necessary.Expression profiles of soybean leaves revealed that gene transcripts related to the phenylpropanoid and isoflavonoid pathways were upregulated within 6 h of  at 12 h . Consistculation . We demol leaves . Furtherl leaves . TherefoP. pachyrhizi, a causal agent of ASR. Moreover, CNF-treatments can change leaf surface hydrophobicity, resulting in CHSs gene suppression related to CHS, which is associated with reduced formation of pre-infection structures including P. pachyrhizi germ-tubes and appressoria (In summary, CNF-treatments confer resistance against ressoria . Since CThe original contributions presented in the study are included in the article/HS, NSa, and YI contributed to conception and design of the study and performed the statistical analysis. HS, YY, NSa, TI, NSh, GU, VN, EY, and YI performed the experiments. HS wrote the first draft of the manuscript. NSa, YY, and YI wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Integrated community case management (iCCM) is a child health program designed to provide integrated community-based care for children with pneumonia, malaria, or diarrhea in hard-to-reach areas of low- and middle-income countries. The foundation of the intervention is service delivery by community health workers (CHWs) who depend on reliable provision of drugs and supplies, consistent supervision, comprehensive training, and community acceptance and participation to perform optimally. The effectiveness of the program may also depend on a number of other elements, including an enabling policy environment, financing mechanisms from the national to the local level, data transmission systems, and appropriate monitoring and evaluation. The extent to which these factors act upon each other to influence the effectiveness and viability of iCCM is both variable and challenging to assess, especially across different implementation contexts.In this paper, we describe a mixed methods systems-based study protocol to assess the programmatic components of iCCM that are associated with intervention effectiveness and report preliminary results of data collection.This protocol uses a mixed qualitative and quantitative study design based on a systems thinking approach within four iCCM programs in Malawi, Democratic Republic of the Congo, and Niger State and Abia State in Nigeria. Routine monitoring data are collected to determine intervention effectiveness, namely testing, treatment, and referral outcomes. Surveys with CHWs, supervisors, and caregivers are performed to collect quantitative data on their demographics, activities, and experiences within the program and how these relate to the areas of intervention effectiveness. Focus group discussions are conducted with these stakeholders as well as local traditional leaders to contextualize these data. Key informant interviews are undertaken with national- and district-level program stakeholders and officers knowledgeable in critical program processes.We performed 3836 surveys and 45 focus group discussions of 379 participants with CHWs, supervisors, caregivers, and traditional leaders, as well as 120 key informant interviews with district- and national-level program managers, health officers, and ministry officials. Policy and program documents were additionally collected for review.We expect that evidence from this study will inform child health programs and practice in low- and middle-income settings as well as future policy development within the iCCM intervention.DERR1-10.2196/33076 Integrated community case management (iCCM) is a child health strategy that aims to provide equitable access to care for children with pneumonia, malaria, and diarrhea in some of the world’s poorest and low-access areas . It is fAs an integrated package of services, the intervention relies on a host of elements to ensure programmatic success. Generally, CHWs should be adequately supplied with quality commodities; receive comprehensive training, supervision, and oversight; be embedded in an environment of enabling policy, supervision, and support; and treat communities that are sufficiently knowledgeable and mobilized, among other requisites -7. AlthoBecause of the intricate relationships of these elements and the various ways in which different contexts shape their impact, we require an approach that elevates these properties from program isolates acting in silos to interconnected determinants behaving in a complex system. We therefore apply a systems thinking lens to our assessment of the iCCM intervention. Systems thinking is an approach to scientific inquiry that emphasizes the interrelated nature of the composite parts of a system; how these operate within a specific setting; and how these integrate, relate to, and are embedded within the surrounding environment .This protocol builds upon existing systems thinking theory and a methodological approach to assess complexity in community health interventions . This stThe overall aim of this study is to identify gaps and bottlenecks within critical areas and processes of 4 iCCM programs in Africa, assess factors that are attributable to these, and analyze determinants of programmatic success. Specifically, we are interested in investigating how program design, provider demographics, intervention context, service delivery practices, care recipient experiences and support, and other key health systems areas influence, drive, or are otherwise associated with program outputs of effective coverage. Effective coverage is a metric designed to evaluate the health gain that is experienced by a population, given a certain set of conditions of the health service delivery model .We applied a mixed methods concurrent triangulation design with an intersecting systems theoretical lens -12. DataTranche 1: surveys conducted with service providers and recipients of the iCCM intervention (quantitative)Tranche 2: focus group discussions (FGDs) conducted with service providers and recipients of the iCCM intervention Tranche 3: key informant interviews with program managers, ministry of health (MoH) officers, and other stakeholders at national and district level involved in iCCM activities Tranche 4: routine data on cases, service delivery, population and demographics, commodity stocks, reporting, and supervision (quantitative)Tranche 5: a policy and document reviewAn illustration of these tranches is provided in The study was performed recognizing the existence of different levels of outputs and subsequent outcomes for analysis that will be emergent during the data collection and preliminary analysis period. For example, it is generally accepted that frequent supervision of CHWs is a precondition to successful implementation of community-based programs and thus may serve as an endogenous factor or a process in itself for analysis . AnalogoThe study was implemented in 4 large, geographically distinct territories of 3 sub-Saharan African countries: Malawi, Democratic Republic of the Congo (DRC), and Niger State and Abia State in Nigeria. Within these countries, the iCCM program was administered by the respective state and national ministries of health, with implementation support from local nongovernmental organizations (NGOs) and oversight by the World Health Organization. The program was rolled out across 7 districts in the central and northern regions of Malawi; 10 health zones in the province of Tanganyika in DRC; 6 local government areas (LGAs) in Niger State, Nigeria; and 15 LGAs in Abia State, Nigeria. At the time of the study, iCCM implementation had been ongoing for at least two years. Data were expected to be collected across all these administrative areas where iCCM was implemented.The study required both qualitative and quantitative primary and secondary data from different stakeholders and experts within key thematic areas. Primary data were collected from three sources: (1) surveys with CHWs and their supervisors; (2) FGDs with CHWs, supervisors, caregivers and traditional leaders; and (3) key informant interviews with a variety of program partners and country-level stakeholders. An additional survey of caregivers was conducted in Abia State, Nigeria.We also obtained secondary data to inform the analysis, namely routine monitoring records; household surveys of care-seeking behavior; routine health facility and hospital data (where possible); catchment area demographics, geographical data, and population statistics for communities, health facility areas, and districts; and documentation on program guidelines, manuals, and country child health policies.We began with protocol development and drafting of data collection and training materials, specifically survey instruments, FGD guides, and key informant interview templates. We developed 9 survey instruments, 12 FGD guides, and 75 interview guides, varying according to country context. The survey instruments contained between 73 and 137 questions each, the FGD tools contained between 66 and 108 questions per stakeholder group, and the key informant interview guides contained between 25 and 69 questions per informant. These were reviewed for quality and comprehensiveness by funding partners and country team members, which included local academic institutions, country technical representatives, program managers, and MoH members within the country’s child health network. These individuals were identified by the research team through a snowball approach. Each item and country protocol was developed in English and translated into 1 of 10 languages by at least two trained translators recruited either through institutional or local contacts. Translations for the surveys were then subject to a roundtable in-country participatory translation workshop consisting of at least 10 country actors, including program managers or stakeholders, to verify accuracy, relevance, audience appropriateness, and adherence to original question intent.Surveys and FGDs conducted with CHWs and supervisors focused on their personal profiles, core iCCM processes, inputs, and activities; the caregivers and communities they served; and motivations and opinions. Those conducted with caregivers centered on their knowledge, care-seeking behavior, and adherence, whereas the FGDs conducted with traditional leaders discussed community support, buy-in, and local ownership. The key informant guides collected data on specific iCCM processes, policy, and management of the program, including but not limited to: procurement and distribution of key iCCM commodities; health management information systems; child health policy and program financing processes; human resources; local mobilization; and program coordination, integration, and sustainability at different administrative levels.The targeted survey participants were CHWs and supervisors. An additional survey with caregivers in Abia State was warranted by the local interest in a statistical measure of the perceived applicability of the intervention in a setting that was geographically considerably smaller and more densely populated than those of the other 3 programs. Eligible CHWs were those who had been trained in iCCM and had participated in the implementation of activities in their communities, whether belonging to a pre-existing health worker cadre or recruited for the specific purpose of this program. Eligible supervisors were health facility attachés who were charged with the supervision of at least one CHW throughout the life of the program. Caregivers in Abia State were eligible participants if they were the primary caretaker of a child aged 2-59 months and resided within the catchment areas of iCCM implementation. Stratified systematic sampling was used for caregiver participant selection. For the CHW and supervisor surveys, bias was mitigated by enumerators cycling through a complete list of all CHWs and supervisors operating in the 38 administrative areas, rather than relying upon local actors to choose participants for the survey.Results section.A single-stage cluster sampling scheme was used for the surveys. All administrative divisions where the iCCM program was implemented in each of the 4 country areas were expected to be sampled. This treated each administrative area as its own independent sampling frame, allowing for full saturation across implementation areas and enabling robust analysis of district-specific effects. The sampling frame for supervisors was at the country area level, with even distribution across all administrative areas. CHW and supervisor population data were sourced from national statistics offices or program records. Survey sample sizes were calculated from these based on probability proportional to size sampling, with aimed representation within a CI of 95% . Figure The FGDs aimed for an average of 8 participants per focus group, which is considered optimal for clarity and representative participation . SaturatEnumerator and FGD facilitator guidelines, protocols, and other materials were developed as part of the enumerator training package. We recruited 8-10 survey enumerators per country area according to predetermined criteria with the support of local research teams. These enumerators participated in a round of training resulting in the final selection process; this was followed by a 10-day, 80-hour training course in question content, survey strategy, tablet use, and surveying etiquette. At the end of the course, each enumerator performed 2 test runs of all questions with the survey director from the Swiss Tropical and Public Health Institute and codirectors, usually from the MoH, the supporting NGO, and local university partner. All survey questions were presented with multiple response scenarios, and enumerators were marked based on performance. This also allowed survey supervisors to address any shortcomings in survey structure and design. FGD facilitators were recruited and trained in a similar fashion, where teams consisted of a timekeeper, notetaker, and discussion facilitator.We adhered to strict compensation guidelines that aim to ensure fair and advantageous remuneration set forth by the International Labor Organization’s fundamental conventions -19. As tThe surveys were piloted over the course of a week, after which final adjustments were made to the questionnaires and enumeration procedures. The official survey data collection lasted on average 2 months per country area. Surveys were carried out with CHWs and their supervisors by trained enumerators by telephone for practicality and cost-effectiveness. CHWs and supervisors were alerted to the study by district health officers at the behest of the investigators and country program managers. Contact information of all CHWs and supervisors was thereafter provided for participant recruitment. Recruitment for the caregiver survey (Abia State) was facilitated by village heads and randomly selected individuals from identified communities. The survey was conducted with electronic data collection using Open Data Kit (ODK), which was programmed on tablets during the tool development stage. Phone credit and headphones were provided to survey participants to carry out the survey. Data were uploaded daily to the secure institutional server. Surveys were conducted in all administrative areas of the iCCM country sites participating in the program.Establishing contact with CHWs and supervisors proved challenging in some settings as a result of ubiquitous network issues, respondent availability, and general electricity outages. Furthermore, some CHWs had either moved, transferred, resigned, or were deceased, and many had been added who were not updated in the program files. We attempted to control for bias associated with poor network coverage by ensuring a proportional distribution of hard-to-reach (HTR) and easily reached respondents. HTR respondents, meaning those with whom contact was unsuccessful even after 3 attempts, were registered as HTR and were targeted specifically through their supervisor or through the administrative area focal person, who encouraged them to move toward areas of reception or regroup directly at the health facility for the survey. Some enumerators in Abia State traveled to their assigned areas to conduct interviews in person because LGAs were clustered closely together.The survey interviews typically lasted for 70 minutes each for both survey types. The length of the interview did not deter participants during piloting; therefore, the length was retained. Targeted sample sizes were reached across all country areas, and survey participation was high; 100% of all CHWs and supervisors reached consented to participate. Participants expressed appreciation in having the opportunity to voice their opinions, concerns, and experiences.For each administrative area, a group of caregivers, supervisors, and CHWs each was chosen to participate in FGDs, averaging 3 FGDs per administrative area and 12 FGDs per country area with these stakeholders. In Niger State and Abia State, additional FGDs were held with local development committees and traditional leaders because of specific interest in these country sites. Participants were recruited with assistance from district health officers and NGO program officers, with a recruitment strategy based on a random sample of participants across communities, health facilities, and districts. The discussions typically lasted between 1½ hours and 2½ hours and up to 3 hours. They were intensive, and hourly breaks were necessary; a stipend, drinks, and food were provided to participants and facilitators. Transport to and from data collection areas was organized either independently, in collaboration with the local ministry or NGO, or through the local research team.After the pilots and official launch of the survey, further steps were taken to ensure survey quality. In addition to daily supervision, the principal investigator held triweekly individual meetings with each of the enumerators to discuss results, obtain feedback, and check survey entries. Enumerators were also instructed to obtain correct administrative area, community, and population information for all CHWs and supervisors to revise existing records that were often misaligned with project areas. These data points were corrected in a master registry on institutional servers. Each survey that was conducted was checked against its original entry in the master database, where any errors were rectified. In addition, various roundtable discussions were held and recorded among all enumerators to review emerging themes, outlier anecdotes, concerns, shortcomings, or administrative tasks. Enumerators were also required to take notes and report on specific questions, which were shared with the survey director and recorded in the master file as auxiliary information.This study was approved in 2016 by the institutional review boards of Malawi (NHSRC 16/6/1610), DRC (ESP/CE/046/2016), and Nigeria (NHREC 01012007- 15122016), as well as the Ethics Commission of Northwest and Central Switzerland (EKNZ REQ-2016-00478). All subjects provided informed consent before participating in interviews, discussions, or surveys. All individual data used were anonymized upon collection or extraction; routine monitoring data used existed within a deidentified format. All iCCM programs operated under the supervision of each country’s respective MoH and aligned with national standards of care.Data collection was undertaken from 2016 to 2017. The following sections outline the experience of preliminary data collection and cleaning in detail. Results and analysis of the implementation of this protocol from each country are in preparation.We successfully collected survey data from CHWs and supervisors across all 38 administrative divisions where iCCM was implemented within the 4 country sites. A total of 3836 surveys were completed. FGDs were conducted in 3-5 administrative areas of each country site resulting in 45 FGDs comprising 379 participants. Statistics on survey and FGD implementation are provided in We conducted 120 key informant interviews with a variety of actors fulfilling different roles related to iCCM, including district and zonal government stakeholders; national ministry representatives; national program managers, coordinators, and NGO officers; data managers, pharmacists, and central medical stores affiliates; and field implementers. Program managers and local teams assisted in identifying and requesting participation of key informants. Some follow-up key informant interviews were necessary because of scheduling conflicts. A list of these is provided in supplementary Tables S1-S4 .Routine monitoring data were extracted from independent databases held by the iCCM implementing agent (NGO) or the MoH. Country-owned data on care-seeking behavior before and after program implementation were also provided. Permission was requested to access the country’s national health system or to obtain all records and data used, which were usually submitted in digitized format. Country demographic data were obtained from national statistics offices directly or from programmatic registers. These entities also provided access to policy and program documentation.Statistical data were extracted, cleaned, coded, and analyzed using Stata software . We used nonparametric tests, specifically the Fisher exact test, to assess change and magnitude of effective coverage at critical areas of the iCCM program. Bivariate and multivariate logistic and linear regression analyses were performed to assess factors associated with these critical areas, as well as other emergent programmatic factors. Structural equation modeling was used to measure relationships between variables and latent constructs. Comparative descriptive analyses on routine monitoring data and forms were also performed to evaluate data strength, systems performance, and health provider activities.Interviews with key informants and FGDs were facilitated, recorded, transcribed, and translated by trained personnel. Transcripts were coded for emergent themes and analyzed according to the Framework Method . ProcessThis systems evaluation protocol benefits from design elements that give ample consideration to the complexity inherent to health systems and programs in low- and middle-income countries. It steps outside the collection of isolated indicators or siloed phenomena to allow exploration of relationships among tangible and intangible facets of the iCCM intervention. As it concentrates not only on program performance, but also on systems performance, it inherently takes into account appropriateness, applicability, and sustainability of the intervention, enabling simultaneously a focused study and an extensive evaluation.The study protocol includes certain limitations. Data collection of this order is time consuming and can require considerable human resources in both fieldwork and analyses. In addition, because systems studies are necessarily large in scope, parsing apart emergent health systems themes for evaluation can be challenging, while introducing a data burden to the research plan. Potential solutions to address these issues could be using a 2-stage cluster sampling method and samples representative of the national or state level as opposed to administrative areas, a lower threshold for qualitative data saturation , a narrower focus on specific systems thematic areas, condensed surveys and discussion guides, and remote interviews for those key informants with stable internet access.Our proposed study, which capitalizes on the application of the same child health program at wide scale in different contexts, has the potential to advance our understanding of how iCCM programs and other community-based health interventions can operate more effectively and sustainably, what unintended consequences might emerge from their application, and what factors drive the key outputs and impacts of the program. These are essential to achieving Sustainable Development Goal 3.2 of reducing child mortality.