The Baby Friendly Hospital Initiative was created to enhance breastfeeding, although its impact on infant healthcare utilization is unclear. Breast feeding infants are vulnerable to readmission soon after birth secondary to dehydration and hyperbilirubinemia. Breastfeeding can also protect infants from unnecessary health care utilization later in life by preventing infection. The objective of this study was to examine the impact of the Baby Friendly Hospital Initiative on readmissions and emergency department utilization among Medicaid births in Delaware.The study was a quasi-experimental design. Medicaid claims files were used to study births at five hospitals in Delaware born between January 1, 2014, and December 31, 2018, and covered under Medicaid at time of birth. Three hospitals were designated Baby Friendly, two were not and served as controls. Outcomes included Emergency Department (ED) utilization and readmissions within 30 days and one-year of birth hospitalization. Exposure to the Baby Friendly Hospital Initiative was determined by year and hospital of birth. Logistic regression and interrupted time series segmented regression analysis with controls were used to assess the effect of Baby Friendly Hospital Initiative on healthcare utilization.In total, 19,695 infants were born at five hospitals with 80%  born at hospitals that were designated Baby Friendly. ED utilization and readmissions over the 1st year of life for breastfeeding related diagnosis at the Baby Friendly hospitals occurred in 240 (1.5%) and 226 (1.4%) of infants, respectively. Exposure to the Baby Friendly Hospital Initiative was associated with increased odds of all cause 30-day readmission  but not readmissions over the 1st year of life. While 30-day ED visits did not change after BFHI, one-year ED visits were reduced . A significant negative trend was seen over time for ED utilization post BFHI compared to controls .There was a small observed increase in the odds of all cause 30-day readmissions with no change in one-year readmissions after BFHI in Delaware. Although there were no observed changes in 30-day ED utilization, there was a reduction in one-year ED utilization following the implementation of the Baby Friendly Hospital Initiative in Delaware birth hospitals. Our data help to inform policy and decision making for statewide systems of care that may be used to support breast feeding. The medical benefits of breast feeding are clear and well established for both baby and mother. Despite the well-known advantages of providing mother’s milk, breast feeding rates differ by region, race, insurance status and socioeconomic status –4. Baby The aims of this research were to investigate if the BFHI influences both short term (30 day) and longer term (one year) health care utilization at a state level. We hypothesized that BFHI would increase 30 day and reduce one-year readmissions and Emergency Department (ED) utilization. To meet these aims, hospital readmission and ED utilization were investigated in temporal association with initiation of Baby Friendly designation at birth hospitals in a single state. The study sample included a population of babies covered by Medicaid insurance in the State of Delaware.We conducted a quasi-experimental study of births at all five birth hospitals in the state of Delaware between January 1, 2014, and December 31, 2018. All patients studied were covered under Medicaid at the time of birth. Approximately 45% of births were covered by Medicaid between 2014 and 2018 in Delaware. This study was approved by ChristianaCare and the State of Delaware Institutional Review Boards.Data source for the study was the Medicaid administrative claim files. The study sample included infants having Medicaid as their sole payer born within the years 2014–2018. From these data, the following were recorded for the infants: sex, age in months, race, and year of birth. The birth facility for each infant was determined and infants were included in the study population if they were born at one of the five Delaware birth hospitals and were covered under Medicaid at time of birth, according to infants’ Medicaid claims. Infant diagnoses, preterm status, and healthcare utilization variables were obtained. Infants born out of the state of Delaware or who were not eligible for Medicaid during the first month of life were excluded. All data were provided by the University of Delaware Center for Community Research and Service who hold an agreement with the Delaware Division of Medicaid and Medical Assistance. A de-identified data set was provided to ChristianaCare under a Delaware INBRE Core access award for the current study. Data are not publicly available.In order to investigate both short-term and longer-term health care utilization, we examined hospital readmissions and ED utilization both at 30 days and one year following initial hospital discharge. Thus, outcomes investigated included all cause 30-day readmission, all cause total readmissions within 1 year, all cause 30-day ED visits, and all cause total ED visits within 1 year. To compare frequency of utilization, we also analyzed the data based on a categorical stratification of zero, one, or two or more readmissions or ED visits. For the short term, 30-day analyses, we also investigated breast feeding related readmissions and breast-feeding related ED visits. Breast feeding related diagnoses included dehydration, hypernatremia, weight loss, failure to thrive, hyperbilirubinemia, and jaundice determined by ICD-9/10 coding. The date of birth of the infant was utilized as the baseline date to calculate 30-day and one-year outcomes.Three hospitals in the cohort were designated as Baby Friendly Hospitals (BFHI) during the study time-period and two were not designated as BFHI. The temporal clustering of hospital choosing to start the BFHI in 2016 was related to coordinated state-wide public health initiatives to increase breast feeding. The decision to ultimately implement the BFHI as an intervention was made at the individual hospital level. Demographic characteristics of infants and mothers comparing those born at BFHI and those not born at BFHI were examined using Chi squares tests.Logistic and multinomial regression models were used to estimate the association of BFHI on ED visits and readmissions pre and post implementation in the three BFHI designated hospitals. These analyses were performed only on the patients born at the three BFHI hospitals. Exposure to the BFHI was determined by date of birth. Patients born at hospitals that did not adopt the BFHI were not included in these analyses so that readmissions and ED visits could be compared based on the temporal initiation of BFHI within the same hospitals, thus limiting confounding. Overall, four models were created in this series of analysis using the following dependent variables: (1) 30-day readmission, (2) 1-year readmissions , (3) 30-day ED visit, (4) 1-year ED visits . In all models the following independent variables were entered: (1) BFHI (born before or after initiation), (2) race, (3) preterm birth.Two additional negative binomial regression models were fit to determine the effect of BFHI in babies born in the three BFHI hospitals. In these models the dependent variables were 1)number ofall cause one year ED visits and 2) number of all cause one year readmissions. Independent variables in these models included (1) BFHI (born before or after initiation), (2) race, (3) preterm birth.We performed further analyses on the entire cohort, including those hospitals that did not participate in BFHI. In this series of analyses, patients born at the non-BFHI were included and served as controls. Interrupted Time Series Segmented Regression analysis was used to assess the effect the BFHI on the aggregate count of total ED visits and total readmission in all five hospitals - three BFHI designated hospitals and two control hospitals; 2016 was used as the interruption in the time series because all three BFHI designations occurred close to this time point. Interrupted time series can be used to study population-based intervention and segmented regression to study an outcome of interest. Interrupted time series also has the strength of being unaffected by some confounders that are likely to remain constant including population level socioeconomic status . AnalyseThe study sample included 19,695 babies with Medicaid insurance born at five hospital systems in Delaware. This included 15,939 (79.8%) that were born at three hospital systems that were part of the BFHI and 3,756 (20.2%) that were born in two hospital systems that did not participate in the BFHI. The demographics of the study sample are shown in Table ED utilization and readmissions over the first year of life for breastfeeding related diagnoses at the BFHI hospitals occurred in 240 (1.5%) and 226 (1.4%) of infants, respectively. These low rates of utilization precluded further analysis of specific breast-feeding related ED visits and readmissions by BFHI stratification.Following initiation of BFHI at Delaware hospitals, there was an approximate 15% increased odds of all cause readmission in the 30 days following hospital discharge after adjusting for race and preterm birth, adjusted odds ratio 1.15, 95%CI 1.03–1.28 (Table There were no differences in all cause 30-day ED visits in BFHI hospitals after adjusting for race and preterm birth, adjusted odds ratio 0.90, 95%CI 0.80–1.01 Table . There wOne-year readmissions and ED visits were compared in the babies born in the three hospitals systems that initiated BFHI to the two hospital systems that did not adopt the BFHI. Interrupted time series analysis showed that all cause ED visits were reduced in BFHI hospitals compared to non BFHI hospitals, β -5.90, p < 0.01 Fig. .The main findings of our study were that, in a statewide population of babies with Medicaid insurance, initiation of BFHI was associated with a small increase in all-cause 30-day readmission but no change in the odds of all cause one-year readmissions. There were no changes in 30-day all cause ED visits but one-year all cause ED visits were reduced following BFHI. Readmissions and ED visits directly related to breast feeding were uncommon in the study population.To our knowledge, our study is unique in looking at the association of BFHI with readmission and ED utilization at the state level in a Medicaid population. While one study has shown that BFHI at a state level does not improve exclusive breast feeding at 3- and 6-months  other stIn contrast to the short-term increase in readmission associated with BFHI, our data showed a reduction in ED utilization over the first year following initial hospital discharge. To our knowledge, this study is the first to report an association of BFHI with a reduction in one year ED utilization after the initial hospital discharge. The observed reduction in ED utilization may have resulted from some of the known beneficial health effects of breast feeding including the reduction in respiratory related and other infections. We cannot rule out that other temporal factors including other unmeasured changes in statewide health care delivery, including improvements in primary care, could have led to the observed reduction. The findings from our study are important in evaluating the risks and benefits of adopting the BFHI. The low rate of breast-feeding related readmissions and ED utilization are reassuring, as is the potential longer-term reduction in ED utilization that was observed in our population. To provide better context of our findings, between 132 and 348 total babies in our study sample, had a reduction in two or more ED visits in the one year after birth associated with BFHI. On the other hand, between 20 and 184 babies in our study sample had a 30-day readmission associated with BFHI implementation in Delaware. The observed increase in all cause 30-day readmissions raises some concerns about the potential risks of BFHI and indicates the need to continuously monitor outcomes and mitigate any factors that may contribute to readmissions following birth. As our data are from a single state, further research on BFHI is necessary to validate and determine the generalizability of our findings.Our study has several important strengths including the evaluation of BFHI at a state level and the use of Medicaid data to best allow ascertainment of healthcare utilization that crosses institutional boundaries. Our analysis is limited by not being able to show causality between BFHI and the observed outcomes. There was also likely unmeasured confounding that could have contributed to the observed results including variables such as maternal ethnicity, maternal body mass index, maternal diabetes and mode of delivery that were not available in our data set. Based on the source of our data we were not able to measure breast feeding at the individual level. Our data therefore best reflect system level changes on a population of newborns and not patient level decisions on breast feeding. Importantly, from our data we cannot determine if there were any changes in initiation or exclusivity of breast feeding based on BFHI and/or if any changes in these important feeding metrics influenced our observed outcomes. The choice to obtain BFHI designation is voluntary and thus the observed results may be reflective of many other hospital or multiple community level factors associated with the systems that chose to obtain certification. Our study sample only included patients with Medicaid insurance and thus may not be generalizable to other populations including commercial insurance. In addition, because we studied statewide healthcare utilization our data may not be generalizable for outcomes attributed to any one single center.In summary, our study is the first to describe readmissions and ED utilization following BFHI at a statewide level. Our data show a small increase in 30 day all cause readmissions after BFHI balanced by a reduction in all cause ED utilization over the first year of life. Importantly, our findings must be interpreted with caution in the absence of knowing whether rates of breast feeding changed in babies with Medicaid insurance in Delaware associated with three hospitals starting the BFHI. Our study adds to the literature on the benefits and risks of BFHI and potentially helps to inform policy and decision making for statewide systems of care.


Many trauma patients are at risk of pulmonary embolism due to unrecognized deep vein thrombosis (DVT). Restricted ankle dorsiflexion (AD) range of motion during leg immobilization is known to cause reduced venous blood flow. The aim of the present study was to assess whether AD at plaster cast removal is related to the incidence of DVT and to patient outcome.Prospective observational cohort study.Level 1 Trauma Center.A total of 124 patients  with plaster cast leg immobilization after surgical repair of Achilles tendon rupture were assessed.At 2 weeks postoperatively, assessments of AD and the incidence of DVT using compression duplex ultrasound were performed with observers blinded to patient grouping. Patients were dichotomized into 2 groups; poor or good AD, according to the mean AD, −7°. At 3- and 12 months patient-reported outcome was examined using validated questionnaires (ATRS and FAOS), and functional outcome using the heel-rise test.P = .036). Logistic regression analysis corroborated this finding . AD was not linked to any long-term functional or patient-reported outcome.Patients with poor AD sustained 42% DVTs, while patients with good AD exhibited a DVT-rate of 23% (Reduced AD after plaster cast removal is associated with a higher risk of DVT. The results of this observational study warrant further prospective studies to confirm the effects of ankle dorsiflexion on the risk of developing venous thromboses.Level of evidence: II Thus, at present, predictive factors and markers relating to the risk of DVT during limb immobilization are lacking.Lower limb immobilization, such as after trauma or surgery, is associated with a high risk (up to 40%) of DVT, according to a meta-analysis. Asymptomatic patients, with lower limb immobilization, generally only receive a score of 1 if there is no calf swelling. Recently, however, asymptomatic DVTs were demonstrated to exhibit an up to 72% risk of pulmonary embolism. Therefore, investigating other signs of DVT during leg immobilization is important for prevention as well as risk assessment.To evaluate the probability of DVT the Wells score is used, where a score of ≥2 indicates that DVT is likely and that the patient should undergo a diagnostic ultrasound scan. Moreover, previous studies on leg immobilization have indicated that fixation in plantar flexion was associated with a significant reduction in venous blood flow as compared with the ankle in a neutral position. It is therefore plausible that plaster casts fixed in more plantar flexion, i.e., less AD results in more venous stasis and thereby increased risk of blood clot formation.A recent study demonstrated that ankle dorsiflexion exercises during limb immobilization induced 2- to 6-fold increases in blood velocity in the popliteal vein. A recent meta-analysis comparing early postoperative ankle motion and weightbearing, with traditional ankle immobilization with a non-weightbearing rigid cast, demonstrated superior patient-reported outcomes and faster return to prior sporting activities in the weightbearing group. However, immobilization in a non-weightbearing plaster cast is still widely used postoperatively. Thus, whether decreased AD, per se, after immobilization is related to impaired patient-reported outcome after ATR has been unknown.DVT during leg immobilization was recently shown to be associated with poor patient outcome 1 year after acute ATR.In the present study, it was therefore hypothesized that AD after the removal of a non-weightbearing plaster cast would be associated with the risk of DVT as well as patient outcome after surgical repair of ATR. The primary aim of the study was to assess AD in relation to DVT. The secondary aim was to assess if AD was associated with patient-reported outcome at 3 and 12 months postoperatively as well as functional outcome at 1 year.2Ethical approval was obtained from the Regional Ethical Review Committee in , (Dnr: 2009/2079-31/2 and Dnr: 2013/1791-31/3).2.1 Preoperatively all patients received crutches and were advised to be non-weightbearing, and were immobilized either in an elastic wrap or in a plaster back slab.Between March 2011 and February 2018, a total of 124 plaster-casted control-patients, without any intervention, from 2 different randomized controlled trials were eligible for analysis in the study . A trained nurse and 2 experienced ultrasonographers, blinded to the outcome of the other tests, performed all the CDU scans using a Philips CX 50 ultrasound machine . The standard procedure included evaluation of all deep proximal and distal veins as previously described.,4 Patients diagnosed with a DVT received anticoagulation treatment according to the protocol at the hospital. One patient exhibited a proximal DVT and 1 patient developed a symptomatic pulmonary embolism diagnosed with computer tomography. In this study, we choose not to perform screening of the contralateral nonimmobilized limb with ultrasound Doppler, since this was not within the scope of this article.Most DVTs found were asymptomatic. The exact number of asymptomatic/symptomatic DVTs was not further assessed since earlier studies have demonstrated difficulties in differentiating symptoms of DVT from normal postoperative findings.2.4.2AD was in this study defined as the maximum ankle dorsiflexion range of motion the patient could perform and was assessed at 2 weeks postoperatively. An experienced physiotherapist, blinded to the DVT examination, performed all AD assessments. After removal of the plaster cast, the patient was first asked to perform 10 repetitions of active plantar-/dorsiflexion movements with both feet. For testing, the patient was sitting with his/her feet in full contact on the ground and was asked to slide the foot backward as far as tolerated without lifting the heel off the floor. The patient was instructed to slide backward with the injured leg as much as possible but without inducing pain or discomfort. A goniometer parallel to the floor and the fibula was used to record the amount of maximal ankle dorsiflexion range of motion. Each leg was measured 3 times and an average degree of dorsiflexion was calculated. Both ankles were examined separately, with the healthy side tested first. For analysis, AD was dichotomized according to the mean value  consists of 41 items, evaluating patient symptoms and pain, foot- and ankle function and quality of life. The questionnaire is divided into 5 subscales, and the score ranges from 0 (“Worst”) to 100 (“Best”).Patient-reported outcome was assessed with self-administered questionnaires specific for symptoms from the foot and ankle. The Achilles tendon Total Rupture Score (ATRS) consists of 10 items and responses ranging from 0 (“Worst”) to 10 (“Best”).The physical activity score evaluates and compares the patient physical activity before and after the injury. It is scored from 1  to 6 .The ATRS was completed at 3 months (n = 62) and 12 months (n = 95) and the FAOS at 12 months (n = 94). For the analysis of the ATRS at 3 months, only the fourth item (pain) was used. Physical activity score was assessed both pre- (n = 103) and postinjury (n = 90).2.5.2,17 The Limb Symmetry Index (LSI = (injured/uninjured) × 100) was calculated for heel-rise height, repetitions, and total work.Muscular endurance testing was conducted at 12 months postoperatively on both limbs. The MuscleLab  measurement system was used for the evaluations and was performed as previously described in the literature.2.6Recent studies have demonstrated the rate of compression Doppler ultrasound verified DVTs after ATR surgery to be 40%. Based on earlier studies of ankle dorsiflexion we estimated a 60% risk reduction of the incidence of DVT between patients with poor as compared with good ankle dorsiflexion. Thus, 54 patients per group would be required to detect a difference in DVT with 80% power when alpha was set equal to 5%.Descriptive data were reported as mean, standard deviation, and frequency. All variables were checked for severe skewness. Pearson correlations coefficient was used for correlations between variables and outcome for normally distributed data. The correlations were verified with multiple linear regressions analyses . This was done to investigate the unique relationships between the independent variables  and the dependent variable. Logistic regression analysis was performed to investigate the relationship between DVT and AD. All data were analyzed in SPSS version 22 . The level of significance was ≤5% for all analyses.33.1P < .001) in the immobilized, injured-  compared with the contralateral noninjured limb  .The ankle dorsiflexion range of motion  at 2 weeks’ post leg immobilization was significantly lower (3.2P = .036) . 42% (26/62) of the patients with poor AD sustained a DVT, while only 23% (11/48) of the patients with good AD suffered a DVT  nor with the risk of exhibiting a DVT (P = .317).The calf circumference of the patients at 2 weeks of immobilization was neither significantly associated with AD (3.4P = .045) (Table P = .11). Multiple linear regression corroborated that decreased AD was significantly associated with more pain in the limb when taking DVT, age, gender, and BMI into consideration .Patients with poor AD exhibited at 3 months significantly lower scores of the ATRS subscale “Pain in the calf/tendon/foot”  or at 12 months’ follow-up (P = .292)  Table .3.6Functional outcome was measured at 12 months with the heel-rise test—the limb symmetry index (LSI) of the number of repetitions, LSI of the heel-rise height, and total work. There were no significant differences between the patients with poor or good AD in any of the functional tests Table .4The present study established that patients with Achilles tendon rupture surgery who exhibited reduced ankle dorsiflexion during plaster cast removal after leg immobilization were associated with an increased risk of suffering a DVT. The calf circumference, however, was not related to the incidence of DVT. Moreover, decreased ankle dorsiflexion was related to more pain in the limb at 3 months postoperatively, but without any signs of long-term adverse events in terms of functional and patient-reported outcome. While hypercoagulability and endothelial damage are presumably not related to ankle dorsiflexion during immobilization, it is more likely that ankle positioning and mobility during plaster casting may affect venous stasis. The observed decreased ankle dorsiflexion among half of the limb immobilized patients, which were more prone to develop DVT, may suggest that their plaster casts were fixed in more plantar flexion due to, for example, that the Achilles tendon was surgically fixed in more plantar flexion or genetic differences, allowing less ankle mobility and less venous return. Increased plantar flexion (equinus) and more rigidity of the lower limb during immobilization may be 2 factors, which according to recent studies could increase both venous stasis and the risk of DVT.,10When exploring a potential causal link between ankle dorsiflexion and the risk of DVT it may be useful to review the risk factors responsible for the development of a thrombosis, which according to Virchow's triad are hypercoagulability, endothelial damage, and venous stasis.The most important finding in this study thus pertained to establishing that patients with greater ankle dorsiflexion during limb immobilization exhibited half the risk of sustaining a DVT as compared with patients with lesser ankle dorsiflexion. Such a difference in the risk of sustaining a DVT suggests that it may be crucial to find other interventions to increase circulation during leg immobilization to reduce the risk of venous thromboembolism. Equinus position may also lead to only partial weightbearing, which decreases venous circulation. We therefore suggest prospective randomized trials to examine leg immobilization with less rigid plantar flexion and more mobility in the ankle joint compared to equinus positioning in relation not only to blood flow but also to the risk of venous thromboembolism.An earlier study suggested that leg immobilization in a walking boot with the ankle in neutral compared to equinus position significantly increased venous return. Thus, ankle dorsiflexion may be a more prognostic measure of DVT than calf circumference in patients with leg immobilization. This conclusion, however, warrants further research.Whether poor AD caused an increased risk of DVT or whether DVT triggered, for example, increased swelling leading to poor AD, is unclear from the present data. The observation that increased calf circumference was neither associated with ankle dorsiflexion nor the risk of DVT, however, indicates that the asymptomatic DVTs did not result in swelling of the calf and is therefore in line with the concept that poor AD preceded the DVT. The finding that calf circumference was not associated with the risk of DVT is of importance since increased calf circumference is 1 criterion of Wells score for diagnosing the risk of DVT.The results from the multiple linear regression analyses confirmed the association between ankle dorsiflexion and risk of DVT when taking patient characteristics into account. This analysis furthermore demonstrated that the odds of a DVT were 3 times higher with a poor ankle dorsiflexion than the odds for a DVT with good ankle dorsiflexion. Such a high odds ratio, equal to the odds ratio of DVT in patients over compared to under the age of 40, suggests that it may be worthwhile to further study ankle dorsiflexion after limb immobilization as a prognostic marker for the risk of DVT. The patients with poor AD, however, were not affected in their functional outcome at 1 year as assessed with the calf muscle endurance (heel-rise) test.The second main finding of this study pertains to the fact that patients with greater ankle dorsiflexion after plaster cast removal exhibited better patient-reported outcome at 3 months postoperatively. The observation of less pain in the limb at 3 months in patients with greater ankle dorsiflexion at 2 weeks, in both uni- and multivariate statistics, suggests that a plaster cast with less equinus position and more flexibility may result in less early pain in the limb. The observation that ankle dorsiflexion did not affect the patient-reported outcome at 1 year suggests that the early increased experience of pain related to decreased ankle dorsiflexion does not produce any long-term subjective disabilities. It has earlier been shown that pain at 3 months after ATR surgery was associated with poor functional outcome at 1 year assessed with the calf muscle endurance test. Our conclusion that increased ankle dorsiflexion is not associated with tendon lengthening is supported by a meta-analysis comparing bracing and casting, which demonstrated no complications or tendon elongations in the bracing group.Our finding of ankle dorsiflexion not associated with the heel-rise height suggests that no major tendon lengthening occurred in the patients with greater ankle dorsiflexion. Less heel-rise height in patients with ATR repair has earlier been shown to correlate with tendon elongation, which is a limiting factor for optimal limb function.A potential limitation of this study is that the underlying factors relating to increased ankle dorsiflexion are not further known. AD could presumably be due to more surgical tension of the tendon or genetic differences leading to a plaster cast in more plantar flexion. Other factors affecting the amount of ankle dorsiflexion directly after the removal of the plaster cast could be pain due to more or less motion within the plaster cast, a DVT, fear of movement/re-rupture, pull in the wound/scar, discomfort, and personality. To counteract some of these aspects the patients performed standardized active exercises before the measurements and were assured that this movement was safe for the tendon.The strengths of our study are that all patients underwent the same study protocol, regarding local anesthesia and surgical techniques, as well as a meticulous assessment of DVT and AD. The study was also well enough powered to establish differences in ultrasound diagnosed DVTs in relation to AD.5We therefore conclude that decreased ankle dorsiflexion assessed after removal of lower limb immobilization may be associated with a higher risk of DVT, but not of any long-term impairments of outcome. The results of this observational study warrant further prospective studies to confirm the effects of ankle dorsiflexion on the risk of developing venous thromboses.


Stroke is a leading cause of disability worldwide and upper limb hemiparesis is the most common post-stroke disability. Recent studies suggest that clinically significant motor recovery is possible in chronic stroke survivors with severe impairment of the upper limb. Three promising strategies that have been investigated are (1) high dose rehabilitation therapy (2) bilateral motor priming and (3) vagus nerve stimulation. We propose that the future of effective and efficient upper limb rehabilitation will likely require a combination of these approaches. Today, there are over 7 million stroke survivors in the United States alone . It is eUpper limb (UL) hemiparesis is the most common post-stroke impairment and is significantly associated with a loss of independence in activities of daily living, decreased quality of life, and increased risk of institutionalization , 3. As sThe purpose of this perspective is to explore 3 treatment approaches that have shown promise to induce meaningful recovery in chronic stroke survivors with moderate-to-severe UL hemiparesis including (1) high doses of therapy (2) bilateral motor priming (BMP), and (3) vagus nerve stimulation (VNS). We aim to highlight the potential of BMP to enhance the effects of high dose UL therapy and suggest that, in combination with VNS, this approach may lead to improved functional outcomes for people with chronic UL impairments.The dose of therapy can refer to the amount of time scheduled for therapy, the time spent in active practice, or the number of repetitions achieved within a session . Most ofThese studies, led by Ward and McCabe respectively, found that large doses of therapy (90–300 h) were well-tolerated and led to significant improvement of motor deficits , 11. TheMcCabe and colleagues reported similarly impressive results . Thirty-The Ward and McCabe studies demonstrate improvements approximately double in magnitude compared to prior studies and substantially exceeds the established clinically important difference (CID) for the FMUE defined as a range of 4.25–7.25 points in chronic stroke . TogetheIn the context of the findings of Ward and McCabe, the amount of scheduled therapy in the United States (US) is far below what is needed to optimize recovery. A recent multi-site study  in the US tracked amount of therapy that patients received over 1 year post-stroke . The meaIn addition to limited therapy hours, the dose of therapy when defined by the number of UL repetitions delivered during a single session, is also low. One observational study of post stroke standard of care rehabilitation services found that individuals complete just 32 functional movement repetitions of the UL per therapy visit . MinimalTo achieve their respective results, Ward and McCabe provided interventions that included self-directed and therapist-led UL activities with a general goal of high repetitions of functional tasks (the exact number of repetitions was not reported). One way to interpret the data from these collective studies is to conclude that one needs at least of 90 h of therapy to see therapeutic benefit and improvement on the FMUE of 9–10 points. Another takeaway is that the therapy provided should aim to include a combination of customized, highly intensive, and progressive activities that challenge motor skill.is possible using fewer therapy hours if a comprehensive UL training protocol is preceded by motor priming  to induce priming. Both hands are strapped into vertically oriented plates attached via a mechanical link. Prior to therapy, participants move both wrists in rhythmic, symmetrical wrist flexion and extension for 15 min at a frequency of 1 Hz with a goal of 900 repetitions. Participants do not need to have active flexion and extension of the affected hand, as the less affected arm drives the weaker one in in-phase bilateral symmetrical movement. Thus, precluding wrist contractures and severe spasticity, individuals at all levels of post-stroke motor recovery can use this priming method.A study by Stoykov and colleagues showed that 7.5 h of BMP and 22.5 h of task-specific training (TST) over an intended duration of 5 weeks led to similar improvement as the previously discussed large-dose therapy trials . In eachThe causal mechanisms of BMP remain under investigation. When combined with different kinds of UL therapy, BMP appears to induce specific neurophysiological changes, namely, increased corticomotor excitability in the lesioned hemisphere and increased transcallosal inhibition from the lesioned hemisphere to the non-lesioned hemisphere , 26. ThiBMP appears to amplify the positive effect of rehabilitation and is non-invasive, safe, and inexpensive to implement. In addition, when the dose (defined in hours) of rehabilitation that can be provided is limited, BMP may be particularly attractive as an adjunct. BMP has the potential for broad clinical application.Vagus nerve stimulation combined with upper limb training has demonstrated efficacy for treatment of the hemiparetic UL and holds great clinical potential , 31. In Participants in the VNS group saw a significantly higher change in the FMUE from baseline to 1 day post treatment than the control group who received sham stimulation and the same UL treatment (mean change of 5.0 compared to 2.8) . AdditioA subsequent review and meta-analysis of the effect of VNS on UL recovery post-stroke further confirms that VNS paired with UL therapy produces significant, immediate, and long-term positive changes in stroke patients . These pAlthough the mechanisms underlying its efficacy are not yet fully known, it is thought that VNS may facilitate neuroplastic changes in the brain by increasing the release of neurotransmitters such as acetylcholine and norepinephrine in the cortex . When stin the entire year following stroke is 31.7 in the U.S. VNS will fail to achieve the gains demonstrated in the 2021 trial if combined with this insufficient number of therapy sessions. There is therefore an urgent need to optimize dose delivery in terms of both hours scheduled and the rigor of UL training in the clinical setting to take advantage of the exciting study results above.If VNS is paired with usual care therapy as it is currently delivered, the dose is arguably too low to achieve the gains demonstrated in the 2021 trial. To see benefit, patients will need to receive a minimum of 27–36 treatment hours over 6 weeks, post VNS implantation. As previously stated, the mean combined number of PT/OT sessions attended The above cited studies advance our understanding of key ingredients necessary to improve UL function in chronic stroke survivors including (1) increased hours of scheduled UL therapy (2) increased emphasis on skilled, progressive movement within the scheduled time (3) BMP and VNS to maximize the effects of an intensive UL therapy protocol. The data presented in Further benefit is possible when a robust UL training protocol is paired with VNS (yellow box) with 27–36 h of an individualized, progressive UL protocol that induced a median change score of 5.0. Improved results occurred when 22.5 h of a TST UL protocol was paired with 7.5 h of BMP producing a median FMUE change score of 11 points pre- follow-up (green box) compared to 2.2 points in the control group (red box) . Both thGiven that both methods have proven safe and effective for people with chronic, severe UL impairment, it is worth considering whether BMP when paired with VNS and a robust UL protocol can produce additive effects for maximal functional improvement. The exact neural mechanisms of the effects of either BMP or VNS on post-stroke UL hemiparesis are not known. However, after 20 min of the mirror symmetric wrist movements (BMP), healthy participants demonstrated an increase in cortical excitability of the resting passive hemisphere up to 20 min post movement . This inBased on principles of metaplasticity, the effects of one technique (BMP or VNS) could reduce the plasticity-inducing effects of the other . AlthougThe potential improvement possible when the three strategies are combined is shown in While the results of these studies are promising, realistic implementation into U.S. clinical practice will require thoughtful consideration. It is necessary to combine and deliver interventions with proven efficacy that are also feasible within the time constraints of the U.S. healthcare system which is unlikely to change drastically in the coming years. One strategy to deliver high dose, rigorous UL therapy is to combine face-to-face therapy sessions with supplemental exercise and education using smartphone apps, which has been effective when used in other diagnoses , 39. TheThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.EK, EP, and SU drafted the manuscript and figures. All authors contributed to the article and approved the submitted version.This research is supported by National Institutes of Health (1RO1HD091492). EK is supported by 1F31HD111318-01. EP is supported by T32HD101395.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.


Patients with cervical lymph node metastasis are undergoing neck dissection. Shoulder complaints are common after neck dissection, with patients reporting symptoms such as pain, weakness, shoulder droop, and disability. However, no safe and effective treatment is available for this condition at present. We will conduct a double-blinded, randomized controlled trial to evaluate the efficacy of carbon dioxide  scores of neck pain from baseline on day 1 (preapplication) to the end of drug application (day 15). Secondary end points include changes in the following parameters from baseline on day 1 to the end of drug application (day 15) or the study (day 29): neck pain VAS score (days 1-29), grip strength (days 1-15 and 1-29), VAS scores for subjective symptoms  for days 1-15 and 1-29, whether the VAS score improved more than 30% (days 1-15), the arm abduction test (days 1-15 and 1-29), shoulder range of motion (abduction and flexion) for days 1-15 and 1-29, occurrence of skin disorders, and occurrence of serious side effects. Periodic monitoring will be conducted for participants during the trial. This study was approved by the certified review board of Kobe University.We will perform this trial at the Kobe University Hospital in Japan. Patients will be randomized 1:1 into the CO2 paste treatment. The primary end point will be compared using the Wilcoxon test, with the 1-sided significance level set at 5%. Each evaluation item will be summarized. Secondary efficacy end points will be analyzed to provide additional insights into the primary analysis. Findings based on the treatment effects are expected to be submitted for publication in 2025.The intervention commenced in May 2021 and will continue until March 2024. The collected data will provide information on the efficacy of the CO2 paste in relieving pain in patients after neck dissection.This trial will provide exploratory evidence of the efficacy and safety of COJapan Registry of Clinical Trials (jRCT) identifier: jRCTs051210028; https://jrct.niph.go.jp/en-latest-detail/jRCTs051210028DERR1-10.2196/50500 Postoperative wound pain in the head and neck region generally improves within 1-2 weeks after surgery. However, patients undergoing cancer treatment often experience continuous, persistent pain, which can cause physical and psychological distress. Surgery and radiation therapy often cause painful scarring and contractures. Musculoskeletal and neuromuscular disabilities after radiotherapy and surgical treatment are major causes of cancer treatment–related side effects. Disabilities in the head and neck region after cancer treatment are related to a patient’s ability to communicate, eat, and work [Shoulder complaints are common 18%-77%) after neck dissection, even if the spinal accessory nerve has been preserved ,4. Sympt8%-77% afThe exact etiology of persistent postsurgical pain remains unclear, but its causes are thought to involve neuropathy -13, infl2) in a hydrogel as an absorption-promoting agent in healthy individuals and various animal models [2 improves vascularization and exercise performance in rats; it also increases local oxygenation, causing the dissociation of oxygen from hemoglobin (Bohr effect) [2 gas, which is difficult to apply to the head and neck. In a recent study, we investigated the usefulness, safety, and feasibility of a CO2 paste by analyzing the changes in blood flow in a phase 1 clinical study in healthy individuals [2 paste reacted with water on the skin surface, could infiltrate CO2 transcutaneously without the use of external CO2 gas, and could be applied to the head and neck region. In the phase 1 clinical study, application of the CO2 paste increased the blood flow in the skin and muscles, as observed by dynamic magnetic resonance imaging, and caused no adverse reactions.We had previously reported the effects of transcutaneous application of carbon dioxide (COl models -23. Tran effect) . Howeverividuals . The CO22 paste in decreasing postoperative neck pain in patients undergoing neck dissection.This double-blind, randomized controlled trial aims to evaluate the efficacy and safety of CO2 paste can reduce postoperative neck pain in patients receiving neck dissection in a double-blinded, randomized controlled trial. The primary objective is to estimate the within-patient differences in visual analog scale (VAS) scores for neck pain ranging from 0 (no pain) to 10 (worst pain) from baseline (day 1: before application) to the end of the study drug application (day 15). The secondary objectives are to evaluate the within-patient differences in the VAS scores for neck pain from baseline (day 1: before application) to the end of study drug application (day 15), grip strength from baseline to the end of the drug application (days 1-15) and the end of the study period (days 1-29), VAS scores for subjective symptoms  from baseline to the end of the drug application (days 1-15) and the end of the study (days 1-29), arm abduction [This study will examine whether the application of a CObduction  from basThis study has been designed as a single-center, placebo-controlled, double-blind, randomized controlled trial. The patient flowchart is shown in Inclusion criteriaAged 20 years or olderHave complaints of postoperative neck pain after unilateral cervical dissectionBetween 6 months and 3 years after neck dissectionA visual analog scale score of 1 or higher for neck painHave given voluntary consent to participate in this clinical studyExclusion criteriaHypersensitivity to drugs, including severe allergiesPeripheral arterial disease, ischemia (Fontaine III-IV), and ischemic cerebral artery diseaseHeart failure (New York Heart Association IV) and ischemic heart disease Female patients who are pregnant, lactating, wishing to become pregnant during the study period, or are fertile and cannot accept an effective contraceptive methodSevere respiratory disease with oxygen saturation (SpO2) less than 90% at restSkin ulcers larger than 4 cm × 4 cm × 1 cm or skin diseases making it difficult to apply the pasteDeemed inappropriate for participation in this clinical study by the investigators2 paste group or the placebo control group at a 1:1 allocation ratio. To ensure that blinding is maintained, the block size will not be disclosed. The allocation sequence for the randomization method will be generated by a biostatistician. All participants who provide consent to participate, fulfill the inclusion criteria, and do not meet any of the exclusion criteria will be randomized. The eligibility of each participant will be confirmed. A subject-enrollment confirmation form containing the eligibility judgment, randomization assignment results from the generated random sequence, and the enrollment number will be issued.Using the permutation random block method stratified by category, participants will be randomly assigned to either the CO2 paste (direCO2t) is manufactured as an experimental drug at the CO2TECH, a limited liability company. The CO2 paste contains 1,3-butylene glycol and other components, including sodium hydrogen carbonate, malic acid, sodium dihydrogen phosphate, an alkyl-modified carboxyvinyl polymer, and carboxyvinyl polymer. The placebo paste is a formulation in which the sodium bicarbonate in the CO2 paste is replaced by a nonreactive material (sodium chloride).The CO2 to the affected neck area once per day for 14 consecutive days. The duration of each application will be 10 minutes, and the paste will be wiped off after application.Within 4 weeks of enrollment, the VAS score for neck pain will be evaluated 1 week before the administration of the experimental drug during the preobservation period. On the first day of treatment, body temperature, blood pressure, oxygen saturation, and pulse rate will be measured by a physician, dentist, or nurse before and after the application of the experimental drug. The paste will be applied at 0.2 g-0.3 g/100 cmThe data collection schedules are presented in The primary end point for efficacy is the change in the VAS score for neck pain from baseline (day 1: before application) to the end of the study drug application (day 15).The secondary efficacy end points are as follows:Change in the VAS score for neck pain from baseline (day 1: before application) to the end of the clinical study (day 29).Changes in grip strength from baseline to the end of the drug application (days 1-15) and the end of the study (days 1-29).Changes in VAS scores for subjective symptoms  from baseline to the end of the drug application (days 1-15) and the end of the study (days 1-29).Whether the VAS score for neck pain showed a ≥30% improvement from baseline to the end of the drug application (days 1-15) and the end of the study (days 1-29).Change in arm abduction  from basChange in shoulder joint range of motion (abduction and flexion) from baseline to the end of drug application (days 1-15) and the end of the study (days 1-29).The secondary end point for safety is the presence or absence of adverse events such as skin disorders and serious diseases. The relationships among the interventions, outcomes, other assessments, and visits associated with the participants in this study are shown in 2 paste versus the placebo in terms of the change in VAS scores for neck pain (the primary end point). For the comparison of the primary end point, the Wilcoxon test will be performed for the null hypothesis, “There is no difference in the change in VAS values for neck pain at day 15 between the placebo group and the CO2 paste group.” The significance level will be set at 5.0% (1-sided). Each evaluation item will be summarized. Secondary efficacy end points will be analyzed to provide additional insights into the primary analysis. No adjustment for multiplicity will be made in the analyses of the secondary efficacy end points. The significance level for hypothesis testing is 5% (2-sided) with 2-sided 95% CIs. The incidence and rate of disease will also be evaluated. The safety end point is the frequency of the occurrence of adverse reactions. Tables will be prepared for the end points, and exact 2-sided 95% CIs of the binomial distribution will be calculated for each group to estimate the proportions.The primary objective of this clinical study was to evaluate the efficacy of the CO2 paste application and placebo groups would be 2 (SD 1.5) cm. A Wilcoxon test (a nonparametric test) will be performed considering the possibility that participants with a baseline score of less than 2 cm might be enrolled. The number of cases based on the Wilcoxon test can be calculated by multiplying the number of cases based on the t test [t test with a 1-sided significance level of 5.0% and a power of 80%, a total of 7 participants were required per group. When the number of cases was multiplied by 1.2, the total number of cases was 8.4. Therefore, considering drop out cases, 20 cases would be sufficient to maintain power.Most patients are expected to have a baseline VAS score of 2-3 cm. For the primary end point , we estimated that the mean difference in change between the COe t test . AlthougMonitoring will be conducted periodically to check whether the human rights and safety of the participants are protected and to confirm that the regulatory requirements of the Clinical Trials Act are followed. To ensure an appropriate assessment, the principal investigator is responsible for dealing with personal data and items specified in the written procedure. Any requirements made by the ethics committee will be immediately announced to the participants by the study investigators.This study will be conducted without patient or public involvement. Neither the patients nor the public will be involved in the development of the research question, study design, or implementation of the trial. Patients will not be invited to develop patient-relevant outcomes, interpret the results, or participate in the writing or editing of the final manuscript. Since the interventions in this study are routine clinical procedures, the burden of the interventions will be assessed by the patients themselves.Any protocol changes that affect the study conduct or participant risk-benefit profile will require approval from the relevant institutional review board, including changes in the objectives, design, sample size, participant characteristics, staff changes, or significant administrative features. Minor protocol corrections or clarifications that do not affect the study conduct or the participant risk-benefit profile will be viewed as administrative changes and documented internally. The study investigators will have full access to and ownership of all the data. Anonymized data will be made available to other interested investigators for additional analyses on reasonable request, following reports of primary outcomes and with an appropriate data use agreement. The findings of this study will be disseminated through scientific and professional conferences and a peer-reviewed journal.The study is being conducted in compliance with the principles of the Declaration of Helsinki (1996), the principles of good clinical practice, and all applicable regulatory requirements. This study has been approved by the Clinical Research Review Board of Kobe University (CRB5180009), and the trial has been registered with the Japan Registry of Clinical Trials (jRCT) (jRCTs051210028). All participants will be required to provide written informed consent before any study procedures are conducted. The participants will have the opportunity to review the consent form and confirm that they have fully understood the details of the study procedures. Secondary use of the data will occur only if the patients provide written informed consent for additional use of their data. Secondary use of the data will adhere to appropriate ethical review and approvals, as per institutional guidelines. No funding was received for this study, including institutional or departmental support. The study is not commissioned, externally peer reviewed.The subject recruitment began on May 24, 2021. The entry period for participants is up to March 31, 2024, three years after the jRCT registration. Data analyses of all enrolled participants will be conducted in 2024. This manuscript is based on the current version of the protocol (version 3.0), last updated on December 23, 2022.The data sets generated in this study will be available on the jRCT website. The final report is expected to be published in a peer-reviewed journal in 2025. The findings will be disseminated through scientific and professional conferences and peer-reviewed journal publications in 2025.2 paste to patients who undergo neck dissection and experience postoperative complaints. A neck dissection is a surgical procedure performed to remove cervical lymph nodes. During surgery, the blood vessels are ligated to prevent bleeding. In addition, the internal jugular vein, which drains blood from important organs such as the brain, face, and neck, is removed depending on the type of neck dissection. These blood flow interruptions lead to wound ischemia and various postoperative symptoms or dysfunctions.This report describes the protocol for a study evaluating the application of COPain, the main side effect of neck dissection, often aggravates patient QOL ,7. As it2 paste application increases blood flow to the skin and muscles without any side effects [2 application induces angiogenesis by inducing an artificial Bohr effect, we hypothesize that this simple and adaptable treatment can alleviate side effects and improve the QOL of patients undergoing neck dissection.In a phase 1 clinical study, we reported that CO effects . Since t2 paste to postoperative skin. Since it is composed of food ingredients, the CO2 paste is considered to have few life-threatening side effects. However, there is no evidence on whether its application may induce dermatitis. Therefore, the occurrence of dermopathies such as erythema and exanthema should be carefully monitored during the trial. To address potential safety concerns, the CO2 paste will be applied to the postoperative neck for only 10 minutes a day.This study will be the first to apply CO2 paste application on postoperative neck pain in patients undergoing neck dissection. Since the efficacy of CO2 paste for neck pain has never been reported, this will be the first well-designed clinical evaluation study on this topic. Our primary hypothesis is that CO2 paste application can reduce pain in patients undergoing neck dissection. We also expect that the application of this paste will reduce subjective symptoms, including feelings of strangulation, numbness, swelling, and warmth, and will improve grip strength, arm abduction, and shoulder joint range of motion (abduction and flexion).Through this study, we aim to determine the curative effect of CO2 paste application, this will be the first protocol to be performed as a phase 2, double-blinded, randomized controlled trial, evaluating the efficacy of CO2 paste in a small number of patients with neck pain after neck dissection. Nonetheless, this clinical trial has some limitations that should be acknowledged. First, the number of evaluated patients is relatively small to conclusively determine the efficacy of the CO2 paste. Second, since some patients underwent neck dissection as part of larger resections, a small amount of heterogeneity is expected. Finally, this study is limited by its short duration (28 days).We previously conducted a clinical trial on a small number of healthy individuals. To explore the adequacy and applicability of CO2 paste to patients complaining of pain after neck dissection.Considering the general condition of the patients and the side effects of drug therapy, postoperative pain after neck dissection is difficult to manage. Therefore, establishing a widely applicable treatment with fewer adverse effects is essential. The results of this study will provide valuable evidence for the future application of CO


Traditional problem-based learning (PBL) relying on tutored learning in small groups is very resource-intensive. Little is known about the benefits of PBL in a large classroom setting. This paper introduced a PBL case into the traditional didactic biochemistry course and investigated the acceptability of total online or partial online PBL in a large classroom setting introduced during the coronavirus pandemic.The students were allocated into either total online Group 1, partial online Group 2, or partial online and with poorer academic performance Group 3. A questionnaire comprising of 8 closed-ended questions and 2 open-ended questions and final exam performances were used to evaluate the acceptability of total online or partial online PBL in a large classroom setting. The 8 closed-ended questions were analysed by the Kruskal–Wallis test or chi-square tests. The word cloud analysis of the 2 open-ended questions were conducted by Wenjuanxing. Students’ performances in the final examination were analysed by One-way Anova.Both total online and partial online PBL were rated highly by the students. Overall, there were no significant differences in the effectiveness evaluation of PBL between Group 2 and Group 3. There were no significant differences in final exam performances between Group 1 and Group 2. However, Group 1 rated the effectiveness of PBL much higher than Group 2 and 3. Word cloud analysis of the 2 open-ended questions showed students’ positive perspectives of PBL. In biochemistry teaching, from the perspective of the students, the expected optimal number of useful PBL cases might be 2.Both total online and partial online PBL in a large classroom setting were widely accepted as a beneficial supplement to traditional biochemistry classes.The online version contains supplementary material available at 10.1186/s12909-023-04767-3. Problem-based learning (PBL) originated in the Medical School of McMaster University in Canada in 1969 is a student-centered learning approach, in which problems drive the learning . It is aBiochemistry is a mandatory course for medical undergraduates. However, students usually have significant difficulties in understanding and comprehending of the complicated basic medical science covered by it . MoreoveIn biochemistry, knowledge of metabolic networks is essential and most challenging. To explain various phenomena under normal and pathological conditions, medical undergraduates must understand the composition and interactive relationships of metabolic networks . It is rCurrently, there is a paucity of research about the benefits of total online and partial online Hybrid-PBL in a large classroom setting. In this research, we showed and discussed the results obtained from the application of total online and partial online large class PBL case scenario sessions integrating amino acid metabolism and the biochemistry of the liver during the coronavirus pandemic.In the first semester of their second academic year, 689 (100%) medical undergraduates at our university were enrolled during their regular biochemistry classes in this study. All the students had no prior experience with PBL in their medical courses. The global coronavirus disease (COVID-19) pandemic forced universities in China to conduct partial or total online teaching. In this study, the students were grouped according to their learning performances and the pandemic control regulations: Group 1 is a total online group, Groups 2 and 3 are two partial online groups , with 327, 163 and 199 students in the three groups, respectively. There were no gender or age differences between the three groups. For the first two groups, there were also no academic performances differences before the start of the course. The students of the third group are from a special group in China. They are known as public-funded students, and most of them will be assigned to township hospitals after graduating from university. It was known that the learning ability and motivation of the first two groups were significantly higher than those of the third group. The three groups were further randomly divided into many subgroups. Each PBL subgroup constituted ten to eleven students with a chair and a recorder to organise case discussions and record the discussion processes. The facilitators responsible for instructing PBL groups were biochemistry teachers. The PBL case scenario sessions were conducted in large classrooms with approximately 5 subgroups in each classroom. The online and face-to-face PBL case scenario sessions were guided by a facilitator via video conference and face-to-face, respectively. For both online and face-to-face PBL sessions, the ratio of facilitators to subgroups was one facilitator per the 5 subgroups.After traditional lectures about carbohydrate and lipid metabolism were finished, the students were offered some online resources including learning objectives, PPT, and micro-lectures to study amino acid metabolism and the biochemistry of the liver by themselves. Then a PBL case about alcoholic liver, which involved the progression of alcoholic fatty liver to alcoholic hepatitis and then, at last, hepatic encephalopathy, was offered to the students. The case was modified from real cases by a trained PBL writing team with biochemistry teachers and clinical experts to suit the learning objectives of the curriculum. While constructing the case, the team members constructed a detailed tutor’s guide. PBL case scenario experts of our college approved the case. The case covered most key knowledge about amino acid metabolism and the biochemistry of the liver. In addition, it also involved some knowledge about carbohydrates metabolism, lipids metabolism, and the cross-talk of the metabolism of the three nutrients. The case was designed for two sessions with each lasting 2.5 h. Training sessions for the teaching faculty and questionnaire were standardised before the research. Due to the students’ having no prior experience with PBL, before the first PBL session, they were trained on PBL philosophy and general procedures. Senior students with rich PBL experience shared their experience. To help the students determine the reliability and feasibility of the resources acquired from the network in the following sessions, evidence-based medicine (EBM) philosophy which is the use of high-quality clinical research to determine the care of patients was also introduced. In addition, in order to promote the learning in PBL sessions, a learning contract which stated the responsibilities of the tutor, chair, recorder and other student members was signed. During each PBL session, the students were required to identify essential clues or problems, list hypotheses, list proofs supporting the hypotheses, generate a series of learning issues and learn the issues from biochemistry and other medical disciplines’ perspectives. The students were advised to access online resources and refer to textbooks, including biochemistry, diagnostics, internal medicine, etc. The recorders recorded the sessions, and the contributions of all the members in every subgroup were marked. After each session, all subgroups were required to submit a report containing the four items mentioned above to the facilitator. Before and after the second session, the facilitators commented on the reports of the first and second sessions respectively, praised the strengths of each group, pointed out their shortcomings, and gave some suggestions for improvement. At last, the facilitators concluded the key learning objectives and the relevant biochemical knowledge hidden in the case.www.wjx.cn) was used to develop a questionnaire comprising of 8 closed-ended questions and 2 open-ended questions for the analysis of students’ perceptions of the effectiveness of the PBL case scenario sessions. The survey had two spaces for their free response comments on the following 2 open-ended questions: (a) What have you learned the most from PBL? (b) What advantages and disadvantages do the PBL sessions have compared with traditional teaching methods? What do you think the current PBL sessions need to be improved?Based on previous studies , 14–16, strongly disagree or disagree, 1 = neutral, 2 = agree, and 3 = strongly agree. The participation of students in the survey was voluntary and the anonymous nature of their responses was assured.The evaluations were completed immediately after the case scenario sessions. Respondents scored the 6 survey items in Table A 2 on a 4-point rating scale, with 0 = The learning effectiveness of PBL was appraised in the in-person final written biochemistry examination. The examination questions included Multiple Choice (40 marks), True or False (10 marks), Terminology (24 marks), and Essay Questions (26 marks). The last essay question was a 6-point question that asked the students to write the first scenario of a PBL case, extract relevant biochemistry problems from it and then explain the problems. Besides the PBL case essay question, there were also some other questions related to the PBL case they had studied, including 1 Multiple Choice and 4 True or False questions. These questions were used to evaluate the learning effectiveness of the PBL case scenario sessions.SPSS for Windows, version 25 (IBM SPSS), was applied for all analysis. The 8 items were analysed by the Kruskal–Wallis test or chi-square tests. In addition, comparisons of the performances of the students including PBL case related question marks and total scores in the final examination between the three groups were analysed by One-way Anova.In the PBL sessions, with the guidance of the facilitators, students from the 3 groups worked actively and excitedly together to analyse the case scenarios, identify important clues, make their preliminary disease judgments, list proofs to support their judgements, discuss the hidden learning issues related to medical sciences mainly biochemistry, ‘population’ health and humanistic care.p < 0.001). There was no evaluation difference between Group 2 and Group 3 (p > 0.05).Among the 689 clinical medical undergraduates, 685 (99.42%) students completed the questionnaire. Table A1 showed students’ evaluations of the overall effectiveness of PBL case scenario sessions. All the three groups of students rated the PBL sessions highly. Students of Group 1 rated the PBL sessions higher than those of Group 2 and Group 3 (p > 0.05). Based on the data in Table Table p < 0.001, p < 0.01, or p < 0.05). Except for the item ‘beneficial to develop deeper self-awareness’, no difference between Group 2 and Group 3 was noted.Table A2  depicted students’ perceptions of PBL in cultivating their self-directed learning skills. Most students from the 3 groups believed that they had obtained more abilities from PBL than from conventional learning methods. Data from Table A2 showed the ratings of students on the 6 items, with the mean ± SD ranging from 2.06 ± 0.82 to 2.71 ± 0.48 . Moreover, students of Group 1 showed higher ratings on all the 6 items than Group 2 and Group 3 (‘Wenjuanxing’ is a professional online questionnaire survey platform widely used in China. It can automatically extract the keywords contained in all the answers of the two free-response comment questions and automatically classify and analyse them to provide word clouds. A word cloud, a form of data visualization, is a graphic representation of words or phrases that gives greater prominence to those that appear more frequently . The hotTable A3 showed that there were no academic performance differences between Group 1 and Group 2. In addition, as we expected, the academic performance of the Groups 1 and 2 was significantly higher than Group 3.The essence of PBL is its connotation and theoretical principles of learning which include contextualised learning, constructive learning, collaborative learning, and self-directed learning. These elements lead to its unique advantages over traditional didactic teaching methods. However, traditional PBL relying on tutored learning in small groups is very resource-intensive. This has seriously hindered the implementation of PBL in many medical schools, including most medical schools in China. Therefore, the study of large class PBL is of great significance. To our knowledge, this is the first study to explore the feasibility of the introduction of total online or partial online large class PBL in biochemistry course. Our questionnaire and final exam analysis indicated that both total online and partial online PBL in a large classroom setting were considered as a beneficial complement to traditional biochemistry teaching. The cultivation of students’ abilities and skills is a long-term process. Therefore, we cannot expect one or two PBL cases to significantly improve students’ multifaceted abilities and skills. However, PBL undoubtedly gives students a learning idea and approach different from traditional teaching.A few studies had validated the feasibility of different approaches to face-to-face large class PBL. Qiu Yan et al  had succHowever, some factors restricted the implementation of large class face-to-face PBL, for example, pandemics, cross-regional collaborative PBL or others. Our questionnaire survey and final examination showed that most enrolled students had deeply understood and experienced the essence of PBL. Therefore, when face-to-face large class PBL is restricted, total online and partial online PBL might provide a new alternative approach to PBL implementation.Both the survey about students’ expectations for the number of PBL cases and word-cloud analysis of the second open question indicated that most students were accustomed to traditional didactic teaching, which was considered as the most efficient way to acquire knowledge in a short term. Therefore, too many PBL sessions may burden the students and not be conducive to the current academic situation. Jie Li et al.  claimed Tutor quality, student motivation, and realistic cases are the three known difficulties that strongly influence the effect of PBL, and these factors vary over a broad range . In our The worldwide lockdown restrictions resulting from the COVID-19 pandemic impacted all aspects of life, including the sudden shift from face-to-face teaching to online teaching. Research on the perceptions of 2721 medical students across 39 medical schools from the UK during the pandemic indicated the advantages and disadvantages of online teaching and students’ preference for face-to-face teaching . AdvantaThe hot words analysis about the shortcomings of the current PBL pointed the way for further improvement. Optimizing the internet resources available to the PBL program, group staffing, and timely guidance by tutors should be carried out in the future.This research has some limitations. It is only a preliminary study on the role of total online or partial online large class PBL introduced in biochemistry, with only one PBL case scenario involved. In the future, more detailed and comprehensive studies should be carried out, including other PBL case scenarios that involve other diseases and some related knowledge, the more precise appropriate timing of PBL introduction in biochemistry, the optimizing of group staffing and more timely and effective guidance to maximize the benefits for as many students as possible, etc. Furthermore, all the students enrolled in this study had no prior PBL experience in all their medical courses. Moreover, the curriculum also included lecture content on the theory assessed in the exam. All these factors may modify the effect of PBL.In this study, we successfully combined total online or partial online PBL in a large classroom setting with conventional biochemistry lectures. Our medical undergraduates well accepted total online or partial online PBL as an effective supplement to traditional classes. Our study was an innovative trial that introduced total or partial online PBL in a large classroom setting to medical undergraduate students in a specific discipline. This might provide a perspective for the universal use of PBL in many other disciplines. Moving forward from the pandemic, to improve the efficacy of medical biochemistry teaching, especially the efficacy of online teaching during future possible pandemics or cross-regional collaborative teaching, we suggest that medical school resort to online or partial online PBL introduction in the biochemistry curriculum.Below is the link to the electronic supplementary material.Supplementary Material 1


Most individuals seeking asylum in Germany live in collective housing and are thus exposed to a higher risk of contagion during the COVID-19 pandemic.In this study, we aimed to test the feasibility and efficacy of a culture-sensitive approach combining mobile app–based interventions and a face-to-face group intervention to improve knowledge about COVID-19 and promote vaccination readiness among collectively accommodated Arabic-speaking adolescents and young adults.We developed a mobile app that consisted of short video clips to explain the biological basis of COVID-19, demonstrate behavior to prevent transmission, and combat misconceptions and myths about vaccination. The explanations were provided in a YouTube-like interview setting by a native Arabic-speaking physician. Elements of gamification (quizzes and rewards for solving the test items) were also used. Consecutive videos and quizzes were presented over an intervention period of 6 weeks, and the group intervention was scheduled as an add-on for half of the participants in week 6. The manual of the group intervention was designed to provide actual behavioral planning based on the health action process approach. Sociodemographic information, mental health status, knowledge about COVID-19, and available vaccines were assessed using questionnaire-based interviews at baseline and after 6 weeks. Interpreters assisted with the interviews in all cases.always wearing masks” was indicated by 43/65, 66% of participants), but practicing behavior that was not considered as effective against COVID-19 transmission was also frequently reported as a preventive measure . By contrast, factual knowledge of COVID-19 was limited. Preoccupation with the information materials presented in the app steeply declined after study enrollment . Of the 61 participants, only 18 (30%) participants could be reached for the follow-up interviews. Their COVID-19 knowledge did not increase after the intervention period (P=.56).Enrollment in the study proved to be very challenging. In addition, owing to tightened contact restrictions, face-to-face group interventions could not be conducted as planned. A total of 88 participants from 8 collective housing institutions were included in the study. A total of 65 participants completed the full-intake interview. Most participants  had already been vaccinated at study enrollment. They also claimed to comply with preventive measures to a very high extent (eg, “The results indicated that vaccine uptake was high and seemed to depend on organizational determinants for the target group. The current mobile app–based intervention demonstrated low feasibility, which might have been related to various obstacles faced during the delivery. Therefore, in the case of future pandemics, transmission prevention in a specific target group should rely more on structural aspects rather than sophisticated psychological interventions. The COVID-19 pandemic has affected different parts of the population in Germany at different intensities . Asylum Knowledge about the COVID-19 disease and its transmission has been shown to be limited among asylum seekers and refugees -10. For Vandormeal et al  tested aIt is against this background that the Deutsche Forschungsgemeinschaft initiated a research program dedicated to the “prevention of disease transmission in specific social settings and subgroups of the population” on December 14, 2020 . At thisWe proposed the COVID apps for young adults for preventing transmission and promoting vaccination among refugees (CAYPVAR) study to this research program, and the decision to grant the study was announced on April 27, 2021. As the correction of misinformation and myths about COVID-19 and available vaccines seems to be a critical requirement to promote preventive behavior against the transmission of the disease ,19, the Can young asylum seekers in Germany be reached to a reasonable extent to roll out a specific prevention campaign during the COVID-19 pandemic?Can a mobile-based intervention with elements from serious games (the CAYPVAR app), providing information in a culture-sensitive and age-adapted mode of presentation, contribute to a better understanding of disease mechanisms and an increased willingness to be vaccinated?Can the potential positive effects of the CAYPVAR app on actual behavior planning be intensified by a face-to-face group intervention? This intervention was planned as a single session and dedicated to addressing the structural barriers prevailing in collective housing and individual needs to understand the disease spread mechanisms. It should contribute to bridging the intention-behavior gap often observed in prevention trials .The study was planned as a phase II analogous feasibility and quasi “dosage finding” study. The potential efficacy of a mobile app–based informative intervention (the CAYPVAR app) was planned as a pretest-posttest comparison in the first group of participants (group A). A randomly allocated group B was scheduled to receive the CAYPVAR app plus a face-to-face group intervention on behavior planning . This shThe study protocol was approved by the Ethics Committee of the HSD University of Applied Sciences  and registered in the German Clinical Trials Registry (study number: DRKS00028825). All participants provided written informed consent before commencing the study. Study data were collected in a pseudonymized manner with different individual codes for the different data sources . Personal contact data were never disclosed to team members who analyzed the data. The code list for data merging was only accessible to UF, DS, LB, and HC and was destroyed after the follow-up interviews. Participants were granted free mobile data or Wi-Fi access via prepaid cards or wireless local area network (WLAN) routers installed by the study team during the intervention period. In addition, participants received a one-time voucher of €10 (US $10.9) for continued app use and a voucher of €20 (US $21.7) for participation in the follow-up interview.Inclusion criteria for participants were that they must (1) be aged 16 to 26 years, (2) possess a mobile phone, (3) speak Arabic, (4) be living in a collective housing facility, and (5) not have a psychiatric condition requiring hospitalization. Female asylum seekers aged 16 to 26 years seldom live in collective accommodation, as was known from earlier studies with refugees to Germany undertaken by the working group of the Catholic University Eichstätt-Ingolstadt -23. TherIn collective accommodations in Germany, most residents are young male individuals who are waiting for a decision regarding their asylum request or have obtained a temporary residence permit . Thus, tAs most asylum requests in Germany have been submitted by Arabic-speaking persons in the last couple of years , the larMost young asylum seekers possess a mobile phone because this has been an important source of information during the flight  and is aThe intervention period was conceptualized over 6 weeks, and new informative video clips were presented each week . Beyond To ensure an age-adapted mode of presentation, the videos were scripted as YouTube-style interviews by a female interviewer  asking a male physician , with both partners sitting in distance on a sofa. Both could be easily recognized as persons from similar cultural backgrounds as the participants. Most interviews contained short sequences such as animated cartoons that explained and visually repeated the verbal information provided by the physician. These sequences stemmed from scientific educational institutions . The interviewer asked the questions in German, which were translated into Arabic using the voice-over technique. The answers of the interviewee were freely formulated (but scripted) in simple Arabic language.In addition, there were videos that presented solo statements of the physician. These clips described real case histories that the physician had treated , drug and vaccine approval procedures, and the safety precautions from his experience as a study physician, and he explained how vaccination from the viewpoint of Islam is justified .Recruitment Strategy section) and lasted slightly longer than 7 minutes.To optimize the video clips for mobile phones, the clips were restricted to a maximum length of 3 minutes, except for a video on vaccination myths, which included a science fiction movie scene from the 1960s .The CAYPVAR app was downloaded by participants from the official Google and Apple app stores using an account provided by the project team during the baseline interview. After the initial log-in, the app downloaded the quiz questions.Results section). To assess knowledge of disease mechanisms and transmission paths, a 12-item knowledge test was used, whereas the amount of one’s own knowledge about infectious diseases was assessed using 12 items .The questionnaire-based baseline and follow-up interviews were collected on separate tablets handed to participants (intake interviews) or interpreters (follow-up interviews) for each interview. Interpreters were present throughout the provision of study information and interviews. During the interviews, sociodemographic information  and vaccination status were obtained. Vaccination readiness (“Do you want to get vaccinated?”) was assessed on a 4-point scale . The Patient Health Questionnaire-4 (PHQ-4)  was usedVideos of the educational events were loaded (streamed) only when needed. The results of the completed quiz questions and other collected data were cached by the apps and transferred to the server when they were connected on the web. Further details on the IT infrastructure and methods for maintaining participant privacy will be published elsewhere in a separate, more technically oriented paper. In general, our apps follow the technical principles described by Pryss et al .The manual of the group intervention was based on the principles of the health action process approach ,40. It iThe setting was prepared as a single group session with 8 participants at maximum lasting for up to 90 minutes. The sessions were to be conducted by DS with the assistance of an interpreter.While planning this feasibility study, a vaccine against COVID-19 was not yet approved. However, rumors on side effects of the potential vaccines had already been spread via social media. Therefore, the base rate of the first major study end point, willingness to get vaccinated, was set to a very low number (2%) for power calculation. A pretest-posttest comparison  of increasing the willingness of only half of the included participants would have reached a statistical power of 0.95 in a sample of n=8 (Fisher exact test). All power analyses were performed using G*Power 3.1 (Heinrich-Heine-Universität Düsseldorf).The second major study end point, knowledge of disease mechanisms, was expected to reach low levels at intake . Expecting that processing the contents of the video clips presented via the app would enable us to solve at least 8 (SD 4.0) test items, 12 participants would be needed to reach a power of 0.95.t tests for independent samples or (depending on score distribution) a Kruskal-Wallis test was planned.To detect significant differences between both groups in the follow-up interview  with a power of at least 0.90, we expected an increase in the willingness to get vaccinated from 50% (group A) to 80% (group B). This required 47 participants in each group. For an additional increase in disease knowledge (study end point 2) of 3 more correctly solved items, a good statistical power (0.95) could be reached by including 40 participants per group. For analysis of group differences, 2-tailed During the recruitment period (October 2021 to December 2021), 8 institutions  out of 56 collective housing facilities contacted (thereof 15 in Berlin) agreed to offer their residents the choice to participate in the CAYPVAR study and allowed the study staff to enter the facility. The Bavarian centers were large (up to 1000 inhabitants), whereas the considerably smaller Berlin centers contributed 5 participants at maximum. Therefore, these small 4 institutions in Berlin were treated as 1 common Berlin center for comparison. This reflects the differing legal regulations in Berlin compared with Bavaria during the observation period.Study enrollment proved difficult in a dynamic pandemic situation and under changing legal regulations. Collective housing institutions, especially in Bavaria, with a greater number of asylum seekers living in one building, were reluctant to allow access to their inhabitants. Some centers even withdrew their willingness to participate in the study because of increased regional incidence rates.The enrollment of participants began on November 8, 2021. At the start of enrollment, Germany’s second  lockdown was put into effect. During the preceding time, when information material had been prepared, the prevailing virus variant was Alpha (B.1.1.7). This had changed to the Delta variant (B.1.617.2) when the last baseline interview took place . The Delta variant had a considerably higher contagiosity than Alpha, causing a higher death toll in susceptible persons. Therefore, collective housing facilities in Bavaria severely tightened contact restrictions, rendering face-to-face group sessions unfeasible. In addition, various housing institutions linked their study acceptance to the precondition that all their inhabitants should profit from the incentives (free or improved WLAN access) of CAYPVAR. Thus, randomization of participants into 2 groups would have been possible only as cluster randomization, covering a very limited number of housing centers. Owing to the difficult enrollment situation in combination with a rapidly changing residential population  and tightened contact restrictions, it was decided to abandon the randomized additional intervention (group B) and to only evaluate the efficacy of the mobile app–based intervention .The number of potentially eligible Arabic-speaking adolescents and young adults in the participating institutions was estimated by the facility staff to be 411 persons on the day of being contacted by our study team. The project team made personal recruitment visits and successfully asked 146 participants for their willingness to participate, but many of them  did not appear at the agreed appointment . Of the The sociodemographic and migration-related characteristics of the participants are shown in As shown in At the baseline interview, 77% (50/65) of participants had already been vaccinated against COVID-19. An additional 20% (13/65) of participants stated their willingness to get vaccinated as soon as possible. Only 5% (3/65) of participants were reluctant to be vaccinated. There were no indications of differing attitudes or behaviors between the different housing facilities.With regard to preventive behaviors, participants were asked about their attitude toward and engagement in various behavioral measures to mitigate the spread of COVID-19 . In the As statistical power was too low to test pretest-posttest differences between baseline and follow-up interviews , only descriptive values on attitudes toward and engagement in preventive behaviors among the follow-up interviewees could be captured as presented in Concerning the possible selection bias of participants answering the follow-up interview, we found no indication of different scores with regard to mental health measures . Of the 18 participants who completed the follow-up interview, 15 (83%) participants declared that they had learned new facts about COVID-19 from the physician (KMA) while watching the video clips via the CAYPVAR app. A high proportion  of the participants expressed their trust in the physician and these new facts. Self-confidence in one’s own knowledge of disease mechanisms, although not statistically tested, tended to increase between baseline and follow-up interviews on a descriptive level with one exception: participants during the follow-up interview less often stated that they had knowledge about infectious diseases .t test for dependent groups was performed, with t15=−0.60, which was not significant (P=.56).In addition to confidence in one’s disease knowledge , a knowlThe CAYPVAR study aimed to impart knowledge about COVID-19 and the available vaccines by implementing a mobile-based intervention with elements from serious games. This feasibility study yielded 2 main results. First, the vaccination rate or readiness among participants was very high at baseline. Second, an evaluation of the feasibility of our preventive intervention strategy could not be successfully achieved with regard to knowledge of disease mechanisms and attitudes toward preventive behaviors because of the small number of participants taking part in the follow-up interview. The enrollment of participants in this study was very difficult, and the dropout rate from the study among the enrolled participants was high.The high vaccination rate reported by the participants at baseline  is in contrast to the current literature. A review of general vaccine uptake in migrant populations in Europe showed that asylum seeker or refugee status increased the risk for undervaccination . AcceptaThere are 2 possible explanations for the high vaccination rates observed in this study. First, participants might have perceived staff working in their collective housing facilities as reliable state representatives and information sources and thus followed their advice to get vaccinated. Tjaden et al  evaluateSecond, we conducted informal talks after the baseline interviews in this study. We learned that many participants feared a negative impact on their asylum proceedings if they had refused to participate in the vaccination campaigns organized by the staff of their collective housing facilities. A review of general vaccine uptake in migrant populations in Europe identified distrust in the health care system and fear of being questioned about one’s legal status as a barrier to accepting vaccination . The oppAn evaluation of the feasibility of the presented intervention strategy could not be achieved because of the severe difficulties with enrollment in this study. Regarding recruitment, the following 2 obstacles may have hampered enrollment in this study. First, there was a large contrast between potentially eligible asylum seekers living in housing facilities and those who agreed to participate in the study. This could be explained by the limited presence of asylum seekers during the daytime in their housing institution during which the study team tried to make personal contact in the form of a recruitment visit. However, the striking difference between the individuals who stated their interest in participating in the study (n=146) and those who signed the informed consent form (n=88) cannot be explained by this. In several cases, the participants were relocated to another institution during the week following the recruitment visit as reported by the housing staff. However, it also seemed that agreeing to the invitation to participate in the study during the first recruitment visit might not have been sufficient to appear at the agreed appointment a few days later. It can be speculated that refugees’ “lifes on hold” provoked “disintegration of time” that already in 2010 has been described in a Swedish study . Early dSecond, perhaps the participants in this study did not feel a “need for cognition” about COVID-19 because most of them had already been vaccinated and therefore had also undergone a consultation with the vaccinating physician. This study showed the young refugees’ limited general and COVID-19–related factual knowledge of infectious diseases and the transmission paths. For example, 30% (20/67) of participants stated that HIV could be transmitted via handshakes, and 36% (24/67) claimed that COVID-19 was only transmitted via aerosols. This finding is in line with other studies on refugees’ knowledge -10. KanaMoreover, continued participation in this study was low, leading to a high number of dropouts during the intervention period and at the follow-up assessment. Drawing on the research on psychological interventions for refugees with mental health problems, further potential explanations for the low adherence of participants can be found. First, prominent postmigration stressors of asylum seekers are overcrowded and inadequate housing conditions or the prolonged or uncertain asylum process . A revieSecond, the participants in this study had settled in Germany only recently, on average, 7 months ago. One could speculate that the problems of these newly settled asylum seekers  might have constituted specific barriers not only to enrollment but also to continued participation. Thus, the current intervention strategy might not have been feasible for the specific group under investigation, but this does not necessarily apply to other groups of asylum seekers and refugees. For example, the initial settlement period  has been described as an additional source of stress for asylum seekers . TherefoThird, the dropout rate was extremely high in this study despite the precautions taken such as age-adapted information materials  and incentives in the form of quizzes and competitions. In addition, we established a cultural match between participants and assessors (DS) and persons shown in the video clips (DS and KMA) and used culture-sensitive modes of delivery of the intervention such as simple language ,32. MoreIn conclusion, the concept of this study aimed at developing and evaluating the feasibility of a primary preventive intervention against COVID-19. The design of the study did not allow us to unambiguously decide which or which exact combination of the observed obstacles was pivotal for the low feasibility. However, a combination of psychological and structural factors should be considered: a combination of sample characteristics , external barriers , and a dynamic pandemic situation with rapidly changing legal regulations as a new virus variant became dominant could have fostered low involvement in this study. Owing to difficulties with enrollment and continued participation, mobile app–based infotainment for providing information  could not be applied to an extent that could be regarded as “minimum dose” for achieving behavioral effects, even if we had a more lenient design . EstabliIn addition, some of the obstacles encountered were beyond the scope of the study design such as the speed of the spread of new variants or rapidly changing legal regulations. In addition, the precarious and unstable living conditions of our target group, recently arrived young asylum seekers, could not be changed. Therefore, we do not recommend optimizing the present intervention strategy for this group, but we do not rule out its potential feasibility for refugees with more stable living conditions.Thus, we doubt the usefulness of a preventive mobile app–based intervention concept in the target group. Possibly, improvements would be achieved if the focus shifted from behavioral (even primary) prevention to primordial prevention . A simpl