Recently, the demand for mechanical ventilation (MV) has increased with the COVID-19 pandemic; however, the conventional approaches to MV training are resource intensive and require on-site training. Consequently, the need for independent learning platforms with remote assistance in institutions without resources has surged.This study aimed to determine the feasibility and effectiveness of an augmented reality (AR)–based self-learning platform for novices to set up a ventilator without on-site assistance.This prospective randomized controlled pilot study was conducted at Samsung Medical Center, Korea, from January to February 2022. Nurses with no prior experience of MV or AR were enrolled. We randomized the participants into 2 groups: manual and AR groups. Participants in the manual group used a printed manual and made a phone call for assistance, whereas participants in the AR group were guided by AR-based instructions and requested assistance with the head-mounted display. We compared the overall score of the procedure, required level of assistance, and user experience between the groups.P=.02). The number of steps that required assistance was also lower in the AR group compared to the manual group . The AR group had a higher rating in predeveloped questions for confidence , suitability of method , and whether they intended to recommend AR systems to others .In total, 30 participants completed the entire procedure with or without remote assistance. Fewer participants requested assistance in the AR group compared to the manual group (7/15, 47.7% vs 14/15, 93.3%; AR-based instructions to set up a mechanical ventilator were feasible for novices who had no prior experience with MV or AR. Additionally, participants in the AR group required less assistance compared with those in the manual group, resulting in higher confidence after training.ClinicalTrials.gov NCT05446896; https://beta.clinicaltrials.gov/study/NCT05446896 Mechanical ventilation (MV) is a lifesaving treatment that reduces the difficulty of breathing in patients and reverses acute life-threatening respiratory failure . During Recently, augmented reality (AR) systems have been widely applied in medical education and training -16. The In this study, we aimed to determine the effectiveness and feasibility of AR-based learning for novices to set up a ventilator by focusing on independently completing the procedures and assessing the degree of assistance required. Additionally, we evaluated the step characteristics in terms of the precision and assistance required.This was a prospective randomized controlled pilot study conducted at Samsung Medical Center, Korea, from January to February 2022. We compared 2 modes of training, namely, the conventional method  and the AR-based instructions. This study followed the CONSORT reporting guidelines .The research design was approved by the institutional review board of Samsung Medical Center (2021-12-112). Prior to inclusion in the study, all participants provided written informed consent.We recruited nurses from the Samsung Medical Center who were interested in AR and ventilator education using a web-based hospital bulletin board. We enrolled nurses who had no prior experience with ventilator setup or AR systems, regardless of their work department or age. We excluded nurses who had already experienced setting up a ventilator or who had trouble wearing or using a head-mounted display (HMD). As this was a preliminary study, we were unable to determine the sample size. However, we referenced to past research on the step-by-step procedures with AR ,24. We sUsing a lottery method, we randomly assigned the participants to 2 groups. One group  used a printed manual to set up a ventilator and the other group (the AR group) used AR-based instructions through an HMD—HoloLens 2 (Microsoft Corporation). The participants in the AR group were provided with 15 minutes of learning and practice time with HoloLens 2. If they needed assistance, participants in the manual group made a phone call, and those in the AR group requested it remotely with HoloLens 2; subsequently, both groups were assisted by the same ICU nurse. In the AR group, the participants shared the same view as the nurse using Microsoft Dynamics 365 Remote Assist, which allowed the ICU nurse to guide the participants through voice commands and drawing marks on their view. Both groups were surveyed immediately after the task.The instructions to set up the Servo-i mechanical ventilator (Maquet) were developed by researchers, including emergency physicians, pediatricians, and ICU nurses. The instructions detailed the entire process, from plugging in a socket to turning on the power, by performing initial ventilator mode setting with 35 steps. The AR instructions were developed as a step-by-step guide with the same text and images as in the printed manual, using the Microsoft Dynamics 365 Guide. The AR instructions were delivered using Microsoft HoloLens 2. The device allows users to go back and forth through the entire procedure by gazing at the screen when required. Some steps had a guide with a hologram of the 3D objects to indicate the location of the steps and direct the action of the connecting parts .The primary outcome is the overall score of the procedure, which is a 100-point scale converted from the original score. Participants scored 1 point for each step if they successfully finished the step within 5 minutes and obtained a maximum score of 35. The secondary outcome was the required level of assistance . We also evaluated the user’s experience with short questions on 3 themes: confidence, suitability, and whether they intended to recommend AR system to others ,26. All P<.05 was considered statistically significant. The statistical analysis was performed using the R software .All continuous variables are described as mean (SD) and median (IQR), and categorical variables are described as numbers and percentages. For continuous variables, we used the Wilcoxon rank-sum test; for categorical values, we used the chi-square test or Fisher exact test. A proportion test was performed to compare the proportions between the two groups. For all statistical analyses, A total of 31 nurses with no prior experience in setting up ventilators were enrolled, with the exception of 1 participant who had an HMD-related technical issue. The remaining 30 nurses completed the entire procedure and the surveys afterward. Each participant was randomly assigned to either the manual or the AR group. The participants ranged in age from 24-53 years and came from a variety of departments: 4 participants from outpatient nursing, 9 participants from inpatient nursing, 11 participants from specialized nursing, and 6 participants from administrative and educational departments. There were no significant differences in sex, age, work experience, prior observation experience, or department of work between the two groups .P=.10) in the AR group. However, if assisted steps were also considered as successful, the median score was 94.29 (IQR 91.43-94.29) in the manual group and 94.29  in the AR group.All 30 participants completed the entire procedure, with or without remote assistance. One participant in the AR group completed the procedure successfully without any assistance. P=.60) minutes in the AR group. With assistance, the median procedure time was 25.32 (IQR 22.41-29.02) minutes in the manual group and 24.18  minutes in the AR group.The duration of the procedure between the two groups was not statistically significant. Without assistance, the median procedure time was 22.95 (IQR 19.37-24.69) minutes in the manual group and 23.95 .The manual group had a greater proportion of participants who requested assistance compared to the AR group , suitability of method , and whether they intended to recommend AR system to others . The median of SUS score was 55 (IQR 47.5-67.5). All the participants answered 3 general questions. Notably, only the AR group answered the SUS questions. In this study, the participants had no prior experience with the ventilator setup or the HMD; additionally, all participants completed the entire procedure, from preparing materials to setting up the initial ventilator mode, prior to connecting to the patient. Moreover, the AR group was able to complete all the procedures following AR-based instructions in the planned design of the study, including a brief HMD practice and self-learning session. They required significantly less assistance compared to the manual group, and all assistance could be provided properly through a remote AR system. There were no technical issues or dropouts in either group.Generally, hands-on training is required and beneficial when training trainees on complex procedures -31. In aAR-based training benefits both sides, as discussed above. The instructors are not required to be on-site, as the remote assistance software enables them to monitor and guide the trainee’s view as well as draw and transfer data, voice, and so on. Additionally, without prior technical knowledge or experience with computer programming, developing instructions for a procedure using HoloLens 2 software was possible in 2-3 hours. From the trainee’s perspective, they can learn frequently without visiting an education center or engaging in on-site instructions. Additionally, the desire to develop a contactless education platform has increased to protect health care workers and save on personal protection equipment .The difference between the median number of assistance requests was not significant between the two groups; however, from a practical view, the difference in the workflow interruption between the two groups was more significant. A request for assistance resulted in procedure interruption by phone calls in the manual group and was difficult to support because they were held on to the phone. However, with an AR-based system, they could request help by speaking and connecting to the supervisor and be supported while continuing procedures.Our results provide new evidence for the feasibility of AR-based independent learning in complex advanced procedures with 35 steps lasting more than 20 minutes. In earlier research, studies also discovered that participants were more satisfied with AR-based instructions than with conventional instructions . We expeAs a pilot study, there was no specific guideline regarding how to deal with technology issues, such as time for battery charging, overheating of the device without break time, and network instability. These issues were observed in a few cases but were solved without affecting the study; however, these issues will be addressed and planned in a larger-scale study.Additionally, in the step-by-step procedures, the content of the errors is important; however, this was not addressed in this study. To extend AR-based training in other step-by-step advanced procedures and explore additional outcomes, considering the characteristics of steps and designing a training platform for suitable technology integration would be required.AR-based instructions to set up mechanical ventilator were feasible for novices with no prior experience with MV and AR. In addition, participants using AR required less assistance, resulting in higher confidence after training.


Precision medicine represents one of the frontiers in oncological treatments as it allows, mainly through the study of patients' genetic profiles, to build a treatment path that is as personalized as possible .The new challenge is to create a rehabilitation program that can be tailored to the patient's needs, to be carried on at a distance, allowing the patient to be educated, and be followed up in the oncological recovery.The National Cancer Institute of Aviano, Italy, is starting a new program called “Rehabilitation Tailor,” aiming to offer a personalized rehabilitation journey to patients with cancer by leveraging the most modern technologies. The institute is not new to creating tailored educational programs for oncological patients, including the Oncology in Motion experience , 3 to stThe project involves the creation of a Personal Rehabilitation Electronic Record (PRER), which is then to be shared with the patient and all the professionals supporting her in the healing process, including the physiotherapist in charge .This personalized path allows to build a specific osteoarticular and muscular profile as a guide for setting up correct physiotherapy and, if necessary, an appropriate muscle strengthening program, educating the patients in the co-production of their cancer rehabilitation . More imThe path includes patients who had breast operations, for whom the need for a rehabilitation process is recognized, and a non-invasive assessment on several levels to create a scorecard.Several referenced indexes are calculated and validated, as described below, with the use of technological devices like sensors. The electronic record is then shared with the patient, with a multidisciplinary approach involving a physiotherapist and a pain therapist.The assessment and creation of the PRER stands as follows. Through the use of inertial sensors  the range of movement of the shoulder is expressed in degrees, and the angular velocity that the patient can reach in the various movements . Subsequently, with surface electromyography , the fluidity of the movement is evaluated (Jerk index), and the percentage contribution of each muscle investigated to the movement is studied, as well as the effort made by the patient in muscular terms to reach certain angles of movement, which is consistent with other experiences described in the literature . A finalThe Rehabilitation Tailor Program and the PRER were generated, thanks to the assessment for allowing to set up a possible course of physical activity and a muscle strengthening to be carried on at home. The use of modern technologies, like sensors and devices, plays a crucial role as knowledge-translation facilitators to educate the patients in carrying on the required rehabilitation tasks, measuring their progress, and allowing the connection between the institute's staff  and the preferred support clinicians, like physiotherapists. Moreover, the amount of data collected may support the progress of rehabilitation programs in general terms, allowing the detailed measurement of the recovery outcomes and stimulating the promising link between fitness activity and cancer rehabilitation .The Rehabilitation Tailor Program is a project that stands as a step forward in the translational application of personalized medicine in oncological care, and its potential is to be applied to all cancer follow-ups and recovery.Written informed consent was obtained from the individuals for the publication of any potentially identifiable images or data included in this article.GB and LM conceived the idea of the study and took care of data collection and analysis. HB, FD, and LM took care of the drafting of the article. All authors reviewed, read, and approved the final version of the manuscript.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.


Since the beginning of this decade, all countries have faced serious health emergencies, whether due to wars, earthquakes, cyclones, floods, industrial explosions, fires or the global coronavirus disease 2019 (COVID-19) pandemic. These events tragically continue to kill many people; however, the number of people experiencing injury or impairment that require acute and ongoing rehabilitation is far higher – and increasing. Between 2010 and 2019, available data show the number of people injured in disasters (6.7 million) was four times more than those killed (1.5 million).We do not have a true picture of rehabilitation needs in emergencies due to a lack of research and little or no monitoring of health outcomes in emergencies other than mortality. However, health emergencies create significant surges in pressing and often unmet rehabilitation needs. Improved emergency, surgical and critical care are also now saving more lives, and with more survivors, rehabilitation needs may further increase. Early rehabilitation in emergencies is therefore essential: it can maximize the impact of medical and surgical interventions; speed up recovery; optimize functioning; and enhance quality of life of survivors.When rehabilitation needs are not quickly addressed, individuals, their families and communities face far-reaching consequences. For example, a lack of early rehabilitation for a patient with burns after a tanker explosion may result in preventable contractures and a subsequent loss of function and income. A child who loses a limb during a conflict and does not have access to early rehabilitation may develop complications or not receive a prosthesis, and therefore find their participation in education restricted. A patient hospitalized with COVID-19 leaves hospital still dependent on their family for care due to a low prioritization of rehabilitation. In each of these examples, people directly affected by emergencies suffer unnecessarily and have a suboptimal recovery. Moreover, their families and communities are affected as well.,Emergency Medical Teams: minimum technical standards and recommendations for rehabilitation.The origins of modern rehabilitation are in emergencies; it developed as a treatment strategy in part due to a surge in needs as a result of war and polio epidemics in the early 20th century. More recently, key humanitarian operationalDespite its origins, and although many response guidelines exist, rehabilitation is rarely prioritized early in emergencies and a misconception exists that rehabilitation comes later in the continuum of care. Too often, responders cite the humanitarian imperative, with the priority being to save lives. However, this conception is a false dichotomy: the humanitarian imperative includes the prevention or alleviation of human suffering, in which rehabilitation plays a critical role.Response challenges are not just attitudinal; existing rehabilitation services are often under-resourced, poorly integrated into health systems and quickly overwhelmed in emergencies. Such underlying weaknesses and barriers underscore the importance of preparedness to best utilize scarce rehabilitation resources.Research on health system preparedness is lacking, specifically on the status and impact of rehabilitation preparedness. Notwithstanding, rehabilitation appears to be almost universally absent from health emergency preparedness. Data from WHO’s work to strengthen rehabilitation in health systems showed that only one of 19 low- and middle-income countries involved had integrated rehabilitation into health emergency preparedness. The example of Nepal is a key outlier, where specific rehabilitation preparedness, including training of staff, development of protocols and stockpiling of equipment, improved the ability of service providers to respond.An overall approach to rehabilitation in health systems strengthening will improve access to rehabilitation in emergencies, but specific steps must be taken to better prepare rehabilitation services. Preparedness must also be all-hazard, that is, with plans to maintain essential services as well as specific considerations for hazards that may cause a surge in rehabilitation needs, including but not limited to natural hazards such as earthquakes, cyclones, floods and disease outbreaks; societal hazards, such as conflict and terrorism; and technological hazards such as major explosions, fires and chemical or radiological events. The COVID-19 pandemic has provided a stark example of the need for rehabilitation in outbreak preparedness. Rehabilitation services were needed for acute hospitalized patients, patients with post-intensive care syndrome and those with post COVID-19 condition.WHO’s Health Emergency and Disaster Risk Management Framework,,,Those working on health systems preparedness must ensure that rehabilitation considerations are included in national or subnational risk assessments, planning and coordination.,,,Service leads must examine critical gaps; rehabilitation surge support mechanisms should be built,,,Rehabilitation infrastructure must be safe and accessible,Rehabilitation professionals must understand the potential hazards they face and have personal and professional preparedness plans in place.The steps proposed above would help ensure that patients receive the early and ongoing rehabilitation needed in emergencies, and that the long-term outcomes of those affected are not neglected. Importantly, many of these steps support both emergency preparedness and the continued strengthening of rehabilitation within the health system. WHO will contribute to this work by developing a policy brief and practical toolkit to support the integration of rehabilitation into emergency preparedness and response. The new WHO-hosted World Rehabilitation Alliance, which focuses on promoting rehabilitation as an essential health service, will also include emergency preparedness as a key advocacy workstream to further this agenda.


The fusiform face area (FFA) is a widely studied region causally involved in face perception. Even though cognitive neuroscientists have been studying the FFA for over two decades, answers to foundational questions regarding the function, architecture, and connectivity of the FFA from a large (N>1000) group of participants are still lacking. To fill this gap in knowledge, we quantified these multimodal features of fusiform face-selective regions in 1053 participants in the Human Connectome Project. After manually defining over 4,000 fusiform face-selective regions, we report five main findings. First, 68.76% of hemispheres have two cortically separate regions (pFus-faces/FFA-1 and mFus-faces/FFA-2). Second, in 26.69% of hemispheres, pFus-faces/FFA-1 and mFus-faces/FFA-2 are spatially contiguous, yet are distinct based on functional, architectural, and connectivity metrics. Third, pFus-faces/FFA-1 is more face-selective than mFus-faces/FFA-2, and the two regions have distinct functional connectivity fingerprints. Fourth, pFus-faces/FFA-1 is cortically thinner and more heavily myelinated than mFus-faces/FFA-2. Fifth, face-selective patterns and functional connectivity fingerprints of each region are more similar in monozygotic than dizygotic twins and more so than architectural gradients. As we share our areal definitions with the field, future studies can explore how structural and functional features of these regions will inform theories regarding how visual categories are represented in the brain. TheoretThese gaps in knowledge persist for two main reasons. First, most human brain imaging studies perform analyses at the group level in which data are collapsed across participants and analyzed in volume space  data were used to define two face-selective regions on the fusiform gyrus  and to compare their i) cortical thickness, ii) myelination, iii) face selectivity, and iv) resting-state functional connectivity (RSFC) profiles. Additionally, spatial patterns of these structural and functional features in each region were compared between pairs of monozygotic (MZ) or dizygotic (DZ) twins. The HCP-YA includes behavioral and multi-modal MRI data from 1206 healthy young adult participants . After excluding the subjects with incomplete MRI scans or invalid MSMAll registration, 1053 participants  were retained. Behavioral performance was not used to screen participants. Each participant completed structural MRI (sMRI), resting-state functional MRI (rfMRI), and task functional MRI (tfMRI) scans . Among t2.2.The HCP-YA MRI data were acquired on the HCP’s custom 3T Siemens Skyra scanner using a 32-channel head coil. T1-weighted (T1w) images were acquired using the 3D MPRAGE sequence . T2-weighted (T2w) images were acquired using the 3D SPACE sequence . Functional data were acquired using gradient-echo EPI sequence . Four runs of rfMRI data were acquired for each participant from the HCP-YA, each of which were approximately 15 minutes. Details of the HCP-YA MRI acquisition can be found elsewhere .2.3.Face-selective regions were localized using a working memory task in which four stimulus types  were presented in separate blocks . The loc2.4.In each of two runs, participants were presented with 3 face blocks and 3 shape blocks (21 s each) . Each bl2.5.www.fmrib.ox.ac.uk/fsl)  . The boxThe data used in this study were in the 32k_fs_LR space based on MSMAll registration, and no spatial smoothing was implemented.2.6.https://github.com/BNUCNL/FreeROI). Second, author Z.Z. checked the regions and refined them together with X.C. Third, cognitive neuroanatomist K.S.W. finalized the regions.Face-selective regions on the lateral fusiform gyrus (FG) were manually delineated for each hemisphere and each participant based on individual, thresholded  face-selective activation maps (faces versus others). From this thresholded map, regions of interest (ROIs) were labeled as either mFus-faces/FFA-2 or pFus-faces/FFA-1 based on previously published criteria differentiating the cortical location of the two regions relative to sulci within and surrounding the FG . SpecifiHere, we used a liberal threshold  for the main reason that we did not want to artificially inflate the “separate” group by using a strict threshold. Nevertheless, we recognize that thresholded statistical maps  are more susceptible to noise than those from gradient effect size (or beta) maps . However2.7.Overall, we categorized the spatial organization of mFus-faces/FFA-2 and pFus-faces/FFA-1 into three types, or topological groups : separat2.8.https://github.com/the-virtual-brain/tvb-gdist). Geodesic distance is the length of the shortest line between two vertices on a triangulated mesh in three dimensions, such that the line lies on the surface. The cortical distance between the most face-selective vertices  of the two regions was calculated for hemispheres from continuous and separate groups and a 2-way mixed ANOVA was conducted to test the effects of hemisphere  and group  on the distance. In addition, the cortical gap size between the two regions was measured for the separate group by calculating the minimum geodesic distance between the vertices of the two regions, and a paired t-test was performed to test the interhemispheric differences of the gap size.Geodesic distance was used to quantify the cortical distance between pFus-faces/FFA-1 and mFus-faces/FFA-2 by using the tvb-gdist package  to characterize the likelihood that a given vertex belongs to that region across the participants on whom the region had been identified. For each region, the spatial consistency was calculated as the spatial pattern similarity between each pair of group-specific probabilistic maps. Specifically, the spatial patterns in the overlapped portion of each pair of group probabilistic maps were extracted to compute the Pearson correlation coefficient.2.10.We tested if pFus-faces/FFA-1 and mFus-faces/FFA-2 were anatomically distinct by calculating average cortical thickness and myelination values from each region in each individual. The mean thickness and myelination values were generated by averaging each measurement across all vertices within each region in each hemisphere and participant within each of the three groups. Two, 3-way mixed ANOVAs were conducted to further examine the effects of hemisphere , group , and region  on the cortical thickness and myelination content, respectively.2.11.As pFus-faces/FFA-1 and mFus-faces/FFA-2 are defined based on the HCP working memory task, we used face and shape conditions from the emotional processing task, which was also included in the HCP dataset, as an additional independent dataset to compare face selectivity between the two face-selective regions in each of the three groups. These data were acquired in nearly all participants (920/1053 participants) and were completely independent from the data used to define each face-selective region. Face selectivity was quantified as the average z-value of the contrast (faces vs. shapes) within each functional region in each individual participant. A 3-way mixed ANOVA with hemisphere , group , and region  as factors was conducted to test if pFus-faces/FFA-1 or mFus-faces/FFA-2 differed in their mean face-selectivity.2.12.To quantify functional connectivity differences between these two face-selective regions, we considered three scales i) areal, ii) network, and iii) global. At the areal level, we quantified the resting-state functional connectivity (RSFC) from each FG face-selective region to each of the HCP MMP areas  except t2.13.In addition to our previous analyses, we also aimed to compare spatial patterns of functional, architectural, and connectivity features of pFus-faces/FFA-1 and mFus-faces/FFA-2 between pairs of MZ and DZ twins. We were able to do so because a subset of the 1053 participants within the HCP dataset are from 121 MZ pairs and 75 DZ pairs. If MZ twins show more similar spatial patterns than DZ twins in an anatomical or functional feature, it indicates that genes contribute to that feature to some extent. To this end, we measured the spatial pattern similarity of each pair of twins with a Pearson correlation coefficient, which requires that the spatial masks  are the same. For this, the maximum probability maps  of mFus-faces/FFA-2 and pFus-faces/FFA-1 were used as the group-level spatial masks for each participant in each twin pair. Specifically, the spatial patterns of face selectivity, thickness, and myelination of pFus-faces/FFA-1 and mFus-faces/FFA-2 were directly extracted from the MPM masks and the spatial pattern of RSFC of each face-selective region was characterized as the RSFC fingerprint between its MPM mask and the 12 RSNs. A 3-way mixed ANOVA with zygosity , region , and hemisphere  as factors was conducted to statistically compare similarities in each functional (face selectivity), connectivity (RSFC), and architectural  feature.2.14.To further understand brain features of the cortical gap between pFus-faces/FFA-1 and mFus-faces/FFA-2, we implemented a fourfold approach. First, the cortical gap between pFus-faces/FFA-1 and mFus-faces/FFA-2 was automatically defined in each participant from the separate group by merging the vertices which fall in the FFC and between pFus-faces/FFA-1 and mFus-faces/FFA-2. Second, the average cortical thickness and myelination values across vertices were calculated respectively for pFus-faces/FFA-1, the cortical gap, and mFus-faces/FFA-2 in each participant. A 2  × 3  repeated measures ANOVA was then conducted to examine if the cortical gap is different from the two face areas on each architectural feature. Third, the RSFCs from pFus-faces/FFA-1, the cortical gap, and mFus-faces/FFA-2 to the 12 RSNs were calculated in each participant and a 3-way repeated measures ANOVA with hemisphere , region , and network (12 RSNs) as factors was conducted to examine if the cortical gap had a different RSFC fingerprint compared to pFus-faces/FFA-1 and mFus-faces/FFA-2. Fourth, the category-selective response to face, body, place, and tool conditions were examined using the test-retest working memory task fMRI data from HCP. Specifically, pFus-faces/FFA-1, the cortical gap, and mFus-faces/FFA-2 were defined on the original HCP test data and activation (beta) values of the four categories  were extracted from the independent, retest data. Only participants who had two separate face-selective regions were used in the analysis (N=27/28 for the left/right hemispheres). A 3-way repeated measures ANOVA with hemisphere , region , and category  as factors was conducted to examine the functional selectivity difference among the three regions.3.3.1.We manually delineated face-selective regions on the lateral aspect of the fusiform gyrus (FG) in 1053 participants  from theF=182.53, p<.001, η2=.22, 90% confidence interval (CI) ). Furthermore, the distance between the most selective vertices was larger in the LH compared to the RH within the separate group =10.88, p=.001, η2=.02, 90% CI ), but not within the continuous group =1.06, p=.304, η2=.00, 90% CI ). Additionally, within the separate group, there was a 0.59-centimeter cortical gap (on average) between mFus-faces/FFA-2 and pFus-faces/FFA-1 (t(529)=9.03, p<.001, d=.39, 95% CI [.30 .48]), which supports previous qualitative observations in a much smaller sample size  separated the most face-selective vertices of pFus-faces/FFA-1 and mFus-faces/FFA-2 . A 2-wayize N=7; .F=7.53, p=.006, η2=.01, 90% CI ) and left separate group =4.62, p=.032, η2=.01, 90% CI ). Moreover, in the separate group, both regions were larger in the RH compared to the LH >=24.23, ps<.001, η2>.03). In the continuous group, right pFus-faces/FFA-1 was larger than left pFus-faces/FFA-1 =6.51, p=.011, η2=.01, 90% CI ).Surface area differences in FG face-selective regions were also revealed by a 3-way mixed ANOVA with hemisphere , group , and region  as factors . Specifi3.2.A probabilistic map was created for each FG face-selective region in each group , which pF=4.83, p=.028, η2=.01, 90% CI ). Further, we found that pFus-faces/FFA-1 is more face-selective than mFus-faces/FFA-2 in the continuous group =77.62, p<.001, η2=.12, 90% CI ) and separate group =659.38, p<.001, η2=.55, 90% CI ) in both hemispheres. Importantly, these effects were retained after regressing out temporal contrast-to-noise-ratio (CNR)  .3.3.Are there architectural differences between pFus-faces/FFA-1 and mFus-faces/FFA-2 that could serve as underlying anatomical substrates for the functional differences between these two regions? Two complementary approaches from previous studies suggest that pFus-faces/FFA-1 and mFus-faces/FFA-2 are likely architecturally distinct from one another. First, previous studies showed that microstructurally, pFus-faces/FFA-1 and mFus-faces/FFA-2 are located in different cytoarchitectonic territories . Second,F=470.21, p<.001, η2=.43, 90% CI ) and right hemisphere =315.41, p<.001, η2=.33, 90% CI ) >28.79, all ps<.001, all η2>.04)  ; ii) mFu η2>.04) . Additio η2>.04) -4.3.4.ts>1.99, all ps<.050, all ds>.07, FDR corrected; ts(227)>2.05, all ps<.047, all ds>.13, FDR corrected; ts(291)>2.11, all ps<.039, all ds>.12, FDR corrected; ts(704)>2.38, all ps<.019, all ds>.08, FDR corrected; ts(636)>2.12, all ps<.037, all ds>.08, FDR corrected; To quantify potential functional connectivity differences between these two face-selective regions, we considered three scales: i) areal, ii) network, and iii) global. At the areal level, we quantified the intrinsic resting-state functional connectivity (RSFC) between face-selective regions and regions from the multimodal parcellation (MMP) of the human cerebral cortex by ts>2.42, all ps<.016, all ds>.14, FDR corrected); mFus-faces/FFA-2 showed stronger RSFC than pFus-faces/FFA-1 only in the ventral multimodal network .At the network level, the RSFCs of all MMP areas were summarized into 12-dimension RSFC “fingerprints” according to Cole-Anticevic Brain Network Parcellation (CAB-NP) . This apF=359.91, p<.001, η2=.38, 90% CI ). Importantly, this effect was retained after regressing out CNR , group , and region  as factors  revealed out CNR .3.5.F=42.06, p<.001, η2=.18, 90% CI ) and for RSFC =44.74, p<.001, η2=.21, 90% CI ). Although there were interactions among zygosity, region, and hemisphere >4.01, all ps<=.047, all η2>.02) for RSFC, the effects of zygosity within each level of hemisphere and region were significant >18.53, all ps<.001, all η2>.09). Comparatively, there was no significant main effect of zygosity for either cortical thickness =2.27, p=.133, η2=.01, 90% CI ) or myelination =2.87, p=.092, η2=.02, 90% CI ).Are there heritable components contributing to the functional, architectural, and connectivity differences between pFus-faces/FFA-1 and mFus-faces/FFA-2? Previous research indicates a genetic contribution to face processing ability  and to t3.6.F=599.97, p<.001, η2=.53, 90% CI ) and cortical thickness = 363.17, p<.001, η2=.41, 90% CI ). Second, the cortical gap showed different RSFC to 12 RSNs compared to the two face-selective regions =377.49, p<.001, η2=.42, 90% CI ) and a significant interaction between region and RSN =589.89, p<.001, η2=.53, 90% CI ). Third, the cortical gap showed a distinct response profile compared to both face-selective regions =30.37, p<.001, η2=.60, 90% CI ), a significant main effect of category =52.38, p<.001, η2=.72, 90% CI ) and a significant interaction between region and category =35.17, p<.001, η2=.64, 90% CI ). These findings indicate that the separation of pFus-faces/FFA-1 and mFus-faces/FFA-2 may be the result of another functional region, as occurs in frontal cortex for cases that area 55b forms a gap between the premotor eye field (PEF) and the frontal eye field (FEF)  .4.Parcellating the cerebral cortex into areas continues to be a major goal in neuroscience. Over the last twenty-five years, the fusiform face area (FFA) is one of the most widely studied – and heavily debated – brain areas . In addi4.1.For more than a decade, dozens of studies have identified at least two face-selective regions on the FG  in additTogether, these results are surprising considering that it is widely accepted that identifying a single FFA is the norm, not the exception. Yet, our results empirically support the opposite in the largest group of manually defined face-selective regions on the FG to date (to our knowledge). For the 26.69% of hemispheres in the continuous group, the most likely factor contributing to the continuity of the regions is the spatial coarseness of the BOLD signal. That is, there is likely a cortical gap in these individuals, but the coarseness of the spatial spread of the BOLD signal causes the two regions to blur together. Indeed, the measured anatomical and functional differences between pFus-faces and mFus-faces was comparable in the continuous and separate groups. Additionally, since there is a relationship between the mid-fusiform sulcus (MFS) and the location of face-selective regions as identified in our previous work , it’s liThe present findings in combination with previous findings showing cytoarchitectonic  and func4.2.Recent research indicates systematic relationships among gradients of genetic expression (e.g. transcriptomics) relative to architectural  cortical features . AdditioFor instance, does genetic expression contribute to the number of face-selective regions on the FG, which in turn, contributes to face processing ability? More broadly, what are the behavioral implications for only having one of these face-selective regions on the FG – or none at all? For example, there is recent causal evidence showing that electrical brain stimulation (EBS) to mFus-faces/FFA-2 results in deficits in naming faces, while EBS to pFus-faces/FFA-1 results in face-specific perceptual distortions . Such a 4.3.A continued debate in the broader neuroimaging field is the balance between averages and group analyses compared to individual differences and analyses at the level of individual participants . DirectlMoving forward, then, how do we i) strike a balance between group averages and individual differences (when both are necessary and complement one another) and ii) overcome the fact that defining regions of interest (ROIs) manually is monotonous, requires expertise, typically limits sample sizes, and limits the cortical expanse a particular study can explore? Here, we propose that a deep learning approach implemented previously on just the cortical anatomy, could also be implemented on functional definitions to improve the accuracy of automated definitions of functional brain regions in individual participants. Specifically, two recent studies  used dee5.In sum, we examined individual differences of fusiform face area(s) in a large group (N>1000) of participants for the first time. Our results show that identifying a single FFA is actually the exception, not the norm as described in the broader literature. Instead, it is most common to identify two face-selective regions on the lateral FG that are 2.27 cm apart on average between the most face-selective vertices, as well as are dissociable based on functional, architectural, and connectivity features. This organization of clustered regions or patches as opposed to a single larger area aligns well with face-selective patches identified in other species, such as macaques. Additionally, spatial patterns of functional (face selectivity) and connectivity (RSFC) features are more highly correlated in monozygotic compared to dizygotic twins, while architectural features  are not. Future studies can leverage the fact that we are sharing our 4,116 manual areal definitions with the field to further explore how functional and structural features of these regions relate to cognitive and behavioral metrics also acquired in each participant within the rich multimodal HCP dataset.1


Special Issue – Combatting Anthelmintic resistance in ruminantsInvited Editors: Johannes Charlier, Hervé Hoste, and Smaragda SotirakiCattle, sheep and goats are parasitized by various helminth species, the most important being the gastrointestinal nematodes (GIN) and liver fluke. These pathogens can cause severe disease and affect productivity in all classes of livestock and are worldwide amongst the most important production-limiting diseases of grazing ruminants . EssentiFor more than 50 years, the control of these helminth infections has largely relied on the use of (broad spectrum) anthelmintics, belonging to different families of molecules. However, around the world, farmers and veterinarians are increasingly confronted with treatment failures due to anthelmintic resistance (AR). Frequent, indiscriminate or inappropriate use of anthelmintic drugs to control these parasites has resulted in selection of drug-resistant helminth populations. As shown in one of the papers in this special issue, AR in ruminants is now widespread for all the major GIN and is likely underreported in liver fluke . AR has https://www.combar-ca.eu) was to create a network and foster the exchange of scientific knowledge required to COMBAT AR and bring recognised experts in the field of sustainable control of helminth parasites in livestock, from across Europe and beyond, together. An important achievement has been the development of the STAR-IDAZ IRC research road maps on helminths and AR, offering a framework to coordinate research in the field at a global level and speed up the delivery of required control tools [Previous research projects had attempted to tackle AR nationally or via projects focused on a specific component of the AR conundrum. These had led to limited progress in several areas including diagnostics to detect AR, socio-economic aspects and integration of the different control tools. The COST Action COMBAR therefore came at a time of high need to coordinate research efforts and exchange approaches at the European and international level. The main aim of COMBAR  and institutions involved. The development of resistance to synthetic molecules is a general phenomenon which has been described for a wide range of pathogens and molecules [COMBAR was organised according to three working groups: (i) Improving diagnosis; (ii) Socio-economic aspects, and (iii) Innovative control approaches. This special issue in olecules . Within Dicrocoelium dendriticum [Haemonchus contortus infections in areas where they were previously rarely encountered [in vitro egg hatch test can accurately estimate in vivo efficacy following treatment of H. contortus infections with benzimidazoles in goats and that it also reflects the percentage of resistance alleles in the parasite population [H. contortus in small ruminant faecal samples [H. contortus) and their resistance status. Today, on farm diagnosis of anthelmintic efficacy against all nematode species is based on assessing FEC reduction following treatment. Morgan et al. evaluate the wide range of factors that can confound such a diagnostic approach and recommend how this can be taken into account to enhance correct interpretation [A major effort was made by Vineer et al., who created an open database summarising 535 AR surveys in 22 countries to represent the most up to date situation on the prevalence of AR in sheep, goats and cattle in Europe . Knowingountered . Gravdalountered . Both stountered . Sustainpulation . Khangem samples . Both stretation . Diagnosretation . Ježek eretation . Maestriretation .The results reported in this COMBAR special issue represent a very small step for the new tools and approaches that are needed to combat AR. Nonetheless, we hope they will encourage the reader to continue along the path to sustainable helminth control. Besides the continuous needs for fundamental research to understand the mechanisms of AR, there is also a very large need for applied research to develop sustainable control methods with the current tools at hand. Finally, as shown by the work of Vande Velde et al. , communiParasite, for his unwavering support. Finally, a big thank you to all COMBAR participants for their contributions that enabled us to leave a strong COMBAR legacy for the future.We would like to thank all contributing authors, reviewers and the COMBAR Core Group members for their important contributions and making this special issue possible. Special thanks go to Jean-Lou Justine, Editor-In-Chief of


The emergence of atypical response (AR) has challenged the process of response evaluation and the subsequent management of non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 inhibitors. We conducted a multicenter retrospective analysis and found that AR was not an uncommon event in patients with metastatic NSCLC treated with the PD1/PD-L1 inhibitor. The median time to AR occurrence was 2.0 months, and patients with ≥3 metastatic organs at baseline were more likely to develop AR. For patients with AR, the common sites of progressive lesions were the lymph nodes and lungs. Furthermore, the majority of patients with AR had only 1–2 progressive tumor lesions, and most of the progressive lesions developed from originally existing tumor sites. Patients with AR had a comparable prognosis to those with a typical response (TR). Proper local therapy targeting progressive tumor lesions while maintaining the PD1/PD-L1 inhibitor may be a feasible treatment selection for patients with AR.p = 0.038). The common sites of progressive lesions were lymph nodes (33.8%) and lungs (29.7%). The majority (78.2%) of patients with AR had only 1–2 progressive tumor lesions, and most (89.1%) of the progressive lesions developed from originally existing tumor sites. There was no significance in terms of survival between patients with AR and those with typical response (TR). Local therapy was an independent predictor for PFS of patients with AR (p = 0.025). Conclusions: AR was not an uncommon event in patients with metastatic NSCLC treated with PD-1/PD-L1 inhibitors, and it had a comparable prognosis to those with TR. Proper local therapy targeting progressive lesions without discontinuing original PD-1/PD-L1 inhibitors may improve patient survival.Purpose: To explore the clinical characteristics, management, and survival outcomes of advanced NSCLC patients treated with PD-1/PD-L1 inhibitors who presented with an atypical response (AR). Methods: A total of 926 PD-1/PD-L1-inhibitor-treated patients with metastatic NSCLC from three academic centers were retrospectively reviewed. All measurable lesions were evaluated by RECIST version 1.1. Results: Fifty-six (6.1%) patients developed AR. The median time to the occurrence of AR was 2.0 months. Patients with no fewer than 3 metastatic organs at baseline were more prone to develop AR in advanced NSCLC ( The emergence of immune checkpoint inhibitors has resulted in significant progression in the treatment of advanced non-small cell lung cancer (NSCLC) ,2,3. AdmLocal consolidative therapy is an interesting topic for the treatment of oligo-progressive sites, and it has been increasingly provided in clinical practice. A wealth of research has demonstrated the essential role of local cancer treatments in improving survival among NSCLC patients with oligo-progressive or oligometastic disease ,12,13. RIn this study, AR was defined as the simultaneous occurrence of an objective response in some tumor lesions and disease progression in others within the PD-1/PD-L1 inhibitor treatment window, as depicted in a previous study ; otherwiPatients were generally followed-up using chest computed tomography (CT), abdominal CT, or ultrasound examination every 6–12 weeks. Brain magnetic resonance imaging (MRI), bone scans, and PET/CT were not mandatory, and they generally performed until indicative symptoms and/or clinical signs were observed. The data were cut-off on 31 January 2022.Considering the potential heterogeneity in response, the full range of radiologic behavior was captured to identify AR at the individual lesion and organ levels. Serial imaging scans of each patient were reviewed by two experienced radiologists. Each tumor lesion with measurable disease was independently evaluated. For patients with AR, the initial time of documentation of AR was recorded. In addition, unidimensional measurements (mm) were used to quantified the absolute size and percent change of the overall tumor burden, which was evaluated in accordance with RECIST version 1.1.p-value < 0.10 in the univariate analysis were finally included in the multivariate analysis. The propensity score matching (PSM) was performed on the basis of the logic of propensity score and one-to-one nearest neighbor matching to further reduce the potential bias of covariates. The caliper was 0.20 [p value < 0.05 was defined as statistical significance. All statistical tests were performed on SPSS . For survival analysis, R software version 4.1.3  was used for computation.For patients with TR, progression-free survival (PFS) was computed from the beginning of PD1/PD-L1 inhibitor treatment to the initial disease progression; the death of any cause; or, if no progression was observed, censored at the data lock. For patients with AR, PFS was calculated from the initiation of the PD1/PD-L1 inhibitor to the time of the first disease progression after the occurrence of AR , or death. OS was computed from the beginning of the PD1/PD-L1 inhibitor to death of any cause or, if no death was observed, censored at the time point of the final follow up. The patients’ survival was plotted using the Kaplan–Meier method, and the differences in the variables were estimated by log-rank test. Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). All of the significant factors with a was 0.20 , and a tA total of 327 of the 926 immune-checkpoint-inhibitor-treated patients with metastatic NSCLC were enrolled, with 271 cases in the TR group and 56 in the AR group. The details of patient enrollment are shown in The frequency of AR in the current case cohort was 6.1% , and the median time between the beginning of PD1/PD-L1 inhibitor to the documentation of AR was 2.0 (range of 1.0–5.0) months. At the time of the initial documentation of AR, the response patterns per RECIST version 1.1 were determined to be PRs, SD, and disease progression in 12, 35, and 9 patients, respectively. For each patient with AR, the site and number of initial progressive tumor lesions that led to their classification as AR were carefully recorded. The common organs with progressive lesions were lymph nodes (33.8%), lungs (29.7%), bones (10.8%), brain (9.5%), pleura (5.4%), adrenal gland (5.4%), and liver 2.7%, A. Meanwhp = 0.038, Univariate analysis revealed that the number of baseline metastatic organs and metastatic sites was related to AR. There was no significance between age, sex, ECOG PS score, smoking status, histology, treatment regimens, treatment lines, PD-L1 expression, and the occurrence of AR. In multivariate analysis, the number of baseline metastatic organs was found to be a significant factor of AR (n = 327), the median OS and PFS were not reached and 13.0 (95% CI: 12.0–15.0) months, respectively (With a median follow-up of 16 (range of 2–52) months, 199 patients developed disease progression per RECIST version 1.1, and 75 patients died. In the whole population , to reduce the potential confounding factors that may exist between patients with AR and TR. The baseline characteristics of the matched cohorts after PSM were well balanced , and no In this study, all AR patients continued their original PD1/PD-L1 inhibitor, and 16 (28.6%) patients received local therapy targeting the paradoxical progressive lesions after the development of AR, including radiotherapy in 13, surgery in 2, and other local interventions in the remaining 1 patient. The baseline characteristics between those with and without local therapy were generally balanced , and locIn the current study, a multicenter retrospective analysis was conducted to investigate the clinical features, prognostic significance, and treatment of patients with stage IV NSCLC with AR receiving immune checkpoint inhibitors. The outcomes of PD1/PD-L1 inhibitor in patients with AR were comparable to those in patients with TR. Moreover, proper local therapy targeting paradoxical progressive lesions may provide survival benefits for patients with AR, which warrants further validation.The clinical features of AR are not fully understood, and this study provides significant information about the frequency and spatiotemporal patterns of AR in patients with metastatic NSCLC treated with PD1/PD-L1 inhibitor. The frequency of AR was reported to be from 5.0% to 13.0% in PD-1/PD-L1 inhibitor-treated metastatic NSCLC ,20, whicHowever, the mechanism underlying AR remains unclear. The heterogeneity and differences of intra-tumoral between metastatic sites may contribute to fluctuations in clinical effects . Moreover, it takes some time to activate the immune system, the start of clinical effects may be delayed, and the interaction between the immune system and the tumor may be a long-term process that could possibly contribute to some sites shrinking while other sites are grow or new lesions emerge . PD-L1 eThe value of local therapy for stage IV NSCLC patients in an AR cohort treated with PD-1/PD-L1 inhibitors has seldom been reported. A retrospective study reported that the duration of PD1/PD-L1 inhibitors could be amplified by local therapy, such as radiotherapy, to solitary or oligo-progressive sites in atypical response, especially among those harboring a biologically more indolent cancer type, such as renal cancer . MoreoveThis study has some limitations. First, selection bias and unrecognized confounding factors could exist between subgroups, in which survival outcomes were compared. Although potential bias was reduced as much as possibly by using Cox analyses and PSM, imbalanced baseline characteristics could be inevitable. Thus, the findings in the present study need to be validated by prospective randomized trials. Second, as a retrospective study, collecting detailed information about treatment toxicities was difficult, and thus the safety profile of adding local therapy needs to be investigated in further prospective studies.In conclusion, AR was not an uncommon event in patients with metastatic NSCLC treated with PD1/PD-L1 inhibitor, and it had a comparable prognosis to those with TR. Proper local therapy targeting progressive tumor lesions while maintaining the PD1/PD-L1 inhibitor may be a feasible treatment selection for patients with AR, thus warranting further investigation.


Symptomatic bifascicular block (BFB) with a reversible high-grade atrioventricular block (AVB) is an overlooked cause of syncope with differing diagnostic and therapeutic approaches. We present a case of a 79-year-old gentleman with multiple episodes of cardiac syncope. Initial electrocardiogram revealed a left bundle branch block and first-degree AVB worsened by bedside carotid sinus massage (CSM) obviating the need for electrophysiologic (EP) studies or continuous electrocardiographic monitoring for further evaluation. This case highlights the importance of CSM as a useful clinical tool in addition to EP studies and internal loop recorder (ILR) placement for assessment and appropriateness of permanent pacemaker (PPM) implantation. It also sheds light on the differing management protocols between EP studies and ILR evaluation versus empiric PPM implantation for patients with cardiac syncope secondary to BFB and AVB. Carotid sinus massage (CSM) is a clinical maneuver frequently used for the evaluation of carotid sinus hypersensitivity due to cardioinhibitory or vasodepressor response. However, it is also a valuable clinical tool for syncope evaluation in patients with a bifascicular block (BFB) and first-degree atrioventricular block (AVB). Here, we present a case of a 79-year-old male admitted with multiple episodes of syncope, who had a BFB and first-degree AVB on electrocardiogram (ECG). He developed symptomatic high-degree AVB with bedside CSM obviating the need for further workup and was subsequently treated with a permanent pacemaker (PPM) with outpatient follow-up.The patient was a pleasant 79-year-old male who was admitted to our facility with multiple episodes of syncope. The patient had a past medical history of hypertension, hyperlipidemia, Crohn's colitis on chronic vedolizumab therapy, and impaired fasting glucose. He denied any previous history of coronary artery disease, arrhythmias, ischemic/hemorrhagic stroke, or carotid artery disease. In the last month, he had endured at least three episodes of non-prodromal syncope. The last episode of syncope led to a traumatic fall and right parietal laceration, prompting admission to the hospital. After admission, his initial vital signs showed blood pressure of 136/72 mmHg, a pulse of 68 beats per minute (bpm), a respiratory rate of 18 per minute, and a temperature of 98.5°F. Physical examination revealed a right parietal scalp laceration; however, the cardiovascular examination was unremarkable. Subsequent syncope workup while admitted to the hospital, including orthostatic vitals, transthoracic echocardiography (TTE), serial troponins, and carotid Doppler, was negative for any abnormalities. However, on telemetry, he was found to have asymptomatic bradycardia at rest with his heart rate intermittently going down to as low as 42 bpm , and a first-degree atrioventricular (AV) block with a PR interval of 208 ms  with a left anterior or posterior fascicular block (LAFB/LPFP), is usually asymptomatic, the presence of first-degree AVB heralds the risk of complete AVB, with 13% complete AVB at a 5.4-year follow-up in one study . The comAlthough intermittent complete AVB is the most common cause of syncope in patients with BFB, other etiologies may also contribute. In a study of 55 patients with syncope and bundle branch block, despite cardiac syncope being the most common cause, neurally mediated syncope was found in 40% of cases, and in 15%, the cause remained elusive . A largeAlthough the American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines also advise ECG monitoring and EP studies in syncope patients with bundle branch disease , the preAfter PPM implantation, there remains a risk for syncope recurrence in bradyarrhythmic syncope patients including patients with syncope and BFB, with a recent study indicating 15.6% recurrence at 50 months follow-up . The risIn essence, the CSM is an inexpensive bedside maneuver for intermittent high-risk AVB diagnosis, which can circumvent the need for further testing including EP studies and ILR placement in patients with BFB and syncope. Further studies are needed to quantify the role of bedside CSM under telemetry in assessing the risk of AVB in BFB patients. Although current guidelines recommend EP studies and ILR evaluation before PPM placement, further studies are also required to evaluate the utility of empiric PPM placement in symptomatic AVB with BFB in patients.


This review explored the investigations on the role of teacher immediacy in English as a Foreign Language (EFL) learners’ foreign language enjoyment. Earlier investigations have proved that teacher immediacy, such as posture, body language, vocal variety, gestures, and smile, can significantly affect learners’ positive emotions like foreign language enjoyment. It means that teachers should try both to control the feelings of their learners and manage their feelings to enhance enjoyment among learners. Moreover, studies have shown that teacher immediacy is significantly related to learner motivation which is a basis for increasing foreign language enjoyment among learners. However, specific strategies can be employed to increase learner motivation, which in return increases learner foreign language enjoyment. Furthermore, the study presented the implications and future directions of this line of research for different people, such as EFL teachers, teacher educators, and foreign language scholars. The ideas can improve their awareness of teacher-student relationships, in particular, teacher immediacy and its role in learners’ foreign language enjoyment. Interaction is regarded as one of the most critical issues in educational contexts. The teacher-learner relationship is one of the most important features of instruction. One of the components of teacher-learner interaction is teacher immediacy. According to On the other hand, Verbal and non-verbal immediacy derives from interpersonal attraction theory . In educTeachers’ immediacy is associated with loving pedagogy that is a quite popular concept in SLA. Some studies have been done on the relationship between teacher immediacy and learners’ positive and negative emotions. Regarding negative emotions, On the other hand, some studies have verified the positive relationship between teacher non-verbal and verbal immediacy and learners’ positive emotional constructs. Regarding the relationship between teacher immediacy and academic engagement, According to Some investigations have been done on the origins of foreign language enjoyment among learners. Foreign language enjoyment has been considered as one of the constructs of positive emotional states in positive psychology . TraditiIn order to highlight the significant effect of positive constructs of psychology in foreign language instruction, and to emphasize the inspection of educators’ positive emotions and experiences, this review ponders into the relationship between foreign language enjoyment and verbal and non-verbal immediacy, as two positive psychological constructs, in pedagogical contexts.Few studies have been done on the relationship between teacher immediacy and learners’ foreign language enjoyment. Bayat, Shirvan, and Barabadi, in their study, investigated teachers’ non-verbal immediacy as multimodal corrective feedback and learners’ enjoyment. They operationalized multimodality in non-verbal immediacy as body postures and movements such as gesture, gaze, facial expressions or the use of technological tools which accompany teachers’ corrective feedback. They analyzed multimodal corrective feedback by systemic functional multimodal discourse analysis. Their study revealed that teacher’s multimodality in their corrective feedback extended the central aspects of enjoyment by increasing the learners’ responsiveness to their errors, amplifying their concentration on the correct form, and intensifying the prominence of their corrective feedback. Using systemic functional multimodal discourse analysis, This review investigated the role of teacher verbal and non-verbal immediacy in learners’ foreign language enjoyment in class. This review improves the instructive knowledge of scholars who are interested in learners’ and teachers’ emotions. Concerning the related literature about the positive role of learner-teacher rapport, in particular, teacher immediacy, in learner enjoyment, it is worth noting that learners should be helped to control and regularize their feelings in instructive contexts. Learners can regulate their feelings to increase their enjoyment, and this issue can stimulate instructors to take into account learners’ positive emotions in classroom contexts. The growth of immediacy among teachers and enjoyment among learners to involve actively in classrooms, can be regarded as one of the pedagogical implications of this review. Learners can employ opportunities that instructors provide to express their thoughts and emotions, which can decrease their stress in front of other learners and inspire them to be responsible for their learning. This study can also encourage teachers, teacher educators, and policymakers to consider EFL learners’ behaviors and their foreign language enjoyment. Also, being aware of learners’ personality traits may encourage teachers to do their best to bring passion to EFL learning contexts. Therefore, L2 instructors are required to talk to learners about their internal and external motivation and ask about their problems to improve learners’ points of view, motivation, and enjoyment to engage in educational contexts. They can increase other positive emotions such as pride, grit, and hope, and reduce negative feelings such as communication apprehension, disengagement, etc., in their classes. Moreover, teacher immediacy and considering learners’ requirements should be one of the rudiments of teaching in language education environments to achieve instructional outcomes. To do so, teachers need to reconstruct and modify the instructional materials. They can find authentic and interactive materials to increase learners’ foreign language enjoyment to attain better results. Incorporating technology into classroom contexts can be a pleasant way to increase learners’ foreign language enjoyment. Using games in the classroom can also arouse learner enjoyment. This can diminish learners’ cognitive load and despair, and arouse their enthusiasm and their concentration on language learning contexts. Teacher immediacy may persuade teachers to change their approach to teaching by incorporating positive emotions in their methodology to increase learners’ foreign language enjoyment. Consequently, they can provide warming-up tasks for learning contexts and brainstorm with learners to increase learner foreign language enjoyment. The challenging projects, lectures, conferences, and workshops may reduce learners’ foreign language enjoyment in academic contexts and put additional strain on learners. In order to motivate and increase learner enjoyment, providing learners with easy-to-difficult questions can be helpful, and teachers can change their assessment approach in classrooms. Teachers can manage the time of classrooms regularly to provide time for learners to communicate and enjoy their learning. Providing a competitive educational context through quizzes boosts learner engagement and enjoyment. Unplanned quizzes are primarily significant to inspire less engaged, and unprepared learners. Collaboration is another way for teachers to increase learners’ foreign language enjoyment. Allowing learners to cooperate can make them keep information for a long time. Cooperation also makes learners enhance critical thinking which makes the instruction more enjoyable. Teachers should accept learners’ creativity. They can provide learners the freedom to make projects and assess their peers’ assignments to increase learner enjoyment.Besides, teacher educators can exploit the related studies through consideration of the instructors’ immediacy and their rapport with the learners. They can identify teacher behavioral characteristics that contribute to increasing students’ level of foreign language enjoyment and take appropriate actions to increase replicating such behaviors. They can hold workshops and provide some strategies to improve teacher immediacy. They can also emphasize modeling immediacy, taking action and improving listening, and trying not to interrupt learners while they are speaking. According to Policymakers can develop programs that help learners enjoy when learning a language and amplify their academic engagement. They can positively support learners and make a context in which learners can take part in positive behaviors. They can hold academic workshops to help teachers control immediacy behaviors. They can provide interesting facilities, technology, and positive learning contexts for increasing positive behaviors among learners. The importance of enjoyment and immediacy may make consultants expand their agendas to diagnose learners’ reasons for unhappiness, and the obstacles they cope with within language learning. They can also offer some suggestions to increase the efficiency of teacher immediacy.Future studies may consist of investigating the influence of other teacher variables such as extroversion, and introversion on learners’ positive behaviors such as enjoyment, grit, pride, and engagement. Teachers’ negative emotions such as boredom, burnout, apprehension, and exhaustion and their role in learners’ foreign language enjoyment should be examined. Other studies can be done to investigate the effect of teacher stroke on learners’ academic engagement and enjoyment. Longitudinal studies are required to shed light on the effect of interpersonal emotions on language learning and learners’ positive emotions. Future studies can investigate the effects of teacher immediacy on learners’ working memory and long-term memory. Moreover, the effects of teacher immediacy on the improvement of language skills ought to be considered in detail. Further studies are needed to determine teacher immediacy in traditional and digital contexts to illuminate how these contexts may affect learners’ positive and negative emotions. Besides, further research can be done to investigate the gender effect and teacher proficiency level on teacher immediacy in language learning contexts. Finally, future studies should determine the relationship between EFL teachers’ immediacy and emotional intelligence in foreign language contexts.The studies involving human participants were reviewed and approved by the Zhejiang Gongshang University Academic Ethics Committee. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.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.


All aspects of prostate cancer evolution are closely related to androgen levels and the status of the androgen receptor (AR). Almost all treatments target androgen metabolism pathways and AR, from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC). Alterations in androgen metabolism and its response are one of the main reasons for prostate cancer drug resistance. In this review, we will introduce androgen metabolism, including how the androgen was synthesized, consumed, and responded to in healthy people and prostate cancer patients, and discuss how these alterations in androgen metabolism contribute to the resistance to anti-androgen therapy. Prostate cancer (PCa), ranked second in incidence and fifth in cancer-related mortality in men worldwide in 2020 , is drivAndrogens are the collective name for a group of 19-carbon steroidal substances, including testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), androstenedione, and so on . T and DAndrogen deprivation therapy (ADT) as a mainstay of PCa treatment to reduce the serum testosterone of patients to “castrate” levels (<50 ng/mL), can relieve the disease and improve overall survival when combined with radiotherapy for locally advanced disease, as well as intermediate- and high-risk localized disease ,14,15. HCRPC is highly clinically and genetically heterogeneous, which accounts for the emergence of drug resistance and often becomes lethal . A new gThis review will focus on the changes in androgen metabolism, including its synthesis, secretion, and catabolism as well as the variations of AR in response to anti-androgen therapy. We expect that a detailed description of the above processes and changes will fundamentally improve our understanding of the causes of anti-androgen therapy resistance in prostate cancer.CYP450) enzymes and the hydroxysteroid dehydrogenases (HSDs) [Under physiological conditions, androgens are mainly de novo synthesized from cholesterol. Many steroidogenic enzymes are involved in androgen biosynthesis. Two main groups of steroidogenic enzymes are the cytochrome P450 (s (HSDs) ,27.CYP450 enzymes are named because their mixture with carbon monoxide has a specific absorption peak at 450 nm. They are localized in the mitochondria and the endoplasmic reticulum, are hemoglobin-coupled monooxygenases, and function with the participation of coenzyme nicotinamide adenine dinucleotide phosphate (NADP(H)) and molecular oxygen to catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids, and other lipids [The r lipids .HSDs catalyze the interconversion between the hydroxysteroid and the ketosteroid, with the participation of NADP(H) or NAD(H). There are four types of HSDs: 3β-HSDs, 11β-HSDs, 17β-HSDs, and 20α-HSDs, classified by the carbon number acted upon [HSDs can also be divided into the short-chain dehydrogenase/reductase (SRD) family and the aldol-keto reductase (AKR) family. SDRs act by binding to membrane structures, while AKRs are soluble and play a catalytic role in facilitating the transfer of protons between steroids [ted upon ,30,31. Hsteroids ,33.The androgen synthesis pathway in organisms can be divided into three types: the “classical pathway”, the “alternative pathway”, and the “backdoor pathway”.CYP11A1 gene; P450scc moves to the inner mitochondrial membrane (IMM) and cleaves cholesterol to pregnenolone through a series of electron transfer reactions [The first and rate-limiting step in the synthesis of steroid hormones is converting cholesterol into pregnenolone . P450scceactions . Given teactions .CYP17A1 gene and located in the endoplasmic reticulum [HSD3B1 and HSD3B2 genes, respectively. 3β-HSD1 is specifically expressed in the placenta and peripheral tissues, including the prostate, while 3β-HSD2 is expressed mainly in the testis, the ovary, and the adrenal [Next, pregnenolone is first hydroxylated to form 17-hydroxypregnenolone (17-Preg), then cleaved to dehydroepiandrosterone (DHEA) by the steroid 17α-hydroxylase/17,20-lyase (P450c17) which is encoded by the eticulum . In para adrenal ,38. In a adrenal .4 is the most abundant steroid in male circulation, with about 400–1000 times the concentration of DHEA, and generates free DHEA by the steroid sulfatase [SRD5A2 gene and mainly expressed in the prostate under normal conditions [In the human body, DHEA exists primarily as sulfate. DHEA-SOulfatase . DHEA canditions . In addinditions . These aIn some specific cases, testosterone is not a direct precursor of DHT: DHEA is first converted to 4-AD by 3β-HSDs, then converted to androstenedione by S5AR1, and finally to DHT by 17β-HSD3 or AKR1C3. As this pathway completely bypasses testosterone synthesis, it is known as the “alternative pathway” of androgen synthesis ,45 Figu. This alSRD5A in human prostate cells, and they have different expression dynamics. SRD5A2 is predominantly expressed in normal prostate and early-stage PCa, while SRD5A1 is overwhelmingly predominant in CRPC [SRD5A3 is upregulated in PCa cells following the treatment of SRD5A inhibitors, which may result from the activation of AR mutants, but contributes little to androgen synthesis [Interestingly, there are three isoforms of  in CRPC ,46. SRD5ynthesis .Studies of the Macropus eugenii  and neonatal genital maturation processes have led to the discovery of the third pathway for androgen synthesis, the “backdoor pathway”, in which 17-OHP is converted to DHT ,50 Figu. First, In CRPC, the backdoor pathway is activated because AKR1C3 and 17β-HSD6 play a multi-step catalytic role. There are three isoforms of aldol-keto reductase  : AKR1C1 In healthy men, the de novo synthesis of androgen occurs essentially only in the testes and adrenal glands, while androgens are synthesized from DHEA intake in the prostate through the classical pathway . In an aIn castration-sensitive prostate cancer (CSPC), in addition to the classic de novo synthesis of androgen, the alternative pathway turns active. The androgen levels in CSPC cells are elevated relative to normal prostate organs. In response to the ADT treatment, DHT levels are decreased, but the intra-serum T levels of CSPC patients are comparable to those of healthy individuals .4 levels are significantly elevated in CRPC patients, for whom the DHEA-SO4 synthesis from cholesterol is accelerated in the adrenal glands, and prostate uptake of DHEA is greatly increased [In CRPC, the de novo synthesis of androgen through the backdoor pathway also becomes active. After the development of CRPC, the T level in the patient’s lesion was elevated relative to that before ADT treatment, and endocrine therapy was effective in reducing the DHT level in the lesion of CRPC patients . Circulancreased ,48.The androgen secretion mainly occurs by the Leydig cells in the testis and is supplemented by the adrenal cortex. The secretion process is regulated by the hypothalamic-pituitary-gonadal axis and the androgens are then transported through the bloodstream to target organs such as the prostate and skin, where androgens enter the cytoplasm in a diffuse manner .Because androgens are hydrophobic, only about 2% of androgens in the blood are in the free state, while most androgens combine reversibly with proteins. In total, 40% of androgens bind to albumins or corticosteroids-binding globulins (CBGs) in a non-specific manner, and 60% of androgens bind specifically to sex hormone-binding globulins (SHBGs) . The proInterestingly, the commensal gut microbiota can promote prostate cancer toward castration resistance by providing an alternative source of androgens ,58. StudThere are two methods of androgen catabolism. One is directly converted to estradiol by aromatase and exerts hormonal effects . AndrogeAll androgens are structurally nonpolar lipophilic compounds, and their lipophilicity facilitates their diffusion across biological membranes, making them more accessible to the site of action, but this same property prevents them from being excreted through the kidneys . TherefoN2) [The human UGT enzyme uses UDP-glucuronic acid (UDPGA) as a raw material to covalently attach a glucuronic acid group to a substrate with a suitable functional group, and the mechanism of this reaction is bimolecular nucleophilic substitution (SN2) . Many clN2) . For andN2) . UGT enzN2) . DependiN2) . For andN2) .UGT2B7 is expressed in the liver, kidney, intestine, skin, brain, and breast, but not in the prostate. UGT2B7 has a broader spectrum of catalytic activity for steroids, and it can covalently attach glucuronide groups to the 3-position hydroxyl group of androstanediol or Androsterone .UGT2B15 is expressed in the liver, kidney, skin, breast, uterus, and in prostate organs . In termUGT2B17 has high homology with UGT2B15 in amino acid sequence, but they are very different in substrate selectivity. Unlike UGT2B15, UGT2B17 has an affinity for both androgen 17-position and 3-position hydroxyl groups, Androstanediol, Androsterone, and DHT are its substrates. In addition, the spatial expression of UGT2B15 and UGT2B17 in the prostate was also very different, with UGT2B17 being expressed only in prostate basal cells and UGT2B15 being expressed only in prostate luminal cells .UGT2B28, a newly identified androgen metabolizing enzyme, has a similar substrate selectivity to UGT2B17, with an affinity for both the hydroxyl groups at the androgen 17- and 3- positions, it is not involved in the metabolism of DHT but can metabolize T  Figure .Androgen acts on prostate normal or cancer cells through its receptor AR. Therefore, the alterations of AR itself and changes in the AR pathway that respond differently to androgen levels will contribute to the anti-androgen resistance in PCa. There are several AR variations, including gene amplification, point mutations, new splicing variants, post-translational modifications, co-activator, and co-repressor modifications, and alternative pathways bypassing AR signaling. These are considered important reasons for anti-androgen resistance ,83,84,85Anti-androgen therapy, represented by ADT and the endocrine therapeutic drug enzalutamide, can significantly reduce the level of free androgens in patients, thereby decreasing the transcriptional activity of AR. As treatment proceeds, AR itself undergoes multiple changes in response to these changes. They all ultimately result in androgen-independent AR activation, which is the underlying cause of resistance to anti-androgen therapies. The gene amplification and some gain-of-function mutations  can lead AR to be activated in the presence of very little androgens, even in the presence of other hormones even drugs  and maintain transcription activity to promote the tumorigenesis and development of PCa ,67,68. SHow to overcome AR alternation during anti-androgen therapy is an enduring topic in prostate cancer resistance research. A deeper understanding of the sources and destinations of androgens may provide new ideas for the field.The metabolism of androgens in the human body is the basis for prostate cancer drug development. DHEA is the center of androgen synthesis in the prostate, and the synthesis of DHEA from cholesterol is of great therapeutic importance, especially for PCa patients who have elevated androgen levels and over-activated AR . The NatCYP17A1 enzyme that effectively blocks the synthesis of androgens in the testis, adrenal gland, and PCa [Abiraterone is a selective irreversible inhibitor of the  and PCa . FDA-app and PCa . Prednis and PCa . Availab and PCa ,20. HoweCYP17A1 and 17β-HSDs activate the de novo synthesis of androgens and increase the level of DHEA in the tumor [3β-HSDs and AKR1C3 enhances the “alternative pathway” and “backdoor pathway” of androgen synthesis, respectively, while reducing the metabolism of the active form of androgens by the glucuronidation pathway, resulting in abiraterone resistance [Many aspects contribute to abiraterone resistance. Overexpression and mutation of he tumor ,87. Abersistance ,87,88,89sistance , and presistance . The addsistance . In addisistance , the actsistance .Enzalutamide is a second-generation androgen receptor antagonist approved by the FDA for patients with both mCRPC and non-metastatic CRPC (nmCRPC) . It inhiPatient resistance to enzalutamide may be influenced by several different mechanisms . ChangesApalutamide is a novel, second-generation AR antagonist that inhibits the nuclear translocation of AR and inhibits the binding of AR to androgen response-like elements (ARE) in the context of AR expression . ApalutaDarolutamide is a novel oral non-steroidal AR inhibitor with a unique chemical structure that binds to AR with high affinity and exhibits strong antagonistic activity, thereby inhibiting receptor function and the growth of prostate cancer cells ,107,108.BRCA1), breast cancer type 1 susceptibility protein (BRCA2)) and those patients could be treated by PARP inhibitors (PARPi), which can increase the survival of those patients [CDK12) and mismatch repair (MMR) gene alterations often benefit from immune checkpoint inhibitor (ICI) therapy [The vast majority of prostate cancers are androgen-dependent malignancies, and ADT therapy has been the most important treatment for prostate cancer for more than 70 years . Althougpatients . Althoug therapy . These t therapy ,117. TheIt is well known that androgen is the ligand of AR to activate AR to take transcriptional function. In the development of PCa, AR always mutated to develop resistance to dealing with various treatments, likely ADT, and antiandrogens. However, in the process to advance prostate cancer, not only AR but also androgen metabolism changed. In healthy men or primary prostate cancer patients, androgen is biosynthesized through the classical or alternative pathway only in the testes and adrenal glands. However, in CRPC patients, the backdoor pathway is activated to synthesize more androgen to meet cancer cell needs. The new generation of hormone therapy drugs could improve the survival time of patients, but it is easy to develop drug resistance. Thus, exploring new methods to treat drug-resistant patients is urgent. A deep understanding of androgen anabolic and metabolic processes in the PCa process, as well as AR changes, helps in the development of new therapies to overcome drug resistance. Multiple metabolic proteins altered in androgens and anabolic changes are also expected to become new drug targets. In CRPC patients, some gene expressions were increased to catabolism of the therapy drugs, such as UTG2B. Developing an inhibitor of those genes might be an opportunity to prolong the drug efficiency for CRPC patients.


Exercise-based cardiac rehabilitation is safe and effective, evidence-based and implemented in national and international cardiac rehabilitation guidelines. Recent data show a decrease in cardiovascular mortality, reduced hospital admissions and an overall improvement in quality of life. To maintain positive effects and to prevent further cardiovascular events a major goal of cardiac rehabilitation is to induce a long-term health behaviour change and the integration of regular physical activity and exercise training in everyday life. The aim of this study is to evaluate the adherence of cardiac patients to exercise-based programs following rehabilitation phase III.A nationwide online cross-sectional survey was conducted. All outpatient aftercare providers who offer sports rehabilitation programs (heart groups) for cardiac patients in Germany were contacted. The questionnaire comprised 15 questions in five subcategories .560 of 2447 outpatient aftercare providers participated in the survey (response rate: 23%). On average, rehabilitation sport facilities hosted 2 (IQR 2) heart groups per week, and 23 patients (IQR 30)  per facility completed rehabilitation sport prescription in 2018. Almost all providers offer follow-up programs on a self-payer basis after rehabilitation sport prescription ends. Adherence to follow-up programs was at 54% . With 60% (IQR 71), patients with a statutory health insurance (mainly pensioners) adhere slightly more often to a follow-up program compared to privately insured persons (mainly population with a high income or civil servants) with 50% and significantly more often compared to persons who were insured by the German pension fund (covering working population) with only 9% (IQR 89) adherence.Almost all outpatient aftercare providers offer follow-up programs for cardiac rehabilitation patients but only half of them actually participate. Younger people (working population) do not adhere sufficiently to sport and exercise programs following rehabilitation phase III. This seems critical to address in terms of achieving long-term rehabilitation goals. The second stage (phase II) includes a 3–4 week in- or outpatient cardiac rehabilitation program with a focus on improving physical capacity, disease management and improving quality of life . The goaIn Germany, every patient has the right to participate in these structured exercise-based outpatient aftercare programs. Only skilled rehabilitation trainers who must be licensed and listed either by the German Society of Cardiovascular Prevention and Rehabilitation (DGPR) or the German Handicapped Sports Association (DBS) can offer these “heart groups”. Patients should exercise 1–2 times a week for at least 60 min. under surveillance of a physician. Heart group participation is usually prescribed by a physician and costs are covered by social insurance agencies. A prescription typically comprises 90 training sessions within 24 months.Depending on age and working ability of the patient either (statutory) health insurances, the German pension fund or private health insurances  have to pay for this service. For the majority of the working population the German pension fund and for pensioners the (statutory) health insurances cover rehabilitation costs.According to data of the DGPR some 9000 heart groups with a total of about 180,000 cardiac patients exist in the German outpatient aftercare setting .What is so far unknown is how many patients continue with regular physical training following rehabilitation phase III, after prescription and cost coverage for rehabilitation sport ends.Therefore, the aim of this study is to evaluate the long-term adherence of cardiac patients to exercise-based programs following rehabilitation phase III.The study was conducted as a nationwide cross-sectional online survey among outpatient aftercare providers for rehabilitation sports. For this reason, all available e-Mail addresses of outpatient rehabilitation providers in Germany who are certified and listed at the DGPR or DBS websites were systematically collected. The analyses are based on aggregated data which were provided by the aftercare providers. No individual data was collected.The questionnaire comprised 15 questions and was grouped in five subcategories. (1) General information about the outpatient aftercare provider (2) structure of rehabilitation sport programs (3) membership structure (4) content of heart groups and follow-up programs (5) adherence to follow-up programs. The main focus of the questionnaire was to analyse the adherence of cardiac patients to follow-up programs. For this reason, all providers were asked how many of their patients did participate in a sport or fitness program after prescription for rehabilitation sports (heart groups) ends in 2018.The questionnaire was implemented in the online software SosciSurvey . Prior tThe main survey was rolled out on January 7th, 2020. All outpatient aftercare providers who offer sports rehabilitation programs (heart groups) for cardiac patients in Germany were contacted via email and were invited to participate in the survey. The survey was online for 45 days. Three reminders were sent via E-Mail to increase participation rate.p < 0.05 was considered to indicate statistical significance.Data were collected electronically via SosciSurvey  and checOverall, 560 of 2447 outpatient aftercare providers participated in the survey (response rate: 23%). On average, rehabilitation sport facilities provided 2 (IQR 2) heart groups per week and most facilities (70%) offer rehabilitation sport programs for other diseases in addition to cardiovascular diseases. For descriptive analysis see Table With 96%, most outpatient aftercare providers indicate gymnastics as a main training aspect of their heart groups, followed by relaxation/stretching (87%) and endurance training/games (86%).Almost all (98%) outpatient aftercare providers who participated in the survey offer follow-up programs after prescription for rehabilitation sport ends. These follow-up programs are offered on a self-payer basis and address mainly (85%) the same aspects as the heart groups . On average, providers offer four different (IQR 3) exercise-based follow-up programs for heart patients. These include: gymnastics, endurance training, relaxing/stretching, strength training or bicycle ergometry. Costs for follow-up programs were 14 ± 13 € (mean ± SD) per month.On average 23 (IQR 30) cardiac patients (61% men) per outpatient aftercare provider completed rehabilitation sport prescription in 2018. The overall adherence to sport and exercise in terms of participation in a follow-up program was 54% (IQR 65) after prescription and cost coverage for rehabilitation sport ends with no sex specific difference. Whereas adherence to a follow-up program according to health insurance status of the patients show large differences between the insurance groups. Potentially younger, working patients whose costs for rehabilitation sport were covered by the German pension fund (GPF) show the lowest adherence to sport and exercise with an average participation rate of 9%. Rather older and non-working persons (mostly pensioners) whose costs were covered by statutory health insurances (SHI) or a private health insurance (PHI) show significantly higher participation rates of 60% and 50%, respectively compared to the GPF group. Detailed results are shown in Table 2 = 0,034, p = 0.537). Effect measures for outpatient aftercare size were OR 1.00 (95% CI 1.00–1.00) for number of follow-up programs OR 0.95 (95% CI 0.76–1.18) and costs OR 0.99 (95% CI 0.97–1.02).The multivariable logistic regression analysis to test for potentially predictive factors  affecting the overall adherence revealed no association between dependent and independent variables  and the statutory health insurances cover the costs for most of the older non-working (retired) population. The huge difference in the adherence to sport and exercise programs between the insurance and age groups may be partly explained by a lack of time in the working population  and a probably not adequate program structure for the target group. So far, previous studies mostly investigated early drop out and non-attendance in phase II rehabilitation. Gaalema et al.  identifiWieczorrek et al. found similar results according to the overall adherence of cardiac rehabilitation phase III as we did. They compared a standard heart group to a Tai-Chi based program. The adherence in both groups was similar, with 50% for the Tai-Chi based program and 48% for the standard heart group . In the To achieve long-term change of health behaviour in cardiac patients and maintain and improve quality of live adherence to regular physical activity is necessary , 4. ThisOne advantage for future exercise-based cardiac rehabilitation programs could be a more personalized approach , 24 e.g.According to our analysis we could not find any predictive factors of outpatient aftercare provider structure influencing the adherence to exercise and fitness in the target group.A loss of almost 50% of cardiac patients after cost coverage for rehabilitation sport ends seems critical in terms of achieving long-term rehabilitation goals. Especially when we know that only a minority of 9.7% to 22.5% of cardiac patients are successfully referred to rehabilitation sport programs (heart groups) following rehabilitation phase II .A strength of the study is that all outpatient aftercare providers who offer heart groups for cardiac patients in Germany were identified and invited to participate in the survey. This is as far as we know the largest survey among outpatient aftercare providers in Germany.Unfortunately, our data give no information regarding whether patients exercise in self-organized or home-based programs. Data was collected on an aggregated level from outpatient aftercare providers, and we have no information about participants on an individual basis. The survey was filled out by employees of the outpatient aftercare providers. Therefore, information regarding predictive factors of (low) participation rate is limited to external factors of the outpatient aftercare providers and not available for each individual separately.Further research using individual data is needed to investigate predictive factors and to adapt existing programs in order to improve adherence to exercise-based cardiac rehabilitation programs. To address these limitations a nationwide patient-based survey would be the method of choice. Health insurance companies usually ask their patients about their satisfaction with the rehabilitation process from time to time. This could be a good starting point for future collaborative health service research.Although almost all outpatient-aftercare providers who completed the survey (response rate: 23%) offer follow-up programs for cardiac rehabilitation patients, only half of them actually participate. In particular, younger patients do not adhere sufficiently to sport and exercise following rehabilitation phase III. This seems critical in terms of achieving long-term rehabilitation goals in this population.