The aim of the present study was to investigate a potential relationship between metabolic parameters and steady-state plasma concentrations of olanzapine (OLA) and its metabolite, 4-N'-desmethyl-olanzapine (DMO) in patients with schizophrenia taking therapeutic doses.A total of 352 inpatients, diagnosed with schizophrenia according to the DSM-V criteria and treated with OLA, were investigated. The plasma concentrations of OLA and DMO were measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). Fasting blood samples were measured for insulin, glucose, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), C-reactive protein (CRP) and homocysteine, and differences in these parameters were investigated in relation to plasma concentrations of OLA and DMO.Lower plasma DMO concentrations were associated with higher glucose and TG levels and homeostasis model assessment of insulin resistance (HOMA-IR), while higher plasma OLA concentrations were associated with higher CRP and homocysteine levels in the OLA-treated patients with schizophrenia.These results demonstrate that OLA and its metabolite DMO may have different effects on OLA-induced metabolic abnormalities. DMO might have a counteracting effects on glucose-insulin homeostasis and lipid metabolic abnormalities, which suggests that regular measure of various metabolic parameters and drug monitoring on both OLA and DMO are recommended in OLA-treated patients with schizophrenia. Olanzapine (OLA) is one of the most prescribed atypical antipsychotics for the treatment of schizophrenia. It has a lower incidence of extrapyramidal adverse effects and better therapeutic efficacy than other antipsychotics , but is OLA has a high affinity for various receptors , and is Numerous studies have investigated the associations between serum or plasma concentrations of OLA and metabolic abnormalities, including weight gain, impaired glucose metabolism, diabetes mellitus, and dyslipidemia –11. A prOLA/CDMO ratio between 3 and 6 might maximize the therapeutic efficacy and minimize the metabolic adverse effects in OLA-treated schizophrenia patients  orally for at least 6 months. The daily doses were determined by the physician who was treating the patients. The following information: demographic data, prescribed dose, time of last dose adjustment, time of last drug intake, date of blood sampling, psychiatric diagnosis, and concomitant medication were obtained from the medical record system. Patients treated with sustained-release OLA, carbamazepine and fluvoxamine and other antipsychotics were excluded from the study. In addition, patients with substance addiction, known diabetes mellitus or other physical disease that could influence metabolic parameters were excluded. The study was approved by the Review Board of Beijing Hui-Long-Guan Hospital. Written informed consent for therapeutic drug monitoring (TDM) of OLA was not required as it was a part of clinical routine of blood test.Blood samples were drawn in the morning generally between 7 and 8 a.m. under fasting conditions, ~12 h after the last dose of OLA. The blood samples were subjected to either biochemical analysis or immediately centrifuged for 10 min at 3,000 g at 4°C. The plasma samples were collected and stored at −20°C until analysis for determination of OLA and DMO, which was completed within 5 days.8-olanzapine) by agitation for 30 s and centrifuged for 10 min, and then 150 μl of supernatant was injected into the HPLC-MS/MS system. The calibration curves of OLA and DMO was linear in the concentration range of 3.2–160 and 1.6–80 ng/ml, respectively. The detection limits of OLA and DMO were 0.4 and 0.3 ng/ml, respectively. The intra and inter-day precision and relative errors were < 15%.The steady-state plasma concentrations of OLA and DMO were measured by the high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method, which was detailed in our previous study . Briefly*fasting glucose (mmol/L)/22.5.The serum levels of insulin, glucose, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), C-reactive protein (CRP) and homocysteine were measured by commercially available kits  using an automatic biochemistry analyzer AU2700 . The homeostasis model assessment of insulin resistance (HOMA-IR), was calculated using the equation HOMA-IR = fasting insulin (mU/L)OLA/D), DMO (CDMO/D), and the CDMO/COLA ratio were calculated. Spearman's rank order correlation analysis was used to assess the correlation between variables. Modified Bonferroni's method was used to correct possible errors during multiple tests  for continuous variables and the rate for discrete variables. The dose-corrected plasma concentrations of OLA  and CDMO , respectively. CDMO was significantly correlated with COLA . Age was negatively correlated with the daily OLA dose , COLA  and CDMO , respectively. Weight was positively correlated with the daily OLA dose , but negatively correlated with COLA  and CDMO . There were no sex differences in the daily OLA dose and CDMO (both p > 0.05), but female patients showed significantly higher COLA than male patients .A total of 352 inpatients with schizophrenia under TDM for OLA were included in this study. OLA was positively correlated with insulin levels, glucose levels, and HOMA-IR. After Bonferroni's correction, only the correlation of COLA with HOMA-IR remained statistically significant (p < 0.05).Simple correlation analysis revealed that CDMO/D and CDMO/COLA ratios were negatively correlated with insulin levels, glucose levels, and HOMA-IR. After Bonferroni's correction, these negative correlations remained statistically significant   .DMO was associated with higher glucose levels  and higher HOMA-IR  after controlling for age, gender, weight, and dose and duration of OLA.Further, multiple regression analysis revealed that lower COLA was positively correlated with TC and LDL-c levels; CDMO positively correlated with TC, HDL-c, and LDL-c levels but negatively with TG levels. After Bonferroni's correction, only the negative correlation of CDMO with TG levels remained statistically significant (p < 0.05).Simple correlation analysis revealed that COLA/D was positively correlated with TC and LDL-c levels; CDMO/D positively correlated with TC, HDL-c, and LDL-c levels but negatively with TG levels; CDMO/COLA ratio positively correlated with HDL-c levels but negatively with TG levels .Simple correlation analysis revealed that CG levels . After BDMO was associated with higher TG levels  after controlling for age, gender, weight, and dose and duration of OLA.Further, multiple regression analysis revealed that lower COLA was positively correlated with CRP levels; CDMO negatively correlated with homocysteine levels. However, neither of the two correlations passed Bonferroni's correction.Simple correlation analysis revealed that COLA/D was positively correlated with homocysteine and CRP levels, but the CDMO/COLA ratio was negatively correlated with both. After Bonferroni's correction, these correlations remained statistically significant   .OLA was associated with higher homocysteine  and CRP levels  after controlling for age, gender, weight, and dose and duration of OLA.Further, multiple regression analysis revealed that higher COLA was associated with higher homocysteine and CRP levels, while lower plasma CDMO was associated with higher glucose and TG levels and HOMA-IR. These results suggest that OLA and its metabolite DMO may have different effects on OLA-induced metabolic abnormalities. DMO might have a counteracting effects on glucose-insulin homeostasis and lipid metabolic abnormalities.Metabolic abnormalities are associated with OLA treatment in patients with schizophrenia. The present study found that higher plasma CDMO was associated with higher glucose and TG levels and HOMA-IR in OLA-treated patients with schizophrenia. The findings are in accordance with those of previous studies by Melkersson (DMO with glucose levels, and CDMO/D with insulin levels (OLA was positively correlated with glucose, insulin levels and HOMA-IR. Patients receiving OLA exhibited significantly higher insulin and glucose levels than those receiving conventional antipsychotics, indicating that OLA has a direct stimulating role on insulin secretion from pancreatic beta cells, or may simultaneously act secondary to insulin resistance (OLA ≥ 22.77 ng/mL is a predictor of moderate clinical efficacy, CDMO > 5.63 ng/mL is associated with reduced risk of metabolic syndrome, and COLA/CDMO ratio between 3 and 6 may maximize the therapeutic efficacy and minimize the metabolic adverse effects in OLA-treated patients with schizophrenia (The first finding of the present study is that lower plasma Clkersson , 16. Simn levels . Addition levels . Althougsistance , 20. Thusistance . Lu et aophrenia , 21. TheOLA was associated with higher CRP levels. Similarly, a recent study found a trend toward a positive correlation between serum COLA/D and CRP levels in a naturalistic setting (OLA in this study, the correlation should be interpreted with more caution.The second finding of the present study is that higher plasma C setting . C-react setting . Previou setting –26; howe setting . TherefoOLA was associated with higher homocysteine levels in the OLA-treated patients with schizophrenia. Few studies have explored the association between homocysteine levels and plasma COLA or CDMO. The only study to do so reported a positive correlation between COLA and homocysteine levels and a marginally positive correlation between CDMO and homocysteine levels (OLA and homocysteine levels might be related to the impaired glucose–insulin homeostasis in the OLA-treated patients with schizophrenia.The third finding of the present study is that higher plasma Ce levels . Homocyse levels –30. Numee levels –33 and ce levels , 34, 35.e levels , others e levels . Furthere levels . TherefoOLA generally being associated with a worsening of metabolic parameters and plasma CDMO the opposite, the strength of these associations was not particularly strong. It is still not enough to accurately clarify the effect of DMO on metabolic parameters in patients with schizophrenia treated with OLA based on available clinical data. Further studies in animal are needed to better understand the metabolic effects of DMO.There are several limitations to the present study. First, this was a retrospective study, several potential confounders, such as diet, exercise, co-medication and disease severity were not considered. Therefore, these correlations should be interpreted with more caution. Second, in the present study, only OLA and its metabolite DMO were analyzed, the possible role of other metabolites  on glucoOLA was associated with higher CRP and homocysteine levels, and lower plasma CDMO was associated with higher glucose and TG levels and HOMA-IR in the OLA-treated patients with schizophrenia. These findings demonstrate that DMO might counteract the effects on OLA-induced metabolic abnormalities, which suggests that maintaining CDMO/COLA ratio in a suitable range may minimize the metabolic side effects in OLA-treated patients with schizophrenia. Therefore, regular measure of various metabolic parameters and drug monitoring on both OLA and DMO are recommended for patients receiving OLA treatment.In conclusion, the present study found that higher plasma CThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the Review Board of Beijing Hui-Long-Guan Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.FY and HA were responsible for the study design, manuscript preparation, and providing the funding for the study. YY, SC, BM, and ZW were responsible for recruiting the patients and collecting clinical data. SQ and JS were responsible for drug assays. HF was responsible for statistical analysis. All authors have contributed to and have approved the final manuscript.This study was supported by grants from Beijing Municipal Science & Technology Commission No. Z191100006619020. The supporters had no role in the design, analysis, interpretation, or publication of this study.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.


The Guidelines for Stroke Rehabilitation are the result of a joint effort by the Scientific Department of Neurological Rehabilitation of the Brazilian Academy of Neurology aiming to guide professionals involved in the rehabilitation process to reduce functional disability and increase individual autonomy. Members of the group participated in web discussion forums with predefined themes, followed by videoconference meetings in which issues were discussed, leading to a consensus. These guidelines, divided into two parts, focus on the implications of recent clinical trials, systematic reviews, and meta-analyses in stroke rehabilitation literature. The main objective was to guide physicians, physiotherapists, speech therapists, occupational therapists, nurses, nutritionists, and other professionals involved in post-stroke care. Recommendations and levels of evidence were adapted according to the currently available literature. Part I discusses topics on rehabilitation in the acute phase, as well as prevention and management of frequent conditions and comorbidities after stroke. The members of the group participated in discussion forums on the web with predefined themes, followed by videoconference meetings in which controversies were discussed, leading to a consensus. For the preparation of the Brazilian Guidelines for Stroke Rehabilitation, several national co-authors, with prior knowledge in their areas of expertise, were asked to write the suggested topics following criteria defined by the coordinators of these guidelines. The original texts were adapted to follow a format in which, after the general information, the recommendations for each intervention were added. The present work focuses on recent clinical trials, meta-analyses, and systematic reviews in stroke rehabilitation literature. The main objective of this paper is to guide physicians, physiotherapists, speech therapists, occupational therapists, nurses, nutritionists, and other professionals involved in post-stroke care. Recommendations and levels of evidence have been adapted according to currently available literature. We have sought to provide visibility to broader rehabilitation aspects based on the intervention concepts proposed in the International Classification of Functioning, Disability, and HealthWe hope that this pioneering Brazilian work will soon be followed by new versions that can improve and update the content presented here. The recommendation rating and level of evidence used in these guidelines is an adaptation of the framework established by the American Heart AssociationClass I: There is evidence and/or consensus that intervention is effective.Class II: There is conflicting evidence and/or divergence of opinions about the effectiveness and usefulness of intervention.a) Although there is divergent evidence on the usefulness and effectiveness of intervention, the recommendations are in favor of intervention;b) Utility and effectiveness are less established by the evidence or opinions.Class III: There is evidence and/or consensus that intervention is not useful or effective and may cause harm.A: Data are obtained from multiple randomized clinical trials or meta-analyses.B: Data are obtained from a single randomized or non-randomized study.C: Consensus and expert opinion, case studies, or usual (standardized) treatments.The ideal organization of post-stroke rehabilitation care includes rehabilitation during the acute phase in stroke units, nursing home facilities, inpatient, home-based and outpatient rehabilitation servicesThe level of care after stabilization of the acute phase will depend on the degree of dependence in activities of daily living, status of comorbidities and neurological impairments and disabilities. It is suggested that the Assessment for Rehabilitation Tool (ART)Organized, coordinated, and multidisciplinary care should be available to patients after stroke. (Recommendation I-A).,This topic will address themes of relevance to rehabilitation in the acute phase of stroke that do not involve reperfusion or clinical stabilization interventions, as there are specific guidelines for that purposeAll patients must be evaluated by a multidisciplinary team using an objective framework, through the application of scales to assess the risk of pulmonary aspiration, malnutrition, pressure ulcers, deep vein thrombosis, neurological deficits, focal and global disabilities, and psychiatric disorders ,All rehabilitative interventions should be initiated as soon as the impairments and disabilities after stroke are diagnosed and should be continued as outpatient rehabilitation in the communityRegarding mobilization in the acute phase, the AVERT,,The Comprehensive Stroke Center (CSC), a combined and integrated service for acute-phase care and rehabilitation, offers the best outcomes,Despite the limited number of CSCs in Brazil, patients must be admitted to these units in the acute phase, preferably within the first hours of the strokeThere is evidence that individuals with mild stroke may have impairments neglected by professionals in multidisciplinary teamsAll patients in the acute stroke phase must be admitted to specialized stroke care units where they can receive care from a multidisciplinary team. (Recommendation I-A);All patients in the acute stroke phase must be seen by specialized professionals and objectively assessed, with the use of scales, for risk of pulmonary aspiration, malnutrition, pressure ulcers, deep vein thrombosis, neurological deficits, focal and global disabilities, and psychiatric disorders. (Recommendation I-A);Very early and high-intensity mobilization within 24 hours of stroke onset is not recommended. (Recommendation III-A);Keeping the head in the horizontal position, without elevation, did not show benefit in the acute post-stroke phase. (Recommendation III-A).Contractures are defined as the shortening or stiffening of muscles, skin, or connective tissue resulting in decreased movement and range of motion-Few studies have addressed the treatment of contractures after stroke. Systematic reviews and randomized studies evaluating passive movement and positioning with limb resting orthoses have shown little evidence of benefits in prevention and treatment of contractureProgressive casting and adjustable orthotics may be considered to reduce mild to moderate contractures of the elbow joints. (Recommendation IIb-B);Resting ankle and wrist orthotics may be used to prevent contractures. (Recommendation IIb-B);The effects of stretching, botulinum toxin, electrical stimulation, physical activity, and robot-assisted therapies have not been well established. (Recommendation IIb-B);Surgical interventions in the brachial, brachioradialis, and biceps muscles in elbow contractures might be considered. (Recommendation IIb-B).People who have had a stroke spend 81% of the day in sedentary time, increasing the risk of glucose intolerance, diabetes, heart disease, mood disorders, cognitive decline, decreased muscle mass, increased dependency for daily activities, stroke recurrence, and death. Physical activity (PA) plays a central role in reducing these risks and improving cardiovascular performance,The recommendations below are based on the American and Canadian guidelinesIt is recommended that all post-stroke individuals participate in PA interventions once they are clinically stable. (Recommendation I-A);Assessment of PA must be performed by qualified professionals. (Recommendation I-B);Monitoring of heart rate, blood pressure, and rating of perceived exertion before, during, and after completion of the test is recommended. Cardiac monitoring is recommended if stress testing is performed. (Recommendation I-A);Aerobic training is recommended in a rehabilitation program with the addition of muscle strengthening, task-oriented activities of motor control, balance, gait, and functional use of the upper limb. (Recommendation I-C);It is recommended that a PA program be developed and supervised by physical therapists or cardiovascular rehabilitation specialists. (Recommendation I-C);Exercises to activate a large group of muscles for a sufficient period to produce aerobic effort are recommended. (Recommendation I-B);A minimum period of eight weeks is recommended to obtain significant effects, followed by PA being maintained indefinitely. (Recommendation I-B);A frequency of three times a week of PA and lighter physical activities on other days is recommended. (Recommendation I-B);Sessions lasting more than 20 minutes are recommended, with a period of five minutes of warm-up and relaxation before and after each session. (Recommendation I-B); It is recommended that exercise intensity has individualized parameter values based on the percentage of heart rate reserve, percentage of maximum heart rate, and individual perceived exertion. (Recommendation I-B); It is recommended that the effects of PA be monitored by measures of cardiovascular capacity, blood pressure, lipid profile, fasting blood glucose, waist circumference, medication adherence, tobacco use, cognition, mood, and sleep quality. (Recommendation I-B); A PA program is recommended to be continued by the patient so that he/she can practice on their own. (Recommendation I-B); Clinical dates and stress tests with sub-maximal limits of tolerance should be used for prior evaluation of PA as a reference. (Recommendation IIa-C). Central pain after stroke is defined as neuropathic pain resulting from spinothalamic or thalamocortical tract lesions in the central nervous system (CNS), affecting patients in the acute or chronic phase after a stroke-Amitriptyline and lamotrigine can be first-line pharmacological treatments,Steroids, intravenous infusions of lidocaine, ketamine propofol, repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation, and spinal electrical stimulation showed favorable resultsAmitriptyline and lamotrigine should be used as first-line treatments for neuropathic pain. (Recommendation I-A);Duloxetine can be considered as an adjuvant treatment. (Recommendation IIa-B);Pregabalin and gabapentin can be used as second-line medication. (Recommendation IIa-B);Fluvoxamine can be considered. (Recommendation IIb-B);rTMS, deep brain, or spinal electrical stimulation may be considered in refractory cases. (Recommendation IIb-B);Levetiracetam, carbamazepine, and opioids are not recommended. (Recommendation III-B). Painful shoulder (PS) after stroke has an incidence range of 9% to 73%, depending on the diagnostic criteria used in the studies,Evidence for the use of shoulder orthoses to prevent dislocation, decrease pain, and improve function is conflicting,Gentle joint alignment movements and mobilization with external rotation and abduction may be beneficialConventional acupuncture and electroacupuncture have shown uncertain benefitsFunctional bandages are recommended for PS after stroke. (Recommendation I-A);Botulinum toxin injection in the subscapular and pectoral muscles is recommended, mainly if PS is associated with spasticity. (Recommendation I-A);Arm position and support during rest, arm protection, and support during functional movements can be considered to prevent PS. (Recommendation IIa-C);Functional electrical stimulation can be considered in the prevention of PS. (Recommendation IIa-A);PS can be treated with gentle alignment movements and mobilization with external rotation and abduction. (Recommendation IIa-B);Analgesics, such as acetaminophen and ibuprofen, and neuromodulators, can be used. (Recommendation IIa-A);Subacromial corticosteroid injections and suprascapular nerve block are reasonable options for hemiplegic PS. (Recommendation IIb-B); Acupuncture, as an adjunctive treatment, has an uncertain value. (Recommendation IIb-B);The use of orthotics to prevent dislocations is uncertain. (Recommendation IIb-B);The pulley system should not be used for the prevention of PS. (Recommendation III-A). Pressure injury (PI) is defined as localized injury to the skin and/or underlying tissues, usually over a bony prominence, resulting from pressure or pressure in combination with shearThe PI classification of the Associação Brasileira de Estomatoterapia (SOBEST) and Associação Brasileira de Enfermagem em Dermatologia (SOBENDE) is recomended in these guidelinesAlthough not specific to patients after stroke, the Braden Scale is a widely used tool for assessing pressure injury risk and had moderate predictive validity The recommendations for the prevention and care of PI after stroke are based on an adaptation of the latest version of the Prevention and Treatment of Pressure Ulcers/Injuries Quick Reference Guide published by the European Pressure Ulcer Advisory Panel, National Pressure Injury, Advisory Panel, and Pan Pacific Pressure AllianceSkin assessment for the risk of pressure injuries over pressure points is recommended in subjects with impaired mobility, sensory perception, older age, and diabetes. (Recommendation I-A);Structured PI risk assessment and PI classification are recommended. (Recommendation I-C);The skin of individuals at risk of PI should be inspected to identify the presence of erythema. (Recommendation I-A);The skin of individuals at risk of PI should be kept clean and appropriately hydrated. (Recommendation I-C);Full-thickness excision of pressure sores, including abnormal skin as well as granulation and necrotic tissues, should be performed. (Recommendation I-B); The following factors should be considered for PI surgery: comorbidities, surgical risk, the individual’s clinical condition, and the likelihood of healing with non-surgical versus surgical interventions. (Recommendation I-C);Airflow mattresses can be considered for stroke patients at risk of developing PI. (Recommendation IIa-B);Pulsed current electrical stimulation to facilitate wound healing in recalcitrant PI should be considered. (Recommendation IIa-A);High absorbency incontinence products can be used to protect the skin in stroke patients with urinary incontinence at risk of PI. (Recommendation IIa-B);Post-stroke individuals at risk of PI can undergo nutritional assessment. (Recommendation IIa-B);Stroke patients with, or at risk of, pressure injuries can be repositioned on an individualized schedule. (Recommendation IIa-B);Hydrogels, hydrocolloids, and polymeric wound dressings for non-infected stage II PI can be considered. (Recommendation IIa-B); Wound dressing with calcium alginate for stages III and IV PI with moderate exudates can be considered. (Recommendation IIa-B); Hydrogel for stage III and IV non-infected PI with minimal exudate is recommended. (Recommendation IIa-B);Subjects at risk of PI may be encouraged to sit out of bed for limited periods. (Recommendation IIb-B);Offering high-calorie, high-protein fortified foods or nutritional supplements in addition to the usual diet might be considered for stroke individuals at risk of PI. (Recommendation IIb-C);The benefits of topical antiseptics that are active against biofilms are uncertain. (Recommendation IIb-C).After a stroke, individuals are susceptible to nutritional changes due to a variety of symptoms and sequelae. The risk factors for nutritional changes after stroke are dysphagia, immobility, impaired cognition, as well as reduced food and macro- and micronutrient intakeFor individuals without dysphagia and who are not malnourished or at risk of malnutrition, the use of oral nutritional supplements is not indicatedIndividuals with dysphagia who need food texture modification or fluid thickening should be referred to a dietitian to ensure adequate nutrition and water intake,Sarcopenia is a complication of malnutrition after stroke, and it is associated with an increased risk of falls, fractures, functional disability, rehabilitation difficulties, and mortalityScreening for the risk of malnutrition is highly recommended within the first 48 hours of hospital admission. (Recommendation I-C);If oral feeding is not possible, feeding by a nasogastric/enteric tube is recommended. (Recommendation I-A);Every patient with dysphagia who needs food texture modification or fluid thickening should be referred for nutritional assessment to ensure adequate nutrition and water intake. (Recommendation I-C);Percutaneous endoscopic gastrostomy is recommended when there has been a need for enteral nutrition for more than three weeks. (Recommendation I-A);Patients should be screened for the risk of sarcopenia using the SARC-F questionnaire. (Recommendation I-C);The use of oral nutritional supplements is probably recommended for individuals who are able to eat and have been diagnosed with malnutrition or were at risk of malnutrition during hospital admission. (Recommendation IIa-C);For patients with severe dysphagia lasting longer than seven days, early enteral nutrition is probably recommended. (Recommendation IIa-C);The use of oral nutritional supplements is not recommended for patients without dysphagia and those who are not malnourished or at risk of malnutrition. (Recommendation III-C). Post-stroke depressive disorder (PSDD) is defined by the presence of a significantly depressed mood or a marked decrease in interest or pleasure that occurs as a consequence of a stroke,Adequate social support is necessary to prevent PSDDPharmacological treatment with antidepressants, such as SSRIs, can be recommended for the treatment of PSDD. (Recommendation IIa-A);Selective serotonin reuptake inhibitors may be used prophylactically after stroke. (Recommendation IIb-B);Family support, cognitive behavioral therapy, and lifestyle interventions can be considered. (Recommendation IIa-B);Exercise training may be used as a complementary treatment option in cases of PSDD. (Recommendation IIb-B);The combination of pharmacological and non-pharmacological treatments may be considered. (Recommendation IIb-B);Transcranial magnetic stimulation has unclear benefits. (Recommendation III-B).. The main risk factors for post-stroke DVT are advanced age, atrial fibrillation, limb paresis, or plegiaAcute stroke survivors are at high risk of deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE), with incidence ranging from 10% to 75% in this population Non-pharmacological interventions have been effective in preventing DVT and PTE. The randomized CLOTS 3 study showed that in patients with ischemic or hemorrhagic stroke, intermittent pneumatic compression was effective in reducing DVT and possibly improved survivalFor the prevention of DVT or PTE in patients with ischemic stroke, a meta-analysis A double-blind randomized study showed that in critically ill patients, including 15% of patients with ischemic stroke, after hospital discharge, rivaroxaban at a dose of 10 mg/day for 45 days reduced the combined risk of fatal and severe thromboembolism by approximately 28%, without a significant increase in bleeding tendencies- Regarding hemorrhagic stroke, a prophylactic dose of heparin between the second or fourth day did not increase the risk of intracranial bleeding, despite the low quality of the evaluated studies In patients with ischemic stroke and DVT or PTE, the anticoagulation maintenance period will be three months, unless another overlapping medical condition increases the risk of recurrence, Literature lacks studies using the inferior vena cava filter (IVCF) in cases of hemorrhagic stroke. However, considering its use in other conditions with contraindications for the use of anticoagulants, the use of inferior vena cava filters in patients with hemorrhagic stroke can be considered *Recommend dose of unfractionated heparin: < 15.000 UI/day. ** Recommended dose for low molecular weight heparin: 30 to 60 mg/day. Intermittent pneumatic compression is recommended in immobilized post-stroke patients to prevent DVT. (Recommendation I-A);In ischemic stroke, prophylactic doses of UFH or LMWH should be used during the hospital stay or even after discharge until the patient regains mobility. (Recommendation I-A); In ischemic stroke, a prophylactic dose of LMWH over UFH can be used to prevent DVT. (Recommendation IIa-A);Rivaroxaban at a dose of 10 mg/day for 45 days can be considered as prophylaxis for thromboembolism. (Recommendation IIa-B);IVCF can be considered in immobilized hemorrhagic stroke patients if anticoagulation is contraindicated. (Recommendation IIa-B);In hemorrhagic stroke, it may be reasonable to use a prophylactic dose of UFH or LMWH to start between the second and fourth days of hospitalization rather than no prophylaxis. (Recommendation IIb-C);The use of elastic compression stockings is not recommended. (Recommendation III-B). After an ischemic stroke or a transient ischemic attack (TIA), the risk of recurrence without treatment was 10% in the first week, 15% at one month, and 18% at three months, Meta-analysis of individuals with cardiovascular disease through long-term follow-up identified that a reduction of 1 g/d sodium  was associated with a decrease in cardiovascular eventsAntihypertensive therapy reduces the risk of ischemic or hemorrhagic strokePrediabetes and diabetes are associated with increased risk of initial ischemic strokeAntiplatelet agents should be prescribed to patients with non-cardiac-embolic stroke or TIA. Short-term use of aspirin plus clopidogrel for up to 21 days is recommended in patients with acute minor stroke or high-risk TIAPatients with cardiac embolism, particularly those with atrial fibrillation, should be treated with anticoagulantsPatent foramen ovale (PFO) closure is recommended for patients with cryptogenic stroke aged < 60 years, large PFO, or pronounced right-to-left shunt, without other concomitant etiologiesSevere symptomatic intracranial stenosis or occlusion should be treated with antiplatelet agents, and the combination of clopidogrel with aspirin for 90 days may be reasonableThe approach to stroke rehabilitation does not differ in the presence of comorbidities. Antiplatelet agents are recommended in patients with non-cardioembolic stroke or TIA for secondary stroke prevention. (Recommendation I-A);Anticoagulation with warfarin or DOACs is recommended for stroke or TIA with a cardioembolic source, with a preference for DOACs over warfarin. (Recommendation I-A);Patients with diabetes should control their blood glucose with physical activity, lifestyle modifications, and glucose-lowering agents with proven effectiveness in reducing risk for major cardiovascular events. (Recommendation I-A);In severe symptomatic intracranial stenosis or occlusion, a combination of clopidogrel and aspirin should be used. (Recommendation I-A);An exercise program by a health care professional, in addition to routine rehabilitation, is beneficial for secondary stroke prevention. (Recommendation I-A);Blood pressure control with a goal of systolic pressure less than 140 mmHg and diastolic pressure less than 90 mmHg is recommended. (Recommendation I-A); It is recommended that LDL values be kept below 70 mg/dl. (Recommendation I-A);Quitting smoking and reducing alcohol consumption are recommended. (Recommendation I-B);Reducing sodium intake is recommended to reduce the risk of stroke. (Recommendation II-A); PFO closure is recommended for cryptogenic stroke patients aged < 60 years. (Recommendation IIa-B); For severe symptomatic intracranial stenosis or occlusion, the combination of clopidogrel and aspirin for 90 days should be considered. (Recommendation IIa-B).Post-stroke patients experience insomnia, excessive daytime sleepiness, fatigue, non-restorative sleep, nocturia, and sleep fragmentation, often present even before the stroke-Obstructive sleep apnea syndrome (OSAS) affects 50% of stroke patients, and there is a strong interrelationship between the two conditionsMuscle relaxants, including benzodiazepines, are known to worsen OSAS Fully-fledged insomnia or symptoms of insomnia affect one-third to nearly half of all post-stroke patientsExcessive daytime sleepiness is frequent in post-stroke patients and is associated with higher mortality and less successful rehabilitationCPAP is recommended in individuals with post-stroke OSAS. (Recommendation I-A);Excessive daytime sleepiness and restless leg syndrome should be investigated and treated if present. (Recommendation I-B);Trazodone can be considered in individuals with ischemic stroke and OSAS. (Recommendation IIa-A);Conventional polysomnography is probably recommended in individuals with a history of stroke or TIA. (Recommendation IIa-B);Antidepressants should be taken in the morning. (Recommendation IIa-B);Cognitive behavioral therapy can be considered in individuals with post-stroke sleep disorders. (Recommendation IIa-B);Benzodiazepines and muscle relaxants should not be used in the management of post-stroke sleep disorders. (Recommendation III-C). , Falls are one of the most common causes of post-stroke complications. They can occur in the acute or chronic phases,-Falls are associated with motor, sensory, or visual impairment, cognitive dysfunction, hemineglect, and stroke in the posterior circulation,-Prevention of falls can be achieved by supervision, strength training, improvement of balance and cognition, less use of sedative drugs and diuretics, and counseling to avoid risky situationsExercises aimed at preventing falls, with training to improve balance, are recommended. (Recommendation I-B);Prevention of falls through patient supervision, reduction of the use of sedatives and diuretics, and restriction of activities with a risk of falling should be instituted. (Recommendation I-C);Tai chi can be considered for fall prevention. (Recommendation IIa-B);Agility training programs for fall prevention is reasonable. (Recommendation IIa-C). ,Osteoporosis is a metabolic bone disease characterized by an imbalance between bone resorption and accumulation, leading to changes in the bone microarchitecture and a reduction in bone mineral density (BMD),,,The evidence for drug treatment strategies for osteoporosis in stroke patients is limitedSome medications, such as warfarin, pioglitazone, enzyme-inducing anticonvulsant drugsPhysical activity with gait training and resistance exercises may have some beneficial effects on BMD loss, but there is limited evidenceVitamin D and calcium supplementation can be recommended for stroke patients. (Recommendation IIa-C);Bisphosphonates can be used. (Recommendation IIa-B);Statins can be beneficial in preventing osteoporosis after stroke. (Recommendation IIa-B);Physical activity with gait training and resistance exercises can be useful. (Recommendation IIa-C);Selective estrogen receptor modulators, warfarin, pioglitazone, enzyme-inducing anticonvulsants, and selective serotonin reuptake inhibitors can be used with caution. (Recommendation IIb-B);Tibolone should be avoided. (Recommendation III-B). Stroke is the leading cause of epilepsy among individuals over 60 years of age,The risk of acute symptomatic seizures or unprovoked seizures is low. Even in patients with hemorrhagic stroke and cortical involvement, the risk does not exceed 35%. Therefore, the use of antiseizure medication (ASM) as primary prophylaxis is not justifiedConversely, the risk of recurrence after an unprovoked seizure is approximately 70%, which defines epilepsy. In this situation, the use of ASM as secondary prophylaxis should be considered. The decision of a possible future suspension of ASM must be individualized since the risk of seizures after ASM withdrawal is high in patients with structural damageMost patients with post-stroke epilepsy have seizure control with monotherapy aloneLong-term use of antiseizure medication after an unprovoked seizure is recommended. (Recommendation I-B);Recurrent post-stroke seizures must be treated, and the selection of antiseizure medication should consider the patient´s characteristics. (Recommendation I-B); Use of antiseizure medication after an acute symptomatic seizure is generally not recommended, but it can be considered during the acute phase. (Recommendation IIa-B);Use of antiseizure medication as primary prophylaxis of post-stroke seizures is not recommended. (Recommendation III-B). Post-stroke neurogenic lower urinary tract dysfunction (NLUTD) is defined as a dysfunctional condition of the muscles of the bladder, urethra, urethral sphincter, and pelvic floor, and is related to the topography of the damage caused by the stroke, leading to abnormal or difficult control in voluntary and/or involuntary muscle contraction and/or relaxation during the storage and voiding phases of the bladderApproximately one-third of adult stroke survivors have symptoms related to NLUTDFecal incontinence (FI) is the inability to control bowel movements, causing stool to unexpectedly leak from the rectum. The prevalence of FI is approximately 40% in the post-stroke acute phase and 20% during rehabilitation. The risk factors are age and functional limitationsDue to the low quality of the studies, no significant effects on NLUTD in post-stroke individuals have been shown by behavioral interventions, assistance from specialized professionals, complementary therapies such as acupuncture (electroacupuncture and moxibustion), transcutaneous electrical stimulation, physical therapy techniques, pharmacotherapy with oxybutynin or estrogen, and a combination of interventionsThere are few studies in the literature on interventions for FI in post-stroke individuals, and they show that educational actions and dietary control have inconclusive effectsFor post-stroke NLUTD, behavioral interventions, specialized professional care, complementary therapies such as acupuncture (electroacupuncture and moxibustion), transcutaneous electrical stimulation, physical therapy techniques, pharmacotherapy, and a combination of interventions have uncertain benefits. (Recommendation IIb-B);For post-stroke FI, educational actions and dietary control have inconclusive effects. (Recommendation IIb-B).Sexual dysfunction after stroke is underrecognized. It affects over half of stroke survivors and it is not solely attributed to the physical effects of strokeSexual dysfunction is associated with depression, fear of recurrence of a new stroke, and self-perception of impaired motor function,,Sexual rehabilitation involves counseling and non-pharmacological and pharmacological interventionsThe effectiveness of interventions to treat sexual dysfunction is limited. According to a recent meta-analysis, data indicating the benefits or risks of using sertraline to treat premature ejaculation, pelvic floor physiotherapy and sexual rehabilitation to treat sexual dysfunction after stroke are insufficientIt is recommended that stroke subjects be asked about their sexual function. (Recommendation I-C);Mood disorders and fears should be addressed in sexual dysfunction after stroke.If ED is present in men after stroke, antihypertensive drug use, anxiety, and depression should be investigated. (Recommendation I-B);The benefits of sertraline in treating premature ejaculation are uncertain. Recommendation IIb-B);The effects of sexual rehabilitation for treating sexual dysfunction after stroke are not well established. (Recommendation IIb-B) The Brazilian Guideline for Stroke Rehabilitation - Part I presents recommendations on interventions to manage and prevent complications and comorbidities after stroke. However, this guideline is open to criticism for potential issues in the recommendations: 1) the variety of topics covered; 2) the diverse effects of a single intervention in recovery from neurological deficits and disabilities; 3) the low methodological quality of the studies evaluated in systematic reviews and meta-analyses; 4) the personal experience of each professional; and 5) the complexity of the theme of stroke rehabilitation. We hope that Part I of this guideline helps the multidisciplinary team in offering the best care of the most frequent clinical conditions after stroke.


Subjective cognitive decline (SCD) appears in the preclinical stage of the Alzheimer's disease continuum. In this stage, dynamic features are more sensitive than static features to reflect early subtle changes in functional brain connectivity. Therefore, we studied local and extended dynamic connectivity of the resting brain of people with SCD to determine their intrinsic brain changes.We enrolled cognitively normal older adults from the communities and divided them into SCD and normal control (NC) groups. We used mean dynamic amplitude of low-frequency fluctuation (mdALFF) to evaluate region of interest (ROI)-wise local dynamic connectivity of resting-state functional MRI. The dynamic functional connectivity (dFC) between ROIs was tested by whole-brain-based statistics.N = 40) with NC (N = 45), mdALFFmean decreased at right inferior parietal lobule (IPL) of the frontoparietal network (FPN). Still, it increased at the right middle temporal gyrus (MTG) of the ventral attention network (VAN) and right calcarine of the visual network (VIS). Also, the mdALFFvar (variance) increased at the left superior temporal gyrus of AUD, right MTG of VAN, right globus pallidum of the cingulo-opercular network (CON), and right lingual gyrus of VIS. Furthermore, mdALFFmean at right IPL of FPN are correlated negatively with subjective complaints and positively with objective cognitive performance. In the dFC seeded from the ROIs with local mdALFF group differences, SCD showed a generally lower dFCmean and higher dFCvar (variance) to other regions of the brain. These weakened and unstable functional connectivity appeared among FPN, CON, the default mode network, and the salience network, the large-scale networks of the triple network model for organizing neural resource allocations.When comparing SCD (The local dynamic connectivity of SCD decreased in brain regions of cognitive executive control. Meanwhile, compensatory visual efforts and bottom-up attention rose. Mixed decrease and compensatory increase of dynamics of intrinsic brain activity suggest the transitional nature of SCD. The FPN local dynamics balance subjective and objective cognition and maintain cognitive preservation in preclinical dementia. Aberrant triple network model features the dFC alternations of SCD. Finally, the right lateralization phenomenon emerged early in the dementia continuum and affected local dynamic connectivity. Subjective cognitive decline (SCD) refers to individuals' perceived decline in memory or other cognitive abilities relative to their previous level of performance in the absence of objective neuropsychological deficits  is an essential noninvasive tool in cognitive neuroscience. Functional MRI (fMRI) detects blood oxygenation level-dependent (BOLD) signals to reflect neuronal activities in the human brain Grady, . In addiIn neurodegeneration of the AD continuum, pathological tau deposition is closely related to cognitive performance  . We also looked for their outward dFC to seek emerging alterations of the intrinsic brain function of preclinical dementia.Subjective cognitive decline was defined by the two criteria of the Subjective Cognitive Decline Initiative Working Group: (1) self-experience of a persistent decline of cognitive capacity when compared to a previously normal cognitive status, and the change did not correlate with any acute event, and (2) the performance of standardized cognitive tests met the expected levels   score determined their objective cognitive performance. Impairment of cognitive performance was defined by a MoCA score lower than one standard deviation below the mean of age- and education-adjusted norms  conducted by the Community Medicine Research Center of the Chang Gung Memorial Hospital in Keelung, Taiwan. The cohort was launched in Northeastern Taiwan in 2012 and started cognitive and brain imaging recording in 2018. The Institutional Review Board of Chang Gung Memorial Hospital approved this study . All the participants signed informed consent before entering this study.During 2018–2020, we enrolled healthy, right-handed, older adults aged over 50 years. Participants with major organ failure, including heart failure, renal failure, moderate-to-severe liver disease, and active thyroid diseases, were not recruited. In the initial screening, we excluded the participants who fulfilled the criteria of MCI  and NC group (N = 45)  .p < 0.001) and poorer cognitive performance in MoCA , LNS (p = 0.021), CF of animal (p = 0.004), and color (p = 0.028) than the NC group. Compared to NC, SCD also had higher tendency of anxiety  and depression  , and 10.10 ± 4.19 years of school education. Between-group comparisons confirmed the equality of age, sex, and education level between SCD and NC . The SCD< 0.001) .3 isotropic cube, flip angle (FA) = 8, repeat time (TR) = 2200 ms, echo time (TE) = 2.45 ms, and inverse time = 900 ms) were acquired before the functional scans for localization reference. Customized cushions were used to minimize head motion during each scan. rs-fMRI scans were subsequently acquired using a single-shot, gradient-recalled echo-planar imaging sequence  aligned along the anterior commissure-posterior commissure line, thus allowing whole-brain coverage.Magnetic resonance imaging data were collected using a 3T Siemens Skyra system  and a 20-channel head-neck coil at Keelung Chang Gung Memorial Hospital. High-resolution T1-weighted anatomical images  to improve the signal-to-noise ratio.All the fMRI data were preprocessed by the analysis of functional neuroImages (AFNI) Cox, , FMRIB SThe ROI-based dynamic metrics were generated by the DynamicBC toolbox (version 2.2)  we used the fast Fourier transform (FFT)  of the filtered time series as the power spectrum. Then, the ALFF as the average square root of the power spectrum across 0.01–0.08 Hz was calculated for each voxel  The BOLD times series of all voxels within each ROI were averaged for calculating the Pearson's correlation coefficients in a pairwise manner of the seed ROI to the whole-brain ROIs. (2) These correlation coefficients, considered the dFC, were transformed into Z-scores using Fisher's Z formula for statistical analysis. (3) Then, the temporal series of dFC values from each sliding window were averaged and yielded the mean of dFC (dFCmean) and the variance of dFC (dFCvar) for each participant.Next, we examined the dynamics of inter-regional functional connectivity extended from the regions with significant mdALFF group differences. The ROIs with significant differences of mdALFFpost hoc analysis with the Tukey's method. Statistical significance was considered at a confidence level of 99.5% by a p < 0.005. Next, we used the false discovery rate (FDR) to test the statistical significance in multiple comparisons  to control the family-wise error rate in identifying group difference for the clusters of connected connections. A mean and mdALFFvar were tested for correlations to the scores of AD8, MMSE, MoCA, DSC, DST, CF categories, FMT, HADS-A, and HADS-D using the data from all the participants. A correlation coefficient was considered statistically significant by a p-value < 0.05 after FDR corrections for multiple comparisons.A partial correlation analysis adjusted for age, sex, education, and frame displacement examined the relationship between mdALFF and the clinical variables. The mdALFFIn addition, we tested the mdALFF clinical correlation in separated groups of SCD and NC. The partial correlation coefficients of each group underwent Fisher's Z-transformation and then two-tailed t-tests for group differences. FDR further examined the group comparison of correlation, and an FDR-corrected p-value < 0.05 was defined as statistical significance.mean decreased at ROI(a) that located in the right IPL and belonged to the frontoparietal network (FPN) (p = 0.002). In contrast, we observed an increase of mdALFFmean at ROI(b) in the right middle temporal gyrus (MTG) of the ventral attention network (VAN) (p < 0.001) and ROI(c) in the right calcarine fissure and surrounding cortex (CAL) of the visual network (VIS) (p < 0.001)  .var was higher at ROI(a) in left STG of the auditory network (AUD) (p < 0.001), ROI(b) in right lingual gyrus (LING) of VIS (p = 0.002), ROI(c) in right MTG of VAN (p < 0.001), and ROI(d) in right lenticular nucleus pallidum (PAL) of the cingulo-opercular network (CON) (p = 0.004)  .mean decreases than the NC at an ROI of right Rolandic operculum (ROL) that belonged to AUD (p = 0.006), an ROI in right lobule VI that belonged to the cerebellar regions of frontoparietal network (cFPN) (p = 0.008), and two ROIs in left Crus I/II of the cerebellar regions of default mode network (cDMN) . Moreover, mdALFFvar marginally increased at a VIS ROI in the right CAL , but marginally decreased at a cFPN ROI in the left Crus I (p = 0.006) in SCD than NC.In addition to the significant local dynamic connectivity changes, there were some marginal mdALFF group differences. For example, the SCD had marginal mdALFFmean at right MTG of VAN and right CAL of VIS, as well as for mdALFFvar at right MTG of VAN and left STG of AUD. The whole-brain ROI-wise FDR was not significant.The network-based FDR for mdALFF values was significant for mdALFFmean decreased between the ROIs of FPN-cFPN, FPN-the default mode network (DMN), FPN-the salience network (SAL), FPN-the dorsal attention network (DAN), FPN-the reward network (REW), VIS-cFPN, CON-DMN, and CON-SAL , VIS-FPN, AUD-VIS, AUD-FPN, CON-VIS, within CON, within VIS, and within AUD , but positively correlated with the mdALFFmean in right MTG of VAN (r = 0.30), and right CAL of VIS (r = 0.38). AD8 score was also positively correlated with the mdALFFvar in left STG of AUD (r = 0.51), right LING of VIS (r = 0.42), and right MTG of VAN (r = 0.32). Statistical significance was set at p < 0.05 after FDR correction  and CF score of fruit category   .var in right MTG of VAN was associated with the degree of anxiety, in terms of HADS-A   .var in right MTG of VAN, CF scores for fruit and city categories to mdALFFvar in right PAL of CON, HADS-D scores to mdALFFmean in right IPL of FPN, mdALFFmean in right CAL of VIS, and mdALFFvar in left STG of AUD (FDR-corrected p < 0.05)  .mean and mdALFFvar were mainly located in the right cerebral hemisphere. In addition, the alterations of intrinsic brain activity of SCD were toward a regional-specific mixture of deficiency-compensation mechanisms and unstable local dynamics. In detail, local dynamic connectivity became weak in FPN for central executive control and cognitive flexibility. Still, FPN balanced both subjective and objective cognition and had a crucial role in cognitive reserve in preclinical dementia. In contrast, functional compensation of SCD started in visual and attention networks. To sum up, the temporal fluctuations of local BOLD signals explained regional brain changes of SCD, which responded to the subtle cognitive decline and tried to resume the homeostasis of the brain.This was an rs-fMRI study of local mdALFF and related extension of dFC in community-dwelling cognitively normal older adults, who were divided into the SCD and NC groups for comparisons. In SCD, ROI-based mdALFF local dynamic connectivity analysis showed mixed changes in mean and variance. The ROIs with significant group differences of mdALFFmean of VIS, FPN, and VAN showed decreased dFCmean and increased dFCvar to other brain regions. An increased variance indicated instability and fluctuation of local dynamic connectivity. The CON, VAN, and AUD regions with increased mdALFFvar also showed unstable outward connections with an increased dFCvar. The altered dFC in SCD could result from disconnection and noise signals due to early degeneration or resource relocation to cope with the subtle cognitive decline.The dFC from those ROIs with local dynamic changes also differed between SCD and NC. Those regions with altered mdALFFhemispheric asymmetry reduction in older adults (HAROLD)  that additional networks are recruited in response to the functional decay of the initial network  analysis comparing people with subjective memory complaints, NC, and MCI found lower regional dynamic connectivity in the hippocampus, parahippocampal gyrus, fusiform gyrus, precuneus, paracentral gyrus, and cerebellum in SCD. Furthermore, general concordance was higher in those with subjective memory decline than in NC  also decreased in SCD. We proposed that the above networks are complicated and delicate in connecting outward and may be more vulnerable to disconnection.We found that FPN  lost local dynamic connectivity in SCD. Other studies demonstrated that dynamic connectivity of DMN is affected in SCD  than controls  in SCD and MCI compared to NC; moreover, the dFC variability within FPN is correlated with cognitive performance , in cooperating with the goal-relevant top-down attention by the dorsal attention network  and the mdALFFvar increased at the left STG in SCD (p < 0.001). In previous studies, right ROL was one of the brain regions that showed early functional changes in AD spectrum disorders. For example, the right ROL local property and its subgraph connecting to the right insula could differentiate early MCI from NC , W-YH (CRRPG2K0032), C-PL (CRRPG2G0062 and CRRPG2K0022), C-KC (CRRPG2G0052 and CRRPG2K0012), and the Community Medicine Research Center of Keelung Chang Gung Memorial Hospital (CLRPG2J0011 and CLRPG2L0052). This research was also supported by grants to C-PL from the Ministry of Science and Technology (MOST) of Taiwan .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.


The vagus or “wandering” nerve is the main branch of the parasympathetic nervous system (PNS), innervating most internal organs crucial for health. Activity of the vagus nerve can be non-invasively indexed by heart-rate variability parameters (HRV). Specific HRV parameters predict less all-cause mortality, lower risk of and better prognosis after myocardial infarctions, and better survival in cancer. A non-invasive manner for self-activating the vagus is achieved by performing a slow-paced breathing technique while receiving visual feedback of one’s HRV, called HRV-biofeedback (HRV-B). This article narratively reviews the biological mechanisms underlying the role of vagal activity and vagally mediated HRV in hypertension, diabetes, coronary heart disease (CHD), cancer, pain, and dementia. After searching the literature for HRV-B intervention studies in each condition, we report the effects of HRV-B on clinical outcomes in these health conditions, while evaluating the methodological quality of these studies. Generally, the levels of evidence for the benefits of HRV-B is high in CHD, pain, and hypertension, moderate in cancer, and poor in diabetes and dementia. Limitations and future research directions are discussed. One of the goals of medicine is to identify risk and protective factors of diseases, to prevent negative health consequences, and promote health. It is also crucial to reveal the underlying biological mechanisms leading to health. Therefore, it seems important to reveal the variables and interventions which promote well-being rather than diseases.The leading causes of death worldwide include coronary heart disease (CHD), cancer, stroke, and chronic obstructive pulmonary disease (COPD) . When coOngoing communication between vital organs through the autonomic nervous system (ANS) is a necessary feature of a healthy organism , and it The vagus or “wandering” nerve is the main branch of the PNS, innervating most internal organs which have crucial roles in health and illness . The vagus nerve is the 10th cranial nerve that extends from the brain stem and then near the left and right carotid arteries to innervate most visceral organs. Approximately 20% of its nerve fibers are efferent, while the majority (80%) are afferent, sending various signals from visceral organs to the brain . AnatomiThe vagus has a major neuro-immunological role. The nervous and immune systems constantly influence each other bidirectionally. The nervous system innervates lymphoid glands and immune cells express receptors for neurotransmitters ,9. The iThe vagal nerve transmits information about peripheral inflammation via receptors for interleukin-1 on its paraganglia, and then it regulates peripheral inflammation by two routes. First, it activates the hypothalamic–pituitary–adrenal (HPA) axis, leading to the secretion of cortisol which decreases inflammation. Second, the descending vagus reaches the celiac ganglion where it “converts” to a sympathetic branch that innervates the spleen. There, a sub-class of splenic T-cells produce in return the vagal neurotransmitter acetylcholine, which binds to its alpha-7 nicotinic acetylcholine receptor on macrophages, which inhibits inflammatory cytokine synthesis . These rOne more important parasympathetic role of the vagus is vasodilation which counteracts the sympathetic response. This is achieved specifically by vagal nerve-induced increases in vasoactive intestinal peptide, which then increases coronary blood flow . This anThe heart rate rises during inhalation and falls during exhalation , due to 2, respectively) as we will elaborate on below.The activity of the vagal nerve is non-invasively indexed by different HRV parameters which reflects the fluctuations in the intervals between normal heart-beats . HRV mosHRV is modulated by multiple regulatory mechanisms which operate at different time scales. A 24-h recording of HRV reflects the interactions between circadian rhythms, core body temperature, metabolism, and vagal efferent signals to the heart. In contrast, short-term measurements of HRV  reflect autonomic, cardiovascular, and respiratory effects, and are also a valid marker of parasympathetic cardiac vagal control as mentioned ,20.HRV can be detected using two major different linear domains: frequency and time domains.In the frequency domain, HR oscillations are divided into four frequency bands: ultralow frequencies (ULF ≤ 0.003 Hz)); very-low frequencies (VLF: 0.003–0.04 Hz); low frequencies (LF: 0.04–0.15 Hz); and high frequencies (HF: 0.15–0.40 Hz). The ULF band indexes fluctuations in the inter-beat interval (IBI) with a period from 5 min to 24 h and is usually measured using 24 h recordings and reflects slow biological processes such as circadian rhythms and metabolism. The VLF band reflects physical activity, temperature regulation, and PNS and SNS control and is comprised of rhythms with periods between 25 and 300 s. The LF band reflects baroreflex control and is mostly controlled by the PNS, and to a lesser extent by the SNS. LF is comprised of rhythms with periods between 7 and 25 s and is affected by breathing from 3 to 9 bpm. The HF band reflects changes in heart rate due to respiration and is fully controlled by the PNS. Since the influence of the PNS on the HRV occurs via the vagus nerve, this permits the physiological mechanism of RSA. In normal conditions, the RSA reflects oscillations in HR in correspondence with breathing and very strongly correlates with the HF parameter. The HF domain is influenced by breathing from 9 to 24 bpm . The ratIn the time domain, the amount of variability in the IBI between successive heartbeats is quantified by several indexes . Although HRV guidelines recommend that measurements be based on a minimum of 5-min recordings, the ultra-short measurement of 10-s ECGs are more commonly made during routine medical care and are thus more patient friendly. Furthermore, a 10-s signal is suitable for obtaining the two most commonly used time domain HRV indexes: the standard deviation of the normal-to-normal RR intervals (SDNN) and the root mean square of successive RR interval differences (RMSSD) . ImportaIt is also important to note that vagal activity influences and is controlled by higher brain regions. According to the neurovisceral integration model , vmHRV iSome researchers have investigated the relationship between time and frequency variables. For example, SDNN correlated with LF power, and RMSSD correlated with HF power during sleep in men . RMSSD ip < 0.0001), low-frequency power (p < 0.0001), high-frequency power (p = 0.0014), total power (p < 0.0001), and the standard deviation of total normal RR intervals (p = 0.0019) were significantly associated and predicted less all-cause mortality [This article will show in depth the prognostic role of frequency and time domain HRV measures in multiple health outcomes. Indeed, high HRV levels measured very-low-frequency power  devices have been developed. The nVNS devices were found to reduce chronic headaches ,63, to rThe second, a non-invasive manner of self-activating the vagus, is achieved by performing slow-paced breathing while receiving feedback on one’s HRV, called HRV-biofeedback (HRV-B). This non-invasive way to increase vagal nerve activity aims to reduce breathing rate to approximately six breath cycles per minute . Such de2). The occurrence of hyperventilation is known to be conjoined with psychological stress [Generally, breathing education or training emphasizes decreased respiration rate and increased muscle relaxation of the thoracic area, as well as training in abdominal breathing, also called diaphragmatic breathing (DB). Muscle tension in the abdominal area, pelvis, and lower back tends to restrict movement of the diaphragm, thus requiring the use of the accessory muscles of the chest and shoulders for breathing . This eml stress , which cl stress . Slow-pal stress . Progresl stress ,74,75,76Biofeedback in general includes the measurement and the presentation of audio-visual feedback of biological parameters such as brain activity, muscle activity, heart rate, and measures of skin sweat glands. Biofeedback empowers users to attain control over physiological processes in conjunction with changes to their psychological state.HRV-B specifically teaches people to exhibit optimal breathing patterns and frequency which greatly increase vmHRV while stimulating various autonomic and respiratory regulatory reflexes. As mentioned, HRV-B teaches people to breathe slowly at the rate of about six breaths per minute (a slightly different rate for each person)  which isIt has been proposed that each individual’s cardiovascular system has a unique resonance frequency, which is caused by the delay in the baroreflex . Inertian = 10), this was a rigorous and important experiment.Resonance frequency breathing using HRV-B may increase the cholinergic anti-inflammatory pathway ,87. One Clinically significant effects of HRV-B have been found for a wide variety of disorders. Several meta-analyses and systematic reviews examined the effects on stress and anxiety, depression, and emotional and physical health ,90,91. TThe effectiveness of HRV-B interventions is well established in the field of mental health with an emphasis on anxiety and depression, while a focus aimed at examining the effect on major physical diseases is lacking. In addition, many reviews of HRV-B in various illnesses often lack a deeper explanation of the biological mechanisms linking vagal nerve activity with the particular illness. The current review article aimed to address these two important gaps.Although this is a narrative review, we chose to focus in this chapter on presenting research findings using a structured search. The following section will briefly review, in relation to selected major health conditions, the relationships between different HRV parameters and the etiology or prognosis of each condition, the biological mechanisms linking vagal activity to each illness, and will review studies that tested the effects of HRV-B on patients with each condition. For the latter, we searched PUBMED using the following keywords: “Condition” AND (HRV OR heart rate variability) AND  AND Biofeedback. “Condition” refers to diabetes or hypertension or cancer or pain or CHD or cognitive impairment, dementia, or Alzheimer′s disease. This search was completed separately for each condition.Concerning the effects of HRV-B, we also critically evaluated the methodological level of each identified trial per condition, using a quality assessment instrument for randomized trial studies . An evalFirst, reduced HRV predicts an increased risk of coronary heart disease. In a prospective study on 2501 initially heart-disease-free participants, reduced SDNN was an independent predictor of an excess of 47% risk for future cardiac events . Second,Oxidative stress, excessive sympathetic activity, and inflammation all contribute to atherogenesis since oxidative stress results in oxidized LDL cholesterol, and inflammation causes the recruitment of macrophages to an evolving cardiac plaque, which engulfs oxidized LDL and further increases coronary occlusion ,96. Finan = 46 post-MI patients, half underwent HRV-B, and half did not. HRV-B led to short-term increases in HRV  and to increased self-efficacy, while this did not occur among controls [We examined first the evidence for the effects of HRV-B on people with MI and CHD. First, in 54 CAD patients, those randomized to receive HRV-B showed increases in HRV and reductions in hostility , both incontrols . In a stcontrols . Anothercontrols , found tEpidemiologically, multiple studies have shown inverse relationships between HRV and blood pressure (BP), both cross-sectionally and in prospective studies. For example, a study conducted in the Atherosclerosis Risk in Communities (ARIC) study found in 7099 people initially without hypertension (HT) that reduced SDNN and RMSSD significantly predicted an increased risk of HT over 9 years .The vagal nerve is crucial in the evolution of hypertension since this nerve plays a pivotal role in regulating blood pressure (BP) via the baroreflex. This reflex is based on mechanoreceptors in large vessels such as the aorta which detects intra-arterial pressure. To counteract this, the vagus then commands a reduction in HR via the brain stem, which then reduces cardiac output, resulting in the reduction in BP. In addition, BP may increase due to vasoconstriction, which is also counteracted by the vagus as it is a vasodilator.In an important RCT, 43 people with pre-hypertension received either HRV-B, deep breathing training without biofeedback, or no treatment, and were followed for 3 months. Significant increases in HRV and reductions in SBP and DBP were only found in the HRV-B group . That stThe mean methodological evaluation score for these studies in HT was quite high–4. Thus, for HT, the evidence for the positive effects of HRV-B on BP control is quite strong.The relationship between vagal nerve activity and pain is complex, yet quite convincing in multiple dimensions of evidence. First, SDNN is negatively and significantly correlated with pain . In a reBiologically, pain takes place due to vasoconstriction causing ischemia, oxidative stress found in some pain conditions , inflammDoes HRV-B reduce pain? Several RCTs do provide such evidence. A pilot RCT allocated 14 patients with chronic pain to HRV-B or to usual care only. After treatment, the HRV-B evidenced lower pain than controls . AnotherIn cancer, HRV parameters predict better prognosis (lower tumor marker levels and lower risk of death), independent of confounders, according to two systematic reviews and one meta-analysis ,116,117.Various systemic and local factors in the tumor microenvironment promote tumorigenesis including oxidative stress , inflammHowever, the vagal nerve inhibits oxidative stress , “reflexA few studies have tested the effects of HRV-B in cancer, yet mostly on the “symptom cluster”–pain, distress, fatigue, and depression. One feasibility RCT with 31 patients randomized cancer patients to HRV-B for up to 6 weeks, or to a wait-list control. HRV-B increased HRV-coherence and reduced insomnia, fatigue, pain, and distress . In anotIn a pilot-matched controlled study executed on a very small sample , three pIn a review of 25 case-control studies, HRV was reliably lower in type-2 diabetes than in healthy controls . The relEffects of HRV-B on type-2 diabetes have scarcely been tested. In one non-controlled pilot study, 17 patients with diabetes and neuropathy received 8 weeks of HRV-B training. Patient compliance was 50% and, in some patients, some HRV indices improved . HoweverThe mean methodological score was 3, suggesting that for diabetes, the level of evidence is poor. Given the high prevalence and health consequences of type-2 diabetes, there is an urgent need to perform an RCT testing the effects of HRV-B on clinical outcomes in type-2 diabetes.The world population is aging with the advancements in medical care. One significant consequence is the rise in the prevalence of dementia and specifically Alzheimer’s disease. Concerning the vagal nerve, the authors of  reviewedExecutive functions (EF) encompass cognitive processes involved in controlling, organizing, and integrating information  and alsoContradictory findings were reported concerning the relationship between HRV and dementia. Studies have found reduced , increasCan HRV-B improve cognitive performance and EF in the elderly? A systematic review was performed to summarize the existing literature on the effects of HRV-B on EF. Nine out of the 16 studies (56%) found improvements in one of the EF measures following HRV-B. Specifically, attention and inhibition were improved by HRV-B . HoweverThe methodological score for this category of studies was 3, suggesting that for dementia/cognitive impairment, the level of evidence is poor–medium. Thus, the evidence regarding the effects of HRV-B on EF for certain outcomes (attention and inhibition) is moderate but specifically for elderly people, the level of evidence is poor. To the best of our knowledge, no evidence exists for the effects of HRV-B on elderly people with dementia.The vagal nerve plays a crucial role in predicting a lower risk of many diseases and a better prognosis for such fatal diseases ,94. LookIn surgery, while initially post-operative inflammation is protective , lack ofThe studies reviewed here also show positive clinical effects of HRV-B on disease outcomes with high methodological evidence in CHD and HT. HRV-BF is an effective psychophysiological intervention with short- and long-term effects in cardiovascular disease rehabilitation programs. Regarding pain, though mostly derived from small-scale samples, several RCTs do provide evidence that HRV-B may reduce pain among children and adults. In contrast, the levels of evidence in cancer are moderate and mostly concern the “symptom cluster”–pain, distress, fatigue, and depression, and subjective outcomes. For cognitive enhancement, the evidence regarding the effects of HRV-B on EF exists for certain outcomes (attention and inhibition) among the elderly population, but to the best of our knowledge, no research evidence exists for elderly demented people. Finally, for diabetes, the level of evidence is poor. Thus, future studies need to test the effects of HRV-B on long-term disease outcomes using RCT designs in pain, diabetes, and dementia.From an educational perspective, given the epidemiological, interventional, and neuroimmune evidence linking HRV indices as an index of the vagus nerve regarding the diseases reviewed above, teaching neuroimmunology and specifically neuromodulation in medicine, nursing, and biology needs to take place in the coming years. After RCTs substantiate the effects of HRV-B on CHD, cancer, pain, diabetes, and dementia, then we could recommend its use as an evidence-based adjunct treatment for these challenging conditions.


Due to numerous environmental hazards such as heavy machinery and large livestock, youth who live and work on farms are at high risk of injury, disability, and death. This study described a regional surveillance system for monitoring farm-related injuries in children and adolescents. As the risk of farm-related injuries are not exclusive to farm residents, trends in farm-related injuries over the previous 5 years were reported and compared between children/adolescents who did and did not live on farms in north-central Wisconsin.A retrospective cohort of child and adolescent patients of the Marshfield Clinic Health System was assembled. Incident farm-related injuries, including from agricultural work or other activities in a farm environment, were extracted from medical records from 2017 through 2021. Generalized linear models were created to compare age- and sex-adjusted farm-related injury rates by year.There were 4,730 (5%) in-farm and 93,420 (95%) out-farm children and adolescents in the cohort. There were 65 incident farm-related injury cases in the in-farm group and 412 in the out-farm group. The annual incidence rate of farm-related injuries was higher in the in-farm group, but changes during the 5-year timeframe were not significant in either group. In the in-farm group, rates ranged from a high of 61.8  incident farm-related injuries per 10,000 children/adolescents in 2017 to a low of 28.2  injuries per 10,000 children/adolescents in 2018. In the out-farm group, rates ranged from 10.7  to 16.8  incident farm-related injuries per 10,000 children/adolescents per year between 2017 and 2021. The in-farm group had a higher proportion of injured males and heavy machinery injuries, while the out-farm group had more all-terrain vehicle injuries and pesticide poisonings.Farm residency remains hazardous for children and adolescents, as injury rates were three times higher in the in-farm group and remained stable over 5 years. All-terrain vehicle injuries were high in both groups, and should be a priority in rural safety interventions. With additional adaptations to other states, this surveillance model could be scaled across other healthcare systems. At approximately 23 fatal injuries per 100,000 workers per year in the U.S., agriculture, forestry, and fishing consistently have the highest rates of occupational fatalities of any industry sector .Farm family members live in a hazardous environment that is focused on agricultural production, thus the burden of injuries is prodigious . Young wLittle is known about recent trends in farm-related injury risks, however, because the U.S. lacks a comprehensive surveillance system. National farm injury estimates are particularly limited after 2015 when federal occupational health agencies suspended farm-related injury surveillance activities. There may be some positive developments, as the absolute number of pediatric visits to emergency rooms for agriculture-related injuries in the U.S. has declined by over 40% since 2001 , 10. ThiThe burden of farm-related injury is not exclusive to youth who live on farms. Such injuries, perhaps about one-third, have also been shown to occur in adolescents who work on a farm or in young children playing on a friend's or family's farm , 18. ForThe source population included child and adolescent patients of the Marshfield Clinic Health System (MCHS) who lived in a 20-county region of north-central Wisconsin during the 2017–2021 timeframe , and whoThe analytical cohort included children and adolescents in the source population who: (1) were age 0–17 years for ≥90 continuous days between 01/01/2017 and 12/31/2021, and (2) had reasonably complete capture of medical care within MCHS data systems as evidenced by: (a) “medically homed” to an MCHS medical center , (b) member of the MCHS-affiliated Security Health Plan (SHP) of Wisconsin, or (c) resident of the Marshfield Epidemiologic Study Area (MESA) . Person-www.dtn.com/agriculture/producer/) specific to the target 20-county region. All study procedures were approved by the MCHS Institutional Review Board, including approvals to waive documentation of informed consent and HIPAA authorization.Cohort members were stratified by farm and non-farm residency. Children and adolescents with a residential address that had evidence of agricultural production at any point during the 2017–2021 study timeframe were categorized in the in-farm group. Those with no evidence of farm residence during that timeframe were categorized in the out-farm group. To establish farm residency, cohort members' MCHS residential address history was linked to two separate publicly-available farm data sources, including (1) a registry of licensed dairy producers from Wisconsin's Department of Agriculture, Trade and Consumer Protection, or (2) a commercially-available (purchased) listing of agricultural producers  while the individual was either in a farm location or engaged in (or observing) farm-related work. Farm-related injuries could be agricultural work or other activities in a farm environment. Efforts were also made to identify recreational activities that took place in the farm location . Medically-attended farm-related injuries were ascertained based on adaptations of injury surveillance models outlined by Landsteiner et al.  and Scotvia the electronic case finding logic were subjected to a manual chart review conducted by a trained Research Coordinator. This chart audit included a review of all clinical documentation of the associated medical encounter in order to confirm the presence or absence of a farm-related injury. The Research Coordinator primarily reviewed free-text documents to determine whether the injury occurred while doing or observing a farm activity, related or unrelated recreational activity, or otherwise at a farm location. Chart audits further extracted clinical features of the farm-related injury and documented precipitating circumstances. Approximately 10% of all candidate cases were re-audited by a different Research Coordinator to detect and correct possible interrater discrepancies or inconsistencies. Injury chart reviews have not yet been conducted in the out-farm group due to study budget constraints (thus detailed injury features were only available in the in-farm group), but chart reviews will be done in both groups as part of future farm-related injury surveillance activities.In the in-farm group, all farm-related injuries identified Descriptive characteristics were reported on the farm and out-farm groups. Differences between injured individuals in the farm vs. out-farm group were also summarized. For the injury trends analysis, new injury episodes were required to be separated by ≥30 days and age- and sex-adjusted incidence rates, with robust 95% confidence intervals (CI), were reported using the direct standardization method based on the 2010 Wisconsin Census population. Incident annual injury rates were modeled using generalized linear mixed models. Analytical procedures were conducted using SAS version 9.4 .There were 98,150 unique children and adolescents in the WINS cohort, including 4,730 (5%) in the farm and 93,420 (95%) in the out-farm group. As outlined in There were 69 farm-related injuries in the in-farm group [65 (1.4%) unique individuals] and 412 in the out-farm group [378 (0.4%) unique individuals] during 2017–2021. Among the injuries in the in-farm group, all but two were confirmed upon manual chart review. Both unconfirmed farm-related injuries were miscoded as involving recreational vehicles, one having occurred completely outside of the farm environment or during farming activities, and the other not actually involving a recreational vehicle. Inter-rater agreement with chart re-reviews was 100%. Basic characteristics of the incident farm-related injuries are outlined in As outlined in The early intent of WINS was to establish a (largely) passive farm-related surveillance methodology in children and adolescents. While limited in scope to north-central Wisconsin, we were able to link available data on farm residency to the medical records of child/adolescent patients of the major healthcare provider in the region. This permitted the subsequent examination of farm-related injuries in the WINS cohort. Results indicated that, over the past 5 years, approximately 40 per 10,000 children/adolescents who lived on farms in north-central Wisconsin experienced a farm-related injury. Though modestly lower since the high point in 2017, incident farm-related injury rates in the in-farm group were statistically indistinguishable between years. This relatively “flat” trend in farm-related injuries was similarly observed in the out-farm group, though, as expected based on prior studies indicating the burden of farm-related injuries is highest in children of farm owners , injury Recent data on injury rates in U.S. farm children are sparse, but the risk of farm-related injury in WINS was slightly lower than observed in Alberta, Canada in the early 2000's . The uniInjuries in our study were more common during summer months, as observed by others , 23. InjStrengths of WINS included the objective EHR and claims outcomes, as well as the population-based sample that reflected real-world patterns of farm-related injuries in north-central Wisconsin children and adolescents. The chief limitation was the retrospective use of medical records to identify injury cases. Individuals with minor injuries who did not receive medical care were not captured, thus incidence rates in this study are likely conservative and err toward more severe accidents. In addition, the target population had a limited regional scope that may be somewhat over-representative of dairy production relative to other parts of the U.S. The in-farm group was based solely on residency, assuming all individuals who lived on an active farm had approximately equal risk. While this assumption was perhaps reasonable given that most Wisconsin farms are still family owned and operated , our desFuture iterations of the WINS platform will begin integrating other data sources from the state of Wisconsin  to Direct calls and intimations for improved farm-related injury surveillance in the U.S. are widespread , 12–16. The datasets for this study are unavailable for public access because informed consent to share said data (beyond the research team) was not obtained from study participants, but are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by Marshfield Clinic Research Institute. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the National Legislation and the Institutional Requirements.JV was the study PI and led the methodological design and execution, as well as drafted the initial manuscript. RLB led statistical analyses and critically reviewed manuscript draft. RRB led data collection activities and critically reviewed manuscript drafts. KB managed the study, assisted with data collection activities, and critically reviewed manuscript drafts. BW assisted with the methodological design and critically reviewed manuscript drafts. All authors contributed to the article and approved the submitted version.


The way we respond emotionally to others can impact how we provide care. Emotional intelligence is vital for care team members whose entire day involves interacting with other people. We have developed an interactive, online, self-paced course for people providing care to others with the specific goal of increasing awareness of emotions and helping to identify emotions in others. The training is supported by research indicating that individuals who can better manage their own emotions are better positioned to manage behaviors and emotions in others. The central concept of the training is to build relationships that enhance person-centered care through increasing care providers’ emotional intelligence. These skills allow care providers to better manage their own behavior and emotions, which results in improved quality of their care work. The purpose of this study was to assess the knowledge, self-efficacy, acceptability, and appropriateness of the online training. The data for this study came from n = 130 individuals  who completed assessments pre-and post-training. Knowledge of emotion-focused communication strategies and self-efficacy in using emotion-focused communication strategies both increased significantly with training (t(129) = -5.40 p < .001 and t(124) = -6.42 p < .001). In addition, high levels of acceptability, appropriateness, and satisfaction were reported. Findings indicate the benefits of online training for emotion-focused communication for caregivers. The discussion will focus on recommendations for practice, policy, and research.