Biomarkers and Novel Therapies of Diabetic Neuropathy: An Updated Review.

Diabetic neuropathy is a persistent consequence of the biochemical condition known as diabetes mellitus. As of now, the identification and management of diabetic neuropathy continue to be problematic due to problems related to the safety and efficacy of existing therapies. This study examines biomarkers, molecular and cellular events associated with the advancement of diabetic neuropathy, as well as the existing pharmacological and non-pharmacological treatments employed. Furthermore, a holistic and mechanism-centric drug repurposing approach, antioxidant therapy, Gene and Cell therapies, Capsaicin and other spinal cord stimulators and lifestyle interventions are pursued for the identification, treatment and management of diabetic neuropathy. An extensive literature survey was done on databases like PubMed, Elsevier, Science Direct and Springer using the keywords "Diabetic Neuropathy", "Biomarkers", "Cellular and Molecular Mechanisms", and "Novel Therapeutic Targets".Thus, we may conclude that non-pharmacological therapies along with palliative treatment, may prove to be crucial in halting the onset of neuropathic symptoms and in lessening those symptoms once they have occurred.

Prevalence of Failed Back Surgery Syndrome Across Hospital Corporation of America Healthcare in the United States, Their Correlation With Mood Disorders and Other Lifestyle-Related Comorbidities.

About 16 million adults present with chronic back pain, the sixth most costly condition in the United States (US). Estimates suggest that about 60% of initial back surgeries have a successful outcome; however, many don't, leaving over 80,000 failed back surgeries per year. Failed Back Surgery Syndrome (FBSS) is defined by the International Association for the Study of Pain as back pain, with or without radiating pain, located in the lower limbs, of unknown origin, which persists or begins after surgical procedures are performed to treat lumbar disc herniations. Psychiatric comorbidities and psychosocial factors have been associated with patients presenting with this syndrome. A retrospective cross-sectional study was performed to identify the prevalence of FBSS in a population of patients during the period of January 2019-December 2020 across Hospital Corporation of America (HCA) Healthcare in the US. With a sample of 28,426 patients who underwent back surgery only 8% had FBSS. Those with FBSS (N = 2434) were mainly females (54.27%) with a mood disorder (61.18%), P-value <.0001. Among those with FBSS, there was a statistically significant relationship between mood disorder and smoking (57.37%) and obesity (54.61%) compared to non-smokers and non-obese. Lifestyle interventions may ameliorate disabling symptoms and improve the well-being of this population.

Strengthening Neuroplasticity in Substance Use Recovery Through Lifestyle Intervention.

The incidence of substance use and behavioral addictions continues to increase throughout the world. The Global Burden of Disease Study shows a growing impact in disability-adjusted life years due to substance use. Substance use impacts families, communities, health care, and legal systems; yet, the vast majority of individuals with substance use disorders do not seek treatment. Within the United States, new legislation has attempted to increase the availability of buprenorphine, but the impact of substance use continues. Although medications and group support therapy have been the mainstay of treatment for substance use, lifestyle medicine offers a valuable adjunct therapy that may help strengthen substance use recovery through healthy neuroplastic changes.

Development of the International Federation for Surgery of Obesity and Metabolic Disorders-European Chapter (IFSO-EC) Grade-Based Guidelines on the Surgical Treatment of Obesity Using Multimodal Strategies: Design and Methodological Aspects.

Background: The prevalence of obesity is already a worldwide health concern. The development of straightforward guidelines regarding the whole available armamentarium (i.e., medical, endoscopic, and surgical interventions in conjunction with a guidance program) is paramount to offering the best multimodal approach to patients with obesity. Methods: The International Federation for Surgery of Obesity and Metabolic Disorders-European Chapter (IFSO-EC) identified a panel of experts to develop the present guidelines. The panel formulated a series of clinical questions (based on the patient, intervention, comparison, and outcome conceptual framework), which have been voted on and approved. A GRADE methodology will be applied to assess the quality of evidence and formulate recommendations employed to minimize selection and information biases. This approach aims to enhance the reliability and validity of recommendations, promoting greater adherence to the best available evidence. Results: These guidelines are intended for adult patients with a body mass index (BMI) ≥ 30 kg/m2 who are candidates for metabolic bariatric surgery (MBS). The expert panel responsible for developing these guidelines comprised 25 panelists (92% were bariatric surgeons) and 3 evidence reviewers, with an average age of 50.1 ± 10.2 years. The panel focused on 3 key questions regarding the combined use of structured lifestyle interventions, approved obesity management medications, and endoscopic weight loss procedures with MBS. Conclusions: The complexity of obesity as a chronic disease requires a comprehensive knowledge of all the available and feasible therapeutic options. The IFSO-EC society felt the urgent need to develop methodologically valid guidelines to give a full picture and awareness of the possible surgical and non-surgical therapeutic strategies employed with a multimodal approach.

Lifestyle Interventions in Pediatric Primary Care.

Pediatric clinicians should offer guidance on age-appropriate nutrition, physical activity, sleep and screen time for families of children and adolescents with obesity. They should build rapport with families, ask permission before discussing obesity-related health concerns, use preferred terminology, and recommend whole family change. Using principles of shared decision-making, pediatric clinicians and families should set individualized goals for lifestyle changes, prioritizing reducing sugar-sweetened beverage intake, increasing physical activity, and reducing screen time. Families of children and adolescents with obesity should be connected to the highest level of support accessible to and desired by the family, including intensive health behavior and lifestyle treatment programs.

Nonpharmacologic Management of Hypertension in Older Adults.

Hypertension is ubiquitous among older adults and leads to major adverse cardiovascular events. Nonpharmacologic lifestyle interventions represent important preventive and adjunct strategies in the treatment of hypertension and have benefits beyond cardiovascular disease in this population characterized by a high prevalence of frailty and comorbid conditions. In this review, the authors examine nonpharmacologic interventions with the strongest evidence to prevent cardiovascular disease with an emphasis on the older adults.

Ethnic differences in the effects of lifestyle interventions on adverse pregnancy outcomes among women with gestational diabetes mellitus: A systematic review and meta-analysis.

AIMS: Lifestyle interventions are widely used among women with gestational diabetes mellitus (GDM). This study aimed to assess the ethnic disparities in the effectiveness of lifestyle interventions on reducing adverse pregnancy outcomes, particularly macrosomia and neonatal hypoglycemia among women with GDM. METHODS: We systematically searched the PubMed/MEDLINE, Web of Science, and Cochrane Library databases from January 1, 2000, up to March 31, 2024, to identify randomized controlled trials (RCTs) examining the effects of lifestyle interventions in GDM patients. Subgroup analysis was performed to investigate heterogeneity across different ethnic groups (including Asians, Whites/Caucasians, Hispanics/ Latinos, and Unknown ethnicity). The random effects model was used to calculate the relative risk (RR) and 95% confidence interval (CI). RESULTS: After applying inclusion and exclusion criteria, twenty-one studies comprising 4567 participants were included. Lifestyle interventions significantly reduced the incidence of macrosomia ((RR = 0.54; 95 % CI: 0.42-0.70, P < 0.001), with consistent effects observed across racial groups. Conversely, lifestyle interventions were associated with a significant reduction in the risk of neonatal hypoglycemia only among Asians (RR = 0.56; 95 % CI: 0.38-0.84, P = 0.004), while no significant effects were observed in Whites/Caucasians or Hispanics/Latinos (all P > 0.05). Sensitivity analyses confirmed the robustness of the findings. CONCLUSIONS: Regardless of ethnic background, this study emphasizes the significant benefits of lifestyle interventions in reducing the risk of macrosomia among women with GDM. However, lifestyle interventions seem to reduce the risk of neonatal hypoglycemia only among Asians, which warrants further studies.

The effects of lifestyle interventions on disease activity and quality of life in patients with systemic lupus erythematosus: A systematic review.

INTRODUCTION: Systemic Lupus Erythematosus (SLE) is an autoimmune disease affecting multiple organs, characterized by flares and remission. Treatment aims to reduce flare severity and prevent long-term damage, but remission is often elusive, and patients may still experience flares and a reduced quality of life (QoL). This had led to a growing interest in non-pharmacological therapies to improve patient wellbeing. OBJECTIVE: We aimed to assess and summarize the efficacy of lifestyle interventions in SLE patients on disease activity and QoL. METHODS: A systematic search on lifestyle interventions, SLE, disease activity, and QoL was conducted in PubMed/Medline, Embase and Clinicaltrials.gov in August 2024. Included studies were randomized controlled trials on lifestyle interventions in adult SLE patients. Each trial was appraised using Scottish Intercollegiate Guidelines Network (SIGN) criteria, with participant numbers, study duration, intervention type and outcome measures detailed in separate tables. RESULTS: A total of 3564 articles were screened, resulting in the inclusion of 25 randomized controlled trials with 1521 patients. Study quality varied from high (11 studies) to low (6 studies) with considerable intervention heterogeneity. The interventions fell into five categories: physical activity, psychotherapy, lifestyle coaching, supplements and dietary interventions. Physical activity (2 studies, 116 patients), psychotherapy (5 studies, 507 patients) and coaching (1 study with 30 patients) had no significant effect on disease activity, while fish oil supplementation showed a slight benefit in two studies with a total of 102 patients. Quality of life generally improved with physical activity (4 studies with in total 253 patients) and psychotherapy (9 studies with in total 623 patients), with significant mental health benefits, but coaching (3 studies with in total 186 patients) showed no effect. CONCLUSION: Various lifestyle interventions influence quality of life in SLE patients. Consistent with recent guidelines, both exercise and psychotherapy may positively impact the health-related quality of life in these patients. However, some studies were biased due to self-reported outcomes and the Hawthorne effect, where participants' behavior changed from receiving extra attention. Further research with larger patient cohorts is necessary to reduce the influence of heterogeneity across different studies and to better understand the potential of these promising therapies.

Obesity and cardiovascular disease: an ESC clinical consensus statement.

The global prevalence of obesity has more than doubled over the past four decades, currently affecting more than a billion individuals. Beyond its recognition as a high-risk condition that is causally linked to many chronic illnesses, obesity has been declared a disease per se that results in impaired quality of life and reduced life expectancy. Notably, two-thirds of obesity-related excess mortality is attributable to cardiovascular disease. Despite the increasingly appreciated link between obesity and a broad range of cardiovascular disease manifestations including atherosclerotic disease, heart failure, thromboembolic disease, arrhythmias, and sudden cardiac death, obesity has been underrecognized and sub-optimally addressed compared with other modifiable cardiovascular risk factors. In the view of major repercussions of the obesity epidemic on public health, attention has focused on population-based and personalized approaches to prevent excess weight gain and maintain a healthy body weight from early childhood and throughout adult life, as well as on comprehensive weight loss interventions for persons with established obesity. This clinical consensus statement by the European Society of Cardiology discusses current evidence on the epidemiology and aetiology of obesity; the interplay between obesity, cardiovascular risk factors and cardiac conditions; the clinical management of patients with cardiac disease and obesity; and weight loss strategies including lifestyle changes, interventional procedures, and anti-obesity medications with particular focus on their impact on cardiometabolic risk and cardiac outcomes. The document aims to raise awareness on obesity as a major risk factor and provide guidance for implementing evidence-based practices for its prevention and optimal management within the context of primary and secondary cardiovascular disease prevention.

Very-low-calorie diet-based intensive lifestyle intervention for remission of type 2 diabetes: Real-world experience in a South Asian population.

AIMS: Very low-calorie diet (VLCD) can induce weight loss and diabetes remission (DR) amongst people with obesity and recent-onset type 2 diabetes (T2D). We aimed to determine the effectiveness and acceptability of VLCD in achieving DR amongst Sri Lankan adults with T2D. METHODS: A retrospective analysis was conducted in a diabetes practice where VLCD-based Diabetes Remission Programme (VDRP) was offered for adults (>18 years) with T2D for <3 years and body mass index over 25 kg/m2. VLCD (~800 kcal/day, provided with/without diet replacement formula) was offered for 8-12 weeks, followed by gradual food reintroduction and exercise. DR was defined as HbA1c <6.5% at least 3 months after stopping glucose-lowering medications. RESULTS: A total of 170 participants who enrolled in the VDRP (mean age 38.4 years [±11.1], men 68%, mean baseline HbA1c 86.9 [±18.1] mmol/mol (10.1 [±2.1]%), median duration of T2D 2 years [IQR 1-2]) and 87 (51%) of them followed the programme (attended at least one follow-up visit). Amongst the individuals who followed the VDRP, 40.2% achieved DR (35/87), compared with 2.4% (2/83) amongst those who did not follow the VDRP (aHR 9.3, 95% CI 2.2-16.4, p = 0.002). The proportion achieving normoglycaemia (HbA1c < 6.5%) but continued to take glucose-lowering medication was 20/87 among VDRP followers and 20/85 amongst VDRP non-followers. The commonest reasons for not following the VDRP were too restrictive dietary quantity (92%) and difficulties in finding recommended food items (67%). Majority (79%) would recommend VDRP to others. CONCLUSIONS: VDRP is effective in achieving T2D remission amongst Sri Lankan adults with recently diagnosed T2D and obesity. Over half of the participants followed the programme and over 75% would recommend it to others, indicating good acceptability.

Diet and Physical Activity Interventions for People from Minority Ethnic Backgrounds in the UK: A Scoping Review Exploring Barriers, Enablers and Cultural Adaptations.

BACKGROUND: Type 2 diabetes (T2D) and cardiovascular disease (CVD) are a global pandemic, driven by obesity, poor diet and physical inactivity. In the UK, the prevalence of T2D and CVD is higher in minority ethnic groups. Lifestyle prevention interventions can be effective but uptake amongst minority ethnic groups in the UK is low and the extent of cultural adaptations to increase engagement unknown. AIM: To explore barriers, enablers and culturally adapted lifestyle interventions in UK minority ethnic groups. METHODS: Four electronic databases were searched from to January 2013-2023. Two independent reviewers carried out manuscript selection and data extraction. Barriers and enablers were mapped to the Capability + Opportunity + Motivation = Behaviour (COM-B) theoretical model. Intervention adaptations were linked to behaviour change strategies and reported within a Cultural Adaptation framework. RESULTS: Twenty-three studies were included, reporting barriers/enablers, culturally adapted interventions or both. Barriers and enablers mostly mapped to social and physical opportunity, and reflective motivation. Common adaptation strategies considered behavioural influences related to culture, values, religious beliefs and/or traditions. Most impactful strategies were associated with using credible sources of information and reorganising social and environmental contexts. DISCUSSION AND CONCLUSIONS: The current umbrella approach to preventative intervention delivery is unlikely to promote sustained participation in behaviour change amongst UK ethnic minorities. Engagement strategies for this population should consider key determinants such as social contexts, beliefs and cultural norms. Important research gaps include interventions investigating tailored interventions for Black populations, and the impact of negative social experiences (e.g., racism) on engagement.

Cancer Prevention and Treatment Based on Lifestyles.

Cancer morbidity and mortality incidence are rapidly increasing over the period of time. Cancer prevention, alongside innovative therapies and earlier detection, is considered a key strategy for reducing the overall cancer burden. Substantial evidence indicates a clear correlation between lifestyle factors and changes in nutrient metabolism. Approximately 5-10% of all cancer cases are attributed to genetic factors, whereas 90-95% are due to environmental and lifestyle factors, suggesting that lifestyle interventions have significant prospects for preventing various cancers. Healthy lifestyle changes, in particular healthy diets, physical activity, staying at a healthy weight, reduction or elimination of tobacco/alcohol consumption, and avoiding exposure to radiation and other carcinogens, are significant factors to be considered to tackle the challenges associated with cancer in modern society. This chapter aims to provide lifestyle intervention strategies to improve cancer prevention and risk reduction while promoting the health of cancer patients. The therapeutic role of some dietary regimens and supplements, as well as complementary and alternative health approaches, in cancer treatment is also discussed.

Predicting and comparing the long-term impact of lifestyle interventions on individuals with eating disorders in active population: a machine learning evaluation.

Objective: This study aims to evaluate and predict the long-term effectiveness of five lifestyle interventions for individuals with eating disorders using machine learning techniques. Methods: This study, conducted at Dr. Irandoust's Health Center at Qazvin from August 2021 to August 2023, aimed to evaluate the effects of five lifestyle interventions on individuals with eating disorders, initially diagnosed using The Eating Disorder Diagnostic Scale (EDDS). The interventions were: (1) Counseling, exercise, and dietary regime, (2) Aerobic exercises with dietary regime, (3) Walking and dietary regime, (4) Exercise with a flexible diet, and (5) Exercises through online programs and applications. Out of 955 enrolled participants, 706 completed the study, which measured Body Fat Percentage (BFP), Waist-Hip Ratio (WHR), Fasting Blood Sugar (FBS), Low-Density Lipoprotein (LDL) Cholesterol, Total Cholesterol (CHO), Weight, and Triglycerides (TG) at baseline, during, and at the end of the intervention. Random Forest and Gradient Boosting Regressors, following feature engineering, were used to analyze the data, focusing on the interventions' long-term effectiveness on health outcomes related to eating disorders. Results: Feature engineering with Random Forest and Gradient Boosting Regressors, respectively, reached an accuracy of 85 and 89%, then 89 and 90% after dataset balancing. The interventions were ranked based on predicted effectiveness: counseling with exercise and dietary regime, aerobic exercises with dietary regime, walking with dietary regime, exercise with a flexible diet, and exercises through online programs. Conclusion: The results show that Machine Learning (ML) models effectively predicted the long-term effectiveness of lifestyle interventions. The current study suggests a significant potential for tailored health strategies. This emphasizes the most effective interventions for individuals with eating disorders. According to the results, it can also be suggested to expand demographics and geographic locations of participants, longer study duration, exploring advanced machine learning techniques, and including psychological and social adherence factors. Ultimately, these results can guide healthcare providers and policymakers in creating targeted lifestyle intervention strategies, emphasizing personalized health plans, and leveraging machine learning for predictive healthcare solutions.

Finding Groups in the Portuguese Population Through Lifestyle: A Cross-Sectional Study.

Lifestyle interventions are recognized as essential in the prevention and treatment of noncommunicable diseases, the main causes of multimorbidity. A population-based cross-sectional study was carried out in mainland Portugal. 891 Portuguese patients aged ≥20 years, representative of the population, were personally interviewed. For lifestyle, diet and alcohol consumption, physical activity and sedentarism, use of tobacco and illicit drugs, sleeping habits, screen activities and stress, were studied. The bio-sociodemographic data reported were age, sex, marital status, highest level of education, body mass index and health problems in the last 12 months. This study aimed to apply principal components analysis and clustering to identify distinct groups within the population based on lifestyle. It was possible to identify 3 groups: cardiometabolic, healthy and anxious-depressive. It seems very likely that smoking cessation and other behavioral changes only occur after negative health conditions occur.

A Comprehensive Review of School-Based Lifestyle Interventions to Reduce Childhood Obesity in the Eastern Mediterranean Region.

Childhood obesity prevalence has increased worldwide and substantially in the 22 countries of the Eastern Mediterranean Region (EMRO). Weight-related interventions are urgently required in these countries to tackle childhood obesity and its related consequences. There has been no review to date of obese children in the Eastern Mediterranean Region. This review discusses the different school-based lifestyle interventions conducted among obese children in the EMRO and assesses the applicability of future programs in Saudi Arabia. A thorough search of the literature was conducted on PubMed. A total of 170 studies were found, and eight of them were included in this review. The included studies were all randomized controlled trials or quasi-experimental. This review article showed that school-based lifestyle interventions may reduce childhood obesity by integrating interactive learning about healthy diet and physical activity within a whole school approach, involving children and their parents, modifying the school environment, and facilitating a workshop on healthy food preparation. To motivate children to change their behavior, it is crucial to meet with parents in person and utilize technology and rewards. School-based lifestyle programs can lower childhood obesity by involving all relevant parties, such as families and schools, and using reliable instruments to track results to establish a healthy community. In order to confirm these findings, more research is required for a longer period of time, more than six months.

Obesity and cardiovascular disease: an ESC clinical consensus statement.

The global prevalence of obesity has more than doubled over the past four decades, currently affecting more than a billion individuals. Beyond its recognition as a high-risk condition that is causally linked to many chronic illnesses, obesity has been declared a disease per se that results in impaired quality of life and reduced life expectancy. Notably, two-thirds of obesity-related excess mortality is attributable to cardiovascular disease. Despite the increasingly appreciated link between obesity and a broad range of cardiovascular disease manifestations including atherosclerotic disease, heart failure, thromboembolic disease, arrhythmias, and sudden cardiac death, obesity has been underrecognized and sub-optimally addressed compared with other modifiable cardiovascular risk factors. In the view of major repercussions of the obesity epidemic on public health, attention has focused on population-based and personalized approaches to prevent excess weight gain and maintain a healthy body weight from early childhood and throughout adult life, as well as on comprehensive weight loss interventions for persons with established obesity. This clinical consensus statement by the European Society of Cardiology discusses current evidence on the epidemiology and aetiology of obesity; the interplay between obesity, cardiovascular risk factors and cardiac conditions; the clinical management of patients with cardiac disease and obesity; and weight loss strategies including lifestyle changes, interventional procedures, and anti-obesity medications with particular focus on their impact on cardiometabolic risk and cardiac outcomes. The document aims to raise awareness on obesity as a major risk factor and provide guidance for implementing evidence-based practices for its prevention and optimal management within the context of primary and secondary cardiovascular disease prevention.

Integrating behavioral interventions into a holistic approach to metabolic dysfunction-associated steatotic liver disease.

INTRODUCTION: The therapeutic landscape of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is rapidly evolving with the FDA approval of resmetirom, the first authorized molecule to treat metabolic dysfunction-associated steatohepatitis. Clinical trials are investigating other promising molecules. However, this focus on pharmacotherapy may overshadow lifestyle interventions, which remain the cornerstone of MASLD management. A significant percentage of patients with MASLD struggle with an underlying eating disorder, often a precursor to obesity. The obesity pandemic, exacerbated by the increasing prevalence of binge eating, underscores the need for a psychological approach to address their common roots. AREAS COVERED: We reviewed the current evidence on behavioral interventions for MASLD. Interventions such as self-monitoring, goal setting, and frequent counseling, have proven effective in achieving at least 5% weight loss. Cognitive behavioral therapy is the first-line treatment for eating disorders and has shown efficacy in treating binge eating and obesity. Further research is needed to establish the optimal behavioral therapy for MASLD, focusing on enhancing compliance and achieving sustained weight loss through diet and physical exercise. EXPERT OPINION: The treatment of MASLD should not rely solely on pharmacotherapy targeting a single-organ manifestation. Instead, we must consider behavioral interventions, emphasizing the pivotal role of a holistic approach to this multifaceted disorder. [Figure: see text].

Scale offers the possibility of identifying adherence to lifestyle interventions in patients with non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder, and dietary and lifestyle interventions remain the mainstays of NAFLD therapy. Zeng et al established a prediction system to evaluate adherence to lifestyle interventions in patients with NAFLD and choose optimal management. Here, we discuss the application scenarios of the scale and the areas warranting further attention, aiming to provide a possible reference for clinical recommendations.

Development of a Cognitive Training Support Programme for prevention of dementia and cognitive decline in at-risk older adults.

Background: Evidence for the beneficial effects of cognitive training on cognitive function and daily living activities is inconclusive. Variable study quality and design does not allow for robust comparisons/meta-analyses of different cognitive training programmes. Fairly low adherence to extended cognitive training interventions in clinical trials has been reported. Aims: The aim of further developing a Cognitive Training Support Programme (CTSP) is to supplement the Computerised Cognitive Training (CCT) intervention component of the multimodal Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), which is adapted to different cultural, regional and economic settings within the Word-Wide FINGERS (WW-FINGERS) Network. The main objectives are to improve adherence to cognitive training through a behaviour change framework and provide information about cognitive stimulation, social engagement and lifestyle risk factors for dementia. Methods: Six CTSP sessions were re-designed covering topics including (1) CCT instructions and tasks, (2) Cognitive domains: episodic memory, executive function and processing speed, (3) Successful ageing and compensatory strategies, (4) Cognitive stimulation and engagement, (5) Wellbeing factors affecting cognition (e.g., sleep and mood), (6) Sensory factors. Session content will be related to everyday life, with participant reflection and behaviour change techniques incorporated, e.g., strategies, goal-setting, active planning to enhance motivation, and adherence to the CCT and in relevant lifestyle changes. Conclusions: Through interactive presentations promoting brain health, the programme provides for personal reflection that may enhance capability, opportunity and motivation for behaviour change. This will support adherence to the CCT within multidomain intervention trials. Efficacy of the programme will be evaluated through participant feedback and adherence metrics.