COVID-19 and metabolic disease: mechanisms and clinical management.

Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing severe COVID-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders. In this Review, we provide an update on the mechanisms of how metabolic and endocrine disorders might predispose patients to develop severe COVID-19. Additionally, we update the practical recommendations and management of patients with COVID-19 and post-pandemic. Furthermore, we summarise new treatment options for patients with both COVID-19 and diabetes, and highlight current challenges in clinical management.

Diagnosing type 2 diabetes using Hemoglobin A1c: a systematic review and meta-analysis of the diagnostic cutpoint based on microvascular complications.

AIMS: Diabetic microvascular complications of retinopathy, nephropathy and neuropathy may occur at hemoglobin A1c levels (HbA1c) below the 6.5% (48 mmol/mol) diagnostic threshold. Our objective was to assess the validity of the HbA1c diagnostic cutpoint of 6.5% based upon published evidence of the prevalence of retinopathy, nephropathy and neuropathy as markers of diabetes. METHODS: Data Sources PubMed, Embase, Cochrane, Scopus and CINAHL from 1990-March 2019, grey literature sources. Study Selection All studies reported after 1990 (to ensure standardized HbA1c values) where HbA1c levels were presented in relation to prevalence of retinopathy, nephropathy or neuropathy in subjects not known to have diabetes. Data Extraction Studies were screened independently, data abstracted, and risk of bias appraised. Data Synthesis Data were synthesized using HbA1c categories of < 6.0% (< 42 mmol/mol), 6.0-6.4% (42-47 mmol/mol) and ≥ 6.5% (≥ 48 mmol/mol). Random-effects meta-analyses were conducted for retinopathy, nephropathy and neuropathy prevalence stratified by HbA1c categories. Random-effects multivariable meta-regression was conducted to identify predictors of retinopathy prevalence and sources of between-study heterogeneity. RESULTS: Pooled mean prevalence was: 4.0%(95% CI: 3.2-5.0%) for retinopathy, 10.5% (95% CI: 4.0-19.5%) for nephropathy, 2.5% (95% CI: 1.1-4.3%) for neuropathy. Mean prevalence when stratified for HbA1c < 6.0%, 6.0-6.4% and ≥ 6.5% was: retinopathy: 3.4% (95% CI: 1.8-5.4%), 2.3% (95% CI: 1.6-3.2%) and 7.8%(95% CI: 5.7-10.3%); nephropathy: 7.1% (95% CI: 1.7-15.9%), 9.6% (95% CI: 0.8-26.4%) and 17.1% (95% CI: 1.0-46.9%); neuropathy: 2.1% (95% CI: 0.0-6.8%), 3.4% (95% CI: 0.0-11.6%) and 2.8% (95% CI: 0.0-12.8%). Multivariable meta-regression showed HbA1c ≥ 6.5% (OR: 4.05; 95% CI: 1.92-8.57%), age > 55 (OR: 3.23; 95% CI 1.81-5.77), and African-American race (OR: 10.73; 95% CI: 4.34-26.55), to be associated with higher retinopathy prevalence. Marked heterogeneity in prevalence estimates was found across all meta-analyses (Cochran's Q-statistic p < 0.0001). CONCLUSIONS: The prevalence of nephropathy and moderate retinopathy was increased in subjects with HbA1c values ≥ 6.5% confirming the high specificity of this value for diagnosing T2DM; however, at HbA1c < 6.5% retinopathy increased at age > 55 years and, most strikingly, in African-Americans, suggesting there may be excess microvascular complication prevalence (particularly nephropathy) in individuals below the diabetes diagnostic threshold.

Experience of point-of-care HbA1c testing in the English National Health Service Diabetes Prevention Programme: an observational study.

INTRODUCTION: To report the observations of point-of-care (POC) glycated hemoglobin (HbA1c) testing in people with non-diabetic hyperglycemia (NDH; HbA1c 42-47 mmol/mol (6.0%-6.4%)), applied in community settings, within the English National Health Service Diabetes Prevention Programme (NHS DPP). RESEARCH DESIGN AND METHODS: A service evaluation assessing prospectively collected national service-level data from the NHS DPP, using data from the first referral received in June 2016-October 2018. Individuals were referred to the NHS DPP with a laboratory-measured HbA1c in the NDH range and had a repeat HbA1c measured at first attendance of the program using one of three POC devices: DCA Vantage, Afinion or A1C Now+. Differences between the referral and POC HbA1c and the SD of the POC HbA1c were calculated. The factors associated with the difference in HbA1c and the association between POC HbA1c result and subsequent attendance of the NHS DPP were also evaluated. RESULTS: Data from 73 703 participants demonstrated a significant mean difference between the referral and POC HbA1c of -2.48 mmol/mol (-0.23%) (t=157, p<0.001) with significant differences in the mean difference between devices (F(2, 73 700)=738, p<0.001). The SD of POC HbA1c was 4.46 mmol/mol (0.41%) with significant differences in SDs between devices (F(2, 73 700)=1542, p<0.001). Participants who were older, from more deprived areas and from Asian, black and mixed ethnic groups were associated with smaller HbA1c differences. Normoglycemic POC HbA1c versus NDH POC HbA1c values were associated with lower subsequent attendance at behavioral interventions (58% vs 67%, p<0.001). CONCLUSION: POC HbA1c testing in community settings was associated with significantly lower HbA1c values when compared with laboratory-measured referrals. Acknowledging effects of regression to the mean, we found that these differences were also associated with POC method, location, individual patient factors and time between measurements. Compared with POC HbA1c values in the NDH range, normoglycemic POC HbA1c values were associated with lower subsequent intervention attendance.

The Circadian Syndrome: is the Metabolic Syndrome and much more!

The Metabolic Syndrome is a cluster of cardio-metabolic risk factors and comorbidities conveying high risk of both cardiovascular disease and type 2 diabetes. It is responsible for huge socio-economic costs with its resulting morbidity and mortality in most countries. The underlying aetiology of this clustering has been the subject of much debate. More recently, significant interest has focussed on the involvement of the circadian system, a major regulator of almost every aspect of human health and metabolism. The Circadian Syndrome has now been implicated in several chronic diseases including type 2 diabetes and cardiovascular disease. There is now increasing evidence connecting disturbances in circadian rhythm with not only the key components of the Metabolic Syndrome but also its main comorbidities including sleep disturbances, depression, steatohepatitis and cognitive dysfunction. Based on this, we now propose that circadian disruption may be an important underlying aetiological factor for the Metabolic Syndrome and we suggest that it be renamed the 'Circadian Syndrome'. With the increased recognition of the 'Circadian Syndrome', circadian medicine, through the timing of exercise, light exposure, food consumption, dispensing of medications and sleep, is likely to play a much greater role in the maintenance of both individual and population health in the future.

Black African men with early type 2 diabetes have similar muscle, liver and adipose tissue insulin sensitivity to white European men despite lower visceral fat.

AIMS/HYPOTHESIS: Type 2 diabetes is more prevalent in black African than white European populations although, paradoxically, black African individuals present with lower levels of visceral fat, which has a known association with insulin resistance. Insulin resistance occurs at a tissue-specific level; however, no study has simultaneously compared whole body, skeletal muscle, hepatic and adipose tissue insulin sensitivity between black and white men. We hypothesised that, in those with early type 2 diabetes, black (West) African men (BAM) have greater hepatic and adipose tissue insulin sensitivity, compared with white European men (WEM), because of their reduced visceral fat. METHODS: Eighteen BAM and 15 WEM with type 2 diabetes underwent a two-stage hyperinsulinaemic-euglycaemic clamp with stable glucose and glycerol isotope tracers to assess tissue-specific insulin sensitivity and a magnetic resonance imaging scan to assess body composition. RESULTS: We found no ethnic differences in whole body, skeletal muscle, hepatic or adipose tissue insulin sensitivity between BAM and WEM. This finding occurred in the presence of lower visceral fat in BAM (3.72 vs 5.68 kg [mean difference -1.96, 95% CI -3.30, 0.62]; p = 0.01). There was an association between skeletal muscle and adipose tissue insulin sensitivity in WEM that was not present in BAM (r = 0.78, p < 0.01 vs r = 0.25 p = 0.37). CONCLUSIONS/INTERPRETATION: Our data suggest that in type 2 diabetes there are no ethnic differences in whole body, skeletal muscle, hepatic and adipose tissue insulin sensitivity between black and white men, despite differences in visceral adipose tissue, and that impaired lipolysis may not be contributing to skeletal muscle insulin resistance in men of black African ethnicity.

Cardiometabolic risk factors in Thai individuals with prediabetes treated in a high-risk, prevention clinic: Unexpected relationship between high-density lipoprotein cholesterol and glycemia in men.

AIMS/INTRODUCTION: Relationships between cardiometabolic risk and glycemia have rarely been studied in people under clinical evaluation and treatment for cardiometabolic risk and with prediabetes. We investigated relationships between glycemia and cardiometabolic risk factors in clinic participants with prediabetes. MATERIALS AND METHODS: This was a cross-sectional analysis of data collected at a center in Thailand. Clinic attendees were at high risk of diabetes or cardiovascular disease, with hemoglobin A1c (HbA1c) 39-<48 mmol/mol or fasting plasma glucose (FPG) 5.6-<7.0 mmol/L. The relationships between glycemia and cardiometabolic risk factors were explored. RESULTS: Of 357 participants, two or more insulin resistance-related metabolic disturbances were present in 84%; 61% took a statin and 75% an antihypertensive agent. Independently of age, sex, adiposity, medication use, possible non-alcoholic fatty liver disease and sex-glycemia interaction, neither FPG nor HbA1c were associated with variation in any other cardiometabolic risk factors. High-density lipoprotein cholesterol decreased with HbA1c in women (female-HbA1c interaction, P = 0.03) but, unexpectedly, increased with FPG in men (male-FPG interaction, P = 0.02). CONCLUSIONS: Overall, in Thai people treated for high cardiometabolic risk and with prediabetes defined by FPG and/or HbA1c, neither FPG nor HbA1c were associated with other cardiometabolic risk factors. However, according to sex, high-density lipoprotein cholesterol showed the expected relationship with glycemia in women, but the reverse in men.

Associations Between Pancreatic Lipids and ß-Cell Function in Black African and White European Men With Type 2 Diabetes.

CONTEXT: Intrapancreatic lipid (IPL) has been linked to ß-cell dysfunction. Black populations disproportionately develop type 2 diabetes (T2D) and show distinctions in ß-cell function compared with white populations. OBJECTIVE: We quantified IPL in white European (WE) and black West African (BWA) men with early T2D and investigated the relationships between IPL and ß-cell insulin secretory function (ISF). DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional assessment of 18 WE and 19 BWA middle-age men with early T2D as part of the South London Diabetes and Ethnicity Phenotyping study. MAIN OUTCOME MEASURES: The participants underwent Dixon MRI to determine IPL in the pancreatic head, body, and tail and subcutaneous and visceral adipose tissue volumes. Modeled first- and second-phase ISFs were comprehensively determined using C-peptide measurements during a 3-hour meal tolerance test and a 2-hour hyperglycemic clamp test. RESULTS: The WE men had greater mean IPL levels compared with BWA men (P = 0.029), mainly owing to greater IPL levels in the pancreatic head (P = 0.009). The mean IPL level was inversely associated with orally stimulated first-phase ISF in WE but not BWA men (WE, r = -0.554, P = 0.026; BWA, r = -0.183, P = 0.468). No association was found with orally stimulated second-phase ISF in either WE or BWA men. No associations were found between the mean IPL level and intravenously stimulated ISF. CONCLUSIONS: The IPL levels were lower in BWA than WE men with early T2D, and the lack of inverse association with first-phase ISF in BWA men indicates that IPL might be a less important determinant of the development of T2D in BWA than in WE men.

Association between type 2 diabetes mellitus and disability: What is the contribution of diabetes risk factors and diabetes complications?

BACKGROUND: The aim of this study was to evaluate the association between type 2 diabetes and disability in Mauritius and to assess the extent to which the effect of diabetes is explained by diabetes risk factors and concomitant complications. METHODS: Data from a national survey in the multiethnic nation of Mauritius, which comprises South Asians and African Creoles, were analyzed. Disability was measured using the Katz activities of daily living questionnaire in participants aged >50 years. RESULTS: Among 3692 participants, 487 (13.2%) had some level of disability. Diabetes was associated with significantly higher risk of disability (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.34-2.08). After adjusting for demographic, behavioral, and metabolic factors, as well as comorbidities, disability was significantly associated with diabetes among African Creoles (OR 2.03; 95% CI 1.16-3.56), but not South Asians (OR 1.27; 95% CI 0.98-1.66). Obesity explained much of the association between diabetes and disability (excess percentage of risk: 26.3% in South Asians and 12.1% in African Creoles). Obesity, history of cardiovascular disease (CVD), asthma-like symptoms, and depression together explained 46.5% and 29.0% of the excess risk in South Asians and African Creoles, respectively. CONCLUSIONS: Diabetes is associated with a 67% increased risk of disability. Diabetes risk factors and comorbidities explain more of the association between diabetes and disability among South Asians than Africans. Obesity and history of CVD explained the largest percentage of the relationship between diabetes and disability, indicating that weight and CVD management may be helpful in controlling disability related to diabetes.

Ethnic differences in insulin secretory function between black African and white European men with early type 2 diabetes.

AIM: To test the hypothesis that men of black (West) African ethnicity (black African men [BAM]) with early type 2 diabetes (T2D) would have greater insulin secretory deficits compared with white European men (WEM), following prediabetic hypersecretion. METHODS: In 19 BAM and 15 WEM, matched for age, body mass index and duration of diabetes, we assessed and modelled insulin secretory responses to hyperglycaemia stimulated intravenously (hyperglycaemic clamp) and orally (meal tolerance test). RESULTS: With similar post-challenge glucose responses, BAM had lower second-phase C-peptide responses to intravenous glucose (BAM 70.6 vs WEM 115.1 nmol/L/min [ratio of geometric mean 0.55, 95% confidence interval {CI} 0.37, 0.83]; P = .006) and to oral glucose (BAM 65.4 vs WEM 88.5 nmol/L/min [mean difference -23.2, 95% CI -40.0, -6.3]; P = .009). Peripheral insulin response in BAM to oral glucose was preserved (BAM 47.4 vs WEM 59.4 nmol/L/min [ratio of geometric mean 0.89, 95% CI 0.59, 1.35]; P = .566), with relative reductions in insulin clearance (BAM 506.2 vs WEM 630.1 mL/m2 BSA/min [mean difference -123.9, 95% CI -270.5, 22.6]; P = .095), associated with enhanced incretin responses (gastric inhibitory polypeptide incremental area under the curve: BAM 46.8 vs WEM 33.9 µg/L/min [mean difference 12.9, 95% CI 2.1, 23.7]; P = .021). CONCLUSIONS: In early T2D, BAM had significantly lower insulin secretory responses to intravenous and oral stimulation than WEM. Lower insulin clearance, potentially driven by increased incretin responses, may act to preserve peripheral insulin concentrations. Tailoring early management strategies to reflect distinct ethnic-specific pathophysiology may improve outcomes in this high-risk population.

Fasting plasma glucose and variation in cardiometabolic risk factors in people with high-risk HbA1c-defined prediabetes: A cross-sectional multiethnic study.

AIMS: Variation in cardiometabolic risk in prediabetes and any impacts of ethnicity on such variation have been little studied. In an ethnically diverse dataset, selected according to a high-risk HbA1c-based definition of prediabetes, we have investigated relationships between glycaemia and cardiometabolic risk factors and the influence of ethnicity on these relationships. METHODS: We undertook a cross-sectional analysis of baseline data from a diabetes prevention study in the UK and a chronic care clinic in Thailand, selected for people without diabetes (fasting plasma glucose <7.0 mmol/l) with HbA1c 6.0-6.4% (42-47 mmol/mol). Thai (n=158) and UK White (n=600), South Asian (n=112), Black (n=70) and other/mixed (n=103) groups were distinguished and measurements included fasting plasma glucose (FPG), blood pressure (BP), lipids and insulin resistance-related risk factors (IRFs). RESULTS: Independently of individual characteristics including ethnicity, only systolic BP was weakly associated with FPG (beta coefficient 1.76 (95%CI 0.10-3.42), p 0.03) and only LDL-c with IFG (FPG 5.6 to <7) (adjusted -0.14 (-0.27, -0.003) p 0.04). There were no significant independent associations with cardiometabolic risk factors when categories of impaired fasting glucose (FPG ≥ 6.1 to <7.0 mmol/L) were considered. Relative to White, South Asian ethnicity was independently associated with lower systolic and diastolic BP, Black with lower triglycerides, cholesterol/HDL-c ratio and having 2 or more IRFs, and Thai with lower cholesterol/HDL-c ratio and all three non-white ethnicities with lower total and LDL cholesterol. CONCLUSION: In high-risk HbA1c-defined prediabetes additional measurement of FPG will add little to evaluation of cardiometabolic risk. Additionally, UK Whites tend to have the most adverse cardiometabolic profile of any ethnic group.

Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: a Joint Statement by International Diabetes Organizations.

BACKGROUND: Despite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIM: The 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODS: A multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005-30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28-30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTS: Given its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI ≥40 kg/m2) and in those with class II obesity (BMI 35.0-39.9 kg/m2) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0-34.9 kg/m2 if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m2 for Asian patients. CONCLUSIONS: Although additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies.

Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations.

BACKGROUND: Despite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIM: The 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODS: A multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005-30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28-30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTS: Given its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI≥40 kg/m(2)) and in those with class II obesity (BMI 35.0-39.9 kg/m(2)) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0-34.9 kg/m(2) if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m(2) for Asian patients. CONCLUSIONS: Although additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies.

Diabetes mellitus statistics on prevalence and mortality: facts and fallacies.

Diabetes mellitus is one of the most important public health challenges of the twenty-first century. Until the past decade, it has been seriously underrated as a global health threat. Major gaps exist in efforts to comprehend the burden nationally and globally, especially in developing nations, due to a lack of accurate data for monitoring and surveillance. Early attempts to obtain accurate data, discussed in this article, seem to have been cast aside so, at present, these needs remain unmet. Existing international efforts to assemble information fall far short of requirements. Current estimates are imprecise, only providing a rough picture, and probably underestimate the disease burden. The methodologies that are currently used, and that are discussed in this Perspectives article, are inadequate for providing a complete and accurate assessment of the prevalence of diabetes mellitus. International consensus on uniform standards and criteria for reporting national data on diabetes mellitus prevalence as well as for common complications of diabetes mellitus and mortality need to be developed.

Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations.

BACKGROUND: Despite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIM: The 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODS: A multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005-30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28-30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTS: Given its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI ≥40 kg/m(2)) and in those with class II obesity (BMI 35.0-39.9 kg/m(2)) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0-34.9 kg/m(2) if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m(2) for Asian patients. CONCLUSIONS: Although additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies.