Enhancing diabetes care for the most vulnerable in the 21st century: Interim findings of the National Advisory Panel on Care Home Diabetes (NAPCHD).

Older adults with diabetes may carry a substantial health burden in Western ageing societies, occupy more than one in four beds in care homes, and are a highly vulnerable group who often require complex nursing and medical care. The global pandemic (COVID-19) had its epicentre in care homes and revealed many shortfalls in diabetes care resulting in hospital admissions and considerable mortality and comorbid illness. The purpose of this work was to develop a national Strategic Document of Diabetes Care for Care Homes which would bring about worthwhile, sustainable and effective quality diabetes care improvements, and address the shortfalls in care provided. A large diverse and multidisciplinary group of stakeholders (NAPCHD) defined 11 areas of interest where recommendations were needed and using a subgroup allocation approach were set tasks to produce a set of primary recommendations. Each subgroup was given 5 starter questions to begin their work and a format to provide responses. During the initial phase, 16 key findings were identified. Overall, after a period of 18 months, 49 primary recommendations were made, and 7 major conclusions were drawn from these. A model of community and integrated diabetes care for care home residents with diabetes was proposed, and a series of 5 'quick-wins' were created to begin implementation of some of the recommendations that would not require significant funding. The work of the NAPCHD is ongoing but we hope that this current resource will help leaders to make these required changes happen.

Impact of bariatric surgery on cardiovascular outcomes and mortality: a population-based cohort study.

BACKGROUND: Cohort studies have shown that bariatric surgery may reduce the incidence of and mortality from cardiovascular disease (CVD), but studies using real-world data are limited. This study examined the impact of bariatric surgery on incident CVD, hypertension and atrial fibrillation, and all-cause mortality. METHODS: A retrospective, matched, controlled cohort study of The Health Improvement Network primary care database (from 1 January 1990 to 31 January 2018) was performed (approximately 6 per cent of the UK population). Adults with a BMI of 30 kg/m2 or above who did not have gastric cancer were included as the exposed group. Each exposed patient, who had undergone bariatric surgery, was matched for age, sex, BMI and presence of type 2 diabetes mellitus (T2DM) with two controls who had not had bariatric surgery. RESULTS: A total of 5170 exposed and 9995 control participants were included; their mean(s.d.) age was 45·3(10·5) years and 21·5 per cent (3265 of 15 165 participants) had T2DM. Median follow-up was 3·9 (i.q.r. 1·8- 6·4) years. Mean(s.d.) percentage weight loss was 20·0(13·2) and 0·8(9·5) per cent in exposed and control groups respectively. Overall, bariatric surgery was not associated with a significantly lower CVD risk (adjusted hazard ratio (HR) 0·80; 95 per cent c.i. 0·62 to 1·02; P = 0·074). Only in the gastric bypass group was a significant impact on CVD observed (HR 0·53, 0·34 to 0·81; P = 0·003). Bariatric surgery was associated with significant reduction in all-cause mortality (adjusted HR 0·70, 0·55 to 0·89; P = 0·004), hypertension (adjusted HR 0·41, 0·34 to 0·50; P < 0·001) and heart failure (adjusted HR 0·57, 0·34 to 0·96; P = 0·033). Outcomes were similar in patients with and those without T2DM (exposed versus controls), except for incident atrial fibrillation, which was reduced in the T2DM group. CONCLUSION: Bariatric surgery is associated with a reduced risk of hypertension, heart failure and mortality, compared with routine care. Gastric bypass was associated with reduced risk of CVD compared to routine care.

ANTECEDENTES: Estudios de cohortes han mostrado que la cirugía bariátrica puede reducir la incidencia de enfermedad cardiovascular (cardiovascular disease, CVD) y la mortalidad, pero los estudios basados en datos del mundo real son limitados. Este estudio examinaba el impacto de la cirugía bariátrica (bariatric surgery, BS) en la incidencia de CVD, hipertensión, fibrilación auricular (FA) y mortalidad por cualquier causa. MÉTODOS: Se realizó un estudio retrospectivo de cohortes, controlado por emparejamiento, a partir de la base de datos de atención primaria del The Health Improvement Network (THIN) (1/1/1990 y 31/1/2018) (aproximadamente el 6% de la población del Reino Unido UK). En el grupo de exposición, se incluyeron adultos con un índice de masa corporal (IMC) ≥ 30 kg/m2 que no tenían cáncer gástrico. Cada paciente expuesto (había sido operado de BS) fue emparejado por edad, sexo, IMC y presencia de diabetes tipo 2 (T2D) con 2 controles (sin BS). RESULTADOS: Se incluyeron un total de 5.170 sujetos expuestos y 9.995 participantes controles. La edad media (DE) fue 45,3 (10,5) años, 21,5% (n = 3.265) tenían T2D. La mediana de seguimiento era de 3,9 años (rango intercuartílico 1,8- 6,4). La media ± desviación estándar del % de pérdida de peso fue del 20,0 ± 13,2% en el grupo BS versus 0,8 ± 9,5% en los grupos control. Globalmente, la BS no se asoció con una CVD significativamente más baja (cociente de riesgos instantáneos ajustados, adjusted hazard ratio, HR 0,80; i.c. del 0,62- 1,02, P = 0,074). Solo en el grupo del bypass gástrico se observó un impacto significativo en CVD (0,53, 0,34- 0,81, P = 0,003). BS se asoció con una reducción significativa en la mortalidad de cualquier causa (0,70; i.c. Del 95% 0,55- 0,89, P = 0,004), hipertensión (0,41; 0,34- 0,50, P < 0,001), e insuficiencia cardiaca (0,57, 0,34- 0,96; P = 0.033). Los resultados fueron similares en aquellos pacientes con y sin T2D (expuesto versus control) excepto en la FA incidental que se redujo en el grupo T2D. CONCLUSIONES: La práctica de BS se asoció con una reducción del riesgo de insuficiencia cardiaca y mortalidad.

Temporal and external validation of a prediction model for adverse outcomes among inpatients with diabetes.

AIM: To temporally and externally validate our previously developed prediction model, which used data from University Hospitals Birmingham to identify inpatients with diabetes at high risk of adverse outcome (mortality or excessive length of stay), in order to demonstrate its applicability to other hospital populations within the UK. METHODS: Temporal validation was performed using data from University Hospitals Birmingham and external validation was performed using data from both the Heart of England NHS Foundation Trust and Ipswich Hospital. All adult inpatients with diabetes were included. Variables included in the model were age, gender, ethnicity, admission type, intensive therapy unit admission, insulin therapy, albumin, sodium, potassium, haemoglobin, C-reactive protein, estimated GFR and neutrophil count. Adverse outcome was defined as excessive length of stay or death. RESULTS: Model discrimination in the temporal and external validation datasets was good. In temporal validation using data from University Hospitals Birmingham, the area under the curve was 0.797 (95% CI 0.785-0.810), sensitivity was 70% (95% CI 67-72) and specificity was 75% (95% CI 74-76). In external validation using data from Heart of England NHS Foundation Trust, the area under the curve was 0.758 (95% CI 0.747-0.768), sensitivity was 73% (95% CI 71-74) and specificity was 66% (95% CI 65-67). In external validation using data from Ipswich, the area under the curve was 0.736 (95% CI 0.711-0.761), sensitivity was 63% (95% CI 59-68) and specificity was 69% (95% CI 67-72). These results were similar to those for the internally validated model derived from University Hospitals Birmingham. CONCLUSIONS: The prediction model to identify patients with diabetes at high risk of developing an adverse event while in hospital performed well in temporal and external validation. The externally validated prediction model is a novel tool that can be used to improve care pathways for inpatients with diabetes. Further research to assess clinical utility is needed.

Representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering therapies in Type 2 diabetes.

AIMS: Our aim was to investigate the proportional representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering drugs or strategies in Type 2 diabetes, noting that these are among the most significant pieces of evidence used to formulate the guidelines on which clinical practice is largely based. METHODS: We searched for cardiovascular outcome trials in Type 2 diabetes published before January 2015, and extracted data on the ethnicity of participants. These were compared against expected values for proportional representation of South Asian individuals, based on population data from the USA, from the UK, and globally. RESULTS: Twelve studies met our inclusion criteria and, of these, eight presented a sufficiently detailed breakdown of participant ethnicity to permit numerical analysis. In general, people of South Asian origin were found to be under-represented in trials compared with UK and global expectations and over-represented compared with US expectations. Among the eight trials for which South Asian representation could be reliably estimated, seven under-represented this group relative to the 11.2% of the UK diabetes population estimated to be South Asian, with the representation in these trials ranging from 0.0% to 10.0%. CONCLUSIONS: Clinicians should exercise caution when generalizing the results of trials to their own practice, with regard to the ethnicity of individuals. Efforts should be made to improve reporting of ethnicity and improve diversity in trial recruitment, although we acknowledge that there are challenges that must be overcome to make this a reality.

What factors influence concordance with medications? Findings from the U.K. Asian Diabetes study.

AIMS: To investigate concordance with medication, as assessed at baseline and at 1- and 2-year follow-up, and to examine factors associated with non-concordance in a UK-resident South-Asian population. METHODS: Data from the UK Asian Diabetes Study were analysed. Concordance with medications was assessed and recorded at three time points during the study. Multiple logistic regression was used to investigate the factors associated with non-concordance; the associations of baseline factors with year 1 concordance and baseline plus year 1 factors with year 2 concordance. RESULTS: Data for 403 patients from seven practices participating in the UK Asian Diabetes Study were analysed. The numbers of patients who were non-concordant were: 63 (16%) at baseline; 101 (25%) at year 1; and 122 (30%) at year 2. The baseline-measured variables that were significantly associated with year 1 non-concordance included diabetes duration, history of cardiovascular disease, components of the EuroQol quality of life questionnaire, the EQ-5D score, and number of medications prescribed. In multivariable analyses, the most important determinant of year 1 non-concordance was baseline non-concordance: odds ratio 13.6 (95% confidence limits 4.7, 39.9). Number of medications prescribed for blood pressure control was also significant: odds ratio 1.8 (95% confidence limits 1.4, 2.4). Similar results were observed for year 2 non-concordance. CONCLUSIONS: Non-concordance with medications was common and more likely in people prescribed more medications. The current target-driven management of risk factor levels may lead to increasing numbers and doses of medications. Considering the high cost of medications and the implications of poor health behaviours on morbidity and mortality, further investigation of prescribing behaviours and the factors affecting patient concordance are required.

The relationship between high-sensitivity CRP and polyclonal free light chains as markers of inflammation in chronic disease.

INTRODUCTION: Serum concentrations of polyclonal free light chains (FLC) represent the activity of the adaptive immune system. This study assessed the relationship between polyclonal FLC and the established marker of innate immunity, C-reactive protein (CRP), in chronic and acute disease. METHODS: We utilized four cross-sectional chronic disease patient cohorts: chronic kidney disease (CKD), diabetes, vasculitis and kidney transplantation; and a longitudinal intensive care case series to assess the kinetics of production in acute disease. RESULTS: There was a weak association between polyclonal FLC and high-sensitivity CRP (hs-CRP) in the study cohorts. A longitudinal assessment in acute disease showed a gradual increase in FLC concentrations over time, often when CRP levels were falling, demonstrating clear differences in the response kinetics of CRP and FLC in this setting. CONCLUSION: Polyclonal FLC and hs-CRP provide independent information as to inflammatory status. Prospective studies are now required to assess the utility of hs-CRP and polyclonal FLC in combination for risk stratification in disease populations.

Abnormal retinal vascular function and lipid levels in a sample of healthy UK South Asians.

BACKGROUND/AIMS: To investigate ethnic differences in retinal vascular function and their relationship to traditional risk indicators for cardiovascular disease (CVD). METHODS: A total of 90 normoglycaemic subjects (45 South Asian (SA) and 45 age- and gender-matched white Europeans (WEs)) were recruited for the present study. Retinal vessel reactivity to flickering light was assessed by means of the dynamic retinal vessel analyser according to a modified protocol. Fasting plasma glucose, triglycerides (TG), total, LDL and HDL cholesterol were also measured in all individuals. RESULTS: SA individuals showed higher fasting triglyceride (p=0.001) and lower HDL levels (p=0.007), leading to a higher TG:HDL-C ratio (p=0.001) than age-matched WE subjects. Additionally, in SAs, the retinal arterial reaction time in response to flicker stimulation was significantly longer in the last flicker cycle than in the WEs (p=0.039), and this change correlated positively with measured plasma TG levels (r=0.60; p=0.01). No such relationship was observed in the WEs (p>0.05). CONCLUSION: Even in the absence of overt vascular disease, in otherwise healthy SAs there are potential signs of retinal vascular function impairment that correlates with established plasma markers for CVD risk.

An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference.

AIMS: A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. METHODS: We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case-control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. RESULTS: In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95%CI 0.24-0.67) kg/m(2) per A-allele (P=3.0 × 10(-5) ) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (P=0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95%CI) 1.18 (1.07-1.30); P=0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95%CI 1.14-1.31); P=1.07 × 10(-8) ] even after adjusting for BMI [1.18 (95%CI 1.10-1.27); P=1.02 × 10(-5) ] or waist circumference [1.18 (95%CI 1.10-1.27); P=3.97 × 10(-5) ]. CONCLUSIONS: The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

Enhanced diabetes care to patients of south Asian ethnic origin (the United Kingdom Asian Diabetes Study): a cluster randomised controlled trial.

BACKGROUND: Delivery of high-quality, evidence-based health care to deprived sectors of the community is a major goal for society. We investigated the effectiveness of a culturally sensitive, enhanced care package in UK general practices for improvement of cardiovascular risk factors in patients of south Asian origin with type 2 diabetes. METHODS: In this cluster randomised controlled trial, 21 inner-city practices in the UK were assigned by simple randomisation to intervention (enhanced care including additional time with practice nurse and support from a link worker and diabetes-specialist nurse [nine practices; n=868]) or control (standard care [12 practices; n=618]) groups. All adult patients of south Asian origin with type 2 diabetes were eligible. Prescribing algorithms with clearly defined targets were provided for all practices. Primary outcomes were changes in blood pressure, total cholesterol, and glycaemic control (haemoglobin A1c) after 2 years. Analysis was by intention to treat. This trial is registered, number ISRCTN 38297969. FINDINGS: We recorded significant differences between treatment groups in diastolic blood pressure (1.91 [95% CI -2.88 to -0.94] mm Hg, p=0.0001) and mean arterial pressure (1.36 [-2.49 to -0.23] mm Hg, p=0.0180), after adjustment for confounders and clustering. We noted no significant differences between groups for total cholesterol (0.03 [-0.04 to 0.11] mmol/L), systolic blood pressure (-0.33 [-2.41 to 1.75] mm Hg), or HbA1c (-0.15% [-0.33 to 0.03]). Economic analysis suggests that the nurse-led intervention was not cost effective (incremental cost-effectiveness ratio pound28 933 per QALY gained). Across the whole study population over the 2 years of the trial, systolic blood pressure, diastolic blood pressure, and cholesterol decreased significantly by 4.9 (95% CI 4.0-5.9) mm Hg, 3.8 (3.2-4.4) mm Hg, and 0.45 (0.40-0.51) mmol/L, respectively, and we recorded a small and non-significant increase for haemoglobin A1c (0.04% [-0.04 to 0.13]), p=0.290). INTERPRETATION: We recorded additional, although small, benefits from our culturally tailored care package that were greater than the secular changes achieved in the UK in recent years. Stricter targets in general practice and further measures to motivate patients are needed to achieve best possible health-care outcomes in south Asian patients with diabetes.

Type 2 diabetes and cardiovascular risk in the UK south Asian community.

A popular hypothesis for the greater prevalence of type 2 diabetes and cardiovascular disease in UK south Asians is that they have an increased susceptibility of developing insulin resistance in response to certain environmental factors, including obesity and adoption of a sedentary lifestyle. Insulin resistance is postulated as a central feature of the metabolic syndrome, culminating in type 2 diabetes, atherosclerotic vascular disease and CHD; a pathway potentially accelerated by migration/urbanisation. We describe and compare the prevalence of type 2 diabetes, cardiovascular disease and their associated risk factors in UK south Asian and white Caucasian populations to determine possible reasons for the increased preponderance of these diseases in south Asians, and highlight key evidence for optimal risk factor management. Finally, we describe a UK community-based programme that attempts to reduce the morbidity and mortality from type 2 diabetes and cardiovascular disease in south Asians through a new approach to management.

Inhaled insulin: new technology, new possibilities.

The prevalence of diabetes is reaching epidemic proportions with an increasing need for new therapies. Several new therapies are in development and amongst these is inhaled insulin. Inhaled insulin is a novel way of delivering insulin and has been shown to have an efficacy comparable to subcutaneous insulin in patients with both type 1 and type 2 diabetes. Several inhaled insulin delivery systems are currently in development and the first of these, Exubera has recently been granted license in Europe and in the USA. In this article we review the efficacy and safety profile of Exubera and discuss its potential place in the management of diabetes.

Correlation between increased colloid osmotic pressure and the resolution of refractory ascites after transjugular intrahepatic portosystemic shunt.

BACKGROUND: This study compared the changes in serum albumin, globulin, and colloid osmotic pressure (COP) before and after transjugular intrahepatic portosystemic shunt (TIPS) or large volume paracentesis (LVP) in patients with ascites. METHODS: Of 23 patients with refractory ascites, 17 had TIPS and 6 had LVP with infusion of albumin. Colloid osmotic pressure measurements were calculated, using the formula previously proposed by Hoefs: COP = A (1.058G + 0.163A + 3.11) where A = serum albumin and G = serum globulin. RESULTS: After 1 month, ascites resolved in 9 of the 17 patients who had TIPS and in none of the 6 who had LVP. Colloid osmotic pressure increased significantly in patients whose ascites resolved after TIPS. Colloid osmotic pressure did not change in the patients whose ascites did not resolve after TIPS, and COP decreased significantly in the LVP group. A statistically significant difference was found in the pre-TIPS COP measurements between those patients who had resolution of ascites and those who did not. A pre-TIPS COP of < or =20 mm Hg predicted resolution of ascites with an 88% sensitivity and a 78% specificity. CONCLUSIONS: Serum COP increased significantly in patients with resolution of ascites but remained unchanged in patients with persistent ascites after TIPS. Serum COP decreased after LVP. A statistically significant difference in the pre-TIPS COP was found between patients whose ascites resolved and patients having persistent ascites.

In vivo comparison of esophageal varices at and above the diaphragmatic high pressure zone using high resolution endoluminal sonography.

Our objective in this study was to use high resolution endoluminal sonography to compare the size of esophageal varices within 5 cm of and at the esophageal high pressure zone. We carried out the study in 36 patients with endoscopically proven esophageal varices. A 20-MHz 6.2F ultrasound catheter was passed through a 34F endoscope and used to image esophageal varices as it was slowly withdrawn through the high pressure zone (the level at which the diaphragm was imaged) and into the body of the esophagus approximately 5 cm above the high pressure zone. All images were captured on videotape and reviewed by one of the investigators. The mean, total, and percent cross-sectional surface areas occupied by varices were calculated and then compared within 5 cm and at the esophageal high pressure zone. Six of 36 (17%) patients had no varices imaged at the high pressure zone but did have varices imaged in the distal esophagus. The mean cross-sectional surface area per varix at the high pressure zone (0.036+/-0.006 cm2) was significantly less (p < or = 0.0001) than the mean cross-sectional area per varix 5 cm above the high pressure zone (0.142+/-0.018 cm2). The average total cross-sectional surface area occupied by varices at the high pressure zone (0.137+/-0.034 cm2) was significantly less (p < 0.0001) than the average cross-sectional surface area occupied by varices 5 cm above the high pressure zone (0.672+/-0.080 cm2). The mean percent esophageal wall cross-sectional surface area occupied by varices at the high pressure zone (16%) was significantly less (p < or = 0.0001) than 5 cm above the high pressure zone (49%). We conclude that the mean, total, and percent cross-sectional surface areas of esophageal varices at the high pressure zone are significantly less than those 5 cm above the high pressure zone.

Use of high-resolution endoluminal sonography to measure the radius and wall thickness of esophageal varices.

BACKGROUND: Measurement of variceal wall tension theoretically provides the most accurate method of predicting future variceal bleeding. Using high-resolution endoluminal sonography in 45 patients with known portal hypertension, we measured and correlated the two previously unmeasured variables involved in the calculation of variceal wall tension (radius and wall thickness) by the Laplace equation. METHODS: A 20 MHz 6.2F ultrasound transducer was used to image esophageal varices during standard esophagoscopy. All images were captured on videotape and later reviewed by two blinded investigators. Outer and inner variceal wall circumferences were measured at a cross section of each varix. The radius of each varix and the variceal wall thickness were calculated. The radius of each varix was then correlated with its wall thickness. The interobserver and intraobserver variabilities were measured. RESULTS: The mean variceal radius was .86 +/- .34 cm for the inner radius and 1.48 +/- .41 cm for the outer radius; mean variceal wall thickness was .099 +/- 0.037 cm. Intraobserver and interobserver correlation for the radius was r = .98 and r = .97, respectively. The intraobserver and interobserver correlations for the wall thickness were r = .92 and r = .91, respectively. Variceal radius did not correlate with the wall thickness of the varix. CONCLUSIONS: High-resolution endoluminal sonography provides a method for the accurate measurement of esophageal variceal radius and wall thickness. Variceal radius does not correlate with variceal wall thickness, implying that variceal wall tension cannot be accurately estimated by measurement of variceal size alone. Combining these data with measurements of variceal pressure should allow for the direct determination of wall tension and, subsequently, identification of patients at risk for variceal bleeding.

Liver transplantation for Wilson's disease.

BACKGROUND/AIMS: As has been the case with other metabolic diseases of the liver in the last decade, orthotopic liver transplantation has been applied to the treatment of Wilson's disease with increasing frequency. The experience at the University of Pittsburg with orthotopic liver transplantation for Wilson's disease is reported. METHODS: Between February 1981 and December 1991, 51 orthotopic liver transplants were performed on 39 patients (16 pediatric, 23 adults) with Wilson's disease. Twenty-two patients were transplanted because of a presentation co-existent with fulminant hepatic failure. Seventeen presented with chronic advanced liver disease with (n=9) or without (n=8) associated neurologic dysfunction. RESULTS: The rate of primary graft survival (n-39) was 73% and patient survival was 79.4%. No patient mortality occurred beyond 3 weeks post-orthotopic liver transplantation. Survival was butter for those with a chronic advanced liver disease presentation (90%) than it was for those with a fulminant hepatic failure (73%) presentation, but the difference was not statistically significant. CONCLUSIONS: 1) Currently, orthotopic liver transplantation is the treatment of choice for Wilson's disease presenting as fulminant hepatic hepatic failure; 2) orthotopic liver transplantation should be considered for patients with Wilson's disease with advanced, chronic liver disease for whom no other therapy is possible; 3)orthotopic liver transplantation only partially corrects the underlying metabolic defect of patients with Wilson's disease and converts the copper kinetics from that characteristic of an individual affected with a homozygous disease to that of an individual who is an obligate heterozygote, thereby effecting a phenotypic cure.