ABSTRACT
BACKGROUND: The clinical management of type 2 diabetes mellitus (T2DM) presents a significant challenge due to the constantly evolving clinical practice guidelines and growing array of drug classes available. Evidence suggests that artificial intelligence (AI)-enabled clinical decision support systems (CDSSs) have proven to be effective in assisting clinicians with informed decision-making. Despite the merits of AI-driven CDSSs, a significant research gap exists concerning the early-stage implementation and adoption of AI-enabled CDSSs in T2DM management. OBJECTIVE: This study aimed to explore the perspectives of clinicians on the use and impact of the AI-enabled Prescription Advisory (APA) tool, developed using a multi-institution diabetes registry and implemented in specialist endocrinology clinics, and the challenges to its adoption and application. METHODS: We conducted focus group discussions using a semistructured interview guide with purposively selected endocrinologists from a tertiary hospital. The focus group discussions were audio-recorded and transcribed verbatim. Data were thematically analyzed. RESULTS: A total of 13 clinicians participated in 4 focus group discussions. Our findings suggest that the APA tool offered several useful features to assist clinicians in effectively managing T2DM. Specifically, clinicians viewed the AI-generated medication alterations as a good knowledge resource in supporting the clinician's decision-making on drug modifications at the point of care, particularly for patients with comorbidities. The complication risk prediction was seen as positively impacting patient care by facilitating early doctor-patient communication and initiating prompt clinical responses. However, the interpretability of the risk scores, concerns about overreliance and automation bias, and issues surrounding accountability and liability hindered the adoption of the APA tool in clinical practice. CONCLUSIONS: Although the APA tool holds great potential as a valuable resource for improving patient care, further efforts are required to address clinicians' concerns and improve the tool's acceptance and applicability in relevant contexts.
Subject(s)
Artificial Intelligence , Diabetes Mellitus, Type 2 , Focus Groups , Qualitative Research , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/therapy , Humans , Decision Support Systems, Clinical , Male , Female , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/administration & dosage , Middle Aged , AdultABSTRACT
BACKGROUND: The use of subtalar arthroereisis as an adjunct to the surgical treatment of stage 1 flexible progressive collapsing foot deformity (PCFD) is controversial. The aim was to investigate the clinical outcomes and report the implant removal rate of subtalar arthroereisis as an adjunct for stage 1 PCFD. METHODS: A retrospective study of 212 consecutive feet undergoing operative management of stage 1 PCFD with adjunctive subtalar arthroereisis between October 2010 and April 2018. The primary outcome was the Foot and Ankle Outcome Score (FAOS). Secondary outcomes included Foot and Ankle Disability Index (FADI), Euroqol-5D-5L Index and implant removal rate. RESULTS: Post-operative clinical FAOS outcomes were collected for 153 feet (72.2%). At mean 2.5-year follow-up, the mean ± standard deviation FAOS for each domain was as follows; Pain: 81.5 ± 18.5, Symptoms: 79.5 ± 12.9, Activities of Daily Living: 82.5 ± 15.4 and Quality of Life: 64.2 ± 23.7. EQ-5D-5L Index was 0.884 ± 0.152. Pre-operative scores were available for 20 of these feet demonstrating a statistically significant improvement in all FAOS, FADI and EQ-5D-5L domains (p < 0.05). The implant removal rate for persistent sinus tarsi pain was 48.1% (n = 102). CONCLUSION: Use of a subtalar arthroereisis implant as an adjunct to conventional procedures in stage 1 flexible PCFD can result in significant improvement in pain and function. Patients should be counselled as to the relatively frequent rate of subsequent implant removal. LEVEL OF EVIDENCE: IV.
ABSTRACT
OBJECTIVE: To estimate the 'cost of illness' arising from chronic wounds in Singapore. DESIGN: Incidence-based cost of illness study using evidence from a range of sources. SETTING: Singapore health services. PARTICIPANTS: We consider 3.49 million Singapore citizens and permanent residents. There are 16 752 new individuals with a chronic wound in 2017, with 598 venous ulcers, 2206 arterial insufficiency ulcers, 6680 diabetic ulcers and 7268 pressure injuries.Primary outcome measures expressed in monetary terms are the value of all hospital bed days lost for the population; monetary value of quality-adjusted life years (QALYs) lost in the population; costs of all outpatient visits; and costs of all poly clinic, use of Community Health Assist Scheme (CHAS) and emergency departments (EDs) visits. Intermediate outcomes that inform the primary outcomes are also estimated. RESULTS: Total annual cost of illness was $350 million (range $72-$1779 million). With 168 503 acute bed days taken up annually (range 141 966-196 032) that incurred costs of $139 million (range 117-161 million). Total costs to health services were $184 million (range $120-$1179 million). Total annual costs of lost health outcomes were 2077 QALYs (range -2657 to 29 029) valued at $166 million (range -212 to 2399 million). CONCLUSIONS: The costs of chronic wounds are large to Singapore. Costs can be reduced by making positive investments for comprehensive wound prevention and treatment programmes.
Subject(s)
Asian , Cost of Illness , Ulcer , Humans , Ambulatory Care Facilities , Asian/ethnology , Asian/statistics & numerical data , Emergency Service, Hospital , Emigrants and Immigrants , Ulcer/economics , Ulcer/epidemiology , Ulcer/ethnology , Ulcer/therapy , Chronic Disease/economics , Chronic Disease/epidemiology , Chronic Disease/ethnology , Chronic Disease/therapy , Singapore/epidemiologyABSTRACT
Venous leg ulceration results in significant morbidity. However, the majority of studies conducted are on Western populations. This study aims to evaluate the wound healing and quality of life for patients with venous leg ulcers (VLUs) in a Southeast Asian population. This is a multi-centre prospective cohort study from Nov 2019 to Nov 2021. All patients were started on 2- or 4-layer compression bandage and were reviewed weekly or fortnightly. Our outcomes were wound healing, factors predictive of wound healing and the EuroQol 5-dimensional 5-level (EQ-5D-5L) health states. Within our cohort, there were 255 patients with VLU. Mean age was 65.2 ± 11.6 years. Incidence of diabetes mellitus was 42.0%. Median duration of ulcer at baseline was 0.30 years (interquartile range 0.136-0.834). Overall, the median time to wound healing was 4.5 months (95% confidence interval [CI]: 3.77-5.43). The incidence of complete wound healing at 3- and 6-month was 47.0% and 60.9%, respectively. The duration of the wound at baseline was independently associated with worse wound healing (Hazard ratio 0.94, 95% CI: 0.89-0.99, P = .014). Patients with healed VLU had a significantly higher incidence of perfect EQ-5D-5L health states at 6 months (57.8% vs 13.8%, P < .001). We intend to present longer term results in subsequent publications.
Subject(s)
Quality of Life , Varicose Ulcer , Humans , Middle Aged , Aged , Prospective Studies , Follow-Up Studies , Singapore/epidemiology , Varicose Ulcer/therapy , Compression Bandages , Wound HealingABSTRACT
Background: Little is known about stage 1 and 2 pressure injuries that are health care-acquired. We report incidence rates of health care-acquired stage 1 and stage 2 pressure injuries, and, estimate the excess length of stay using four competing analytic methods. We discuss the merits of the different approaches. Methods: We calculated monthly incidence rates for stage 1 and 2 health care-acquired pressure injuries occurring in a large Singapore acute care hospital. To estimate excess stay, we conducted unadjusted comparisons with a control cohort, performed linear regression and then generalized linear regression with a gamma distribution. Finally, we fitted a simple state-based model. The design for the cost attribution work was a retrospective matched cohort study. Results: Incidence rates in 2016 were 0.553% (95% confidence interval [CI] 0.55, 0.557) and 0.469% (95% CI 0.466, 0.472) in 2017. For data censored at 60 days' maximum stay, the unadjusted comparisons showed the highest excess stay at 17.68 (16.43-18.93) days and multi-state models showed the lowest at 1.22 (0.19, 2.23) days. Conclusions: Poor-quality methods for attribution of excess length of stay to pressure injury generate inflated estimates that could mislead decision makers. The findings from the multi-state model, which is an appropriate method, are plausible and illustrate the likely bed-days saved from lowering the risk of these events. Stage 1 and 2 pressure injuries are common and increase costs by prolonging the length of stay. There will be economic value investing in prevention. Using biased estimates of excess length of stay will overstate the potential value of prevention.
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BACKGROUND: To determine the prevalence of opioid use in Australian hip (THA) or knee (TKA) cohort, and its association with outcomes. METHODS: About 837 primary THA or TKA subjects prospectively completed Oxford Scores, and Knee or Hip Osteoarthritis Outcomes Score(KOOS/HOOS) and opioid use in the previous week before arthroplasty. Subjects repeated the baseline survey at 6 months, with additional questions regarding satisfaction. RESULTS: Opioid use was reported by 19% preoperatively and 7% at 6 months. Opioid use was 46% at 6 weeks and 10% at 6 months after TKR, and 16% at 6 weeks and 4% at 6 months after THR. Preoperative opioid use was associated with back pain(OR 2.2, P = 0.006), anxiety or depression(OR 1.8, P = 0.001) and Oxford knee scores <30(OR 5.6, P = 0.021) in TKA subjects, and females in THA subjects(OR 1.7, P = 0.04). There was no difference between preoperative opioid users and non-users for satisfaction, or KOOS or HOOS scores at 6 months. 77% of patients taking opioids before surgery had ceased by 6 months, and 3% of preoperative non users reported opioid use at 6 months. Opioid use at 6 months was associated with preoperative use (OR 6.6-14.7, P < 0.001), and lower 6 month oxford scores (OR 4.4-83.6, P < 0.01). CONCLUSION: One in five used opioids before arthroplasty. Pre-operative opioid use was the strongest risk factor for opioid use at 6 months, increasing odds 7-15 times. Prolonged opioid use was rarely observed in the opioid naïve (<5% TKA and 1% THA). Preoperative opioid use was not associated with inferior outcomes or satisfaction.
Subject(s)
Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Opioid-Related Disorders , Analgesics, Opioid/therapeutic use , Australia/epidemiology , Female , HumansABSTRACT
BACKGROUND: Osteoarthritis frequently affects multiple joints through the lower limbs. This study sought to examine the incidence of foot pain in subjects undergoing total knee arthroplasty (TKA) and determine if foot symptoms improved following surgery. METHODS: Six hundred ten subjects undergoing TKA completed patient-reported outcome measures preoperatively, and at 6 and/or 12 months after surgery including the incidence and severity of foot or ankle pain, Knee Injury and Osteoarthritis Outcome Scores (KOOS) Joint Replacement, Oxford Knee Scores (OKS), EQ5D, and satisfaction. RESULTS: Foot or ankle pain was reported in 45% before, 32% at 6 months, and 36% at 12 months after TKA. Of those with preoperative foot pain, 42% at 6 months and 50% at 12 months reported no foot pain after TKA, and the Visual Analog Scale severity reduced from a mean of 4.0 before to 1.7 after surgery. Those with preoperative foot pain had lower baseline KOOS (P = .001), OKS (P = .001), and more depression/anxiety (P = .010), but experienced equivalent postoperative KOOS, OKS, and satisfaction with surgery, compared to those without foot pain. CONCLUSION: Foot or ankle pain was reported by nearly half of TKA subjects, but resolved after surgery in 50%. Those with preoperative foot pain experienced at least equivalent improvement in knee-related symptoms and mobility compared to those without foot pain. The presence of foot pain should not be a deterrent to TKA.
Subject(s)
Arthroplasty, Replacement, Knee , Osteoarthritis, Knee , Arthralgia/epidemiology , Arthralgia/etiology , Arthralgia/surgery , Arthroplasty, Replacement, Knee/adverse effects , Humans , Knee Joint/surgery , Osteoarthritis, Knee/complications , Osteoarthritis, Knee/surgery , Patient Reported Outcome Measures , Treatment OutcomeABSTRACT
BACKGROUND: Asian populations are at high risk of diabetes and related vascular complications. We examined risk factor control, preventive care, and disparities in these trends among adults with diabetes in Singapore. METHODS: The sample included 209,930 adults with diabetes aged≥18 years from a multi-institutional SingHealth Diabetes Registry between 2013 and 2019 in Singapore. We performed logistic generalized estimating equations (GEEs) regression analysis and used linear mixed effect modeling to evaluate the temporal trends. RESULTS: Between 2013 and 2019, the unadjusted control rates of glycated hemoglobin (4.8%, 95%CI (4.4 to 5.1) and low-density lipoprotein cholesterol (LDL-C) (11.5%, 95%CI (11.1 to 11.8)) improved, but blood pressure (BP) control worsened (systolic BP (SBP)/diastolic BP (DBP) <140/90 mmHg: -6.6%, 95%CI (-7.0 to -6.2)). These trends persisted after accounting for the demographics including age, gender, ethnicity, and housing type. The 10-year adjusted risk for coronary heart disease (CHD) (3.4%, 95% (3.3 to 3.5)) and stroke (10.4%, 95% CI (10.3 to 10.5)) increased. In 2019, the control rates of glycated hemoglobin, BP (SBP/DBP<140/90 mmHg), LDL-C, each, and all three risk factors together, accounted for 51.5%, 67.7%, 72.2%, and 24.4%, respectively. CONCLUSIONS: Trends in risk factor control improved for glycated hemoglobin and LDL-C, but worsened for BP among diabetic adults in Singapore from 2013 to 2019. Control rates for all risk factors remain inadequate.
Subject(s)
Asian People/genetics , Cardiovascular Diseases/etiology , Cholesterol, LDL/blood , Diabetes Mellitus, Type 2/complications , Glycated Hemoglobin/metabolism , Hypertension/physiopathology , Adolescent , Adult , Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/pathology , Cardiovascular Diseases/therapy , Diabetes Mellitus, Type 2/metabolism , Disease Management , Female , Heart Disease Risk Factors , Humans , Male , Middle Aged , Registries , Retrospective Studies , Singapore/epidemiology , Young AdultABSTRACT
Klinefelter syndrome (KS) is the most common sex chromosome disorder in males. It is the result of two or more X chromosomes in a phenotypic male. In addition to primary hypogonadism affecting male sexual development, it is associated with a series of comorbidities such as osteoporosis, psychiatric and cognitive disorders, metabolic syndromes, and autoimmune diseases. A broad spectrum of phenotypes has been described and many cases remain undiagnosed throughout their lifespan. In this case report, we describe a case of mosaic KS unmasked by acute vertebral fracture.
Subject(s)
Klinefelter Syndrome , Osteoporosis , Spinal Fractures , Comorbidity , Humans , Klinefelter Syndrome/complications , Klinefelter Syndrome/diagnosis , Klinefelter Syndrome/epidemiology , Male , Middle Aged , Osteoporosis/complications , Osteoporosis/epidemiology , Phenotype , Spinal Fractures/complications , Spinal Fractures/diagnostic imagingABSTRACT
Foot care education is an important strategy in reducing lower limb complications. There is evidence that contemporary communication approaches can improve patient education outcomes. To inform the potential of such methods in diabetic foot education, we trialled a collaborative approach in patient education counselling in a podiatry clinic. We conducted a single-blind pragmatic randomised controlled trial on 52 diabetes patients who had an active foot ulcer. Participants were randomised to either collaborative education or traditional didactic education. Outcomes on knowledge and self-care behaviours were collected via a pre and post study questionnaire (max score: 75). The study ended at 12 weeks or when the wound healed prior. 42 (80.7%) participants completed the study. The collaborative patient education group had a significant increase in score post-study (38.8 ± 8.5) compared to pre-study (32.8 ± 6.9; P < .001). The control group had no significant increase in score post study. The difference in scores between groups had a moderate effect size (d = 0.54). The use of a collaborative approach in patient education was able to produce significantly greater increase in knowledge retention and self-care behaviours, without the need for additional consultation time in a podiatry clinic.
Subject(s)
Diabetes Mellitus , Diabetic Foot , Patient Education as Topic , Self Care , Aged , Diabetic Foot/therapy , Female , Foot , Humans , Male , Middle Aged , Single-Blind Method , Surveys and QuestionnairesABSTRACT
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.
Subject(s)
Cellular Reprogramming/genetics , Gene Editing , Genome, Human/genetics , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Animals , Autoimmunity/genetics , CRISPR-Cas Systems/genetics , Cells, Cultured , Humans , Interleukin-2 Receptor alpha Subunit/genetics , Male , Mice , Neoplasm Transplantation , Protein Engineering , Receptors, Antigen, T-Cell/genetics , T-Lymphocytes/cytologyABSTRACT
Although mutations in the proinsulin gene (INS) are the second most common cause of neonatal diabetes mellitus, the natural history of ß-cell death and the most appropriate treatments remains unknown. We describe the management and outcome of two sisters with INS-mediated diabetes (S1 and S2) and suggest that more intensive insulin treatment of S2 may have resulted in better clinical outcomes. S1 was diagnosed with diabetes after presenting with serum glucose of 404 mg/dL (22.4 mmol/L) and started multiple daily insulin injections at age 4 months, followed by continuous subcutaneous insulin infusion (CSII) at age 42 months. S1 had positive genetic testing at age 4 months for the GlyB8Ser or Gly32Ser mutation in proinsulin. S2 had positive research-based genetic testing, age 1 month, before she had consistently elevated blood glucose levels. Continuous glucose monitoring revealed abnormal excursions to 200 mg/dL. Low-dose insulin therapy was initiated at age 2.5 months via CSII. At age-matched time points, S2 had higher C-peptide levels, lower hemoglobin A1c values, and lower estimated doses of insulin as compared with S1. Earlier, more intensive insulin treatment was associated with higher C-peptide levels, decreased insulin dosing, and improved glycemic control. Initiating exogenous insulin before overt hyperglycemia and maintaining intensive insulin management may reduce the demand for endogenous insulin production and may preserve ß-cell function. Studies accumulating data on greater numbers of participants will be essential to determine whether these associations are consistent for all INS gene mutations.
ABSTRACT
Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.
Subject(s)
Diabetes Mellitus, Type 1/congenital , Diabetes Mellitus/genetics , Diarrhea/diagnosis , Forkhead Transcription Factors/genetics , Genetic Diseases, X-Linked/diagnosis , Immune System Diseases/congenital , Registries , Diabetes Mellitus, Type 1/diagnosis , Humans , Immune System Diseases/diagnosis , Infant , Infant, Newborn , MaleABSTRACT
Context: Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes. Objective: Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology. Methods: We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed. Results: Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant ß cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates. Conclusions: Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.
Subject(s)
Diabetes Mellitus/pathology , GATA6 Transcription Factor/genetics , Genetic Variation , Hepatocyte Nuclear Factor 1-alpha/genetics , Lamin Type A/genetics , Pancreas/pathology , Potassium Channels, Inwardly Rectifying/genetics , Adolescent , Adult , Child , Diabetes Mellitus/genetics , Female , Genetic Testing , Humans , Male , Pancreas/metabolism , Prognosis , Retrospective StudiesABSTRACT
BACKGROUND: Neonatal diabetes mellitus (NDM) caused by mutations in KCNJ11 can be successfully treated with high dose oral sulfonylureas; however, little data is available on the risk of hypoglycemia. OBJECTIVE: To determine the frequency, severity, and clinical significance of hypoglycemia in KCNJ11-related NDM. METHODS: Utilizing the University of Chicago Monogenic Diabetes Registry, parents completed an online questionnaire addressing hypoglycemia. Continuous glucose monitoring (CGM) data was available for 7 subjects. RESULTS: Thirty subjects with KCNJ11-related permanent NDM (166 patient-years on sulfonylurea) had median sulfonylurea dose of 0.39 mg/kg/day (0.24-0.88 IQR, interquartile range) with median HbA1c 5.7% (39 mmol/mol) (5.5-6.1 IQR, 37-43 mmol/mol). Hypoglycemia (<70 mg/dL) was reported monthly once or less frequently in 89.3% of individuals, but 3 (10.7%) reported once weekly or more. Of all hypoglycemic episodes reported, none involved seizures or unconsciousness and thus did not meet the current ISPAD definition of severe hypoglycemia. Seven individuals wore a CGM for a total of 912 hours with blood sugars falling below 70 mg/dL for 5.8% of the time recorded, similar to ranges reported for people without diabetes. CONCLUSIONS: In our cohort of KCNJ11-related permanent NDM, hypoglycemia is infrequent and mild despite the high doses of sulfonylurea used and near-normal level of glycemic control. Long-term follow-up on larger numbers will be required to clarify the incidence and determinants of hypoglycemia in this unique population.
Subject(s)
Diabetes Mellitus/genetics , Hypoglycemia/chemically induced , Potassium Channels, Inwardly Rectifying/genetics , Registries , Sulfonylurea Compounds/therapeutic use , Adolescent , Child , Child, Preschool , Diabetes Mellitus/drug therapy , Female , Humans , MaleABSTRACT
OBJECTIVES: Mutations in KCNJ11 are the most common cause of permanent neonatal diabetes mellitus (NDM). Approximately 25% of patients have obvious neurological dysfunction, but whether milder related problems might be more common has been unclear. We sought to assess the prevalence of parental concerns about learning, behavior, attention deficit hyperactivity disorder (ADHD), social competency, and sleep in subjects with KCNJ11-related NDM compared to unaffected sibling controls. STUDY DESIGN: Subjects or their guardians in the University of Chicago Monogenic Diabetes Registry completed a survey examining learning, behavior, ADHD and sleep. Thirty subjects with KCNJ11 -related NDM and 25 unaffected sibling controls were assessed. Data were analyzed using GraphPad Prism 6. Nonparametric analysis was performed using Fisher's exact test for group comparisons. RESULTS: Thirteen (43%) individuals with KCNJ11 -related NDM had treatment for or a diagnosis of ADHD compared to two (8%) of the sibling controls (P < 0.05). Compared to their sibling controls, individuals with KCNJ11 mutations had significant differences in behavior difficulties, social awareness, academic achievement and the need for an Individualized Education Plan (IEP). As seen in other neurodevelopmental disorders, individuals with KCNJ11 mutations also had significantly higher rates of sleep difficulties (P < 0.01). CONCLUSION: Patients with KCNJ11 -related NDM are at an increased risk for delays in learning, social-emotional and behavioral development, ADHD and sleep difficulties based on parent report. Early identification, along with integrated medical and developmental support, may promote better neurodevelopmental outcomes for this unique population. Further investigation utilizing detailed neuropsychological testing will better define the neurodevelopmental consequences of KATP mutations.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Diabetes Mellitus/genetics , Genetic Predisposition to Disease , Learning Disabilities/genetics , Mutation , Potassium Channels, Inwardly Rectifying/genetics , Sleep Wake Disorders/genetics , Adolescent , Amino Acid Substitution , Attention Deficit Disorder with Hyperactivity/epidemiology , Attention Deficit Disorder with Hyperactivity/etiology , Chicago/epidemiology , Child , Child, Preschool , Cohort Studies , Diabetes Mellitus/physiopathology , Female , Hospitals, University , Humans , Learning Disabilities/epidemiology , Learning Disabilities/etiology , Legal Guardians , Male , Parents , Prevalence , Registries , Risk , Self Report , Siblings , Sleep Wake Disorders/epidemiology , Sleep Wake Disorders/etiologyABSTRACT
Context: The most common genetic cause of permanent neonatal diabetes mellitus is activating mutations in KCNJ11, which can usually be treated using oral sulfonylureas (SUs) instead of insulin injections, although some mutations are SU unresponsive. In this work, we provide a report of the pancreatic islet endocrine cell composition and area in a patient with an SU-unresponsive KCNJ11 mutation (p.G334D), in comparison with age-matched controls. Case Description: Pancreatic autopsy tissue sections from a 2-year-old female child diagnosed with KCNJ11-related diabetes at 4 days of age and 13 age-matched controls were stained with insulin, glucagon, somatostatin, pancreatic polypeptide, and Ki67 antibodies to determine islet endocrine cell composition and area. ß-cell ultrastructure was assessed by electron microscopic (EM) analysis. The patient's pancreas (sampling from head to tail) revealed insulin-positive cells in all regions. The pancreatic ß-cell (insulin) area was significantly reduced compared with controls: 0.50% ± 0.04% versus 1.67% ± 0.20%, respectively (P < 0.00001). There were no significant differences in α-cell (glucagon) or δ-cell (somatostatin) area. EM analysis revealed secretory granules with a dense core typical of mature ß-cells as well as granules with a lighter core characteristic of immature granules. Conclusions: Our results suggest that mechanisms exist that allow preservation of ß-cells in the absence of insulin secretion. It remains to be determined to what extent this reduction in ß-cells may be reversible.
Subject(s)
Diabetes Mellitus/drug therapy , Insulin-Secreting Cells/pathology , Insulin/metabolism , Mutation/genetics , Potassium Channels, Inwardly Rectifying/genetics , Sulfonylurea Compounds/pharmacology , Autopsy , Biomarkers/analysis , Blood Glucose/analysis , Case-Control Studies , Child, Preschool , Diabetes Mellitus/metabolism , Diabetes Mellitus/pathology , Drug Resistance , Female , Humans , Infant , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , PrognosisABSTRACT
AIMS: GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our US cohort of GCK-MODY. METHODS: We examined the rates of detection of heterozygous mutations in the GCK gene in individuals referred to the US Monogenic Diabetes Registry with a phenotype consistent with GCK-MODY. We also assessed referral patterns, treatment and demography, including ethnicity, of the cohort. RESULTS: Deleterious heterozygous GCK mutations were found in 54.7 % of Registry probands selected for GCK sequencing for this study. Forty-nine percent were previously unnecessarily treated with glucose-lowering agents, causing hypoglycemia and other adverse effects in some of the subjects. The proportion of probands found to have a GCK mutation through research-based testing was similar across each ethnic group. However, together African-American, Latino and Asian subjects represented only 20.5 % of screened probands and 17.2 % of those with GCK-MODY, despite higher overall diabetes prevalence in these groups. CONCLUSIONS: Our data show that a high detection rate of GCK-MODY is possible based on clinical phenotype and that prior to genetic diagnosis, a large percentage are inappropriately treated with glucose-lowering therapies. We also find low minority representation in our Registry, which may be due to disparities in diagnostic diabetes genetic testing and is an area needing further investigation.
Subject(s)
Diabetes Mellitus, Type 2/epidemiology , Glucokinase/genetics , Registries/standards , Adolescent , Adult , Child , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/therapy , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Mutation , Phenotype , Selection Bias , United StatesABSTRACT
OBJECTIVE: Increased cardiovascular and cerebrovascular morbidity and mortality in hypopituitary subjects may be linked to inappropriate glucocorticoid exposure; however, the pathophysiology remains unclear. We aimed to examine the effect of three commonly prescribed hydrocortisone (HC) regimens on vascular risk factors. DESIGN: An open crossover study randomising ten hypopituitary men with severe adrenocorticotrophic hormone deficiency to three HC dose regimens: dose A (20mg mane and 10mg tarde), dose B (10mg mane and 10mg tarde) and dose C (10mg mane and 5mg tarde). METHODS: Following 6 weeks on each regimen, participants underwent 24-h serum cortisol sampling, 24-h ambulatory blood pressure (BP) measurements, calculation of the Ambulatory Arterial Stiffness Index (AASI), oral glucose tolerance testing and fasting serum osteoprotegerin (OPG) sampling. RESULTS: There were no differences in 24-h BP between dose regimens and controls; however, low-dose HC replacement (dose C) was associated with the lowest AASI, indicating a less stiff arterial tree (P<0.05) compared with the other dose regimens. Loss of the physiologic nocturnal BP dip was more common in higher HC replacement regimens, although only significant for dose B compared with dose C (P=0.03). Twenty per cent of patients had abnormal glucose tolerance, but this was unrelated to dose regimen. OPG correlated strongly with 24-h BP in those on dose A only (r=0.65, P=0.04). CONCLUSION: Currently prescribed HC replacement doses do not result in significant differences in absolute BP levels or improvements in insulin sensitivity. However, lower HC doses may result in lower arterial stiffness and a more physiological nocturnal BP dip. Long-term studies are required to confirm these findings and evaluate their impact on vascular morbidity in this patient group.