Diabetes and Multiple Long-term Conditions: A Review of Our Current Global Health Challenge.

Use of effective treatments and management programs is leading to longer survival of people with diabetes. This, in combination with obesity, is thus contributing to a rise in people living with more than one condition, known as multiple long-term conditions (MLTC or multimorbidity). MLTC is defined as the presence of two or more long-term conditions, with possible combinations of physical, infectious, or mental health conditions, where no one condition is considered as the index. These include a range of conditions such as cardiovascular diseases, cancer, chronic kidney disease, arthritis, depression, dementia, and severe mental health illnesses. MLTC has major implications for the individual such as poor quality of life, worse health outcomes, fragmented care, polypharmacy, poor treatment adherence, mortality, and a significant impact on health care services. MLTC is a challenge, where interventions for prevention and management are lacking a robust evidence base. The key research directions for diabetes and MLTC from a global perspective include system delivery and care coordination, lifestyle interventions and therapeutic interventions.

Evaluating abusive head trauma in children <5 years old: Risk factors and the importance of the social history.

BACKGROUND: Abusive head trauma (AHT) is the leading cause traumatic death in children ≤5 years of age. AHT remains seriously under-surveilled, increasing the risk of subsequent injury and death. This study assesses the clinical and social risks associated with fatal and non-fatal AHT. METHODS: A single-institution, retrospective review of suspected AHT patients ≤5 years of age between 2010 and 2016 using a prospective hospital forensic registry data yielded demographic, clinical, family, psycho-social and other follow-up information. Descriptive statistics were used to look for differences between patients with AHT and accidental head trauma. Logistic regression estimated the adjusted odds ratios (AOR) for AHT. A receiver operating characteristic (ROC) curve was created to calculate model sensitivity and specificity. RESULTS: Forensic evaluations of 783 children age ≤5 years with head trauma met the inclusion criteria; 25 were fatal with median[IQR] age 23[4.5-39.0] months. Of 758 non-fatal patients, age was 7[3.0-11.0] months; 59.5% male; 435 patients (57.4%) presented with a skull fracture, 403 (53.2%) with intracranial hemorrhage. Ultimately 242 (31.9%) were adjudicated AHT, 335(44.2%) were accidental, 181 (23.9%) were undetermined. Clinical factors increasing the risk of AHT included multiple fractures (Exp(ß) = 9.9[p = 0.001]), bruising (Expß = 5.7[p < 0.001]), subdural blood (Exp(ß) = 5.3[p = 0.001]), seizures (Exp(ß) = 4.9[p = 0.02]), lethargy/unresponsiveness (Exp(ß) = 2.24[p = 0.02]), loss of consciousness (Exp(ß) = 4.69[p = 0.001]), and unknown mechanism of injury (Exp(ß) = 3.9[p = 0.001]); skull fracture reduced the risk of AHT by half (Exp(ß) = 0.5[p = 0.011]). Social risks factors included prior police involvement (Exp(ß) = 5.9[p = 0.001]), substance abuse (Exp(ß) = 5.7[p = .001]), unknown number of adults in the home (Exp(ß) = 4.1[p = 0.001]) and intimate partner violence (Exp(ß) = 2.3[p = 0.02]). ROC area under the curve (AUC) = 0.90([95% CI = 0.86-0.93] p = .001) provides 73% sensitivity; 91% specificity. CONCLUSIONS: To improve surveillance of AHT, interviews should include and consider social factors including caregiver/household substance abuse, intimate partner violence, prior police involvement and household size. An unknown number of adults in home is associated with an increased risk of AHT. STUDY TYPE/LEVEL OF EVIDENCE: Prognostic, Level III.

Functional Genomics in Pancreatic ß Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research.

The inheritance of variants that lead to coding changes in, or the mis-expression of, genes critical to pancreatic beta cell function can lead to alterations in insulin secretion and increase the risk of both type 1 and type 2 diabetes. Recently developed clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene editing tools provide a powerful means of understanding the impact of identified variants on cell function, growth, and survival and might ultimately provide a means, most likely after the transplantation of genetically "corrected" cells, of treating the disease. Here, we review some of the disease-associated genes and variants whose roles have been probed up to now. Next, we survey recent exciting developments in CRISPR/Cas9 technology and their possible exploitation for ß cell functional genomics. Finally, we will provide a perspective as to how CRISPR/Cas9 technology may find clinical application in patients with diabetes.

Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management.

Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed.

Inflicted versus unintentional injury: towards improved detection and surveillance of supervisory neglect.

BACKGROUND: Many children evaluated for child abuse have non-inflicted injuries due to supervisory neglect. Despite its prevalence, supervisory neglect has received minimal attention. METHODS: We performed a retrospective review of patients maintained in a hospital forensic registry. Text analytics software was used to classify types of supervisory neglect from reported mechanism of injury (MOI). Logistic regression was used to assess risks associated with supervisory neglect. RESULTS: For 1185 eligible patients, 553 were classified as having unintentional injuries. Text analysis identified four types of supervisory neglect for falls (N = 376): interrupted supervision (53.4%); failure to adapt the home (26.7%); safety equipment non-compliance (12.8%); inadequate substitute care (7.0%); a fifth category was identified for non-falls (N = 54): rough handling (32.0%). Supervisory neglect was associated with MOI consistent with the injury (AOR = 15.5[p < 0.001]), no loss of consciousness (AOR = 6.8(p < 0.001]), no bruising away from the injury site (AOR = 3.7[p < 0.001]), and direct hospital presentation (AOR = 1.8[p < 0.05]). Of the 553 with unintentional injury, 62% had isolated head injuries; 20%, however, had evidence of prior head trauma. CONCLUSIONS: Interrupted supervision was the most common form of supervisory neglect. Twenty percent of forensics patients with head injury found to have non-inflicted injuries had evidence of prior head injury. Supervisory neglect suggests a high-risk population. LEVEL OF EVIDENCE: Level II, Prognosis.

How good is the evidence base for test selection in clinical guidelines?

Clinical guidelines are ubiquitous, manifold and form an integral component of evidence-based clinical practice. Guidelines on test selection are often considered a useful adjunct to aid clinical decision-making, as test selection is a complex process that is influenced by many patient, clinician and laboratory factors. However, it is important to carefully evaluate several aspects of these guidelines, which include the context of the test in the guideline, the quality of the studies underpinning recommendations, the extent of the evaluation of effectiveness (or performance) of the specific test and in the clinical pathway, its applicability and ease of implementation. A robust evaluation of a diagnostic test should incorporate several stages including evaluation in healthy, symptomatic but unaffected and affected populations, and importantly a measurement of impact on patient outcomes. Few diagnostic studies meet these criteria, and therefore crucial aspects of test evaluation are overlooked prior to incorporation into clinical guidelines. Whilst efforts are made to standardise reporting of studies, strength of evidence and quality of guidelines, further work is required to improve the quality of the diagnostic studies that formulate these guidelines. It is important that clinicians using guidelines for test selection appreciate the limitations of the diagnostic test, and the guidelines themselves.

Adjuvant lithium improves the efficacy of radioactive iodine treatment in Graves' and toxic nodular disease.

CONTEXT: Lithium increases iodine retention in the thyroid gland and inhibits thyroid hormone release. Although lithium has been reported to improve the efficacy of radioactive iodine (RAI) treatment in Graves' disease, its role as an adjunct to RAI treatment of hyperthyroidism, particularly in toxic nodular disease, remains contentious. OBJECTIVE: To assess whether adjuvant lithium increases the efficacy of a fixed dose RAI regimen in Graves' and toxic nodular hyperthyroid patients. DESIGN AND SETTING: Retrospective cohort study in a tertiary referral centre. Two hundred and four hyperthyroid patients (163 Graves' disease, 26 toxic multinodular goitre and 15 solitary toxic thyroid adenoma). INTERVENTION: One hundred and three patients received RAI alone (median dose 558 MBq). One hundred and one patients received RAI (median dose 571 MBq) with adjuvant lithium (800 mg/day for 10 days). MAIN OUTCOME MEASURE: Proportion of patients cured at any time over a 1-year period following RAI treatment. Cure was defined as sustained (two or more sequential time points) biochemical euthyroidism or hypothyroidism during the follow-up period. RESULTS: The likelihood of cure at any time was 60% greater in all hyperthyroid patients (Graves' plus toxic nodular disease) receiving adjuvant lithium (n = 204, P = 0·003). In patients with Graves' disease receiving RAI + lithium, there was a similar occurrence in cure (n = 163, P = 0·006). Cure was twice as likely in patients with toxic nodular (non-Graves') disease receiving RAI + lithium compared with RAI alone (n = 41, P = 0·01). CONCLUSIONS: This study supports the use of adjuvant lithium to improve the efficacy of RAI in the treatment of Grave's disease and suggests a novel role in the management of toxic nodular (non-Graves') disease.

Severe hypernatraemia associated with growth hormone replacement therapy in a patient with septo-optic dysplasia.

BACKGROUND: The anti-natriuretic properties of growth hormone (GH) are well established. Growth hormone deficiency (GHD) results in salt and water depletion and studies confirm that replacement leads to sodium and vasopressin-mediated water retention in patients with intact posterior pituitary function. METHODS: We report the case of a 20-year-old male patient with septo-optic dysplasia, fixed cranial diabetes insipidus (DI) and an abnormal thirst threshold. With careful parental support, his sodium levels remained stable for many years on a fixed dose of DDAVP and a supervised fluid intake of 2.5 l/day. Several years after the original diagnosis, he was found to be ACTH deficient and following commencement of hydrocortisone replacement therapy became hypernatraemic. A new sodium homoeostasis was established with a higher dose of DDAVP. Subsequently, he developed symptoms typical of GHD and, after biochemical confirmation, GH replacement was commenced. RESULTS: There was an immediate clinical improvement (increased alertness, improved concentration) but severe hypernatraemia developed (peak 169 mmol/l) necessitating revision of his desmopressin and fluid intake regimen. CONCLUSION: Most GHD patients have intact posterior pituitary function. This case report highlights the powerful anti-natriuretic properties of GH. Endocrine physicians should be alert to this in patients with fixed DI and an abnormal thirst threshold.