Challenges of addressing opioid use disorder in rural settings: A state perspective.

Rural states and communities continue to face significant challenges as they work to address the ongoing opioid epidemic and to implement specific strategies for prevention and treatment of opioid use disorder (OUD) and other substance use disorders (SUDs). While a growing number of innovative strategies have been identified that can offer promise for rural communities, state and clinical leaders from rural communities will need to identify evidence-based approaches that can work best in their communities, and ways to tailor options to meet their unique needs. This article identifies a set of five considerations for rural states and communities as they continue their work to identify solutions to this deadly epidemic.

Uncommon Presentations of Diabetes: Zebras in the Herd.

The majority of patients with diabetes are diagnosed as having either type 1 or type 2 diabetes. However, when encountered in clinical practice, some patients may not match the classic diagnostic criteria or expected clinical presentation for either type of the disease. Latent autoimmune, ketosis-prone, and monogenic diabetes are nonclassical forms of diabetes that are often misdiagnosed as either type 1 or type 2 diabetes. Recognizing the distinguishing clinical characteristics and understanding the diagnostic criteria for each will lead to appropriate treatment, facilitate personalized medicine, and improve patient outcomes.

Precision Medicine: Long-Term Treatment with Sulfonylureas in Patients with Neonatal Diabetes Due to KCNJ11 Mutations.

PURPOSE OF REVIEW: The goal of this review is to provide updates on the safety and efficacy of long-term sulfonylurea use in patients with KCNJ11-related diabetes. Publications from 2004 to the present were reviewed with an emphasis on literature since 2014. RECENT FINDINGS: Sulfonylureas, often taken at high doses, have now been utilized effectively in KCNJ11 patients for over 10 years. Mild-moderate hypoglycemia can occur, but in two studies with a combined 975 patient-years on sulfonylureas, no severe hypoglycemic events were reported. Improvements in neurodevelopment and motor function after transition to sulfonylureas continue to be described. Sulfonylureas continue to be an effective, sustainable, and safe treatment for KCNJ11-related diabetes. Ongoing follow-up of patients in research registries will allow for deeper understanding of the facilitators and barriers to long-term sustainability. Further understanding of the effect of sulfonylurea on long-term neurodevelopmental outcomes, and the potential for adjunctive therapies, is needed.

Supporting Physicians and Practice Teams in Efforts to Address the Opioid Epidemic.

Primary care physicians and practice teams increasingly recognize the need to take a role in addressing the growing epidemic of opioid use disorder (OUD) and opioid-related drug overdose deaths, but face considerable challenges in doing so. Through its work supporting practice transformation efforts, sharing innovations, and connecting key sectors within communities, the Network for Regional Healthcare Improvement and several of its member regional health improvement collaboratives have identified innovative ways to support physicians and practice teams in transforming practice in ways that address a spectrum of issues related to opioid use. These strategies include efforts to prevent, identify, and treat opioid addiction, including reducing inappropriate prescribing; improving opioid prescribing safety; compassionately tapering chronic and/or high-dose opioid regimens; appropriately screening for and identifying OUD; initiating treatment with evidence-based medications for OUD within practice settings; and prescribing life-saving naloxone to reverse opioid overdose. By outlining specific initiatives and practice transformation efforts that several regional health improvement collaboratives across the country have implemented to support clinicians and their teams, this article offers examples of how clinicians can get support from collaboratives in their region to implement practice improvement efforts to advance this critically important work.

Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features.

PURPOSE OF REVIEW: The goal of this review is to provide updates on congenital (neonatal) diabetes from 2011 to present, with an emphasis on publications from 2015 to present. RECENT FINDINGS: There has been continued worldwide progress in uncovering the genetic causes of diabetes presenting within the first year of life, including the recognition of nine new causes since 2011. Management has continued to be refined based on underlying molecular cause, and longer-term experience has provided better understanding of the effectiveness, safety, and sustainability of treatment. Associated conditions have been further clarified, such as neurodevelopmental delays and pancreatic insufficiency, including a better appreciation for how these "secondary" conditions impact quality of life for patients and their families. While continued research is essential to understand all forms of congenital diabetes, these cases remain a compelling example of personalized genetic medicine.

Monogenic diabetes: the impact of making the right diagnosis.

PURPOSE OF REVIEW: Monogenic forms of diabetes have received increased attention and genetic testing is more widely available; however, many patients are still misdiagnosed as having type 1 (T1D) or type 2 diabetes. This review will address updates to monogenic diabetes prevalence, identification, treatment, and genetic testing. RECENT FINDINGS: The creation of a T1D genetic risk score and the use of noninvasive urinary C-peptide creatinine ratios have provided new tools to aid in the discrimination of possible monogenic diabetes from likely T1D. Early, high-dose sulfonylurea treatment in infants with a KCNJ11 or ABCC8 mutation continues to be well tolerated and effective. As the field moves towards more comprehensive genetic testing methods, there is an increased opportunity to identify novel genetic causes. Genetic testing results continue to allow for personalized treatment but should provide patient information at an appropriate health literacy level. SUMMARY: Although there have been clinical and genetic advances in monogenic diabetes, patients are still misdiagnosed. Improved insurance coverage of genetic testing is needed. The majority of data on monogenic diabetes has been collected from Caucasian populations, therefore, research studies should endeavor to include broader ethnic and racial diversity to provide comprehensive information for all populations.

Hypoglycemia in sulfonylurea-treated KCNJ11-neonatal diabetes: Mild-moderate symptomatic episodes occur infrequently but none involving unconsciousness or seizures.

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.

Management and pregnancy outcomes of women with GCK-MODY enrolled in the US Monogenic Diabetes Registry.

AIMS: GCK-MODY is characterized by mild hyperglycemia. Treatment is not required outside of pregnancy. During pregnancy, insulin treatment is recommended if second trimester fetal ultrasound monitoring shows macrosomia, suggesting the fetus has not inherited the GCK gene. There are limited data about GCK-MODY management in pregnancy. The aim of this study was to examine clinical management and pregnancy outcomes amongst women with a known diagnosis of GCK-MODY. METHODS: In this observational, cross-sectional study, a survey was distributed via Redcap to women ≥ 18 years enrolled in the University of Chicago Monogenic Diabetes Registry (n = 94). All or part of the survey was completed by 54 women (128 pregnancies). RESULTS: There were 78 term births (61%), 15 pre-term births (12%), and 24 miscarriages (19%). Of the 39 pregnancies where insulin was given, 22 (56%) had occasional or frequent hypoglycemia including 9 with severe hypoglycemia. Average birth weight for full-term GCK-affected infants was significantly less in cases of maternal insulin treatment versus no treatment (2967 and 3725 g, p = 0.005). For GCK-unaffected infants, conclusions are limited by small sample size but large for gestational age (LGA) was common with maternal insulin treatment (56%) and no treatment (33%), p = 0.590. CONCLUSIONS: The observed miscarriage rate was comparable to the background US population rate (15-20%). Patients treated with insulin experienced a 23% incidence of severe hypoglycemia and lower birth weights were observed in the insulin-treated, GCK-affected neonates. These data support published guidelines of no treatment if the fetus is suspected to have inherited GCK-MODY and highlight the importance of additional studies to determine optimal pregnancy management for GCK-MODY, particularly among unaffected fetuses.

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated.

Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis <6 months) provides important insights into ß-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are four times more likely to have childhood diabetes with an intermediate HLA association. It is not known whether DS can cause PNDM. We found that trisomy 21 was seven times more likely in our PNDM cohort than in the population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected) and none of the 13 DS-PNDM patients had a mutation in the known PNDM genes that explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4 of 9 DS-PNDM patients, but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes (T1D). We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental T1D that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated.

GCK-MODY in the US Monogenic Diabetes Registry: Description of 27 unpublished variants.

We report on 134 unique GCK variants in 217 families, including 27 unpublished variants, identified in the US Monogenic Diabetes Registry in the last decade. Using ACMG guidelines, 26% were pathogenic, 56% likely pathogenic and 18% were of uncertain significance. Those with pathogenic variants had clinical features consistent with GCK-MODY.

Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison With GCK-MODY (MODY2).

Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (n = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase-maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A1c was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose insulin infusion suppressed endogenous glucose production similarly in all groups and suppressed nonesterified fatty acids similarly between control subjects and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control subjects and GCK-MODY but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed that insulinemia-but not glycemia-was significantly associated with muscle insulin sensitivity. These data suggest that iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes.

Congenital forms of diabetes: the beta-cell and beyond.

The majority of patients diagnosed with diabetes less than 6 months of age, and many cases diagnosed between 6 and 12 months of age, have a gene mutation that causes permanent or transient hyperglycemia. Recent research advances have allowed for the discovery of new causes of congenital diabetes, including genes involved in pancreatic development (GATA4, NKX2-2, MNX1) and monogenic causes of autoimmune dysregulation (STAT3, LRBA). Ongoing follow-up of patients with KCNJ11 and ABCC8 mutations has supported the safety and efficacy of sulfonylureas, as well as the use of insulin pumps and continuous glucose monitors in infants with insulin-requiring forms of monogenic diabetes. Future studies are needed to improve clinical care and outcomes for these patients and their families.

Neonatal Diabetes Mellitus: An Update on Diagnosis and Management.

Neonatal diabetes mellitus is likely to be due to an underlying monogenic defect when it occurs at less than 6 months of age. Early recognition and urgent genetic testing are important for predicting the clinical course and raising awareness of possible additional features. Early treatment of sulfonylurea-responsive types of neonatal diabetes may improve neurologic outcomes. It is important to distinguish neonatal diabetes mellitus from other causes of hyperglycemia in newborns. Other causes include infection, stress, inadequate pancreatic insulin production in preterm infants, among others. This review explores the diagnostic approach, mutation types, management, and clinical course of neonatal diabetes.

Early Intensive Insulin Use May Preserve ß-Cell Function in Neonatal Diabetes Due to Mutations in the Proinsulin Gene.

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.

An Ecological and Human Biomonitoring Investigation of Mercury Contamination at the Aamjiwnaang First Nation.

The Aamjiwnaang First Nations community is located in Canada's 'Chemical Valley' situated in southwest Ontario near Sarnia. Mercury pollution in the region has been known since the 1940s but little is known about levels in the environment and area residents. The current study, using ecological and human exposure assessment methods, was conducted at the community's request to help fill these gaps. First, Canada's National Pollutant Release Inventory and the U.S. Toxics Release Inventory were queried to investigate mercury releases from area facilities. In 2010, 700 pounds of mercury were emitted into the air, 25 pounds were released into water bodies, and 93 thousand pounds were disposed of on-site via underground injections or into landfills, and together these show continued releases into the region. Second, mercury levels were measured in stream sediment and nearby soil from sites at Aamjiwnaang (n = 4) and off Reserve (n = 19) in Canada and the U.S. during three seasons that spanned 2010-2011. Total mercury in sediment across all sites and sampling seasons ranged from 5.0 to 398.7 µg/kg, and in soils ranged from 1.2 to 696.2 µg/kg. Sediment and soil mercury levels at Aamjiwnaang were higher than the reference community, and Aamjiwnaang's Talfourd Creek site had the highest mercury levels. Third, a biomonitoring study was performed with 43 mother-child pairs. Hair (mean ± SD of all participants: 0.18 ± 0.16 µg/g) and blood (1.6 ± 2.0 µg/L) mercury levels did not differ between participants studied on- and off-Reserve, likely because of limited seafood intake (<1 serving/week). Urine mercury levels (0.5 ± 0.8 µg/L) were significantly higher (1.5-2.5 times) in mother-child pairs living on-Reserve versus those living off-Reserve. In general, the study links evidence of mercury sources, environmental fate, and human exposures, and in doing so it shows that mercury levels in ecological and human samples are similar to values found in other areas, though there are some trends and evidence of contamination at Aamjiwnaang that warrant attention.

Evaluation of a primary care intervention on body mass index: the Maine Youth Overweight Collaborative.

BACKGROUND: We evaluated the impact of a brief primary-care-based intervention, The Maine Youth Overweight Collaborative (MYOC), on BMI (kg/m(2)) z-score change among participants with obesity (BMI ≥95th percentile for age and sex), overweight (BMI ≥85th and <95th percentile), and healthy weight (≥50th and <85th percentile). METHODS: A quasi-experimental field trial with nine intervention and nine control sites in urban and rural areas of Maine, MYOC focused on improvements in clinical decision support, charting BMI percentile, identifying patients with obesity, appropriate lab tests, and counseling families/patients. Retrospective longitudinal record reviews assessed BMI z-scores preintervention (from 1999 through October 2004) and one postintervention time point (between December 2006 and March 2008). Participants were youth ages 5-18 having two visits before the intervention with weight percentile greater than or equal to 95% (N=265). Secondary analyses focused on youths who are overweight (N=215) and healthy weight youth (N=506). RESULTS: Although the MYOC intervention demonstrated significant provider and office system improvements, we found no significant changes in BMI z-scores in intervention versus control youth pre- to postintervention and significant flattening of upward trends among both intervention and control sites (p<0.001). CONCLUSIONS: This brief office-based intervention was associated with no significant improvement in BMI z-scores, compared to control sites. An important avenue for obesity prevention and treatment as part of a multisector approach in communities, this type of primary care intervention alone may be unlikely to impact BMI improvement given the limited dosage-an estimated 4-6 minutes for one patient contact.

Impact of a primary care intervention on physician practice and patient and family behavior: keep ME Healthy---the Maine Youth Overweight Collaborative.

OBJECTIVE: To evaluate the effect of a pediatric primary care-based intervention, on improved clinical decision support and family management of risk behaviors for childhood overweight. METHODS: An experimental field trial was conducted with 12 intervention sites in urban and rural areas of Maine and nonrandomized control sites. Change was assessed by using clinical and parent measures from 9 intervention and 10 control sites before and during the Maine Youth Overweight Collaborative intervention. Longitudinal information was collected from chart audits of patients aged 5-18 years (n = 600), systematic samples of parents collected before (n = 346) and during (n = 386) the intervention in 12 sites, and systematic samples of parents in 9 intervention (n = 235) and 10 control (n = 304) sites collected during the intervention. Surveys of health care providers (n = 14 and 17) before and during the intervention were also collected. Teams worked over 18 months to implement improvements in clinical decision support, including tracking BMI percentiles, identification of overweight patients, appropriate laboratory tests, counseling of families and patients use of a behavioral screening tool, and other improvements following the chronic-care model targeting patients aged 5 to 18 and their families. RESULTS: Large changes occurred in clinical practice from before to during the Maine Youth Overweight Collaborative: increases in assessment of BMI (38%-94%), BMI percentile for age and gender (25%-89%), use of the 5-2-1-0 behavioral screening tool (0%-82%), and weight classification (19%-75%). Parent surveys indicated improvements in providers' behavior and rates of counseling. Intervention providers reported improvements in knowledge, attitudes, self-efficacy, and practice. CONCLUSIONS: The Maine Youth Overweight Collaborative intervention improved clinical decision support and family management of risk behaviors, indicating a promising primary care-based approach to address overweight risk among children and youth.