Disparities in Diabetes Care: Differences Between Rural and Urban Patients Within a Large Health System.

PURPOSE: We sought to ascertain factors associated with the quality of diabetes care, comparing rural vs urban diabetic patients in a large health care system. METHODS: We conducted a retrospective cohort study assessing patients' attainment of the D5 metric, a diabetes care metric having 5 components (no tobacco use, glycated hemoglobin [A1c] level less than 8%, blood pressure less than 140/90 mm Hg, low-density lipoprotein cholesterol level at goal or statin prescribed, and aspirin use consistent with clinical recommendations). Covariates included age, sex, race, adjusted clinical group (ACG) score as a marker of complexity, insurance type, primary care clinician type, and health care use data. RESULTS: The study cohort consisted of 45,279 patients with diabetes, 54.4% of whom resided in rural locations. The D5 composite metric was met in 39.9% of rural patients and 43.2% of urban patients (P <.001). Rural patients were significantly less likely to have attained all metric goals than urban counterparts (adjusted odds ratio [AOR] = 0.93; 95% CI, 0.88-0.97). The rural group had fewer outpatient visits (mean number of visits = 3.2 vs 3.9, P <.001) and less often had an endocrinology visit (5.5% vs 9.3%, P <.001) during the 1-year study period. Patients with an endocrinology visit were less likely to have met the D5 metric (AOR = 0.80; 95% CI, 0.73-0.86), whereas the more outpatient visits patients had, the greater their likelihood of attainment (AOR per visit = 1.03; 95% CI, 1.03-1.04). CONCLUSIONS: Rural patients had worse diabetes quality outcomes than their urban counterparts, even after adjustment for other contributing factors and despite being part of the same integrated health system. Lower visit frequency and less specialty involvement in the rural setting are possible contributing factors.

Serum 25-Hydroxyvitamin D and Subsequent Cancer Incidence and Mortality: A Population-Based Retrospective Cohort Study.

OBJECTIVE: To determine the relationship between 25-hydroxyvitamin D (25[OH]D) values and subsequent cancer incidence and mortality. PATIENTS AND METHODS: We identified all adult patients living in Olmsted County, Minnesota, between January 1, 2005, and December 31, 2011, who had at least 1 25(OH)D measurement and no prior diagnosis of cancer. Cancer outcomes were retrieved starting 30 days after 25(OH)D measurement and until patients' final clinical visit as an Olmsted County resident; December 31, 2014; or death. Cox proportional hazards regression was used to analyze data. RESULTS: A total of 8700 individuals had a 25(OH)D measurement and no history of cancer, with a mean ± SD 25(OH)D value of 29.7±12.8 ng/mL (to convert to nmol/L, multiply by 2.496). The mean ± SD age was 51.5±16.4 years, and most were women (78.1%; n=6796) and White (85.7%; n=7460). A total of 761 individuals developed cancer (skin cancer, n=360; nonskin cancer, n=401) during a median follow-up of 4.6 (interquartile range, 3.4-6.1) years. Compared with participants with 25(OH)D values of 20 to 50 ng/mL (reference group), those with 25(OH)D values less than 12 ng/mL had a greater nonskin cancer incidence (hazard ratio [HR], 1.56; 95% CI, 1.03 to 2.36; P=.04) after adjustment. There was no association between 25(OH)D values and total cancer or skin cancer incidence. Compared with individuals from the reference group, 25(OH)D levels less than 12 ng/mL (HR, 2.35; 95% CI, 1.01 to 5.48; P=.047) and 12 to 19 ng/mL (HR, 2.10; 95% CI, 1.05 to 4.22; P=.04) were associated with increased cancer mortality. CONCLUSION: Low 25(OH)D levels were associated with increased risk for incident nonskin cancer and cancer-related mortality.

Serum 25-hydroxyvitamin D values and risk of incident cardiovascular disease: A population-based retrospective cohort study.

BACKGROUND: Concentrations of serum 25-hydroxyvitamin D [25(OH)D] below 20 ng/mL and above 50 ng/mL have been associated with chronic adverse events including cardiovascular disease. OBJECTIVE: To conduct a comprehensive population-based study in the United States of the relationship of low and high serum 25(OH)D levels with cardiovascular disease. METHODS: We identified all serum 25(OH)D measurements in adults age 18 years and older residing in Olmsted County, MN between January 1, 2005 and December 31, 2011, using the resources of the Rochester Epidemiology Project. Any new diagnosis of cardiovascular disease was the primary outcome, and time zero was 30 days after first 25(OH)D measurement. Patients were followed until their last clinical visit as an Olmsted County resident, December 31, 2014, or death. Categories of 25(OH)D values were examined using predetermined ranges of interest: <12, 12-19, 20-50 (reference range), and >50 ng/mL. Multivariable Cox proportional hazards models were adjusted for age, BMI, sex, race, smoking history, season of 25(OH)D measurement, hypertension, hyperlipidemia, socioeconomic status and Charlson comorbidity index at time of 25(OH)D measurement. RESULTS: A total of 11,002 unique persons had a 25(OH)D measurement, with a mean (±SD) value of 30.0 ± 12.9 ng/mL. Mean age was 54.3 ± 17.2 years, and the majority were female (77.1 %) and white (87.6 %). There were 4124 new diagnoses of cardiovascular disease in this cohort after a median overall follow-up of 4.8 years (IQR 3.4-6.2). Adjusted cardiovascular disease hazard ratios (HRs) (95 % confidence interval) for 25(OH)D values <12, 12-19, and >50 ng/mL, compared to the reference range 20-50 ng/mL, were 1.28 (1.12-1.46), 1.19 (1.09-1.31), and 1.10 (0.95-1.26), respectively. CONCLUSION: Values of 25(OH)D <20 ng/mL were associated with development of a new diagnosis of cardiovascular disease. There was no significant association between 25(OH)D values >50 ng/mL and cardiovascular disease.

Cardiac, bone and growth plate manifestations in hypocalcemic infants: revealing the hidden body of the vitamin D deficiency iceberg.

BACKGROUND: Whilst hypocalcemic complications from vitamin D deficiency are considered rare in high-income countries, they are highly prevalent among Black, Asian and Minority Ethnic (BAME) group with darker skin. To date, the extent of osteomalacia in such infants and their family members is unknown. Our aim was to investigate clinical, cardiac and bone histomorphometric characteristics, bone matrix mineralization in affected infants and to test family members for biochemical evidence of osteomalacia. CASE PRESENTATION: Three infants of BAME origin (aged 5-6 months) presented acutely in early-spring with cardiac arrest, respiratory arrest following seizure or severe respiratory distress, with profound hypocalcemia (serum calcium 1.22-1.96 mmol/L). All infants had dark skin and vitamin D supplementation had not been addressed during child surveillance visits. All three had severely dilated left ventricles (z-scores + 4.6 to + 6.5) with reduced ejection fraction (25-30%; normal 55-70), fractional shortening (7 to 15%; normal 29-40) and global hypokinesia, confirming hypocalcemic dilated cardiomyopathy. They all had low serum levels of 25 hydroxyvitamin D (25OHD < 15 nmol/L), and elevated parathyroid hormone (PTH; 219-482 ng/L) and alkaline phosphatase (ALP; 802-1123 IU/L), with undiagnosed rickets on radiographs. One infant died from cardiac arrest. At post-mortem examination, his growth plate showed a widened, irregular zone of hypertrophic chondrocytes. Histomorphometry and backscattered electron microscopy of a trans-iliac bone biopsy sample revealed increased osteoid thickness (+ 262% of normal) and osteoid volume/bone volume (+ 1573%), and extremely low bone mineralization density. Five of the nine tested family members had vitamin D deficiency (25OHD < 30 nmol/L), three had insufficiency (< 50 nmol/L) and 6/9 members had elevated PTH and ALP levels. CONCLUSIONS: The severe, hidden, cardiac and bone pathology described here exposes a failure of public health prevention programs, as complications from vitamin D deficiency are entirely preventable by routine supplementation. The family investigations demonstrate widespread deficiency and undiagnosed osteomalacia in ethnic risk groups and call for protective legislation.

Nutritional rickets around the world: an update.

Worldwide, nutritional rickets continues to be an evolving problem with several causes. This paper provides an updated literature review characterising the prevalence, aetiology, pathophysiology and treatment of nutritional rickets worldwide. A systematic review of articles on nutritional rickets from various geographical regions was undertaken. For each region, key information was extracted, including prevalence, cause of rickets specific to the region, methods of confirming the diagnosis and current treatment and preventive measures. Calcium deficiency continues to be a major cause of rickets in Africa and Asia. Vitamin D deficiency rickets is perhaps increasing in the Americas, Europe and parts of the Middle East. There continues to be a distinct presentation of calcium-predominant versus vitamin D predominant rickets, although there are overlapping features. More careful diagnosis of rickets and reporting of 25-OHD concentrations has improved accurate knowledge of rickets prevalence and better delineated the cause. Nutritional rickets continues to be an evolving and multi-factorial problem worldwide. It is on a spectrum, ranging from isolated vitamin D deficiency to isolated calcium deficiency. Specific areas which require emphasis include a consistent community approach to screening and diagnosis, vitamin D supplementation of infants and at-risk children, prevention of maternal vitamin D deficiency and the provision of calcium in areas with low calcium diets.

Comparison of Clinical Risk Tools for Predicting Osteoporosis in Women Ages 50-64.

OBJECTIVE: The objective of this study was to compare the performance of the US Preventive Services Task Force (USPSTF) recommended WHO Fracture Risk Assessment Tool (FRAX) threshold score of 9.3% (calculated without femoral neck bone density) with the Simple Calculated Osteoporosis Risk Estimate (SCORE), Osteoporosis Self-Assessment Tool (OST), and the Osteoporosis Risk Assessment Instrument (ORAI) to identify osteoporosis in younger women. METHODS: We conducted a retrospective review of women ages 50 to 64 years who underwent dual-energy radiographic absorptiometry (DXA) at our institution over a 6-month period. Scores for the FRAX, ORAI, OST, and SCORE tools were calculated using various thresholds: FRAX ≥9.3%, SCORE ≥6, OST <2, and ORAI ≥9. Sensitivity, specificity, and area under the receiver-operating characteristic curve for detection of densitometric osteoporosis by DXA for each tool were compared. RESULTS: A total of 290 women were identified. Of these, 284 (97.9%) were white, and the mean ± standard deviation age was 56.6 ± 3.4 years. Fifty (17.2%) had osteoporosis of the lumbar spine and/or femoral neck on DXA. Sensitivity, specificity, and area under the receiver-operating characteristic curve for identifying densitometric osteoporosis at the femoral neck and/or spine were 36%, 73%, and 0.55 for FRAX; 74%, 42%, and 0.58 for SCORE; 56%, 69%, and 0.63 for the OST; and 52%, 67%, and 0.60 for the ORAI, respectively. CONCLUSIONS: DXA screening based on the USPSTF-recommended FRAX threshold score of 9.3% has a low sensitivity to identify densitometric osteoporosis in women ages 50 to 64. Lowering the threshold score would increase sensitivity but would also increase the number of women sent for screening DXA. Use of the validated SCORE tool would improve sensitivity to identify osteoporosis in this age group.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.

BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.

BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Increasing incidence of nutritional rickets: a population-based study in Olmsted County, Minnesota.

OBJECTIVE: To determine temporal trends in incidence and risk factors of nutritional rickets in a community-based population. PATIENTS AND METHODS: Rochester Epidemiology Project data were used to identify all children (aged <18 years) residing in Olmsted County, Minnesota, between January 1, 1970, and December 31, 2009, with diagnostic codes corresponding to rickets, vitamin D deficiency, hypovitaminosis D, rachitis, osteomalacia, genu varum, genu valgum, craniotabes, hypocalcemia, hypocalcemic seizure, and tetany. Record abstraction was performed to select individuals with radiographic confirmation of rickets. Age- and sex-matched controls were identified for the evaluation of risk factors. The main outcome measure was radiographic evidence of rickets without identifiable inherited, genetic, or nonnutritional causes. Incidence rates were calculated using Rochester Epidemiology Project census data. RESULTS: Of 768 children with eligible diagnostic codes, 23 had radiographic evidence of rickets; of these, 17 children had nutritional rickets. All 17 children were younger than 3 years, and 13 (76%) were of nonwhite race/ethnicity. Clinical presentation included poor growth (n=12), leg deformity (n=8), motor delay (n=5), leg pain (n=3), weakness (n=3), and hypocalcemia or tetany (n=2). The incidence of nutritional rickets in children younger than 3 years was 0, 2.2, 3.7, and 24.1 per 100,000 for the decades beginning in 1970, 1980, 1990, and 2000, respectively (P=.003 for incidence trend). Nutritional rickets was associated with black race, breast-feeding, low birth weight, and stunted growth (P<.05 for all). Four of 13 patients (31%) who underwent 25-hydroxyvitamin D testing had values less than 10 ng/mL. CONCLUSION: Nutritional rickets remains rare, but its incidence has dramatically increased since 2000. Not all cases of rickets can be attributed to vitamin D deficiency.

Enzyme-replacement therapy in life-threatening hypophosphatasia.

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

Vitamin D insufficiency.

Vitamin D deficiency, which classically manifests as bone disease (either rickets or osteomalacia), is characterized by impaired bone mineralization. More recently, the term vitamin D insufficiency has been used to describe low levels of serum 25-hydroxyvitamin D that may be associated with other disease outcomes. Reliance on a single cutoff value to define vitamin D deficiency or insufficiency is problematic because of the wide individual variability of the functional effects of vitamin D and interaction with calcium intakes. In adults, vitamin D supplementation reduces the risk of fractures and falls. The evidence for other purported beneficial effects of vitamin D is primarily based on observational studies. We selected studies with the strongest level of evidence for clinical decision making related to vitamin D and health outcomes from our personal libraries of the vitamin D literature and from a search of the PubMed database using the term vitamin D in combination with the following terms related to the potential nonskeletal benefits of vitamin D: mortality, cardiovascular, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, psychiatric, and pain. Conclusive demonstration of these benefits awaits the outcome of controlled clinical trials.

A comparison of iron and folate with folate alone in hematologic recovery of children treated for acute malaria.

Concern has been raised that iron supplementation for treatment of acute malaria may worsen the severity of malaria. We compared the effect of iron and folate with folate alone on hematologic recovery in children treated for acute malaria. We randomized 82 children 6-60 months of age from Nigeria with smear-positive malaria and anemia (hematocrit < 33%) to receive iron (2 mg/kg/day) plus folate (5 mg/day) or folate alone in addition to antimalarial drugs. The mean ± SD hematocrit at baseline was 28.5% ± 2.9%. At four weeks, the mean hematocrit increased by 2.5% ± 1.6% in the iron plus folate group and by 1.4% ± 1.0% in the folate alone group (P = 0.001). Baseline hematocrit, iron supplementation, weight for height, and weekly meat intake were significant predictors of final hematocrit. The effect of iron was not significantly modified by baseline hematocrit, weekly meat intake, nutritional status, mother's education, sex, or age of the child. Iron supplementation improved hematologic recovery in children with malarial anemia.

Genital tract abnormalities among female sex workers who douche with lemon/lime juice in Nigeria.

Vaginal douche products have been associated with cervical cancer. We examined female sex workers (FSWs) in Nigeria who douche with lemon or lime juice and compared the findings with that of nonusers. We obtained Pap smears and performed colposcopy of the vulva, vagina and cervix. A total of 374 FSWs comprising 81 Lemon users (LUs) and 293 non lemon users (NLUs) were examined. Their mean age was 27.8 +/- 6.7 (range 16-63) years. At colposcopy, 17 (4.5%) had genital warts [LUs 5 (6.2%); NLUs 12 (4.1%); p=0.43], 61 (16.3%) had suspected squamous intraepithelial lesions (SILs) [LUs 17 (21.0%); NLUs 44 (15.0%); p=0.20] and 65 (17.4%) had other findings. Pap smear cytology showed that 87 (24.6%) had SILs [LUs 26 (33.3%); NLUs 61 (22.1%); p=0.03]. Lemon/lime use was associated with cervical dysplasia after controlling for HIV status (Adjusted OR=1.8; 95% CI, 1.0-3.0). Our data suggests an association between the practice of douching with citrus juice and cervical dysplasia.

Nutritional rickets in ichthyosis and response to calcipotriene.

Nutritional rickets has occasionally been described in children with lamellar ichthyosis, but their vitamin D endocrine status has not been described. We report 3 cases of vitamin D-deficiency rickets associated with ichthyosis in African children. A 13-month-old Nigerian boy with lamellar ichthyosis had rib beading, elevated alkaline phosphatase, and rachitic changes on radiographs. His rickets did not resolve with calcium therapy, and his 25-hydroxyvitamin D level was low. His rickets resolved with parenteral vitamin D treatment, but his skin did not improve. Topical 0.005% calcipotriene (an analog of 1,25-dihydroxyvitamin D that has been useful in treating adults with psoriasis) was similarly ineffective in improving the child's skin condition. An 8-year-old Nigerian boy with life-long skin findings consistent with lamellar ichthyosis had windswept deformity of the legs with rib beading and enlargement of the wrists and ankles. Radiographs showed active rickets, and the boy had an elevated alkaline phosphatase level and a decreased calcium level. Before knowing that his 25-hydroxyvitamin D level was low, he was treated with calcium and showed radiologic improvement. The skin did not improve with resolution of the rickets but did improve with unilateral topical application of 0.005% calcipotriene. A 7-year-old South African girl presented with progressive windswept deformities of the legs and a 4-year history of skin disease (and a skin biopsy consistent with X-linked ichthyosis). Radiographs and biochemical data confirmed active rickets. Her rickets improved dramatically with vitamin D treatment. Thus, 3 African children with ichthyosis developed vitamin D-deficiency rickets, probably because of a combination of impaired skin production and sunlight avoidance. This is consistent with previous findings of hypovitaminosis D in adults with ichthyosis and other disorders of keratinization. Measurement of 25-hydroxyvitamin D may be indicated in children with ichthyosis to identify those at risk for vitamin D-deficiency rickets, because it is possible that the cutaneous synthesis of vitamin D in such children is impaired. Although the ichthyosis did not improve with resolution of vitamin D deficiency and rickets, 1 of 2 children treated with topical calcipotriene showed improvement in the treated areas of skin. Calcipotriene does not seem to be effective in reversing systemic vitamin D deficiency but can be effective in improving the severity of skin disease in children with ichthyosis.

Oral manifestations of HIV-AIDS in Nigerian patients.

Because of the unique features of the AIDS epidemic in West Africa, we sought to determine if the spectrum of oral lesions among Nigerian patients with HIV-AIDS differs from that found in other regions. Of 500 patients examined, 266 (53%) had oral lesions. Lesions due to candidiasis were present in 244 (49%), while other oral lesions were infrequent (<3% for each of the other types). Oral lesions were associated with advanced disease stage (P < 0.001), a history of urethritis in men (P < 0.001), and alcohol (P < 0.001) and tobacco use (P = 0.03). A significantly lower prevalence of oral lesions (6%) was found among the 32 patients receiving antiretroviral drug treatment.