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To compare the clinicians' characteristics of "high adopters" and "low adopters" of an artificial intelligence (AI)-enabled electrocardiogram (ECG) algorithm that alerted for possible low left ventricular ejection fraction (EF) and the subsequent effectiveness of detecting patients with low EF.Clinicians in 48 practice sites of a US Midwest health system were cluster-randomized by the care team to usual care or to receive a notification that suggested ordering an echocardiogram in patients flagged as potentially having low EF based on an AI-ECG algorithm. Enrollment was between June 26, 2019, and July 30, 2019; participation concluded on March 31, 2020. This report is focused on those clinicians randomized to receive the notification of the AI-ECG algorithm. At the patient level, data were analyzed for the proportion of patients with positive AI-ECG results. Adoption was defined as the clinician order of an echocardiogram after prompted by the alert.A total of 165 clinicians and 11,573 patients were included in this analysis. Among patients with positive AI-ECG, high adopters (n=41) were twice as likely to diagnose patients with low EF (33.9%) vs low adopters, n=124, (16.9%); odds ratio, 1.62; 95% CI, 1.21 to 2.17). High adopters were more often advanced practice providers (eg, nurse practitioners and physician assistants) vs physicians, Family Medicine vs Internal Medicine specialty, and tended to have less complex patients.Clinicians who most frequently followed the recommendations of an AI tool were twice as likely to diagnose low EF. Those clinicians with less complex patients were more likely to be high adopters.Clinicaltrials.gov Identifier: NCT04000087.

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 [A(1c)] 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

BACKGROUND Nutritional rickets is believed to result from the interaction of inadequate serum 25-hydroxyvitamin D [25(OH)D] concentration and dietary calcium intake, but this interaction has not been confirmed in children with rickets. Determining the vitamin D requirements to prevent nutritional rickets has been thwarted by inconsistent case definition, inadequate adjustment for calcium intake and other confounders, and 25(OH)D assay variability. OBJECTIVES To model the 25(OH)D concentration associated with nutritional rickets in calcium-deprived Nigerian children, adjusted for confounding factors, and develop a general approach to define vitamin D status while accounting for calcium intake. METHODS Logistic regression was used to model the association of serum 25(OH)D with having rickets adjusted for calcium intake in a reanalysis of a case-control study in Nigerian children. The matching variables age, sex, weight-for-age z score, and 4 additional significant variables were selected [religion, age began walking, phosphorus intake, and the 25(OH)D × calcium intake interaction] using a rigorous 7-step algorithm. RESULTS Cases had significantly (P

Rates of infant vitamin D supplementation fall short of guideline recommendations. We explored this discrepancy from the clinician perspective as they advise and affect this important intervention to prevent rickets. We compared infant and high-dose maternal vitamin D supplementation prescribing attitudes and practices between infant-only clinicians (IC) and clinicians who care for mothers and infants (MIC).We surveyed clinicians in departments of family medicine, obstetrics/gynecology, primary care pediatrics, neonatology, newborn nursery, and members of vitamin D and rickets working groups and a social media group for lactation medicine providers about their perspectives and practices regarding vitamin D supplementation.360 clinician survey responses were analyzed. In current practice, IC were more likely than MIC to recommend vitamin D supplementation to exclusively (MIC are more likely than IC to embrace high-dose maternal vitamin D supplementation to provide adequate vitamin D for infants. This highlights an opportunity for further education of clinicians about this option.

Context Nutritional rickets results from the interaction of low vitamin D status and limited calcium intake. Serum alkaline phosphatase (AP) activity is a biomarker of impaired mineralization in rickets. Objective To assess the performance of serum AP activity in identifying nutritional rickets in calcium-deprived Nigerian children. Methods We reanalyzed data from a case-control study of children with active rickets and matched control subjects without rickets, using a multivariate logistic regression to assess the odds of rickets associated with AP activity, adjusting for age, sex, and weight-for-age z-score. Results A total of 122 children with rickets and 119 controls were included. Rachitic children had a mean (±SD) age of 54 ± 29 months, and 55 (45.1%) were male. Cases and controls had low dietary calcium intakes (216 ± 87 and 214 ± 96 mg/day, respectively). Serum AP activity levels in cases and controls were 812 ± 415 and 245 ± 78 U/L, respectively (P 350 U/L identified nutritional rickets in Nigerian children with sensitivity 0.93, specificity 0.92, positive likelihood ratio 11.3, and negative likelihood ratio 0.07. Conclusion An AP > 350 U/L effectively discriminated between Nigerian children with and without nutritional rickets. AP is a low-cost biochemical test that could be used to screen for nutritional rickets, but cutoff values require validation in other populations, and laboratory values need to be standardized for widespread population studies.

We have conducted a pragmatic clinical trial aimed to assess whether an electrocardiogram (ECG)-based, artificial intelligence (AI)-powered clinical decision support tool enables early diagnosis of low ejection fraction (EF), a condition that is underdiagnosed but treatable. In this trial ( NCT04000087 ), 120 primary care teams from 45 clinics or hospitals were cluster-randomized to either the intervention arm (access to AI results; 181 clinicians) or the control arm (usual care; 177 clinicians). ECGs were obtained as part of routine care from a total of 22,641 adults (N = 11,573 intervention; N = 11,068 control) without prior heart failure. The primary outcome was a new diagnosis of low EF (≤50%) within 90 days of the ECG. The trial met the prespecified primary endpoint, demonstrating that the intervention increased the diagnosis of low EF in the overall cohort (1.6% in the control arm versus 2.1% in the intervention arm, odds ratio (OR) 1.32 (1.01–1.61), P = 0.007) and among those who were identified as having a high likelihood of low EF (that is, positive AI-ECG, 6% of the overall cohort) (14.5% in the control arm versus 19.5% in the intervention arm, OR 1.43 (1.08–1.91), P = 0.01). In the overall cohort, echocardiogram utilization was similar between the two arms (18.2% control versus 19.2% intervention, P = 0.17); for patients with positive AI-ECGs, more echocardiograms were obtained in the intervention compared to the control arm (38.1% control versus 49.6% intervention, P

Objective To determine the relationship of the emotional exhaustion domain of burnout with care team composition in a Midwestern primary care practice network. Participants and Methods We studied 420 family medicine clinicians (253 physicians and 167 nurse practitioners/physician assistants [NP/PAs]) within a large integrated health system throughout 59 Midwestern communities. The observational cross-sectional study utilized a single-question clinician self-assessment of the emotional exhaustion domain of burnout on a scale of 0 (never) to 6 (daily) conducted between March 1 and April 2, 2018, and administrative data collected between January 1, 2017, and December 31, 2017. We used a multivariable linear mixed model for data analysis, adjusted for clinical- and team-level factors, including clinician sex, panel size and complexity, clinician type (physician or NP/PA), clinician full-time equivalent (FTE), total care team panel size, and number of clinicians on the care team. Results Among 217 survey respondents (51.7%), the median frequency of the emotional exhaustion domain of burnout was once per week. Adjusted analyses revealed that a greater proportion of physician FTE on the care team was associated with a lower emotional exhaustion domain of burnout among individual clinicians (P=.05). Female clinicians had a higher emotional exhaustion domain of burnout than male clinicians (P=.05). None of the other variables in the model were associated with emotional exhaustion. Conclusion Primary care teams containing both physicians and NP/PAs had lower levels of emotional exhaustion with increasing proportion of physician FTE. More work is needed to explore what other variables may be associated with burnout in primary care team-based practices.

Background: Vitamin D deficiency may increase the risk of severe COVID-19 disease. Objectives: To determine if 25-hydroxyvitamin D [25(OH)D] levels in patients hospitalized for COVID-19 were associated with the clinical outcomes of days on oxygen, duration of hospitalization, ICU admission, need for assisted ventilation, or mortality. Methods: We conducted a retrospective study of 92 patients admitted to the hospital with SARS-CoV-2 infection between April 16, 2020 and October 17, 2020. Multivariable regression was performed to assess the independent relationship of 25(OH)D values on outcomes, adjusting for significant covariates and the hospitalization day the level was tested. Results: About 15 patients (16.3%) had 25(OH)D levels Conclusion: Vitamin D status was not related to any of the primary outcomes reflecting severity of COVID-19 in hospitalized patients. However, our sample size may have lacked sufficient power to demonstrate a small effect of vitamin D status on these outcomes.

Background:Thiamin deficiency is a major public health concern in several low- and middle-income countries (LMICs)—current attention to the problem is lacking.Aim:This review discusses prevalence of thiamin insufficiency and thiamin-deficiency disorders (TDDs) in LMICs, outlines programmatic experience with thiamin interventions, and offers recommendations to improve public-health and research attention to thiamin in LMICs.Discussion:Thiamin insufficiency, i.e. low-blood-thiamin status, is endemic among several Southeast Asian countries: Cambodia (70–100% of infants and 27–100% of reproductive-age women); Laos (13% of hospitalized infants); Thailand (16–25% of children and 30% of elderly adults). Thiamin deficiency accounts for up to 45% of under-5 deaths in Cambodia, 34% of infant deaths in Laos, and 17% of infant deaths in Myanmar. Deficiency also exists in Africa, Asia, and the Americas, but these instances have typically been isolated. Exclusively breastfed infants of thiamin-deficient mothers are at highest risk for TDD and related death. Intervention strategies that have been employed to combat thiamin deficiency include food processing, fortification, supplementation, dietary diversification, and dietary behaviors, all of which have shown varying levels of effectiveness.Conclusions:We recommend universal thiamin-fortification of context-specific staple-foods in LMICs as a promising solution, as well as thiamin supplementation, particularly for pregnant and lactating women. Food processing regulations, dietary diversification, and modification of dietary behaviors to increase consumption of thiamin-rich foods may provide benefits in some circumstances, especially in countries without universal fortification programs or in populations dependent on food aid.

Background Rickets is a primary manifestation of pediatric X-linked hypophosphatemia (XLH) – a rare progressive hereditary phosphate-wasting disease. Severity is quantified from radiographs using the Rickets Severity Scale (RSS). The Radiographic Global Impression of Change (RGI-C) is a complementary assessment in which a change score is assigned based on differences in the appearance of rickets on pairs of radiographs compared side by side. Objective The current study evaluated the reliability, validity, and sensitivity to change of the RGI-C specifically in pediatric XLH. Methods The reliability, validity, and sensitivity to change of the RGI-C were evaluated using data from two studies in pediatric XLH (113 children aged 1–12 years) in which burosumab treatment significantly improved rickets severity. Intra-rater and inter-rater reliability were assessed by three pediatric radiologists. Results Intra-rater reliability for RGI-C global score was >90% for agreement within 1 point, with weighted kappa values >0.5, indicating moderate to almost perfect agreement. Inter-rater reliability was also >90% (0.47–0.52 for all reader pairs; moderate agreement). The RGI-C global score showed significant relationships with changes from baseline to week 64 in serum phosphorus (r = −0.397), alkaline phosphatase (−0.611), total RSS (−0.672), standing height (0.268), and patient-reported global functioning (0.306) and comfort/pain functioning (0.409). Based on standardized response means, RGI-C global scores were sensitive to change in RSS, differentiating between those considered improved and greatly improved. Results for validity and sensitivity to change were similar for the RGI-C wrist, knee, and standing long leg scores. Conclusion The RGI-C is a reliable, valid, and sensitive measure in pediatric XLH, and complementary to the RSS.

The objective was to determine if a greater proportion of physician full-time equivalent (FTE%) relative to nurse practitioners/physician assistants (NPs/PAs) on care teams was associated with improved individual clinician diabetes quality outcomes. The authors conducted a retrospective cross-sectional study of 420 family medicine clinicians in 110 care teams in a Midwest health system, using administrative data from January 1, 2017 to December 31, 2017. Poisson regression was used to examine the relationship between physician FTE% and the number of patients meeting 5 criteria included in a composite metric for diabetes management (D5). Covariates included panel size, clinician type, sex, years in practice, region, patient satisfaction, care team size, rural location, and panel complexity. Of the 420 clinicians, 167 (40%) were NP/PA staff and 253 (60%) were physicians. D5 criteria were achieved in 37.9% of NP/PA panels compared with 44.5% of physician panels (

Introduction: Previous studies suggest a lack of confidence among primary care providers in managing patients on chronic opioid therapy (COT) for chronic non-cancer related pain (CNCP). The US Department of Health and Human Services (HHS) recently introduced guidelines on opioid tapering. In light of these recommendations, our group developed an opioid tapering software to assist healthcare providers in managing patients on COT. Methods: The initial iteration of our software utilizes RedCap for the application programming interface (API). This tool is designed to reduce a patient9s prescribed chronic opioids by 5-10% every month, or 5 morphine milligram equivalents per day (MME), whichever is the greatest, in line with HHS guidelines. Users can also adjust the rate of taper. Discussion: Our group plans to use this software in an upcoming pilot study to taper patients on COT for CNCP. We are exploring the possibility of transitioning our software into other available APIs with the goal of integrating this software into major electronic health record systems. Our group envisions that our software will provide an additional tool within a patient-centered, multi-modal framework in managing patients on COT for CNCP.

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

To determine the relationship between 25-hydroxyvitamin D (25[OH]D) values and all-cause and cause-specific mortality.We identified all serum 25(OH)D measurements in adults residing in Olmsted County, Minnesota, between January 1, 2005, and December 31, 2011, through the Rochester Epidemiology Project. All-cause mortality was the primary outcome. Patients were followed up until their last clinical visit as an Olmsted County resident, December 31, 2014, or death. Multivariate analyses were adjusted for age, sex, race/ethnicity, month of measurement, and Charlson comorbidity index score.A total of 11,022 individuals had a 25(OH)D measurement between January 1, 2005, and December 31, 2011, with a mean ± SD value of 30.0±12.9 ng/mL. Mean age was 54.3±17.2 years, and most were female (77.1%) and white (87.6%). There were 723 deaths after a median follow-up of 4.8 years (interquartile range, 3.4-6.2 years). Unadjusted all-cause mortality hazard ratios (HRs) and 95% CIs for 25(OH)D values of less than 12, 12 to 19, and more than 50 ng/mL were 2.6 (95% CI, 2.0-3.2), 1.3 (95% CI, 1.0-1.6), and 1.0 (95% CI, 0.72-1.5), respectively, compared with the reference value of 20 to 50 ng/mL. In a multivariate model, the interaction between the effect of 25(OH)D and race/ethnicity on mortality was significant (P.001). In white patients, adjusted HRs for 25(OH)D values of less than 12, 12 to 19, 20 to 50, and greater than 50 ng/mL were 2.5 (95% CI, 2.2-2.9), 1.4 (95% CI, 1.2-1.6), 1.0 (referent), and 1.0 (95% CI, 0.81-1.3), respectively. In patients of other race/ethnicity, adjusted HRs were 1.9 (95% CI, 1.5-2.3), 1.7 (95% CI, 1.1-2.6), 1.5 (95% CI, 1.0-2.0), and 2.1 (95% CI, 0.77-5.5).White patients with 25(OH)D values of less than 20 ng/mL had greater all-cause mortality than those with values of 20 to 50 ng/mL, and white patients had greater mortality associated with low 25(OH)D values than patients of other race/ethnicity. Values of 25(OH)D greater than 50 ng/mL were not associated with all-cause mortality.

OBJECTIVE: Supplementing lactating mothers with high doses of vitamin D(3) can adequately meet vitamin D requirements of the breastfed infant. We compared the effect of bolus versus daily vitamin D(3) dosing in lactating mothers on vitamin D(3) catabolism. We hypothesized that catabolism of 25(OH)D(3) to 24,25(OH)(2)D(3) would be greater in the bolus than in the daily dose group. DESIGN, SETTING AND PATIENTS: Randomized controlled trial (clinicaltrials.gov NCT01240265) in 40 lactating women. INTERVENTIONS: Subjects were randomized to receive vitamin D(3) orally, either a single dose of 150,000 IU or 5000 IU daily for 28 days. Vitamin D metabolites were measured in serum and breast milk at baseline, 1, 3, 7, 14 and 28 days. MAIN OUTCOME MEASURE: Temporal changes in the serum 24,25(OH)(2)D(3)/25(OH)D(3) ratio. RESULTS: The concentration of serum 24,25(OH)(2)D(3) was directly related to that of 25(OH)D in both groups (r(2)=0.63; p

Background: The American Academy of Pediatrics and the National Academy of Medicine recommend vitamin D supplementation for breastfeeding infants. However, compliance with this recommendation is poor. Maternal supplementation with vitamin D is a safe and effective alternative to achieving vitamin D sufficiency in breastfeeding infants, and mothers have indicated a preference for self-supplementation over infant supplementation. Research aim: We sought to explore Family Medicine clinicians’ knowledge, attitudes, and practices regarding vitamin D supplementation recommendations for breastfeeding dyads. Methods: Fifty-six Family Medicine clinicians (including faculty physicians, resident physicians, and nurse practitioners/physician assistants) completed an online, anonymous survey regarding their knowledge and practices concerning vitamin D supplementation for breastfeeding infants. Results: The vast majority of clinicians (92.9%) correctly identified the American Academy of Pediatrics’ 2008 recommended dose for vitamin D supplementation in breastfeeding infants and estimated recommending vitamin D supplementation of exclusively breastfeeding infants 70.1% of the time. If all options were equivalent, clinicians would prefer to offer maternal or infant supplementation (50%) or maternal supplementation (37.5%) over infant supplementation (12.5%). Most (69.6%) preferred daily over monthly supplementation regimens. Conclusion: Family Medicine clinicians are knowledgeable regarding current recommendations for vitamin D supplementation in breastfeeding infants. They are also open to recommending maternal supplementation or offering parents a choice of maternal or infant vitamin supplementation.

We found a positive relationship between bone density in Nigerian children with and without rickets and that of their mothers. After treatment, children with rickets had greater bone density than children without rickets, indicating that children genetically programmed to have greater bone density may have a higher risk of rickets.To determine the relationship between bone density in children with and without rickets and that of their mothers METHODS: Using an unmatched case-control design, forearm areal bone mineral density (aBMD) was measured in 52 and 135 Nigerian children with and without rickets and their mothers, respectively. We performed multivariate linear regression analyses to assess the relationship between maternal and child aBMD Z-scores.Forearm aBMD Z-scores in children were associated with maternal aBMD Z-scores at metaphyseal (effect estimate 0.23; 95% CI 0.08 to 0.37) and diaphyseal (effect estimate 0.16; 0.01 to 0.30) sites, after adjustment for rickets in the child, child's age and sex, height-for-age Z-score, and weight-for-age Z-score. In the adjusted model, rickets was inversely associated with child's aBMD Z-score at the diaphyseal site only (- 0.45, - 0.65 to - 0.24). The positive relationship between maternal and child aBMD Z-scores was marginally greater in children with rickets (slope 0.56, r = 0.47) than without rickets (slope 0.19, r = 0.20) at the diaphyseal site only (P = 0.06 for interaction) but not at the metaphyseal site (slopes 0.35 and 0.30, respectively, P = 0.48). After treatment with calcium for 6 months, metaphyseal aBMD Z-scores were greater in children with treated rickets (effect estimate 0.26; 95% CI 0.02 to 0.49) than in those without rickets.In Nigerian children with and without rickets, forearm aBMD Z-scores were positively associated with maternal aBMD Z-scores. Active rickets in the child marginally modified the relationship at the diaphyseal site only. After treatment, children with rickets had greater metaphyseal aBMD Z-scores than children without rickets.

Background Snakebite envenoming causes considerable morbidity and mortality in northern Nigeria. The clinician's knowledge of snakebite impacts outcome. We assessed clinicians' knowledge of snakebite envenoming to highlight knowledge and practice gaps for possible intervention to improve snakebite outcomes. Methods This was a cross-sectional multicentre study of 374 doctors selected from the accident and emergency, internal medicine, family medicine/general outpatient, paediatrics and surgery departments of nine tertiary hospitals in northern Nigeria using a multistage sampling technique. A self-administered questionnaire was used to assess their sociodemographics, knowledge of common venomous snakes, snakebite first aid, snake antivenom treatment and prevention. Results The respondents' mean age was 35.6±5.8 y. They were predominantly males (70.6%) from urban hospitals (71.9%), from the northwest region (35.3%), in family medicine/general outpatient departments (33.4%), of

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: 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 4,124 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 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 50 ng/mL and cardiovascular disease.

CYP2R1 is the principal hepatic 25-hydroxylase responsible for the hydroxylation of parent vitamin D to 25-hydroxyvitamin D [25(OH)D]. Serum concentrations of 25(OH)D reflect vitamin D status, because 25(OH)D is the major circulating metabolite of vitamin D. The 1α-hydroxylation of 25(OH)D in the kidney by CYP27B1 generates the fully active vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D). The human CYP2R1 gene, located at 11p15.2, has five exons, coding for an enzyme with 501 amino acids. In Cyp2r1-/- knockout mice, serum 25(OH)D levels were reduced by more than 50% compared wild-type mice. Genetic polymorphisms of CYP2R1 account for some of the individual variability of circulating 25(OH)D values in the population. We review the evidence that inactivating mutations in CYP2R1 can lead to a novel form of vitamin D-deficiency rickets resulting from impaired 25-hydroxylation of vitamin D. We sequenced the promoter, exons and intron-exon flanking regions of the CYP2R1 gene in members of 12 Nigerian families with rickets in more than one family member. We found missense mutations (L99P and K242N) in affected members of 2 of 12 families. The L99P mutation had previously been reported as a homozygous defect in an unrelated child of Nigerian origin with rickets. In silico analyses predicted impaired CYP2R1 folding or reduced interaction with substrate vitamin D by L99P and K242N mutations, respectively. In vitro studies of the mutant CYP2R1 proteins in HEK293 cells confirmed normal expression levels but completely absent or markedly reduced 25-hydroxylase activity by the L99P and K242N mutations, respectively. Heterozygous subjects had more moderate biochemical and clinical features of vitamin D deficiency than homozygous subjects. After an oral bolus dose of 50,000 IU of vitamin D2 or vitamin D3, heterozygous subjects had lower increases in serum 25(OH)D than control subjects, and homozygous subjects had minimal increases, supporting a semidominant inheritance of these mutations. No CYP2R1 mutations were found in 27 Nigerian children with sporadic rickets, a cohort of 50 unrelated Nigerian subjects, or in 628 unrelated subjects in the 1000 Genomes Project. We conclude that mutations in CYP2R1 are responsible for an atypical form of vitamin D-deficiency rickets, which has been classified as vitamin D dependent rickets type 1B (VDDR1B, MIM 600081).

Factors that affect maternal bone mineral density may be related to the risk of nutritional rickets in their offspring. Our aim was to determine the relationship between maternal areal bone mineral density (aBMD) and rickets in Nigerian children. Using a case-control design, we measured forearm aBMD in 56 and 135 mothers of children with and without nutritional rickets, respectively. Active rickets was confirmed or excluded in all children radiographically. Using logistic regression, we assessed the association of maternal aBMD, adjusted for parity, pregnancy and lactation status, duration of most recent completed lactation, age of menarche, height, body mass index, and maternal age with nutritional rickets. The median (range) age of all mothers was 30 years (17–47 years), and parity was 4 (1 − 12). A total of 36 (19%) were pregnant and 55 (29%) were currently breast feeding. Mean (± SD) metaphyseal forearm aBMDs were 0.321 ± 0.057 and 0.316 ± 0.053 g/cm 2 in mothers of children with and without rickets, respectively (P = 0.60). Diaphyseal forearm aBMDs were 0.719 ± 0.071 and 0.715 ± 0.072 g/cm 2 , respectively (P = 0.69). In an adjusted analysis, maternal forearm aBMD, bone mineral content and bone area at metaphyseal and diaphyseal sites were not associated with rickets in the child. In the adjusted analysis, rickets was associated with shorter duration of most recently completed lactation (aOR 0.91 for each additional month; 95% CI 0.83–0.99), older maternal age (aOR 1.07 for each additional year; 1.00–1.14), and less frequent maternal use of lead-containing eye cosmetics (aOR 0.20; 95% CI 0.05–0.64), without any difference in maternal blood lead levels. Maternal age, parity, age of menarche, height, and body mass index were not associated with having had a child with rickets in multivariate analysis. Nutritional rickets in Nigerian children was not associated with maternal forearm aBMD. Other unidentified maternal characteristics and practices likely contribute to the risk of rickets in Nigerian children.

Our study investigates 25-hydroxyvitamin D levels and fracture risk using population-level data. 25-Hydroxyvitamin D values 12, 12-19, and 50 ng/mL were not associated with increased risk of fractures overall compared with values 20-50 ng/mL. Severely low levels may be associated with increased risk of osteoporotic fracture, particularly of the wrist.Studies of the relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and fracture risk have been inconsistent. We hypothesized that high 25(OH)D concentrations ( 50 ng/mL) would be associated with increased risk of fracture.We identified all adult patients living in Olmsted County, Minnesota, between January 1, 2005 and December 31, 2011, who had at least one 25(OH)D measurement. Fracture 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. Data were analyzed using Cox proportional hazard regression.Of 11,002 individuals with a 25(OH)D measurement, 5.8% had a 25(OH)D value ˂ 12 ng/mL, and 5.1% had a value 50 ng/mL. Compared with subjects with 25(OH)D values 20-50 ng/mL (reference group), values 12, 12-19, and 50 ng/mL displayed no association with overall fracture risk. After adjusting for a prior diagnosis of osteoporosis/osteopenia, only individuals with values ˂ 12 ng/mL had increased risk of any osteoporotic fracture (aHR = 1.41; 95% CI 1.05-1.89) and wrist fracture (aHR = 2.11; 95% CI 1.27-3.48) compared with the reference group. Compared with the reference group, values ˂ 12 ng/mL were associated with increased risk of any fracture (aHR = 1.35; 95% CI 1.01-1.80), osteoporotic fracture (aHR = 2.18; 95% CI 1.44-3.31), and wrist fracture (aHR = 2.39; 95% CI 1.19-4.81) in subjects without a prior diagnosis of osteoporosis/osteopenia, but not in those with a prior diagnosis of osteoporosis/osteopenia.Severely low 25(OH)D levels may be associated with increased risk of osteoporotic fracture, particularly of the wrist, but 25(OH)D values 50 ng/mL were not associated with increased fracture risk.

Objective: The primary aim of this study was to evaluate the feasibility of collecting risk factor information and accessing digitized mammographic data in a medically marginalized population. A secondary aim was to examine the association between vitamin D status and mammographic density. Methods: Breast-screening examinations were provided for age-appropriate patients, and a referral for no-cost screening mammography was offered. Study participants were asked to undergo 25-hydroxyvitamin D testing at mammography and 1-year follow-up. Results: Of 62 women approached, 35 (56%) consented to participate. Of 32 participants who had baseline mammography, the median mammographic density measured by VolparaDensity (Volpara Solutions Limited) was 5.7%. After 1 year, 9 women obtained follow-up mammograms, with a median density of 5.7%. Vitamin D status was measured for 31 participants at baseline and 13 participants in the following year. Insufficient vitamin D status (Conclusions: On the basis of this small pilot study, vitamin D insufficiency is common in this study population. Owing to the small sample size, an association between vitamin D insufficiency and breast density was not clear. Additional unexpected findings included substantial barriers in initial access to care and longitudinal follow-up in this population. Further study of these issues is needed.

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.

Graduate medical education is an excellent means of building the capacity of health care systems in low and middle Income Countries (LMIC) and a growing way for physicians in the U.S to get involved in integral mission – the proclamation and demonstration of the Gospel. This white paper purposes to provide a “best practices” recommendations on family and internal medicine (“medical”) residency program development in majority world settings. An expert panel of residency educators convened in November 2015 at the Global Missions Health Conference (GMHC) in Louisville, Kentucky and through an iterative process identified themes that were then further defined and clarified by medical residency faculty unable to be present. Participants largely agreed that integration and cooperation with the country’s Ministry of Health (MOH) is essential for sustainable residency development. Recognition of family medicine as a specialty will enable graduates to succeed in the country’s physician job market and health systems leadership. Recognition by the national church of the unique needs of their mission hospitals’ educational programs to control their revenue in order to fund their programs’ growth and development exemplifies the common wisdom to provide authority and resources where responsibility for good outcomes is expected. Co-training of general surgeons and medical residents who can provide essential surgical call coverage may lead to on-going synergies. Teaching by medical and surgical subspecialists is essential in medical residencies to provide the depth of instruction residents need to develop as excellent clinicians. Dependable scheduling of their specialty instruction allows residency program directors to assure inclusion of their content in the residency curriculum. In summary, participants agreed that teaching in medical residency programs in LMIC present excellent opportunities for national and expat Christian physician educators interested in integral mission.

Calcium supplementation is indicated for the treatment of nutritional rickets. Our aim was to determine the optimal dose of calcium for treatment of children with rickets. Sixty-five Nigerian children with radiographically confirmed rickets were randomized to daily supplemental calcium intake of 500 mg (n = 21), 1000 mg (n = 23), or 2000 mg (n = 21). Venous blood, radiographs, and forearm areal bone density (aBMD) were obtained at baseline and at 8, 16, and 24 weeks after enrollment. The primary outcome was radiographic healing, using a 10-point radiographic severity score. The radiographic severity scores improved in all three groups, but the rate of radiographic healing (points per month) was significantly more rapid in the 1000-mg (-0.29; 95% confidence interval [CI] -0.13 to -0.45) and 2000-mg (-0.36; 95% CI -0.19 to -0.53) supplementation groups relative to the 500-mg group. The 2000-mg group did not heal more rapidly than the 1000-mg group. Of those who completed treatment for 24 weeks, 12 (67%), 20 (87%), and 14 (67%) in the 2000-mg, 1000-mg, and 500-mg groups, respectively, had achieved a radiographic score of 1.5 or less (p = 0.21). Serum alkaline phosphatase decreased and calcium increased similarly in all groups. Forearm diaphyseal aBMD improved significantly more rapidly in the 2000-mg group than in the 500-mg and 1000-mg groups (p < 0.001). Daily calcium intakes of 1000 mg or 2000 mg produced more rapid radiographic healing of rickets than 500 mg, but 2000 mg did not have greater benefit than 1000 mg. Some children require longer than 24 weeks for complete healing of nutritional rickets. © 2016 American Society for Bone and Mineral Research.

PURPOSE The demand for comprehensive primary health care continues to expand. The development of team-based practice allows for improved capacity within a collective, collaborative environment. Our hypothesis was to determine the relationship between panel size and access, quality, patient satisfaction, and cost in a large family medicine group practice using a team-based care model. METHODS Data were retrospectively collected from 36 family physicians and included total panel size of patients, percentage of time spent on patient care, cost of care, access metrics, diabetic quality metrics, patient satisfaction surveys, and patient care complexity scores. We used linear regression analysis to assess the relationship between adjusted physician panel size, panel complexity, and outcomes. RESULTS The third available appointments (P < .01) and diabetic quality (P = .03) were negatively affected by increased panel size. Patient satisfaction, cost, and percentage fill rate were not affected by panel size. A physician-adjusted panel size larger than the current mean (2959 patients) was associated with a greater likelihood of poor-quality rankings (≤25th percentile) compared with those with a less than average panel size (odds ratio [OR], 7.61; 95% confidence interval [CI], 1.13-51.46). Increased panel size was associated with a longer time to the third available appointment (OR, 10.9; 95% CI, 1.36-87.26) compared with physicians with panel sizes smaller than the mean. CONCLUSIONS We demonstrated a negative impact of larger panel size on diabetic quality results and available appointment access. Evaluation of a family medicine practice parameters while controlling for panel size and patient complexity may help determine the optimal panel size for a practice.

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.

Background Primary care providers often manage skin abscesses in the outpatient setting. Estimating the size and depth of an abscess, and distinguishing abscess from cellulitis by clinical examination can be challenging due to surrounding firm tissue induration. Definitive treatment of abscess requires incision and drainage, and the approach chosen may be altered by abscess size, depth, and surrounding neurovascular structures. Methods For 31 consecutive patients seen in the primary care outpatient clinic, we prospectively compared the estimated size of skin abscesses by clinical examination with that determined by ultrasound. Prior to incision and drainage, a limited point-of-care ultrasound examination was performed and the abscess dimensions were measured, the depth was determined, and adjacent vascular structures were noted. Based on ultrasound findings, physicians reported whether the decision to perform the procedure or the techniques used to perform the procedure were altered by the scan. Results The clinical examination was inaccurate for size estimation by >0.5 cm in 16 of 31 patients (52%). Ultrasound examination changed the physician decision of whether or not incision and drainage should be performed in 7 patients (23%) and altered the technique/approach in an additional 10 patients (32%); thus, management was changed in 55% of cases. Physician confidence in performing the procedure was improved in 16 cases (52%). Conclusion Outpatient procedural management of skin abscesses by primary care physicians was altered in more than half the cases by performing point-of-care ultrasound prior to incision and drainage.

Socioeconomic status (SES), defined as the ability to access desired resources, is associated with behaviors that may affect vitamin D status. Most studies of the effect of vitamin D status on outcomes do not account for individual-level SES. The ability to adjust for SES in epidemiologic studies, when data on conventional SES measures have not been obtained, would be advantageous. We identified all serum 25(OH)D measurements in adults age 18 years and older residing in Olmsted County, MN, a mixed urban-rural setting, between January 1, 2005 and December 31, 2011, through the Rochester Epidemiology Project. The first 25(OH)D measurement was considered the index measurement for each subject. SES was determined for each subject by the HOUsing-based SocioEconomic Status (HOUSES) index, derived from real property data. The HOUSES index is an aggregated z-score of assessed housing value, area of living space, number of bedrooms, and number of bathrooms, with higher scores indicating higher SES. Multivariable analyses were adjusted for age, BMI, sex, race, season of 25(OH)D measurement, and Charlson comorbidity index. HOUSES was matched for 10,378 of 11,002 subjects (94 %) with 25(OH)D measurements available. The mean (SD) age was 54.3 (17.1) years with 26.9 % ≥65 years; 77.3 % were women, and 12.1 % were non-white. The mean 25(OH)D concentration was 30.0 (12.9) ng/mL, and 598 (5.8 %) had a 25(OH)D value12 ng/mL. The mean (SD) HOUSES was -1.55 (3.09),-0.97 (3.34), 0.14 (3.52), 0.24 (3.51) for serum 25(OH)D categories of12, 12-19, 20-50, and50 ng/mL, respectively (P = 0.12 for trend). 25(OH)D increased by 0.43 (95 % CI 0.36-0.50) ng/mL for each unit increase in HOUSES in univariate analysis and by 0.28 (0.21-0.35; P0.001) ng/mL in multivariable analysis. This represents a change of 4 ng/mL across the entire range of observed HOUSES, an effect similar in magnitude to the seasonal variation of 25(OH)D values. SES was independently associated with serum 25(OH)D concentrations in a dose-response manner after adjustment for important covariates. HOUSES is a useful tool to assess the role of individual-level SES in health outcomes when other SES measures are unavailable and to control for confounding by SES in examining the effect of 25(OH)D on clinical and metabolic outcomes.

Objectives To determine the incidence of potentially life-threatening complications of hypocalcemia in infants and children in Olmsted County, Minnesota; and to determine if vitamin D deficiency contributed to these events and was, at the time of clinical presentation, considered as a possible cause. Study design In this population-based descriptive study, data were abstracted from the Rochester Epidemiology Project, a medical record linkage system covering 95% of patients in Olmsted County, Minnesota. Participants were children aged 0-5 years who resided in Olmsted County between January 1, 1996 and June 30, 2017, and who received diagnoses of seizures, cardiomyopathy, cardiac arrest, respiratory arrest, laryngospasm, and/or tetany. The incidence of hypocalcemia plus a potentially life-threatening complication was calculated. Results Among 15 419 patients aged 0-5 years in Olmsted County during the study period, 1305 had eligible complications: 460 had serum calcium checked within 14 days of presentation and 85 had hypocalcemia. Patients were excluded when causes other than hypocalcemia likely triggered the complication, leaving 16 children whose complication was attributed to hypocalcemia. Three of these 16 patients had a serum 25-hydroxyvitamin D measurement and 2 were deficient (≤6 ng/mL [15 nmol/L]). Among children aged 0-5 years, the incidence of hypocalcemia plus a potentially life-threatening complication was 6.1 per 100 000 person-years (95% CI, 3.5-10.0). Conclusions Vitamin D deficiency is an underinvestigated cause of complications of hypocalcemia in children. Serum calcium and 25-hydroxyvitamin D should be measured in children with these complications to identify possibly life-threatening vitamin D deficiency.

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.

Genetic forms of vitamin D-dependent rickets (VDDRs) are due to mutations impairing activation of vitamin D or decreasing vitamin D receptor responsiveness. Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D. Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4). In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites. As CYP3A4 mutations have not previously been linked to rickets, these findings provide insight into vitamin D metabolism and demonstrate that accelerated inactivation of vitamin D metabolites represents a mechanism for vitamin D deficiency.

Production of the active vitamin D hormone 1,25-dihydroxyvitamin D requires hepatic 25-hydroxylation of vitamin D. The CYP2R1 gene encodes the principal vitamin D 25-hydroxylase in humans.This study aimed to determine the prevalence of CYP2R1 mutations in Nigerian children with familial rickets and vitamin D deficiency and assess the functional effect on 25-hydroxylase activity.We sequenced the CYP2R1 gene in subjects with sporadic rickets and affected subjects from families in which more than one member had rickets.Function of mutant CYP2R1 genes as assessed in vivo by serum 25-hydroxyvitamin D values after administration of vitamin D and in vitro by analysis of mutant forms of the CYP2R1.CYP2R1 sequences were normal in 27 children with sporadic rickets, but missense mutations were identified in affected members of 2 of 12 families, a previously identified L99P, and a novel K242N. In silico analyses predicted that both substitutions would have deleterious effects on the variant proteins, and in vitro studies showed that K242N and L99P had markedly reduced or complete loss of 25-hydroxylase activity, respectively. Heterozygous subjects were less affected than homozygous subjects, and oral administration of vitamin D led to significantly lower increases in serum 25-hydroxyvitamin D in heterozygous than in control subjects, whereas homozygous subjects showed negligible increases.These studies confirm that CYP2R1 is the principal 25-hydroxylase in humans and demonstrate that CYP2R1 alleles have dosage-dependent effects on vitamin D homeostasis. CYP2R1 mutations cause a novel form of genetic vitamin D deficiency with semidominant inheritance.

The US Preventative Services Task Force (USPSTF) recommends consideration for screening for osteoporosis in women under age 65 who have an estimated 10-year major osteoporotic fracture risk of 9.3 % or higher. We found that this threshold for osteoporosis screening in women ages 50–64 years old has a low sensitivity to detect osteoporosis. The US Preventative Services Task Force (USPSTF) recommends consideration of dual-energy X-ray absorptiometry (DXA) in women under ages 50–64 with a major osteoporotic fracture (MOF) risk of 9.3 % or higher, as estimated by the fracture risk assessment tool (FRAX) tool. We assessed the performance of the 9.3 % MOF risk threshold for detecting osteoporosis and evaluated whether DXA indication appeared appropriate, based on USPSTF criteria and other risk factors, at our institution. We performed a retrospective record review of women ages 50–64.5 years old to determine clinical factors and FRAX scores of women undergoing a DXA at our institution over a 6-month period after the USPSTF recommendations were released and evaluated the sensitivity and specificity of the 9.3 % MOF threshold to detect densitometric osteoporosis. Additionally, using the USPSTF criteria and several additional risk factors, we evaluated the extent of potentially inappropriate DXA use in women ages 50 to 64 years in a large primary care practice in an academic medical center. The analysis included 465 DXA tests. The overall sensitivity and specificity of a FRAX-calculated MOF risk ≥9.3 % was 37 and 74 %, respectively, for the detection of osteoporosis. The receiver operator characteristic curve (ROC) demonstrated an area under the curve of 0.58. Lowering the FRAX risk threshold to 5.5 % would increase the sensitivity of detecting osteoporosis in our population from 37 to 80 % while reducing the specificity from 74 to 27 %. Out of 465 DXAs, 371 (79.8 %) were classified as appropriately ordered per our pre-specified criteria. Of the 120 women with osteoporosis at the hip and/or spine based on T-score values of −2.5 or less, 14 DXAs (11.7 %) were classified as potentially inappropriate based on a FRAX-predicted MOF risk less than 9.3 % and lack of additional pre-specified risk factors. We found that the USPSTF-recommended MOF risk threshold of 9.3 % for osteoporosis screening in women ages 50–64 years old has a low sensitivity to detect osteoporosis.