Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1^asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1^asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1^asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1^asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

The Accuracy of Incident Vertebral Fracture Detection in Children Using Targeted Case-Finding Approaches

Vertebral fractures are clinically important sequelae of a wide array of pediatric diseases. In this study, we examined the accuracy of case-finding strategies for detecting incident vertebral fractures (IVF) over 2 years in glucocorticoid-treated children (n = 343) with leukemia, rheumatic disorders, or nephrotic syndrome. Two clinical situations were addressed: the prevalent vertebral fracture (PVF) scenario (when baseline PVF status was known), which assessed the utility of PVF and low lumbar spine bone mineral density (LS BMD; Z-score <−1.4), and the non-PVF scenario (when PVF status was unknown), which evaluated low LS BMD and back pain. LS BMD was measured by dual-energy X-ray absorptiometry, vertebral fractures were quantified on spine radiographs using the modified Genant semiquantitative method, and back pain was assessed by patient report. Forty-four patients (12.8%) had IVF. In the PVF scenario, both low LS BMD and PVF were significant predictors of IVF. Using PVF to determine which patients should have radiographs, 11% would undergo radiography (95% confidence interval [CI] 8–15) with 46% of IVF (95% CI 30–61) detected. Sensitivity would be higher with a strategy of PVF or low LS BMD at baseline (73%; 95% CI 57–85) but would require radiographs in 37% of children (95% CI 32–42). In the non-PVF scenario, the strategy of low LS BMD and back pain produced the highest specificity of any non-PVF model at 87% (95% CI 83–91), the greatest overall accuracy at 82% (95% CI 78–86), and the lowest radiography rate at 17% (95% CI 14–22). Low LS BMD or back pain in the non-PVF scenario produced the highest sensitivity at 82% (95% CI 67–92), but required radiographs in 65% (95% CI 60–70). These results provide guidance for targeting spine radiography in children at risk for IVF. © 2021 American Society for Bone and Mineral Research (ASBMR).     

ASO Author Reflections: The Time to Incorporate Opioid-Minimizing Initiatives in Your Institution is now

Annals of Surgical Oncology -     

Measuring physician practice site characteristics: A comparison of data from SK&A and a practice site survey

ObjectiveTo evaluate the comparability of commercially available practice site data from SK&A with survey data to understand the implications of using SK&A data for health services research.Data sourcesResponses to the Comprehensive Primary Care Plus (CPC+) Practice Survey and SK&A data.Study designComparison of CPC + Practice Survey responses to SK&A information for 2698 primary care practice sites.Data collectionCPC + Practice Survey data collected through a web‐only survey from April through September 2017, and SK&A data purchased in November 2016.Principal findingsInformation was similar across data sources, although some discrepancies were common. For example, 56% of practice sites had differences in the reported number of practitioners, and larger sites tended to have larger differences. Among practice sites with 1 practitioner in the survey, only 1.3% had a difference of 3 or more practitioners between the data sources, whereas 63% of practice sites with 11 or more practitioners had a difference of 3 or more practitioners.ConclusionsDiscrepancies between data sources could reflect differences of interpretation when defining practice site characteristics, changes over time in those characteristics, or data errors in either SK&A or the survey. Researchers using SK&A data should consider possible ramifications for their studies.     

Twenty Years of the Ryan Residency Training Program in Abortion and Family Planning

ObjectiveTo summarize the effects of routine, opt-out abortion and family planning residency training on obstetrics and gynecology (ob-gyn) residents’ clinical skills in uterine evacuation and intentions to provide abortion care after residency.MethodsData from ob-gyn residency programs supported during the first 20 years of the Kenneth J. Ryan Residency Training Program in Abortion and Family Planning were analyzed. Postrotation surveys assessed residents’ training experiences and acquisition of abortion care skills. Residency program director surveys assessed benefits of the training to residents and the academic department from the educators’ perspectives.ResultsA total of 2775 residents in 89 ob-gyn programs completed postrotation surveys for a response rate of 72%. During the rotation, residents – including those who only partially participated – gained exposure to and skills in first- and second-trimester abortion care. Sixty-one percent intended to provide abortion care in their postresidency practice. More than 90% of residency program directors (97.5% response rate) reported that training improved resident competence in abortion and contraception care and 81.3% reported that the training increased their own program's appeal to residency applicants.ConclusionOver 20 years, the Ryan Program has supported programs to integrate abortion training to give ob-gyn residents the skills and inspiration to provide comprehensive reproductive health care, including uterine evacuation and abortion care, in future practice. Residency program directors noted that this integrated training meets resident applicants’ expectations.ImplicationsRyan Program residents are trained to competence and are prepared, both clinically and in their professional attitudes, to care for women's reproductive health.     

Developing network adequacy standards for VA Community Care

ObjectivesTo inform how the VA should develop and implement network adequacy standards, we convened an expert panel to discuss Community Care Network (CCN) adequacy and how VA might implement network adequacy standards for community care.Data Sources/Study settingData were generated from expert panel ratings and from an audio‐recorded expert panel meeting conducted in Arlington, Virginia, in October 2017.Study DesignWe used a modified Delphi panel process involving one round of expert panel ratings provided by nine experts in network adequacy standards. Expert panel members received a list of network adequacy standard measures used in commercial and government market and were provided a rating form listing a total of 11 measures and characteristics to rate.Data Collection MethodsItems on the rating form were individually discussed during an expert panel meeting between the nine expert panel members and VA Office of Community Care leaders. Attendees addressed discordant views and generated revised or new standards accordingly. Recorded audio data were transcribed to facilitate thematic analysis regarding opportunities and challenges with implementing network adequacy standards in VA Community Care.Principal FindingsThe five highest ranked standards were network directories for Veterans, regular reporting of network adequacy data to VA, maximum wait time/distance standards, minimum ratio of providers to enrolled population, and qualitative assessments of network adequacy. During the expert panel discussion with VA Community Care leaders, opportunities and challenges implementing network adequacy standards were highlighted.ConclusionsOur expert panel shed light on priorities for network adequacy to be implemented under CCN contracts, such as developing comprehensive provider directories for Veterans to use when selecting community providers. Remaining questions focus on whether the VA could reasonably develop and implement network adequacy standards given current Congressional restraints on VA reimbursement to community providers.