Identifying nonprescription antibiotic users with screening questions in a primary care setting

Background: Antibiotic use without a prescription (nonprescription use) leads to antibiotic overuse, with negative consequences for patient and public health. We studied whether screening patients for prior nonprescription antibiotic use in the past 12 months predicted their intentions to use them in the future. Methods: A survey asking respondents about prior and intended nonprescription antibiotic use was performed between January 2020 and June 2021 among patients in waiting rooms of 6 public clinics and 2 private emergency departments in economically and socially diverse urban and suburban areas. Respondents were classified as prior nonprescription users if they reported previously taking oral antibiotics without contacting a doctor, dentist, or nurse. Intended use was defined as answering “yes” or “maybe” to the question, “Would you use antibiotics without contacting a doctor, nurse, or dentist?” We calculated the sensitivity, specificity, and positive and negative predictive value (PPV and NPV) of prior nonprescription antibiotic use in the past 12 months for future intended nonprescription use. Bayes PPV and NPV were also calculated, considering the prevalence of nonprescription antibiotic use (24.8%) in our study. Results: Of the 564 patients surveyed, the median age was 51 years (SD, 19–92), with 72% of patients identifying as female. Most were from the public healthcare system (72.5%). Most respondents identified as Hispanic or Latino(a) (47%) or African American (33%), and 57% received Medicaid or the county financial assistance program. Prior nonprescription use was reported by 246 (43%) of 564 individuals, with 91 (16%) reporting nonprescription use within the previous 12 months. Intention to use nonprescription antibiotics was reported by 140 participants (25%). The sensitivity and specificity of prior nonprescription use in the past 12 months to predict the intention to use nonprescription antibiotics in the future were 75.9% (95% CI, 65.3–84.6) and 91.4% (95% CI, 87.8–94.2), respectively. After the Bayes’ adjustment, the PPV and NPV of prior use to predict future intention were 74.5% (95% CI, 66.7–80.9) and 92.0% (95% CI, 88.7–94.4) (Table 1). Conclusions: These results show that prior nonprescription antibiotic use in the past 12 months predicted the intention to use nonprescription antibiotics in the future (PPV of 75%). As a stewardship effort, we suggest clinicians use a simple question about prior nonprescription antibiotic use in primary-care settings as a screening question for patients at high risk for future nonprescription antibiotic use

Vibrational spectroscopic analysis of hydroxyapatite in HYP mice and individuals with X-linked hypophosphatemia

Background: X-linked hypophosphatemia (XLH) is the most common form of familial phosphate-wasting disorders, due to an inactivating mutation in the phosphate-regulating neutral endopeptidase, X-linked gene. Persistent osteomalacia, enthesophytes, osteophytes, degenerative arthritis and dental abscesses/periodontal disease dominate the adult disorder. However, the impact of insufficient phosphate on hydroxyapatite composition, the major inorganic component of bone and teeth, is unknown in individuals with XLH. Methods: Using Raman spectroscopy, the carbonate (CO32−) to phosphate (PO43−) ion ratio was measured in HYP and wild-type mice and in primary and permanent teeth from XLH individuals and unaffected controls. Results: There was a significant difference in carbonate ion substitution between the HYP and wild-type femoral cortical bone (0.36 ± 0.08 versus 0.24 ± 0.04; p < 0.001). Carbonate ion substitution levels were also higher in permanent XLH teeth compared with unaffected individuals (0.39 ± 0.12 versus 0.23 ± 0.04; p < 0.001), but not in primary teeth (0.29 ± 0.11 versus 0.26 ± 0.02; p = 0.29). Complementary Fourier transform infrared analyses demonstrated higher relative intensities of the four major vibrational bands originating from the carbonate anion in XLH teeth compared with unaffected controls. Conclusion: Ionic substitution within the crystal lattice is a common feature of hydroxyapatite and one that confers the physiological properties of bone that impact mechanical strength and the process of bone remodeling. Our data demonstrating anionic substitution in human dentin from individuals with XLH validate the use of dentin as a proxy for bone and to better understand the molecular adaptations that occur in the biochemical milieu of XLH

Vibrational spectroscopic analysis of hydroxyapatite in HYP mice and individuals with X-linked hypophosphatemia

Background: X-linked hypophosphatemia (XLH) is the most common form of familial phosphate-wasting disorders, due to an inactivating mutation in the phosphate-regulating neutral endopeptidase, X-linked gene. Persistent osteomalacia, enthesophytes, osteophytes, degenerative arthritis and dental abscesses/periodontal disease dominate the adult disorder. However, the impact of insufficient phosphate on hydroxyapatite composition, the major inorganic component of bone and teeth, is unknown in individuals with XLH. Methods: Using Raman spectroscopy, the carbonate (CO32−) to phosphate (PO43−) ion ratio was measured in HYP and wild-type mice and in primary and permanent teeth from XLH individuals and unaffected controls. Results: There was a significant difference in carbonate ion substitution between the HYP and wild-type femoral cortical bone (0.36 ± 0.08 versus 0.24 ± 0.04; p < 0.001). Carbonate ion substitution levels were also higher in permanent XLH teeth compared with unaffected individuals (0.39 ± 0.12 versus 0.23 ± 0.04; p < 0.001), but not in primary teeth (0.29 ± 0.11 versus 0.26 ± 0.02; p = 0.29). Complementary Fourier transform infrared analyses demonstrated higher relative intensities of the four major vibrational bands originating from the carbonate anion in XLH teeth compared with unaffected controls. Conclusion: Ionic substitution within the crystal lattice is a common feature of hydroxyapatite and one that confers the physiological properties of bone that impact mechanical strength and the process of bone remodeling. Our data demonstrating anionic substitution in human dentin from individuals with XLH validate the use of dentin as a proxy for bone and to better understand the molecular adaptations that occur in the biochemical milieu of XLH

De novo missense variants in phosphatidylinositol kinase PIP5KIγ underlie a neurodevelopmental syndrome associated with altered phosphoinositide signaling

Phosphoinositides (PIs) are membrane phospholipids produced through the local activity of PI kinases and phosphatases that selectively add or remove phosphate groups from the inositol head group. PIs control membrane composition and play key roles in many cellular processes including actin dynamics, endosomal trafficking, autophagy, and nuclear functions. Mutations in phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] phosphatases cause a broad spectrum of neurodevelopmental disorders such as Lowe and Joubert syndromes and congenital muscular dystrophy with cataracts and intellectual disability, which are thus associated with increased levels of PI(4,5)P2. Here, we describe a neurodevelopmental disorder associated with an increase in the production of PI(4,5)P2 and with PI-signaling dysfunction. We identified three de novo heterozygous missense variants in PIP5K1C, which encodes an isoform of the phosphatidylinositol 4-phosphate 5-kinase (PIP5KIγ), in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. We provide evidence that the PIP5K1C variants result in an increase of the endosomal PI(4,5)P2 pool, giving rise to ectopic recruitment of filamentous actin at early endosomes (EEs) that in turn causes dysfunction in EE trafficking. In addition, we generated an in vivo zebrafish model that recapitulates the disorder we describe with developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities, further demonstrating the pathogenic effect of the PIP5K1C variants. We describe a neurodevelopmental disorder associated with de novo gain-of-function variants in PIP5KIγ kinase. The variants cause perturbed endosomal function resulting from increased production of phosphatidylinositol 4,5 bisphosphate and enhanced association of F-actin at endosomes. Moreover, mutant zebrafish larvae recapitulate the phenotypes observed in affected individuals from our cohort