Buprenorphine dispensing before and after the April 2021 X-Waiver exemptions: An interrupted time series analysis.

BACKGROUND: Until the end of 2022, a special registration, known as the X-waiver, was required to prescribe buprenorphine in the US. Before its removal, US federal regulations trialed an X-waiver exemption, initiated on April 28, 2021, which permitted buprenorphine prescribing for up to 30 patients without additional training. We aimed to understand if these regulatory changes impacted buprenorphine dispensing. METHODS: We conducted an interrupted time series analysis to understand changes in buprenorphine dispensing during the 26 weeks after the X-waiver exemption compared to the expected baseline trend established in the 26 weeks before using the IQVIA Longitudinal Prescription claims database. The primary outcome was number of new buprenorphine prescribers nationwide (defined as no prior buprenorphine prescription dispensed in the last 26 weeks). Segmented regression estimated relative changes in buprenorphine dispensing at 1, 13, and 26 weeks post-X-waiver change. RESULTS: A total of 15,517,525 prescriptions filled for 1,328,172 patients (43.4 % female) ordered by 62,312 providers were included for analysis. At 26 weeks post-X-waiver change, there was no change in the number of new prescribers compared to the expected baseline trend (-2.7 % [95 % CI:-8.3,2.9]). The number of new (15.2 % [4.6,25.8]) and existing (1.7 % [0.9,2.4]) patients and patients per prescriber (4.3 % [3,5.6]) increased. Buprenorphine prescriptions reimbursed by Medicaid increased (7.5 % [6.6,8.4]) while commercial fills decreased (-3.4 % [-5.3,-1.5]). CONCLUSIONS: The number of new prescribers did not increase six months post-X-waiver exemption while new patients continued to enter treatment at higher-than-expected rates. These findings suggest that additional interventions beyond the recent X-waiver removal may be needed to increase access to buprenorphine.

Performance Evaluation of Allplex Respiratory Panels 1, 2, and 3 for Detection of Respiratory Viruses and Influenza A Virus Subtypes.

The Allplex respiratory panels 1, 2, and 3 (Allplex) comprise a one-step real-time reverse transcription-PCR assay for the detection of respiratory viruses (RVs) and influenza A subtypes based on multiple detection temperature (MuDT) technology. The performance of the Allplex assay was compared with those of the AdvanSure RV real-time PCR kit (AdvanSure) and the PowerChek pandemic H1N1/H3N2/H5N1 real-time PCR kit (PowerChek) using 417 clinical respiratory specimens. In comparison with the AdvanSure assay for RV detection by each virus, the ranges of positive percent agreement, negative percent agreement, and kappa values with the Allplex assay were 82.8 to 100%, 95.5 to 100%, and 0.85 to 1.00, respectively. For influenza A virus (INF A) subtyping, the kappa values between the Allplex and PowerChek assays were 0.67 and 1.00 for the INF A H1N1-pdm09 and H3 subtypes, respectively. Uniplex PCR and sequencing for samples with discrepant results demonstrated that the majority of results were concordant with those from the Allplex assay. When testing 24 samples, the turnaround and hands-on time required to perform the Allplex assay were 4 h 15 min and 15 min, respectively. In conclusion, the Allplex assay produced results comparable to those from the AdvanSure and PowerChek assays.

Analytical and clinical evaluation of the Abbott RealTime hepatitis B sequencing assay.

BACKGROUND: Long-term nucleoside analogue (NA) treatment leads to selection for drug-resistant mutations in patients undergoing hepatitis B virus (HBV) therapy. The Abbott RealTime HBV Sequencing assay (Abbott assay; Abbott Molecular Inc., Des Plaines, IL, USA) targets the reverse transcriptase region of the polymerase gene and as such has the ability to detect NA resistance-associated mutations in HBV. OBJECTIVES: We evaluated the analytical performance of the Abbott assay and compared its diagnostic performance to that of a laboratory-developed nested-PCR and sequencing method. STUDY DESIGN: The analytical sensitivity of the Abbott assay was determined using a serially-diluted WHO International Standard. To validate the clinical performances of the Abbott assay and the laboratory-developed assay, 89 clinical plasma samples with various levels of HBV DNA were tested using both assays. RESULTS: The limit of detection of the Abbott assay, was 210IU/ml and it successfully detected mutations when the mutant types were present at levels ≥20%. Among 89 clinical specimens, 43 and 42 were amplification positive in the Abbott and laboratory-developed assays, respectively, with 87.6% overall agreement (78/89; 95% confidence interval [CI], 78.6-93.4). The Abbott assay failed to detect the minor mutant populations in two specimens, and therefore overall concordance was 85.3% (76/89), and the kappa value was 0.79 (95% CI, 0.67-0.90). CONCLUSIONS: The Abbott assay showed comparable diagnostic performance to laboratory-developed nested PCR followed by direct sequencing, and may be useful as a routine method for detecting HBV NA resistance-associated mutations in clinical laboratory settings.

Identification and characterization of NF1 splicing mutations in Korean patients with neurofibromatosis type 1.

Neurofibromatosis type I (NF1) is an autosomal dominant genetic disorder caused by NF1 mutations. Although mutations affecting mRNA splicing are the most common molecular defects in NF1, few studies have analyzed genomic DNA (gDNA)-mRNA correlations in Korean NF1 patients. In this study, we investigated 28 unrelated NF1 patients who showed splicing alterations in reverse transcription-PCR of NF1 mRNA and identified 24 different NF1 splicing mutations, 9 of which were novel. These mutations can be categorized into five groups: exon skipping resulting from mutations at authentic 5' and 3' splice sites (type I, 46%), cryptic exon inclusion caused by deep intronic mutations (type II, 8%), creation of new splice sites causing loss of exonic sequences (type III, 8%), activation of cryptic splice sites due to disruption of authentic splice sites (type IV, 25%) and exonic sequence alterations causing exon skipping (type V, 13%). In total, 42% of all splicing mutations did not involve the conserved AG/GT dinucleotides of the splice sites, making it difficult to identify the correct mutation sites at the gDNA level. These results add to the mutational spectrum of NF1 and further elucidate the gDNA-mRNA correlations of NF1 mutations.

Genome-wide association study of periodontal health measured by probing depth in adults ages 18-49 years.

The etiology of chronic periodontitis clearly includes a heritable component. Our purpose was to perform a small exploratory genome-wide association study in adults ages 18-49 years to nominate genes associated with periodontal disease-related phenotypes for future consideration. Full-mouth periodontal pocket depth probing was performed on participants (N = 673), with affected status defined as two or more sextants with probing depths of 5.5 mm or greater. Two variations of this phenotype that differed in how missing teeth were treated were used in analysis. More than 1.2 million genetic markers across the genome were genotyped or imputed and tested for genetic association. We identified ten suggestive loci (p-value ≤ 1E-5), including genes/loci that have been previously implicated in chronic periodontitis: LAMA2, HAS2, CDH2, ESR1, and the genomic region on chromosome 14q21-22 between SOS2 and NIN. Moreover, we nominated novel loci not previously implicated in chronic periodontitis or related pathways, including the regions 3p22 near OSBPL10 (a lipid receptor implicated in hyperlipidemia), 4p15 near HSP90AB2P (a heat shock pseudogene), 11p15 near GVINP1 (a GTPase pseudogene), 14q31 near SEL1L (an intracellular transporter), and 18q12 in FHOD3 (an actin cytoskeleton regulator). Replication of these results in additional samples is needed. This is one of the first research efforts to identify genetic polymorphisms associated with chronic periodontitis-related phenotypes by the genome-wide association study approach. Though small, efforts such this are needed in order to nominate novel genes and generate new hypotheses for exploration and testing in future studies.

Genome-wide association scan of dental caries in the permanent dentition.

BACKGROUND: Over 90% of adults aged 20 years or older with permanent teeth have suffered from dental caries leading to pain, infection, or even tooth loss. Although caries prevalence has decreased over the past decade, there are still about 23% of dentate adults who have untreated carious lesions in the US. Dental caries is a complex disorder affected by both individual susceptibility and environmental factors. Approximately 35-55% of caries phenotypic variation in the permanent dentition is attributable to genes, though few specific caries genes have been identified. Therefore, we conducted the first genome-wide association study (GWAS) to identify genes affecting susceptibility to caries in adults. METHODS: Five independent cohorts were included in this study, totaling more than 7000 participants. For each participant, dental caries was assessed and genetic markers (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Due to the heterogeneity among the five cohorts regarding age, genotyping platform, quality of dental caries assessment, and study design, we first conducted genome-wide association (GWA) analyses on each of the five independent cohorts separately. We then performed three meta-analyses to combine results for: (i) the comparatively younger, Appalachian cohorts (N = 1483) with well-assessed caries phenotype, (ii) the comparatively older, non-Appalachian cohorts (N = 5960) with inferior caries phenotypes, and (iii) all five cohorts (N = 7443). Top ranking genetic loci within and across meta-analyses were scrutinized for biologically plausible roles on caries. RESULTS: Different sets of genes were nominated across the three meta-analyses, especially between the younger and older age cohorts. In general, we identified several suggestive loci (P-value ≤ 10E-05) within or near genes with plausible biological roles for dental caries, including RPS6KA2 and PTK2B, involved in p38-depenedent MAPK signaling, and RHOU and FZD1, involved in the Wnt signaling cascade. Both of these pathways have been implicated in dental caries. ADMTS3 and ISL1 are involved in tooth development, and TLR2 is involved in immune response to oral pathogens. CONCLUSIONS: As the first GWAS for dental caries in adults, this study nominated several novel caries genes for future study, which may lead to better understanding of cariogenesis, and ultimately, to improved disease predictions, prevention, and/or treatment.

PHOX2B mutations in patients with Ondine-Hirschsprung disease and a review of the literature.

Congenital central hypoventilation syndrome (CCHS), also known as Ondine's curse, is characterized by idiopathic failure of autonomic breathing and is often associated with neurocristopathies such as Hirschsprung disease (HSCR). CCHS is caused by mutations in the paired-like homeobox 2B (PHOX2B) gene, often manifest as polyalanine repeat expansions. Herein, we report the cases of two unrelated Korean patients with Ondine-Hirschsprung disease. The patient's clinical manifestations were apnea and cyanosis requiring immediate endotracheal intubation, recurrent hypoventilation with hypercapnia, hypoxia after ventilator removal, and abdominal distension since birth. Intestinal biopsies were performed and the absence of ganglion cells in the colon was consistent with HSCR. We performed direct sequencing analysis in the PHOX2B and RET genes and fluorescence polymerase chain reaction in order to determine the polyalanine tract expansion in exon 3 of the PHOX2B gene. Expansion mutations were detected in both patients; one had 20/24 repeats and the other had 20/27 repeats. The 20/24 genotype has not been previously described in severe CCHS phenotypes and associated HSCR. We believe that the information in this report will improve our understanding of the phenotypic and genotypic heterogeneities of CCHS and HSCR.

Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.

CONTEXT: Tamoxifen has been approved for breast cancer risk reduction in high-risk women, but how raloxifene compares with tamoxifen is unknown. OBJECTIVE: To compare the differences in patient-reported outcomes, quality of life [QOL], and symptoms in Study of Tamoxifen and Raloxifene (STAR) participants by treatment assignment. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: STAR was a double-blind, randomized phase 3 prevention trial designed to evaluate the relative efficacy of raloxifene vs tamoxifen in reducing the incidence of invasive breast cancer in high-risk postmenopausal women. Between July 1, 1999, and November 4, 2004, 19,747 participants were enrolled at centers throughout North America, with a median potential follow-up time of 4.6 years (range, 1.2-6.5 years). Patient-reported symptoms were collected from all participants using a 36-item symptom checklist. Quality of life was measured with the Medical Outcomes Study Short-Form Health Survey (SF-36), the Center for Epidemiologic Studies-Depression (CES-D), and the Medical Outcomes Study Sexual Activity Questionnaire in a substudy of 1983 participants, median potential follow-up 5.4 years (range, 4.6-6.0 years). Questionnaires were administered before treatment, every 6 months for 60 months and at 72 months. MAIN OUTCOME MEASURES: Primary QOL end points were the SF-36 physical (PCS) and mental (MCS) component summaries. RESULTS: Among women in the QOL analysis, mean PCS, MCS, and CES-D scores worsened modestly over the study's 60 months, with no significant difference between the tamoxifen (n = 973) and raloxifene (n = 1010) groups (P>.2). Sexual function was slightly better for participants assigned to tamoxifen (age-adjusted repeated measure odds ratio, 1.22%; 95% CI, 1.01-1.46). Of the women in the symptom assessment analyses, the 9769 in the raloxifene group reported greater mean symptom severity over 60 months of assessments than the 9743 in the tamoxifen group for musculoskeletal problems (1.15 vs 1.10, P = .002), dyspareunia (0.78 vs 0.68, P<.001), and weight gain (0.82 vs 0.76, P<.001). Women in the tamoxifen group reported greater mean symptom severity for gynecological problems (0.29 vs 0.19, P<.001), vasomotor symptoms (0.96 vs 0.85, P<.001), leg cramps (1.10 vs 0.91, P<.001), and bladder control symptoms (0.88 vs 0.73, P<.001). CONCLUSIONS: No significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical health, mental health, and depression, although the tamoxifen group reported better sexual function. Although mean symptom severity was low among these postmenopausal women, those in the tamoxifen group reported more gynecological problems, vasomotor symptoms, leg cramps, and bladder control problems, whereas women in the raloxifene group reported more musculoskeletal problems, dyspareunia, and weight gain. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003906.