A multi-analyte assay of opioids in API and drug products using HPLC and HRMS.

Surveillance testing is an essential component to ensuring safe, effective, and high-quality drug products are available in the commercially marketed US supply chain. Surveillance allows the agency to assess product quality and monitor for potential adulteration of drug products being used by consumers. Opioid drug products can be adulterated to enhance the effect of the intended active ingredient. Numerous accounts have been reported where fentanyl has been used as an adulterant in illicit street drugs such as heroin, cocaine, or methamphetamine. To efficiently surveil the legitimate opioid supply chain, an analytical method with the ability to simultaneously detect, identify and quantify opioid molecules is desired. In this study, a multi-opioid protocol (MOP) using liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) technology was developed and validated for the detection and quantification of 27 opioid drugs. The MOP analytical procedure was applied to the analysis of drug substance and finished dosage forms. MOP was used to identify and quantify active pharmaceutical ingredients (API) listed on the label claim, and in the case of suspected economically motivated adulteration could identify and quantify undeclared opioid APIs. The analytical method analysis time was 16 minutes and the LOD and LOQ in full MS mode were (average) 0.3 and 0.8 ng/mL, respectively. The validation criteria parameters were satisfactory based on international guidelines (ICH). The MOP was successfully applied to the analysis of over 160 drug substances and finished products. For all samples tested in the study, their identities were confirmed, and assays met specifications. Overall, there was no evidence of illegal substitution or adulteration in any of the ingredients and products tested from the legitimate commercial marketed US supply chain.

Educational competencies for telehealth physical therapy: Results of a modified Delphi process.

BACKGROUND: Telehealth is becoming more prevalent in physical therapy, involving a whole host of clinical services. These services are often provided without structured training in telehealth, and no formal curricula currently exist for this purpose. OBJECTIVE: To develop a set of educational competencies (ECs) to guide instruction of telehealth-related skills in entry-level programs (i.e., Doctor of Physical Therapy), existing programs (i.e., residencies and fellowships), and potential future post-graduate programs specific to telehealth physical therapy. METHODS: Physical therapists and physical therapist assistants from diverse geographic locations and practice areas were invited to participate on an expert panel. A modified Delphi process was then used to evaluate the acceptability of draft ECs gathered from the extant literature by a steering group. Draft ECs were presented to the expert panel on a questionnaire, which asked expert participants to rate each draft EC according to applicability and clarity. Draft ECs were accepted if they met a priori established criteria for acceptability and clarity. Unendorsed ECs were revised by the steering group according to open-ended comments from respondents and presented during a subsequent round. Three rounds of surveys were undertaken. RESULTS: Thirty-eight participants formed the expert panel; 38 participants completed the Round 1 survey, 28 participants completed the Round 2 survey, and 24 participants completed the Round 3 survey. Delphi group members approved 48 ECs in the first round, 23 ECs in the second round, and 2 ECs in the third round. There were 4 ECs that remained unendorsed after the modified Delphi process. Endorsed ECs spanned 7 conceptual areas. Distinct sets of ECs characterized expected end points of first professional degree, existing residency and fellowship, and potential future telehealth physical therapy post-graduate program. CONCLUSIONS: Consensus-based ECs identified in this study may guide instruction in knowledge and skills relevant to physical therapy telehealth.

Quality of New Domestic Hand Sanitizer Drug Product Manufacturers During COVID-19.

The FDA initiated a cross-sectional, statistically based sampling and testing study to characterize the quality of marketed alcohol-based hand sanitizer (ABHS) by evaluating the alcohol content and impurities present in ABHS products manufactured by establishments that registered with the FDA during March-April 2020. A stratified sampling design divided the population of manufacturers into independent groups based on each establishment's level of experience with FDA oversight and its geographic location. ABHS products were collected and analyzed by spatially offset Raman spectroscopy and gas chromatography with mass spectrometry (GC-MS). The GC-MS results for 310 products, from 196 newly registered domestic manufacturers, showed that 71.6% (± 5.7%) of these manufacturers had violative products. In 104 (33.5%) cases, the alcohol content did not meet label claim assay specifications but still fell within CDC efficacy ranges. Ethanol ABHS products failed more often overall (assay and impurities) (84.3%) and for impurities (84.3%), than isopropanol ABHS products (11.2% and 6.2%, respectively). Differences in test results across active ingredients were statistically significant. Ethanol ABHS products often (63.5% of cases) failed due to the presence of acetal or acetaldehyde, particularly in products with pH ≤ 6. Other impurities were also detected in several ABHS products, suggesting the use of low-grade alcohol in the manufacture of these products. Evidence was insufficient to conclude that having experience manufacturing FDA-regulated products, or lack thereof, influenced product-level violative results. This study highlights the importance of sourcing and testing active pharmaceutical ingredients to produce quality drug products.

WAGR, Sex Reversal, Bilateral Gonadoblastomas, and Intralobar Nephrogenic Rests: Uncertainties of Pre-Biopsy Chemotherapy in a High Risk Syndrome for Nephroblastoma.

Background: WT1 deletions are associated with nephroblastomas, WT mutations are associated with 46, XY sex reversal. It is unclear why only a few WT1 deletions are associated with sex reversal. Case report. This 46, XY female had a 15.2 MB interstitial deletion of 11p14.1p11.2, which included WT1 and FSHB. No pathogenic abnormalities were identified in 156 other genes associated with disorders of sexual development. Bilateral gonadoblastomas were incidentally diagnosed at 17 months of age at the time of prophylactic gonadectomies. She was treated without biopsy for bilateral nephroblastomas radiologically identified at 18 months of age. Bilateral partial nephrectomies contained treated intralobular nephrogenic rests. Conclusion: It is unclear why WT1 deletions are less associated with 46, XY sex reversal than WT1 mutations. Treating suspected nephroblastomas without biopsy, even in patients with syndromes associated with bilateral nephroblastomas, may still lead to diagnostic and therapeutic uncertainties.

Elevated preoptic brain activity in zebrafish glial glycine transporter mutants is linked to lethargy-like behaviors and delayed emergence from anesthesia.

Delayed emergence from anesthesia was previously reported in a case study of a child with Glycine Encephalopathy. To investigate the neural basis of this delayed emergence, we developed a zebrafish glial glycine transporter (glyt1 - / -) mutant model. We compared locomotor behaviors; dose-response curves for tricaine, ketamine, and 2,6-diisopropylphenol (propofol); time to emergence from these anesthetics; and time to emergence from propofol after craniotomy in glyt1-/- mutants and their siblings. To identify differentially active brain regions in glyt1-/- mutants, we used pERK immunohistochemistry as a proxy for brain-wide neuronal activity. We show that glyt1-/- mutants initiated normal bouts of movement less frequently indicating lethargy-like behaviors. Despite similar anesthesia dose-response curves, glyt1-/- mutants took over twice as long as their siblings to emerge from ketamine or propofol, mimicking findings from the human case study. Reducing glycine levels rescued timely emergence in glyt1-/- mutants, pointing to a causal role for elevated glycine. Brain-wide pERK staining showed elevated activity in hypnotic brain regions in glyt1-/- mutants under baseline conditions and a delay in sensorimotor integration during emergence from anesthesia. Our study links elevated activity in preoptic brain regions and reduced sensorimotor integration to lethargy-like behaviors and delayed emergence from propofol in glyt1-/- mutants.

Missed radiographic and clinical findings in a case of non-idiopathic scoliosis resulting from chondroblastoma.

PURPOSE: Chondroblastoma is a cartilaginous neoplasm which rarely presents in the spine, where it has been shown to exhibit aggressive behavior. We present a case of a late diagnosis of a T12 chondroblastoma causing paraparesis in an 11-year-old girl. Several missed classical radiographic and clinical features are highlighted. METHODS: We reviewed clinical, imaging, and pathology data from the time of transfer to our institution, followed by review of all outside clinical records and imaging data from 14 months prior to admission until onset of paraplegia. RESULTS: The patient was transferred to our center for emergent treatment of a large, expansile, exophytic lesion compressing the spinal cord at T12. Intravenous steroids improved her neurologic status to ASIA Grade B, and an en bloc posterior element resection was performed emergently within 24 h. She rapidly improved to an ASIA Grade E. After obtaining all prior imaging during detailed histopathologic work-up, the final diagnosis was that of spinal chondroblastoma. Subsequent anterior en bloc resection was performed. The patient remains disease-free with a stable, residual scoliosis 7 years postoperatively. CONCLUSIONS: Detailed review of radiographs is essential for scoliosis patients. Earlier recognition of the "winking owl" sign, a kyphotic sagittal alignment, and more concern about a child with a painful curve may have resulted in earlier diagnosis before the onset of neurologic deficits.

Intratumoral Translocation Positive Heterogeneity in Pediatric Alveolar Rhabdomyosarcoma Tumors Correlates to Patient Survival Prognosis.

Alveolar rhabdomyosarcoma (ARMS) is characterized by one of three translocation states: t(2;13) (q35;q14) producing PAX3-FOXO1, t(1;13) (p36;q14) producing PAX7-FOXO1, or translocation-negative. Tumors with t(2;13) are associated with greater disease severity and mortality than t(1;13) positive or translocation negative patients. Consistent with this fact, previous work concluded that a molecular analysis of RMS translocation status is essential for the accurate determination of prognosis and diagnosis. However, despite this knowledge, most diagnoses rely on histology and in some cases utilize fluorescence in situ hybridization (FISH) probes unable to differentiate between translocation products. Along these same lines, diagnostic RT-PCR analysis, which can differentiate translocation status, is unable to determine intratumoral translocation heterogeneity, making it difficult to determine if heterogeneity exists and whether correlations exist between this heterogeneity and patient outcomes. Using newly developed FISH probes, we demonstrate that intratumoral heterogeneity exists in ARMS tumors with respect to the presence or absence of the translocation product. We found between 3 and 98% of cells within individual tumor samples contained a translocation event with a significant inverse correlation (R 2 = 0.66, p = 0.001) between the extent of intratumoral translocation heterogeneity and failure-free survival of patients. Taken together, these results provide additional support for the inclusion of the molecular analysis of these tumors and expand on this idea to support determining the extent of intratumoral translocation heterogeneity in the diagnosis of ARMS to improve diagnostic and prognostic indicators for patients with these tumors.

Long-term prognosis of patients treated by coronary sinus-based percutaneous annuloplasty: single centre experience.

AIMS: This study aims to report long-term mortality, echocardiographic, and clinical outcomes of patients receiving treatment for functional mitral regurgitation (FMR) with the Carillon device. METHODS AND RESULTS: This was a single centre analysis of prospectively collected data from patients treated with the Carillon Mitral Contour System for symptomatic congestive heart failure despite guideline-directed medical therapy, who were included from a single centre from the TITAN II study. All patients presented with New York Heart Association (NYHA) class 2 or greater symptoms, grade 2+ to 4+ FMR, left ventricular enlargement, and reduced ejection fraction. Surviving patients were evaluated for long-term follow-up post-procedure, averaging 6.9 years. Fifteen (15) patients (mean age 72 years, 60% male, 100% NYHA class III or IV, 50% MR grade 3+ or 4+) were treated with the Carillon device. The Kaplan-Meier mortality rate was 40% at 6 years of follow-up. Long-term survival through 6 years was associated with echocardiographic improvement in mitral regurgitation (change in effective regurgitant orifice area in survivors versus non-survivors from baseline to 1 year follow-up, -9.0 ± 5.6 vs. -1.7 ± 1.5, P = 0.02) and clinical status at 12 months (difference in NYHA at 1 year follow-up between survivors versus non-survivors, P = 0. 05) which was sustained throughout follow-up. All patients at 6 year follow-up had ≤2+ MR, with 6 of 7 having 0-1+ MR. Left ventricular end-diastolic volume was reduced from 154.0 ± 65.7 mL at baseline to 104.5 ± 59.2 mL at 6 year follow-up, P = 0.03 in survivors with both measurements. CONCLUSIONS: Among patients with congestive heart failure treated with the Carillon device, long-term survival is associated with favourable 1 year and sustained improvements in mitral regurgitation, left ventricular volume, ejection fraction, and clinical status.

The REDUCE FMR Trial: A Randomized Sham-Controlled Study of Percutaneous Mitral Annuloplasty in Functional Mitral Regurgitation.

OBJECTIVES: This study sought to evaluate the effects of the Carillon device on mitral regurgitation severity and left ventricular remodeling. BACKGROUND: Functional mitral regurgitation (FMR) complicates heart failure with reduced ejection fraction and is associated with a poor prognosis. METHODS: In this blinded, randomized, proof-of-concept, sham-controlled trial, 120 patients receiving optimal heart failure medical therapy were assigned to a coronary sinus-based mitral annular reduction approach for FMR or sham. The pre-specified primary endpoint was change in mitral regurgitant volume at 12 months, measured by quantitative echocardiography according to an intention-to-treat analysis. RESULTS: Patients (69.8 ± 9.5 years of age) were randomized to either the treatment (n = 87) or the sham-controlled (n = 33) arm. There were no significant differences in baseline characteristics between the groups. In the treatment group, 73 of 87 (84%) had the device implanted. The primary endpoint was met, with a statistically significant reduction in mitral regurgitant volume in the treatment group compared to the control group (decrease of 7.1 ml/beat [95% confidence interval [CI]: -11.7 to -2.5] vs. an increase of 3.3 ml/beat [95% CI: -6.0 to 12.6], respectively; p = 0.049). Additionally, there was a significant reduction in left ventricular volumes in patients receiving the device versus those in the control group (left ventricular end-diastolic volume decrease of 10.4 ml [95% CI: -18.5 to -2.4] vs. an increase of 6.5 ml [95% CI: -5.1 to 18.2]; p = 0.03 and left ventricular end-systolic volume decrease of 6.2 ml [95% CI: -12.8 to 0.4] vs. an increase of 6.1 ml [95% CI: -1.42 to 13.6]; p = 0.04). CONCLUSIONS: The Carillon device significantly reduced mitral regurgitant volume and left ventricular volumes in symptomatic patients with functional mitral regurgitation receiving optimal medical therapy. (Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation [REDUCE FMR]; NCT02325830).

Regeneration and expansion of autologous full-thickness skin through a self-propagating autologous skin graft technology.

New autologous skin regeneration technology yielded full-thickness skin as evidenced by clinical observation and skin biopsy 5 months after surgery, providing relief for debilitating split-thickness skin graft contracture in a pediatric burn case.

Eruptive xanthoma in the setting of hypertriglyceridemia and pancreatitis.

BACKGROUND: Undifferentiated dermatologic complaints are often encountered in the emergency department. While a patient's exposures, risk factors, and comorbidities may help guide emergency department evaluation, the accurate diagnosis of dermatologic findings is critical to allowing rapid identification and treatment of disease. CASE: In this vignette we discuss a case of eruptive xanthoma in a 33-year-old male with diabetic ketoacidosis and pancreatitis. DISCUSSION: Dermatologic complaints pose a unique challenge to the emergency physician. Many dermatologic findings are benign; however, some may represent underlying serious disease even in young, otherwise healthy appearing patients. Eruptive xanthomas are cutaneous lesions often indicating severe hypertriglyceridemia and uncontrolled diabetes. Likely presentations and risk factors for eruptive xanthomas will be discussed as well as ED evaluation and management.

Pediatric Chondromyxoid Fibroma-Like Osteosarcoma.

Chondromyxoid fibroma-like osteosarcoma (CMF-OS) is a low-grade osteosarcoma, often misdiagnosed on initial biopsy as a benign lesion, with five cases previously described. We report a 13-year-old male with an intramedullary lytic CMF-OS of the right tibial proximal metaphysis with cortical destruction and soft tissue extension. Diagnosis was based on malignant new bone formation, increased mitotic figures, lamellar bone permeation with bony destruction, and correlation with imaging studies. There were no metastasis at presentation and the tumor showed good response to standard chemotherapy with >95% necrosis.

Fatal Scopulariopsis brumptii in a Pediatric Immunocompromised Host.

Scopulariopsis species cause a broad range of disease, from superficial skin infections to often fatal disseminated disease in the immunocompromised that is refractory to standard antifungal treatment. This report describes the first case of fatal disseminated Scopulariopsis brumptii in a pediatric patient with hyper-IgM syndrome status post bone marrow transplant.

Unusual case of neonatal hypercalcemia.

We present a rare case of neonatal hyperparathyroidism secondary to a homozygous calcium sensing receptor (CASR) mutation, diagnosed by the genetics team. The CASR mutation is a homozygous inactivating mutation at the calcium sensing receptor. Inactivation of the receptor leads to hypercalcemia and activation leads to hypocalcemia. Heterozygous mutations can cause mild forms of asymptomatic hypercalcemia that often run in families. The homozygous mutation causes a rare form of neonatal severe hyperparathyroidism.

Randomized controlled study of excimer laser atherectomy for treatment of femoropopliteal in-stent restenosis: initial results from the EXCITE ISR trial (EXCImer Laser Randomized Controlled Study for Treatment of FemoropopliTEal In-Stent Restenosis).

OBJECTIVES: The purpose of this study was to evaluate the safety and efficacy of excimer laser atherectomy (ELA) with adjunctive percutaneous transluminal angioplasty (PTA) versus PTA alone for treating patients with chronic peripheral artery disease with femoropopliteal bare nitinol in-stent restenosis (ISR). BACKGROUND: Femoropopliteal stenting has shown superiority to PTA for lifestyle-limiting claudication and critical limb ischemia, although treating post-stenting artery reobstruction, or ISR, remains challenging. METHODS: The multicenter, prospective, randomized, controlled EXCITE ISR (EXCImer Laser Randomized Controlled Study for Treatment of FemoropopliTEal In-Stent Restenosis) trial was conducted across 40 U.S. centers. Patients with Rutherford Class 1 to 4 and lesions of target lesion length ≥4 cm, vessel diameter 5 to 7 mm were enrolled and randomly divided into ELA + PTA and PTA groups by a 2:1 ratio. The primary efficacy endpoint was target lesion revascularization (TLR) at 6-month follow up. The primary safety endpoint was major adverse event (death, amputation, or TLR) at 30 days post-procedure. RESULTS: Study enrollment was stopped at 250 patients due to early efficacy demonstrated at a prospectively-specified interim analysis. A total of 169 ELA + PTA subjects (62.7% male; mean age 68.5 ± 9.8 years) and 81 PTA patients (61.7% male; mean age 67.8 ± 10.3 years) were enrolled. Mean lesion length was 19.6 ± 12.0 cm versus 19.3 ± 11.9 cm, and 30.5% versus 36.8% of patients exhibited total occlusion. ELA + PTA subjects demonstrated superior procedural success (93.5% vs. 82.7%; p = 0.01) with significantly fewer procedural complications. ELA + PTA and PTA subject 6-month freedom from TLR was 73.5% versus 51.8% (p < 0.005), and 30-day major adverse event rates were 5.8% versus 20.5% (p < 0.001), respectively. ELA + PTA was associated with a 52% reduction in TLR (hazard ratio: 0.48; 95% confidence interval: 0.31 to 0.74). CONCLUSIONS: The EXCITE ISR trial is the first large, prospective, randomized study to demonstrate superiority of ELA + PTA versus PTA alone for treating femoropopliteal ISR. (Randomized Study of Laser and Balloon Angioplasty Versus Balloon Angioplasty to Treat Peripheral In-stent Restenosis [EXCITE ISR]; NCT01330628).

Plasma FGF23 and the risk of stroke: the Northern Manhattan Study (NOMAS).

OBJECTIVE: To examine fibroblast growth factor 23 (FGF23) as a risk factor for incident stroke in a racially/ethnically diverse population-based urban cohort. METHODS: Stroke-free Northern Manhattan Study participants with FGF23 measurements (n = 2,525) were followed for a mean of 12 (±5) years to detect incident strokes. We used Cox proportional hazards models to estimate the association of baseline FGF23 with incident total, ischemic, and hemorrhagic stroke. RESULTS: Median FGF23 was 57 relative units (RU)/mL (interquartile range = 44-81 RU/mL). Each unit increase of natural log-transformed FGF23 conferred a 40% greater overall stroke risk after adjusting for estimated glomerular filtration rate and sociodemographic and vascular risk factors (hazard ratio = 1.4, 95% confidence interval 1.1-1.6, p = 0.004). Penalized spline analysis revealed a linear association with overall stroke risk at ≥90 RU/mL FGF23, compared with <90 RU/mL (hazard ratio = 1.5, 95% confidence interval = 1.2-2.1, p = 0.004). Greater FGF23 conferred a doubling of intracerebral hemorrhage (ICH) risk but no significant increased risk of ischemic stroke. The associations of elevated FGF23 levels with greater risks of overall stroke and ICH events were independent of phosphate and parathyroid hormone levels and were similar among participants without chronic kidney disease. CONCLUSIONS: Elevated FGF23 was a risk factor for overall stroke and ICH events, in particular in a racially and ethnically diverse urban community, independent of chronic kidney disease.