Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that ...fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1
). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1
FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive and catastrophic heterotopic ossification (HO) of skeletal muscle and associated soft tissues. FOP ...is caused by dominantly acting mutations in the gene encoding the bone morphogenetic protein (BMP) type I receptor, ACVR1 (ALK2), the most prevalent of which results in an arginine to histidine substitution at position 206 (ACVR1R206H). The fundamental pathological consequence of FOP-causing ACVR1 receptor mutations is to enable activin A to initiate canonical BMP signaling in fibro-adipogenic progenitors (FAPs), which drives HO. We developed a monoclonal blocking antibody (JAB0505) against the extracellular domain of ACVR1 and tested its effect on HO in 2 independent FOP mouse models. Although JAB0505 inhibited BMP-dependent gene expression in wild-type and ACVR1(R206H)-overexpressing cell lines, JAB0505 treatment profoundly exacerbated injury-induced HO. JAB0505-treated mice exhibited multiple, distinct foci of heterotopic lesions, suggesting an atypically broad anatomical domain of FAP recruitment to endochondral ossification. This was accompanied by dysregulated FAP population growth and an abnormally sustained immunological reaction following muscle injury. JAB0505 drove injury-induced HO in the absence of activin A, indicating that JAB0505 has receptor agonist activity. These data raise serious safety and efficacy concerns for the use of bivalent anti-ACVR1 antibodies to treat patients with FOP.
Introduction: Despite recent advances in applied instruments and surgical techniques, the incidence of iatrogenic durotomies caused by traditional techniques remains significant. The ultrasonic bone ...scalpel (UBS) has been shown to improve speed and reduce complications in laminectomies in the cervical and thoracic spine when compared to traditional methods utilizing high-speed burr, punch forceps, or rongeurs. Thus, in this study, we aim to evaluate whether the use of the UBS in the lumbar spine would result in equivalent safety, efficacy, and patient-reported outcomes (PROs) improvement when compared to traditional methods of laminectomy.Methods: Data from a prospectively collected, single-institution registry was queried between January 1, 2019 and September 1, 2021 for patients with a primary diagnosis of lumbar stenosis who received a laminectomy (with or without fusion) using traditional methods or UBS method. Outcomes included 3-month and 12-month values for all PROs Measurement Information System (PROMIS) subdomains, Numerical Rating Scale (NRS) pain score, Oswestry Disability Index (ODI) percentage, Patient Health Questionnaire 9 (PHQ-9) score, operative complications, reoperations, and readmissions. Covariates selected for matching included age, operation type, and number of levels. A variety of statistical tests were utilized.Results: As per our findings, 2:1 propensity matching resulted in 64 "traditional group" patients and 32 "UBS group" patients. Post-match analysis found no differences between the traditional and UBS groups for demographic and baseline measures except for race and ethnicity. For the matched sample, no differences were noted in PROs, reoperations, or readmissions. There was a significant difference in rates of durotomies between the traditional and UBS groups (12.5% vs. 0.0%, p=0.049).Conclusions: Results showed the high-frequency oscillation technology implemented by the UBS helps to decrease the rate of injury to the dura, thus reducing the overall incidence of iatrogenic durotomies. We believe these data provide valuable information to surgeons and patients about the safety and efficacy of the UBS in performing lumbar laminectomies.
Dual mobility (DM) constructs for revision total hip arthroplasty (THA) have continued to grow in popularity to mitigate instability. This benefit comes at the cost of potential unique modes of ...failure, and there are theoretical concerns that combining femoral and acetabular components from different manufacturers could lead to increased failure rates. We aimed to investigate rates of reoperation between matched and unmatched DM implants used in revision THA.
We retrospectively reviewed 217 revision THAs performed with DM constructs between July 2012 and September 2021 at a single institution. Dual mobility (DM) constructs were classified as “matched” if the acetabular and femoral components were manufactured by the same company. They were classified as “unmatched” if the acetabular and femoral components were manufactured by different companies. The primary outcome was reoperation for any reason.
There were 136 matched DM constructs and 81 unmatched constructs. Average follow-up was 4.6 years (range, 2.0 to 9.6 years). There was no difference in reoperation rate between matched and unmatched groups (11.0 versus 13.6%, P = .576). The most common reasons for reoperation in both groups were instability and periprosthetic joint infection. There was 1 revision for intraprosthetic dislocation in the matched group.
The use of unmatched DM components in revision THA was common and did not increase the risk of reoperation at an average of 4.6-year follow-up. This information can be helpful in operative planning, but further research on long-term survival will be necessary.
To investigate the isolated and combined effects of medial patellofemoral ligament (MPFL) and medial patellotibial ligament (MPTL) deficiency and reconstruction on patellofemoral kinematics.
Sixteen ...matched-paired female cadaveric knee specimens with a mean age of 53.5 years (range, 26-65) were tested in 5 conditions: (1) intact, (2) MPFL or MPTL cut, (3) MPFL and MPTL combined cut, (4) MPFL or MPTL reconstruction, and (5) MPFL and MPTL combined reconstruction. Dynamic testing allowed continuous analysis of kinematics from 0° to 90° of knee flexion. Knees were also tested statically using a lateral load of 45 N at 0°, 30°, 60°, and 90° of flexion. In both dynamic and static loading tests, a motion capture system detected patellar position for each testing state to distinguish changes in patellar kinematics. Random-intercepts linear mixed-effects models were used to compare patellar kinematics.
The MPFL is the primary restraint to lateral translation of the patella at all knee flexion angles. MPTL deficiency alone did not create significant patella instability, but further increased instability when the MPFL was deficient. Isolated MPFL and combined reconstruction provided improved stability. Through full range of motion native patella tracking was best recreated with combined ligament reconstruction.
The MPFL plays the greatest role in medial patellar stability, but the MPTL appears to have an influence on patella tracking. This study provides further understanding to the impact of the MPFL and MPTL on patellofemoral motion with implications for reconstruction to improve stability and optimize patellofemoral tracking.
This study provides further understanding of the role of the MPFL and MPTL on patellofemoral motion with implications for reconstruction to improve stability and optimize patellofemoral tracking.
With the significant increase in the use of household cleaners, disinfectants, and hand sanitizers among the general population in an effort to prevent SARS‐CoV‐2 transmission, and the notable ...knowledge gaps about their safe preparation, use, and storage, this report underscores the importance of educating transplant candidates and recipients on the proper use of such cleaning and disinfecting products.
Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively ...accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored. We show that female FOP mice exhibit both significantly greater and more variable HO responses after muscle injury. Additionally, the incidence of spontaneous HO was significantly greater in female mice. This sex dimorphism is not dependent on gonadally derived sex hormones, and reciprocal cell transplantations indicate that apparent differences in osteogenic activity are intrinsic to the sex of the transplanted cells. By circumventing the absolute requirement for activin A using an agonist of mutant ACVR1, we show that the female-specific response to muscle injury or BMP2 implantation is dependent on activin A. These data identify sex as a critical variable in basic and pre-clinical studies of FOP.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2
. In FOP, ALK2 ...variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2
inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2
binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2
with high affinity, inhibiting signaling from ALK2
and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2
mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2
mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2
mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.
Abstract
Purpose
The University of Kentucky Drug Quality Study team briefly reviews the growing concerns over pharmaceutical manufacturing quality in the globalized environment, reviews the ...historical approach by the US Food and Drug Administration (FDA) that prioritizes process over product in enforcing quality with manufacturers, reviews the science of process analytical technology (PAT) such as near-infrared (NIR) spectroscopy, illustrates the use of PAT methods for assessing uniformity and quality in injectable pharmaceuticals, and demonstrates the application of NIR spectroscopy in a health-system pharmacy setting while maintaining current good practice quality guidelines and regulations (cGxP).
Summary
Given that the current approach to monitoring quality in pharmaceutical manufacturing was developed in the late 1960s at a time when manufacturing was mostly domestic, the current approach prioritizes process over product, and the global footprint of manufacturing is straining federal resources to fulfill their task of monitoring quality, an approach to augment the quality monitoring process has been developed. PAT methodologies are supported by FDA for monitoring quality and offer a fast, low-cost, nondestructive solution. Given that the Accreditation Council for Pharmacy Education has not required qualitative/quantitative analysis and drug assaying in the pharmacy curriculum for several decades, the authors spend time explaining the science behind one of these PAT methodologies, NIR spectroscopy. This primer reviews the application of this technology in the health-system pharmacy setting and the relevant clinical applications.
Conclusion
Utilizing PAT methodologies such as NIR spectroscopy, health-system pharmacies can gain insights about whether process controls are in place or lacking in FDA-approved formulations.
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