Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP).

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials

Duhemian Themes in Expected Utility Theory

This monographic chapter explains how expected utility (EU) theory arose in von Neumann and Morgenstern, how it was called into question by Allais and others, and how it gave way to non-EU theories, at least among the specialized quarters of decion theory. I organize the narrative around the idea that the successive theoretical moves amounted to resolving Duhem-Quine underdetermination problems, so they can be assessed in terms of the philosophical recommendations made to overcome these problems. I actually follow Duhem's recommendation, which was essentially to rely on the passing of time to make many experiments and arguments available, and evebntually strike a balance between competing theories on the basis of this improved knowledge. Although Duhem's solution seems disappointingly vague, relying as it does on "bon sens" to bring an end to the temporal process, I do not think there is any better one in the philosophical literature, and I apply it here for what it is worth. In this perspective, EU theorists were justified in resisting the first attempts at refuting their theory, including Allais's in the 50s, but they would have lacked "bon sens" in not acknowledging their defeat in the 80s, after the long process of pros and cons had sufficiently matured. This primary Duhemian theme is actually combined with a secondary theme - normativity. I suggest that EU theory was normative at its very beginning and has remained so all along, and I express dissatisfaction with the orthodox view that it could be treated as a straightforward descriptive theory for purposes of prediction and scientific test. This view is usually accompanied with a faulty historical reconstruction, according to which EU theorists initially formulated the VNM axioms descriptively and retreated to a normative construal once they fell threatened by empirical refutation. From my historical study, things did not evolve in this way, and the theory was both proposed and rebutted on the basis of normative arguments already in the 1950s. The ensuing, major problem was to make choice experiments compatible with this inherently normative feature of theory. Compability was obtained in some experiments, but implicitly and somewhat confusingly, for instance by excluding overtly incoherent subjects or by creating strong incentives for the subjects to reflect on the questions and provide answers they would be able to defend. I also claim that Allais had an intuition of how to combine testability and normativity, unlike most later experimenters, and that it would have been more fruitful to work from his intuition than to make choice experiments of the naively empirical style that flourished after him. In sum, it can be said that the underdetermination process accompanying EUT was resolved in a Duhemian way, but this was not without major inefficiencies. To embody explicit rationality considerations into experimental schemes right from the beginning would have limited the scope of empirical research, avoided wasting resources to get only minor findings, and speeded up the Duhemian process of groping towards a choice among competing theories

Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system\u27s role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application

Comparing Treatment Effectiveness and Patient-Reported Outcomes of Four Treatment Alternatives for Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a sleep disorder involving apneic and hypopneic episodes, most often related to restrictions in a patient’s airway during sleep. OSA can have significant health consequences, including metabolic and cardiac issues as well as risks associated with chronic hypoxia. Severity of OSA is usually defined by apnea hypopnea index (AHI), which involves the number of apneic and hypopneic events per hour of sleep. While there are multiple therapeutic options for dealing with sleep apnea, there is a lack of research that compares the four most effective treatment methods for moderate to severe OSA—continuous positive airway pressure (CPAP), mandibular advancement device (MAD), upper airway stimulation (UAS), and maxillary mandibular advancement surgery (MMA). The current study assessed retrospective data for 119 patients treated at Thomas Jefferson University Hospital who received one of these therapies. The main outcome variable was Mean Disease Alleviation (MDA), which is a calculated variable based on post-treatment improvement of measures of AHI adjusted by compliance. Secondary outcomes included clinical assessments by polysomnography and patient reported outcome measures (PROMs) completed pre- and post-treatment. The adjusted compliance was also evaluated for each of the therapies to determine its impact on the respective therapies. The four therapies were assessed using ANOVA. The findings from this comparative study indicated that MDA was highest for MMA surgery (M = 36.08, SD = 28.56), when compared to UAS (M = 22.88, SD = 3.16), MAD (M = 6.80, SD = 8.13), and CPAP (M = 5.00, SD =14.80), F (3,115) = 18.95, p \u3c 0.001. Significant predictors of MDA included race (F = 15.57, p \u3c 0.00), BMI (F =5.12, p= 0.026), age (F = 8.84, p= 0.004), hours of sleep (F = 7.524, p= 0.007) and pre-treatment AHI (F = 96.76, p \u3c 0.001). However, additional analyses controlling for these factors demonstrated that the effect of treatment was still significant (F = 11.74, p \u3c 0.001). Ultimately, there was no significant effect of adjusted compliance across the four treatment conditions, and compliance was not a significant predictor of MDA. While each of the PROMs showed significant improvement across all four-treatment conditions, ANOVA analysis showed no significant differences across the four treatment conditions, except for a significant improvement in daytime sleepiness for MMA surgery. These findings were used to construct new treatment recommendations for patients with OSA

Access Gaps in Dental Procedure Coverage for Medicare Beneficiaries and Dental Coverage Perceptions in Philadelphia

Dental care is not included in Medicare benefits, so many beneficiaries, 65 and older, are left to pay out of pocket for services or pay for private dental insurance. A lack of dental coverage can lead to patients electing to opt-out of a needed dental procedure, later affecting their overall health and quality of life. Participants from Thomas Jefferson University’s Department of Oral and Maxillofacial Surgery were analyzed through a random chart review of payment methods. Those that are not covered by Medicare Advantage were surveyed on their dental coverage and knowledge of it, as well as overall health. The results showed that the majority of participants paid for dental procedures out pocket and only a small percentage had a procedure covered by Medicare alone. Nine individuals were surveyed over the phone. The majority of people interviewed felt that dental insurance was not necessary or important. It was acknowledged by participants that dental procedures were very expensive and they had to cover the cost, since they did not have insurance or insurance only covered a small percentage

Reconstruction of Marginal Mandibular Defects Utilizing Bone Marrow Aspirate Concentrate (BMAC) from the Anterior Iliac Crest: A Less Morbid Osteogenic Option

The aim of this case series, is to describe our surgical technique for reconstructing benign mandibular neoplasms using BMAC – a less invasive approach than traditional iliac crest bone graft harvest. BMAC was used in combination with mineralized freeze-dried allograft, platelet rich plasma (PRP) & bone morphogenic protein (rhBMP-2) to reconstruct the hard tissue lost secondary to the ablative tumor resection. 10 patients included in the retrospective case series were treated between 2014 and 2017 by 3 surgeons. Mean age - 44 years (range - 19 to 77 years). BMAC was obtained from the anterior iliac crest (AIC). When appropriate, a custom milled mandibular reconstruction plate was placed. Maxillofacial pathology included benign neoplasms such as Ameloblastoma, Cavernous Hemangioma, Central Giant Cell Granuloma (CGCG), Dentigerous Cyst & Keratocystic Odontogenic Tumor (KOT).https://jdc.jefferson.edu/omsposters/1001/thumbnail.jp