Disease-modifying effects of edasalonexent,an NF-κB inhibitor,in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial

Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-<8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control. Endpoints were safety/tolerability, change from baseline in MRI T₂ relaxation time of lower leg muscles and functional assessment, as well as pharmacodynamics and biomarkers. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly of the gastrointestinal system (primarily diarrhea). There were no serious adverse events in the edasalonexent groups. Edasalonexent 100 mg/kg was associated with slowing of disease progression and preservation of muscle function compared to an off-treatment control period, with decrease in levels of NF-κB-regulated genes and improvements in biomarkers of muscle health and inflammation. These results support investigating edasalonexent in future trials and have informed the design of the edasalonexent phase 3 clinical trial in boys with Duchenne.     

The Radiology Resident as Teaching Consultant: An Innovative Peer-to-Peer Teaching Consultation Service to Strengthen Relationships With Referring Colleagues in the Era of Imaging 3.0

BackgroundThe American College of Radiology Imaging 3.0 paradigm emphasizes the need for radiologists to serve as imaging consultants to their referring colleagues. However, outside the reading room, teaching interactions between radiology and nonradiology residents are limited. Internal Medicine Morning Report (IMMR) is a resident-run educational program widely employed by internal medicine (IM) residencies. Although medical imaging is regularly discussed in IMMR, radiology residents are not typically involved in case preparation. We aimed to develop a peer-to-peer imaging teaching consultation service (TCS) incorporated into the well-established structure of IMMR. By creating illustrative, “dynamic” teaching slides for use at these conferences, we sought to provide salient radiology teaching material, demystify jargon, discuss appropriate imaging use, and review relevant anatomy. We hypothesized that TCS could improve the quality of IMMR as perceived by the IM presenter.MethodsTCS was piloted over a 7-month period. Each referred case was reviewed by a senior radiology resident who produced a set of “dynamic” teaching slides for each case. These included patient imaging overlayed with extensive annotations and animations highlighting teaching points, with particular attention to radiologic terminology. Slides were shared with the IM presenter, who could use them for preparation and include the animations in the talk if desired. TCS effectiveness was evaluated with a survey distributed to participating IM residents.ResultsIn the pilot period, 12 TCS requests were received and 10 were performed in collaboration with 6 IM residents. Survey results indicated that most IM residents did not consult radiologists prior to TCS (5/6, 83%). IM residents used the “dynamic” teaching slides to both prepare for and present at IMMR (5/6, 83%). TCS improved IM residents’ perceived ability to engage their audience (6/6, 100%), confidence in teaching radiology material (4/6, 67%), ability to understand radiology reports (4/6, 67%) and appreciation for what radiologists do (6/6, 100%).ConclusionsThe TCS pilot resulted in successful radiology-IM collaboration and improved knowledge and confidence in teaching imaging concepts. Continuous program evaluation will be performed and future work will assess the effect of TCS on radiologist confidence in real-world clinical consultations.     

Kinetic investigation of the hydrolysis of uranium hexafluoride gas

UF₆ is commonly employed in enrichment technologies and is known to react rapidly with water vapor to form radioactive particulates and hydrofluoric acid vapor. The kinetics of the UF₆ hydrolysis reaction have been observed directly for the first time. The rate appears to be half order and second order for UF₆ and water, respectively, with a rate constant of 1.19 ± 0.22 Torr^−3/2 s⁻¹. The proposed mechanism involves formation of the [UF₆·2H₂O] adduct via two separate reactions.

Direct observation of the hydrolysis reaction kinetics of gaseous UF₆ have been measured under low-pressure conditions.

Uranium hexafluoride (UF₆) is a key compound in the nuclear fuel cycle as the material employed in commercial enrichment, enabling production of the fuel for electricity production in nuclear power reactors. Studies evaluating the safety implications of small or large releases of UF₆ within a processing facility have been performed previously,^1–3 as it is well known that this material undergoes a hydrolysis reaction in ambient air according to the simplified reaction:UF₆(g) + 2H₂O(g) → UO₂F₂(s) + 4HF(g)producing both uranium particulates and hydrofluoric acid vapor. Recent work⁴ has explored the formation of the uranium particulate materials but the precise molecular mechanism of the initiating reaction has yet to be verified. Previous efforts to characterize this reaction have focused on spectroscopic measurements^5–7 and computational studies.^8–13 The experimental studies have focused on the spectroscopic detection of uranium species but lacked the temporal resolution to observe the reaction or identify any transient species. Unfortunately, there are major discrepancies between the experimentally observed reaction and computationally predicted mechanisms. For example, the computational studies suggest large thermodynamic energy barriers that would likely prevent the reaction of UF₆ and water vapor,^9–13 yet the hydrolysis reaction is known to occur quickly and completely under ambient conditions.^5–7 Additionally, one of the long-suspected intermediates of this reaction, UOF₄, has not been successfully identified under extreme conditions designed to optimize its production such as reacting water with a 5000-fold excess of UF₆.¹⁴ Relevant spectroscopy measurements need to be performed to inform computational modelling because the mechanism may not be driven by a stepwise reaction of UF₆ and water molecules.One prior study performed an indirect measurement of the rate of the UF₆ hydrolysis by monitoring the ingrowth of hydrogen fluoride with a laser-based analyzer.¹⁵ The reported rate constant of 4 ± 4 × 10⁻¹⁸ cm³ s⁻¹ remains questionable as limited experimental details were reported. Based on their findings, and assuming pseudo-first order kinetics under these reaction conditions in excess water vapor, the reaction half-life is calculated to be on the order of 1 ms or less. Standard infrared spectroscopy instrumentation cannot scan with submillisecond temporal resolution, requiring specialized instrumentation that has only recently become available.This work focused on observing the disappearance of UF₆ under low pressure conditions by probing the most sensitive infrared (ν₃ antisymmetric stretching) vibrational band,¹⁶ located at 625 cm⁻¹, using a 5 m long-path length cell. The long path length combined with the sensitivity of the band allow the reaction rate to be investigated at sub-Torr partial pressures. The reaction is slow enough at these pressures to allow direct kinetic measurements of the hydrolysis to be made using a typical infrared spectrometer.Experiments were performed in a 5 m long-path length gas cell fitted to an ABB MB3000 Fourier transform infrared spectrometer. The chamber was exposed to fluorine gas to passivate materials of construction and remove water from surfaces within the spectroscopy cell before each experiment. The UF₆ was then introduced into the evacuated cell at pressures between 10 and 30 mTorr and ambient temperature (22.5 ± 0.5 °C). (Warning: UF₆ is a radioactive gas that forms highly toxic hydrogen fluoride in the presence of water.) After initial infrared spectroscopy measurements were made, 60 or 80 mTorr of water vapor was injected into the system and allowed to react. Typical infrared spectra collected during the hydrolysis reaction occurred during 0.5–2 min for these conditions, as shown in Fig. 1A. Note, the reactions that occurred when water vapor was introduced at these partial pressures were approximately an order of magnitude faster than any reactions of UF₆ with materials of construction. The observed rates (Fig. 1B) were significantly slower than those expected from diffusion-limited reactivity, suggesting that mixing occurred rapidly from the injection method.Open in a separate windowFig. 1(A) Select infrared spectra showing the 625 cm⁻¹ band of UF₆ just before introducing water vapor (red) and every 10 s after (blue) for 1 min. (B) Example of absorbance change of the 625 cm⁻¹ band over time during a typical hydrolysis experiment. The rate of disappearance of the UF₆ increased about a factor of 10 when H₂O was introduced.Typical changes in the absorbance due to the reaction are shown in Fig. 2 after correction for reaction with materials of construction. Each figure is the average of three experiments and the data are corrected using a linear regression of the absorbance before time zero extrapolated through the points used for initial rate determination. The initial slope of the decay was fit using a linear regression on the first five data points for each reaction condition. The data were converted from absorbance units to mTorr, and the resulting conditional reaction rates in mTorr s⁻¹ are shown in Open in a separate windowFig. 2The normalized absorbance of the 625 cm⁻¹ band in a 5 m path length cell for various partial pressures of UF₆ and water vapor. Water vapor was injected at time = 0 s.Conditional reaction rates of the hydrolysis of gaseous UF₆ in the presence of H₂O vapor

Orthopaedic Surgeons Receive the Most Industry Payments to Physicians but Large Disparities are Seen in Sunshine Act Data

Background

Industry payments made to physicians by drug and device manufacturers or group purchasing organizations are now reported to the Centers for Medicare and Medicaid Services (CMS) as a part of the Physician Payments Sunshine Act. Initial reports from the program show that orthopaedic surgeons lead all physician specialties in total and average industry payments. However, before further discussion of these payments and their implications can take place, it remains to be seen whether these figures are a true reflection of the field of orthopaedic surgery in general, rather than the result of a few outlier physicians in the field. In addition, the nature and sources of these funds should be determined to better inform the national dialogue surrounding these payments.

Questions/Purposes

We asked: (1) How do industry payments to orthopaedic surgeons compare with payments to physicians and surgeons in other fields, in terms of median payments and the Gini index of disparity? (2) How much do payments to the highest-receiving orthopaedic surgeons contribute to total payments? (3) What kind of industry payments are orthopaedic surgeons receiving? (4) How much do the highest-paying manufacturers contribute to total payments to orthopaedic surgeons?

Materials and Methods

We reviewed the most recent version of the CMS Sunshine Act Open Payments database released on December 19, 2014, containing data on payments made between August 1, 2013 and December 31, 2013. Data on total payments to individual physicians, physician specialty, the types of payments made, and the manufacturers making payments were reviewed. The Gini index of statistical dispersion was calculated for payments made to orthopaedic surgeons and compared with payments made to physicians and surgeons in all other medical specialties. A Gini index of 0 indicates complete equality of payments to everyone in the population, whereas an index of 1 indicates complete inequality, or all income going to one individual.

Results

A total of 15,376 orthopaedic surgeons receiving payments during the 5-month period were identified, accounting for USD 109,846,482. The median payment to orthopaedic surgeons receiving payments was USD 121 (interquartile range, USD 34–619). The top 10% of orthopaedic surgeons receiving payments (1538 surgeons) received at least USD 4160 and accounted for 95% of total payments. Royalties and patent licenses accounted for 69% of all industry payments to orthopaedic surgeons.

Conclusions

Even as a relatively small specialty, orthopaedic surgeons received substantial payments from industry (more than USD 110 million) during the 5-month study period. Whether there is a true return of value from these payments remains to be seen; however, future ethical and policy discussions regarding industry payments to orthopaedic surgeons should take into account the large disparities in payments that are present and also the nature of the payments being made. It is possible that patients and policymakers may view industry payments to orthopaedic surgeons more positively in light of these new findings.

Level of Evidence

Level III, Economic and Decision Analysis.