Four-channel optically pumped magnetometer for a magnetoencephalography sensor array.

We present a novel four-channel optically pumped magnetometer (OPM) for magnetoencephalography that utilizes a two-color pump/probe scheme on a single optical axis. We characterize its performance across 18 built sensor modules. The new sensor implements several improvements over our previously developed sensor including lower vapor-cell operating temperature, improved probe-light detection optics, and reduced optical power requirements. The sensor also has new electromagnetic field coils on the sensor head which are designed using stream-function-based current optimization. We detail the coil design methodology and present experimental characterization of the coil performance. The magnetic sensitivity of the sensor is on average 12.3 fT/rt-Hz across the 18 modules while the average gradiometrically inferred sensitivity is about 6.0 fT/rt-Hz. The sensor 3-dB bandwidth is 100 Hz on average. The on-sensor coil performance is in good agreement with the simulations.

European priority review vouchers for neglected disease product development.

INTRODUCTION: Neglected diseases are a significant global health challenge. Encouraging the development of therapeutics and vaccines for these diseases would address an important unmet medical need. We propose a priority review voucher programme for the European Union (EU). The developer of a drug or vaccine for a neglected disease would receive a voucher for accelerated assessment of a different product at the European Medicines Agency (EMA). METHODS: This study uses retrospective observational data to estimate the potential commercial value of the proposed voucher programme using a five-step approach: (1) estimating the time saved in the EMA accelerated regulatory review; (2) gauging time reductions in accelerated pricing and reimbursement decisions by EU member states; (3) selecting 10 high-revenue products launched between 2015 and 2020 representing typical voucher users; (4) analysing IQVIA MIDAS sales data for the selected products and (5) calculating the net present value (NPV) of the voucher based on the 10 products. RESULTS: The accelerated EMA review would reduce regulatory time by an average of 182 days. Additionally, products could save more than a year in many member states through an expedited 120-day pricing and reimbursement review. The estimated NPV of regulatory acceleration by two quarters would be €100 million. In addition, if France, Italy and Spain reviewed pricing and reimbursement in only 120 days, then the value would double. CONCLUSION: An EU voucher estimated at more than €100 million, coupled with a US$100 million counterpart, offers a meaningful incentive for novel product development. However, the voucher programme should be part of a comprehensive strategy for tackling neglected diseases, rather than a standalone solution.

FDA Global Drug Inspections: Surveillance Of Manufacturing Establishments Remains Well Below Pre-COVID-19 Levels.

During the initial phase of the COVID-19 pandemic, the Food and Drug Administration (FDA) halted inspections of most overseas drug manufacturing establishments. Looking at data from the period 2012-22, we observed steep declines in both foreign and domestic inspections in 2020. By 2022, numbers of inspections remained well below prepandemic levels, with a 79 percent decrease in foreign inspections and a 35 percent decline in domestic inspections compared with 2019. There was no corresponding reduction in drug manufacturing or imports. Also, the resources allocated per inspection surged, although the FDA's overall budget and staffing remained steady. Finally, citations rose dramatically, despite all establishments being given advance notice of inspections. The findings of our study underscore the pressing need to explore alternative methods for ensuring drug safety.

Consequences of a shortage and rationing: Evidence from a pediatric vaccine.

Shortages and rationing are common in health care, yet we know little about the consequences. We examine an 18-month shortage of the pediatric Haemophilus Influenzae Type B (Hib) vaccine. Using insurance claims data and variation in shortage exposure across birth cohorts, we find that the shortage reduced uptake of high-value primary doses by 4 percentage points and low-value booster doses by 26 percentage points. This suggests providers largely complied with rationing recommendations. In the long-run, catch-up vaccination occurred but was incomplete: shortage-exposed cohorts were 4 percentage points less likely to have received the ir booster dose years later. We also find that the shortage and rationing caused provider switches, extra provider visits, and negative spillovers to other care.

A Four-channel Optically Pumped Magnetometer for a Magnetoencephalography Sensor Array.

We present a novel four-channel OPM sensor for magnetoencephalography that utilizes a two-color pump/probe scheme on a single optical axis. We characterize its performance across 18 built sensor modules. The new sensor implements several improvements over our previously developed sensor including lower vapor-cell operating temperature, improved probe-light detection optics, and reduced optical power requirements. The sensor also has new electromagnetic field coils on the sensor head which are designed using stream-function-based current optimization. We detail the coil design methodology and present experimental characterization of the coil performance. The magnetic sensitivity of the sensor is on average 12.3 fT/rt-Hz across the 18 modules while the average gradiometrically inferred sensitivity is about 6.0 fT/rt-Hz. The sensor 3-dB bandwidth is 100 Hz on average. The on-sensor coil performance is in good agreement with the simulations.

The Safety and Immunologic Effectiveness of the Live Varicella-Zoster Vaccine in Patients Receiving Tumor Necrosis Factor Inhibitor Therapy : A Randomized Controlled Trial.

BACKGROUND: The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis factor inhibitors (TNFis). OBJECTIVE: To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis. DESIGN: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341). SETTING: Academic and community-based rheumatology, gastroenterology, and dermatology practices. PATIENTS: Adults aged 50 years or older receiving TNFis for any indication. INTERVENTION: Random assignment to ZVL versus placebo. MEASUREMENTS: Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid. RESULTS: Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL (n = 310) or placebo (n = 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively. LIMITATION: Potentially limited generalizability to patients receiving other types of immunomodulators. CONCLUSION: This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics. PRIMARY FUNDING SOURCE: The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.

​US Tropical Disease Priority Review Vouchers: Lessons In Promoting Drug Development And Access.

The COVID-19 global pandemic has devastated lives and economies. It has served as a reminder of how critical it is to invest in preventing and treating infectious diseases. Until the COVID-19 pandemic, the largest US government-sponsored reward for infectious disease drug and vaccine development was the Tropical Disease Priority Review Voucher program. Under this program, the Food and Drug Administration awards a priority review voucher to the sponsor of a new drug or vaccine for tropical infectious diseases. The voucher then can be exchanged for the faster review of one drug. We provide case studies for tropical disease voucher recipients between 2007 and 2018, examine the effects of the voucher program on product innovation and access, and recommend that policy makers protect the voucher program while creating complementary incentives.

Forecasting Posttreatment Outcome of Hallux Valgus Surgery Patients.

BACKGROUND: Despite advancements in operative techniques and the extraordinary number of procedures described for correcting hallux valgus (HV), there is still uncertainty as to why some patients thrive postoperatively whereas others do not. This study aimed to investigate whether the postoperative outcome of HV surgery could be predicted from patient demographics or functional impairment at the time of referral. METHODS: The prospectively collected data, from 92 patients, were analyzed to determine whether patient demographics significantly influenced outcome 52 weeks after surgery. Potential relationships between socioeconomic deprivation and the outcome, as well as between preoperative functional impairment and postoperative improvement, were examined. The Manchester Oxford Foot Questionnaire (MOXFQ) and Scottish Index of Multiple Deprivation (SIMD) were used in this evaluation. RESULTS: None of the demographics studied were found to be statistically significant determinants of outcome. Preoperative MOXFQ scores for patients from the most deprived areas were significantly worse at the time of referral. Patients living in the least deprived postcodes experienced the lowest improvement in MOXFQ scores. Patients from the most deprived SIMD quintile achieved significantly higher improvement in MOXFQ-walking and standing compared to those from the least deprived quintile. A strong positive correlation was found between the preoperative MOXFQ scores and the improvement in the scores postoperatively. CONCLUSION: In this patient cohort, demographics could not be used to predict the postoperative outcome at week 52. Socioeconomic disparities seem to influence the timing of patients seeking surgery. Lower preoperative MOXFQ scores strongly correlate with a lesser degree of postoperative improvement. LEVEL OF EVIDENCE: Level III, retrospective study with prospective arm.

Persistence with Early-Line Abatacept versus Tumor Necrosis Factor-Inhibitors for Rheumatoid Arthritis Complicated by Poor Prognostic Factors.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling and destruction that leads to severe disability. There are no clear guidelines regarding the order of therapies. Gathering data on treatment patterns outside of a clinical trial setting can provide useful context for clinicians. Objectives: To assess real-world treatment persistence in early-line abatacept versus tumor necrosis factor-inhibitors (TNFi) treated patients with RA complicated by poor prognostic factors (including anti-cyclic citrullinated peptide antibodies [ACPA] and rheumatoid factor [RF] seropositivity). Methods: We performed a multi-center retrospective medical record review. Adult patients with RA complicated by poor prognostic factors were treated with either abatacept or TNFis as the first biologic treatment at the clinic. Poor prognostic factors included ACPA+, RF+, increased C-reactive protein levels, elevated erythrocyte sedimentation rate levels, or presence of joint erosions. We report 12-month treatment persistence, time to discontinuation, reasons for discontinuation, and risk of discontinuation between patients on abatacept versus TNFi. Select results among the subgroup of ACPA+ and/or RF+ patients are presented. Results: Data on 265 patients (100 abatacept, 165 TNFis) were collected. At 12 months, 83% of abatacept patients were persistent versus 66.1% of TNFi patients (P=0.003). Median time to discontinuation was 1423 days for abatacept versus 690 days for TNFis (P=0.014). In adjusted analyses, abatacept patients had a lower risk of discontinuing index treatment due to disease progression (0.3 [95% confidence interval (CI): 0.1-0.6], P=0.001). Among the subgroup of ACPA+ and/or RF+ patients (55 abatacept, 108 TNFis), unadjusted 12-month treatment persistence was greater (83.6% versus 64.8%, P=0.012) and median time to discontinuation was longer (961 days versus 581 days, P=0.048) in abatacept versus TNFi patients. Discussion: Patients with RA complicated by poor prognostic factors taking abatacept, including the subgroup of patients with ACPA and RF seropositivity, had statistically significantly higher 12-month treatment persistence and a longer time to discontinuation than patients on TNFis. Conclusions: In a real-world setting, RA patients treated with abatacept were more likely to stay on treatment longer and had a lower risk of discontinuation than patients treated with TNFis.

Patient-Related Outcome Measures (PROMs) With Nonoperative and Operative Management of Morton's Neuroma.

BACKGROUND: Morton's neuroma is associated with chronic pain and disability. There is a paucity of literature regarding patient-related outcome measures (PROMs) in patients managed nonoperatively. We sought to investigate nonoperative and operative management of Morton's neuroma using PROMs in patients with follow-up to 1 year. METHODS: We conducted a prospective observational study and collected data on all patients with a new diagnosis of Morton's neuroma treated from February 2016 until April 2018. Primary outcome measures were the Manchester-Oxford Foot Questionnaire (MOXFQ) for pain, EuroQoL (EQ) time trade-off (TTO), and EQ visual analog scale (VAS) taken preoperatively and at 52 weeks postoperatively. Forty-four patients were treated nonoperatively and 94 patients were treated operatively. RESULTS: Pretreatment and 52-week scores were 55.7 and 43.10 (nonoperative) and 63.7 and 40.1 (operative) for MOXFQ (pain), 0.72 and 0.82 (nonoperative) and 0.68 and 0.82 (operative) for EQ-TTO, and 71.5 and 76.2 (nonoperative) and 73.1 and 68.7 (operative) for EQ-VAS. There was a statistically significant improvement in MOXFQ (pain) in nonoperative (P = .02) and operative groups (P < .001). There was a statistically significant improvement in EQ-TTO in the operative group only (P = .01). CONCLUSION: This is the largest study investigating outcomes to 12 months of both nonoperative and operatively managed patients with Morton's neuroma. Both nonoperative and operative management lead to symptom improvement at 12 months. LEVEL OF EVIDENCE: Level III, comparative study.

Exploring the Constraints on Simulated Aerosol Sources and Transport Across the North Atlantic With Island-Based Sun Photometers.

Atmospheric aerosol over the North Atlantic Ocean impacts regional clouds and climate. In this work, we use a set of sun photometer observations of aerosol optical depth (AOD) located on the Graciosa and Cape Verde islands, along with the GEOS-Chem chemical transport model to investigate the sources of these aerosol and their transport over the North Atlantic Ocean. At both locations, the largest simulated contributor to aerosol extinction is the local source of sea-salt aerosol. In addition to this large source, we find that signatures consistent with long-range transport of anthropogenic, biomass burning, and dust emissions are apparent throughout the year at both locations. Model simulations suggest that this signal of long-range transport in AOD is more apparent at higher elevation locations; the influence of anthropogenic and biomass burning aerosol extinction is particularly pronounced at the height of Pico Mountain, near the Graciosa Island site. Using a machine learning approach, we further show that simulated observations at these three sites (near Graciosa, Pico Mountain, and Cape Verde) can be used to predict the simulated background aerosol imported into cities on the European mainland, particularly during the local winter months, highlighting the utility of background AOD monitoring for understanding downwind air quality.

Global high-resolution emissions of soil NOx, sea salt aerosols, and biogenic volatile organic compounds.

Natural emissions of air pollutants from the surface play major roles in air quality and climate change. In particular, nitrogen oxides (NOx) emitted from soils contribute ~15% of global NOx emissions, sea salt aerosols are a major player in the climate and chemistry of the marine atmosphere, and biogenic emissions are the dominant source of non-methane volatile organic compounds at the global scale. These natural emissions are often estimated using nonlinear parameterizations, which are sensitive to the horizontal resolutions of inputted meteorological and ancillary data. Here we use the HEMCO model to compute these emissions worldwide at horizontal resolutions of 0.5° lat. × 0.625° lon. for 1980-2017 and 0.25° lat. × 0.3125° lon. for 2014-2017. We further offer the respective emissions at lower resolutions, which can be used to evaluate the impacts of resolution on estimated global and regional emissions. Our long-term high-resolution emission datasets offer useful information to study natural pollution sources and their impacts on air quality, climate, and the carbon cycle.

Trends in Chemical Composition of Global and Regional Population-Weighted Fine Particulate Matter Estimated for 25 Years.

We interpret in situ and satellite observations with a chemical transport model (GEOS-Chem, downscaled to 0.1° × 0.1°) to understand global trends in population-weighted mean chemical composition of fine particulate matter (PM2.5). Trends in observed and simulated population-weighted mean PM2.5 composition over 1989-2013 are highly consistent for PM2.5 (-2.4 vs -2.4%/yr), secondary inorganic aerosols (-4.3 vs -4.1%/yr), organic aerosols (OA, -3.6 vs -3.0%/yr) and black carbon (-4.3 vs -3.9%/yr) over North America, as well as for sulfate (-4.7 vs -5.8%/yr) over Europe. Simulated trends over 1998-2013 also have overlapping 95% confidence intervals with satellite-derived trends in population-weighted mean PM2.5 for 20 of 21 global regions. Over 1989-2013, most (79%) of the simulated increase in global population-weighted mean PM2.5 of 0.28 µg m-3yr-1 is explained by significantly (p < 0.05) increasing OA (0.10 µg m-3yr-1), nitrate (0.05 µg m-3yr-1), sulfate (0.04 µg m-3yr-1), and ammonium (0.03 µg m-3yr-1). These four components predominantly drive trends in population-weighted mean PM2.5 over populous regions of South Asia (0.94 µg m-3yr-1), East Asia (0.66 µg m-3yr-1), Western Europe (-0.47 µg m-3yr-1), and North America (-0.32 µg m-3yr-1). Trends in area-weighted mean and population-weighted mean PM2.5 composition differ significantly.

A Voucher System To Speed Review Could Promote A New Generation Of Insecticides To Fight Vector-Borne Diseases.

Many in the scientific community are concerned about the potential increase in prevalence of insect-borne diseases such as Chagas disease, Chikungunya, dengue fever, malaria, and Zika in the United States and around the world. Beyond vaccines and drugs to prevent and treat these diseases, a comprehensive approach to fighting these diseases should include control of disease-carrying vectors, such as mosquitoes. Vector-control methods, such as using insecticides to treat bed nets and spray the walls of homes, have prevented millions of deaths from malaria. However, mosquitoes are becoming resistant to insecticides, and no new class of insecticides for vector control has been introduced in decades. We recommend the creation of a new type of incentive for the development and commercialization of safe new insecticides: a Vector Expedited Review Voucher, to be awarded to a sponsor that introduces a novel insecticide for public health use. The voucher could be redeemed to expedite registration of a second, more profitable, product by the US Environmental Protection Agency.

Acetabulum-Only Revision Total Hip Arthroplasty Is Associated With Good Functional Outcomes and Survivorship.

BACKGROUND: The coexistence of a stable femoral and a loose acetabular component may pose a clinical dilemma for the surgeon. Our study aims at comparing the intermediate functional outcomes and survivorship of acetabulum-only revision total hip arthroplasty (ArTHA) with an age-matched and gender-matched total revision THA (TrTHA) group. METHODS: We retrospectively reviewed prospectively collected data on the pain, function, and total Harris Hip Scores (HHS) and complication profile for ArTHA and TrTHA cohorts from our regional arthroplasty database. Kaplan-Meier survivorship, with the need for repeat revision surgery as the end point, was used for survival analysis. RESULTS: Among 538 cases, there were fewer acute medical complications in ArTHA and a similar dislocation rate for both cohorts. Preoperative HHS for pain, function, and total were better in the ArTHA cohort, but only the function score reached statistical significance. No significant differences in subsequent years for all aspects of HHS, except the function score was significantly better in the ArTHA cohort at year 1. And 10.0% of ArTHAs and 7.8% of TrTHAs had required rerevision. The 5-year survivorship was 90.3% (95% confidence interval ± 2.1%) for the ArTHA cohort and 92.7% (95% confidence interval ± 1.8%) for the TrTHA cohort (P = .394). The ArTHA with posterior approach (n = 118) group had the lowest dislocation rate and the best trend of functional outcomes. CONCLUSION: ArTHA can provide similar functional outcomes and dislocation rate to TrTHA, with an acceptable rerevision rate. The posterior approach in this study was not associated with a significant dislocation rate.

Integrative analysis of desert dust size and abundance suggests less dust climate cooling.

Desert dust aerosols affect Earth's global energy balance through interactions with radiation1,2, clouds3,4, and ecosystems5. But the magnitudes of these effects are so uncertain that it remains unclear whether atmospheric dust has a net warming or cooling effect on global climate1,4,6. Consequently, it is still uncertain whether large changes in atmospheric dust loading over the past century have slowed or accelerated anthropogenic climate change4,7-9, and the climate impact of possible future alterations in dust loading is similarly disputed9,10. Here we use an integrative analysis of dust aerosol sizes and abundance to constrain the climatic impact of dust through direct interactions with radiation. Using a combination of observational, experimental, and model data, we find that atmospheric dust is substantially coarser than represented in current climate models. Since coarse dust warms global climate, the dust direct radiative effect (DRE) is likely less cooling than the ~0.4 W/m2 estimated by models in a current ensemble2,11-13. We constrain the dust DRE to - 0.20 (-0.48 to +0.20) W/m2, which suggests that the dust DRE produces only about half the cooling that current models estimate, and raises the possibility that dust DRE is actually net warming the planet.

Priorities for the Priority Review Voucher.

The U.S. Congress created the priority review voucher program in 2007 to encourage development of drugs for neglected diseases. Under the voucher program, the developer of a drug for a neglected or rare pediatric disease that is approved by the U.S. Food and Drug Administration receives a bonus priority review voucher for another drug. As of 2016, four vouchers have sold for an average price of $200 million. Recent experience with the voucher program indicates strengths and weaknesses of the program, as well as a need for legislative changes.

Real-World Data: Policy Issues Regarding their Access and Use.

As real-world data (RWD) in health care begin to cross over to the Big Data realms, a panel of health economists was gathered to establish how well the current US policy environment further the goals of RWD and, if not, what can be done to improve matters. This report summarizes these discussions spanning the current US landscape of RWD availability and usefulness, private versus public development of RWD assets, the current inherent bias in terms of access to RWD, and guiding principles in providing quality assessments of new RWD studies. Three main conclusions emerge: (1) a business case is often required to incentivize investments in RWD assets. However, access restrictions for public data assets have failed to generate a proper market for these data and hence may have led to an underinvestment of public RWDs; (2) Very weak empirical evidence exist on for-profit entities misusing public RWD data entities to further their own agendas, which is the basis for supporting access restrictions of public RWD data; and (3) perhaps developing standardized metrics that could flag misuse of RWDs in an efficient way could help quell some of the fear of sharing public RWD assets with for-profit entities. It is hoped that these discussions and conclusions would pave the way for more rigorous and timely debates on the greater availability and accessibility of RWD assets.

The Commercial Market For Priority Review Vouchers.

In 2007 the US Congress created the priority review voucher program to encourage the development of drugs for neglected diseases. Under the program, the developer of a drug that treats a neglected disease receives both a faster review of the drug by the Food and Drug Administration and a voucher for a faster review of a different drug. The developer can sell the voucher. We estimated the commercial value of the voucher using US sales of new treatments approved in the period 2007-09. A third of the commercial value of a voucher comes from capturing market share from competitors, nearly half from the value of earlier sales because of the expedited review, and less than a quarter from lengthening the time between approval and the launch of a generic competitor. We estimate that if only one priority review voucher is available in a year, it will be worth more than $200 million, but if four vouchers are available, the value could fall below $100 million. Congress should be cautious about expanding the voucher program, because increasing the number of vouchers sharply decreases the expected price. Lower voucher prices could undermine the incentive to develop new medicines for neglected diseases.