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.

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.

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.

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.

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.

Payments, promotion, and the purple pill.

Understanding competition in the US drug market requires knowing how sensitive demand is to prices. The relevant prices for insured consumers are copayments. There are many studies of copayment elasticity in the health literature, but they are of limited applicability for studies of competition. Because of a paucity of data, such studies typically control for neither competitor copayment nor advertising. Whereas previous studies examined copayment sensitivity when copayments for branded drugs move in unison, this study examines copayment sensitivity when copayments diverge. This study uses unique panel data of insurance copayments and utilization for 77 insurance groups, as well as data on advertising. The results indicate that demand can be much more sensitive to copayment than previously recognized. Manufacturers selling drugs with higher copayments than branded competitors can lose substantial market share. Manufacturers can offset the loss of demand by increasing advertising to physicians, but it is costly.

The effects of tocilizumab on osteitis, synovitis and erosion progression in rheumatoid arthritis: results from the ACT-RAY MRI substudy.

OBJECTIVE: To examine the imaging-detected mechanism of reduction of structural joint damage progression by tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) using MRI. METHODS: In a substudy of a randomised, double-blind, phase 3b study (ACT-RAY) of biologic-naïve patients with RA who were methotrexate (MTX)-inadequate responders, 63 patients were randomised to continue MTX or receive placebo (PBO), both in combination with TCZ 8 mg/kg every 4 weeks, with optional additional disease-modifying antirheumatic drugs at week 24 if Disease Activity Score of 28 joints < 3.2. The most symptomatic hand was imaged with 0.2 Tesla extremity MRI at weeks 0, 2, 12 and 52. MR images were scored using Outcome Measures in Rheumatology-Rheumatoid Arthritis Magnetic Resonance Imaging Score. Predictors of week 52 erosion progression were determined by logistic regression analysis. RESULTS: TCZ + PBO (n=32) demonstrated mean improvements in synovitis from baseline to weeks 2 (-0.92; p=0.0011), 12 (-1.86; p<0.0001) and 52 (-3.35; p<0.0001), while TCZ + MTX (n=31) had mean improvements in synovitis at week 12 (-0.88; p=0.0074), but not week 52 (-1.00; p=0.0711). TCZ+PBO demonstrated mean reductions in osteitis at weeks 12 (-5.10; p=0.0022) and 52 (-8.56; p=0.0006), while TCZ+MTX had mean reductions at weeks 2 (-0.21; p<0.05) and 12 (-3.63; p=0.0008), but not week 52 (-2.31; p=0.9749). Mean erosion scores did not worsen in either group. MRI erosion scores at weeks 12 and 52 correlated strongly with radiography erosion scores at week 52 (r>0.80). Baseline synovitis and worsening of osteitis predicted erosion progression. CONCLUSIONS: Rapid suppression of synovitis and osteitis with reduction in structural joint damage progression occurred with TCZ, as monotherapy or in combination with MTX, through week 52.

Oxford unicompartmental knee arthroplasty versus age and gender matched total knee arthroplasty - functional outcome and survivorship analysis.

We compared the medium-term outcomes of age and gender matched patients with unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA). We retrospectively reviewed the pain, function and total knee society scores (KSS) for 602 UKAs and age and gender matched TKAs between 2001 and 2013. Function scores remained significantly better in UKAs from preoperative until 3years follow up. The change of function scores was not significantly different. TKAs performed better than UKAs for pain scores. Total KSS for both groups were not significantly different in the study. Fewer medical complications were reported in UKA group. 6.30% of UKAs and 2.99% of TKAs were revised. The theoretical advantages of UKA were not borne out, other than in immediate postoperative complications.

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.

Introduction of European priority review vouchers to encourage development of new medicines for neglected diseases.

Every year 1 billion people worldwide are affected by traditionally neglected diseases, such as malaria, tuberculosis, leishmaniasis, and lymphatic filariasis, which impose tremendous public health burdens. Governments, foundations, and drug manufacturers have, however, started to support development of new treatments. European Union Member States have been leaders in implementing so-called push mechanisms (payment for drug development) and pull funding (reward for output), such as the advance market commitment, which creates a market for vaccines by guaranteeing prices. We propose an additional step that could be taken to encourage development of medicines for neglected diseases. A priority review voucher scheme, as is already in place in the USA, would reward a manufacturer that developed a new medicine for neglected diseases with a voucher that could be redeemed for priority review of a future medicine, probably a potential blockbuster drug. Unlike the US system a European voucher would also accelerate pricing and reimbursement decisions. This scheme would be likely to provide substantial benefits to voucher holders, society, and public health organisations.

​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.

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.

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.

Patients with fixed flexion deformity after total knee arthroplasty do just as well as those without: ten-year prospective data.

Range of motion (ROM) is an important outcome variable after total knee arthroplasty (TKA). This may be compounded by a pre-existing fixed flexion deformity (FFD). We therefore examined the long-term outcomes of patients with a flexion deformity undergoing TKA compared to those without a preoperative fixed flexion deformity. Participants who had undergone TKA at our centre between 1989 and 2002 were examined preoperatively, one, five and ten years after TKA (Kinemax PS; Howmedica, Rutherford, NJ, USA). Examining those with a preoperative FFD of greater than ten degrees with complete ten year follow-up data revealed 77 individuals. Seventy seven age, sex and body mass index matched patients were identified and the effect of TKA on indices of knee function (fixed flexion, maximum flexion, total ROM and Knee Society score (KSS) in both groups were analysed using repeated measures ANOVA. A significant difference between the groups with respect to fixed flexion (p < 0.001), total ROM (p = 0.001) and KSS (p < 0.001) was observed between baseline and year one suggesting that those with a preoperative FFD improved more than those without. A significant difference with regard to fixed flexion was also observed between years one to five (p = 0.001) and just failed to reach statistical significance between five to ten years (p = 0.052) between the groups. This study demonstrates that patients with a preoperative fixed flexion deformity show continued improvement in their fixed flexion up to ten years post arthroplasty and have similar outcomes to those with no preoperative fixed flexion.