Patients with Hip Osteoarthritis Have a Higher Rate of Spinal Reoperation Following Lumbar Spinal Fusion.

BACKGROUND: Lumbar spinal pathology is known to affect outcomes following total hip arthroplasty (THA). However, the effect of hip osteoarthritis (OA) on outcomes following lumbar fusion has not been well studied. The purpose of this study was to determine the association between hip OA and spinal reoperation following lumbar spinal fusion. METHODS: The 5% Medicare Part B claims database was queried for all patients who underwent primary elective lumbar fusion from 2005 to 2019. Patients were divided into 2 groups: those who underwent elective THA within 1 year after primary lumbar fusion, indicating that they had severe hip OA at the time of lumbar fusion, and those who underwent lumbar fusion with no diagnosed hip OA and no THA during the study period. Exclusion criteria included THA as a result of trauma, revision THA or primary THA in the 5-year period before primary lumbar fusion, <65 years of age, and no enrollment in the database for 5 years before and 1 year after primary lumbar fusion. The primary outcome was spinal reoperation within 1, 3, and 5 years. Multivariable Cox regression was performed with age, sex, diabetes, heart disease, obesity, smoking status, osteoporosis, number of levels fused, use of posterior instrumentation, use of an interbody device, use of bone graft, and surgical approach as covariates. RESULTS: Overall, 1,123 patients (63.4% female; 91.3% White; mean age, 76.8 ± 4.1 years) were included in the hip OA group and 8,893 patients (56.2% female; 91.3% White; mean age, 74.8 ± 4.9 years) were included in the control group. After multivariable analysis, patients with severe hip OA had significantly greater rates of revision surgery at 3 years (odds ratio [OR], 1.61; p < 0.001) and 5 years (OR, 1.87; p < 0.001) after the index lumbar fusion. CONCLUSIONS: Patients with severe hip OA at the time of primary lumbar fusion had a significantly increased risk of spinal reoperation at 3 and 5 years postoperatively. These data provide further evidence to support performing THA prior to lumbar fusion in the unsettled debate regarding which surgery should be prioritized for patients with simultaneous degenerative diseases of the hip and lumbar spine. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

NIH funding for patents that contribute to market exclusivity of drugs approved 2010-2019 and the public interest protections of Bayh-Dole.

Previous studies have shown that National Institutes of Health (NIH) funding contributed >$187 billion for basic or applied research related to the 356 drugs approved 2010-2019. This analysis asks how much of this funding led to patents cited as providing market exclusivity, patents that would be subject to the provisions of the Bayh-Dole Act that promote and protect the public interest. The method involves identifying published research in PubMed related to the approved drugs (applied research) or their targets (basic research). NIH-funded projects (grants) funding these publications and patents arising from these projects were both identified in RePORT. Patents cited as providing market exclusivity were identified in DrugPatentWatch (which incorporates FDA Orange Book). NIH funded basic or applied research related to all 313 FDA-approved drugs 2010-2019 with at least one patent in DrugPatentWatch. This research comprised 350 thousand publications (9% applied research; 91% basic research) supported by 341 thousand fiscal years (project years) of NIH funding and $164 billion in NIH project year costs (17% applied research; 83% basic research). These NIH projects also produced 22,360 patents, 119 of which were cited in DrugPatentWatch as protecting 34/313 drugs. These patents were associated with 769 project years of NIH funding (0.23% total) and project year costs of $0.95 billion (0.59% total). Overall, only 1.5% of total NIH funding for applied research and 0.38% of total NIH funding for basic research was associated with patents in DrugPatentWatch. This analysis shows that very little of the NIH funding for research that contributes to new drug approvals leads to patents that provide market exclusivity and are subject to the provisions of the Bayh-Dole Act that promote the public interest in practical applications of the research, reasonable use and pricing, and a return on this public sector investment. This suggests that the Bayh-Dole Act is limited in its ability to protect the public interest in the pharmaceutical innovations driven by NIH-funded research.

Comparison of Research Spending on New Drug Approvals by the National Institutes of Health vs the Pharmaceutical Industry, 2010-2019.

Importance: Government and the pharmaceutical industry make substantive contributions to pharmaceutical innovation. This study compared the investments by the National Institutes of Health (NIH) and industry and estimated the cost basis for assessing the balance of social and private returns. Objectives: To compare NIH and industry investments in recent drug approvals. Design, Setting, and Participants: This cross-sectional study of NIH funding associated with drugs approved by the FDA from 2010 to 2019 was conducted from May 2020 to July 2022 and accounted for basic and applied research, failed clinical candidates, and discount rates for government spending compared with analogous estimates of industry investment. Main Outcomes and Measures: Costs from the NIH for research associated with drug approvals. Results: Funding from the NIH was contributed to 354 of 356 drugs (99.4%) approved from 2010 to 2019 totaling $187 billion, with a mean (SD) $1344.6 ($1433.1) million per target for basic research on drug targets and $51.8 ($96.8) million per drug for applied research on products. Including costs for failed clinical candidates, mean (SD) NIH costs were $1441.5 ($1372.0) million per approval or $1730.3 ($1657.6) million per approval, estimated with a 3% discount rate. The mean (SD) NIH spending was $2956.0 ($3106.3) million per approval with a 10.5% cost of capital, which estimates the cost savings to industry from NIH spending. Spending and approval by NIH for 81 first-to-target drugs was greater than reported industry spending on 63 drugs approved from 2010 to 2019 (difference, -$1998.4 million; 95% CI, -$3302.1 million to -$694.6 million; P = .003). Spending from the NIH was not less than industry spending considering clinical failures, a 3% discount rate for NIH spending, and a 10.5% cost of capital for the industry (difference, -$1435.3 million; 95% CI, -$3114.6 million to $244.0 million; P = .09) or when industry spending included prehuman research (difference, -$1394.8 million; 95% CI, -$3774.8 million to $985.2 million; P = .25). Accounting for spillovers of NIH-funded basic research on drug targets to multiple products, NIH costs were $711.3 million with a 3% discount rate, which was less than the range of reported industry costs with 10.5% cost of capital. Conclusions and Relevance: The results of this cross-sectional study found that NIH investment in drugs approved from 2010 to 2019 was not less than investment by the pharmaceutical industry, with comparable accounting for basic and applied research, failed clinical trials, and cost of capital or discount rates. The relative scale of NIH and industry investment may provide a cost basis for calibrating the balance of social and private returns from investments in pharmaceutical innovation.

Exposure to ultrafine particles and cognitive decline among older people in the United States.

BACKGROUND: Some studies suggest that ambient particulate air pollution is associated with cognitive decline. However, the findings are mixed, and there is no relevant research examining the influences of ultrafine particles (UFP), which may have more toxicity than larger particles. We therefore conducted this study to investigate whether residential UFP exposure is associated with cognitive decline using data from the Alzheimer's Disease Research Centers in the United States. METHODS: This is a longitudinal study of participants who were aged 65 years and older and had normal cognitive status at baseline. Residential UFP exposure, expressed as particle number concentrations (PNC), was assessed in 2016-2017 using a nationwide land use regression model, and was assigned to each participant using their 3-digit residential ZIP codes. Cognitive functions including memory, attention, language, executive function, and global function were assessed annually using 15 neuropsychological tests from March 2015 to February 2022. Linear mixed-effects models were used to examine the associations after adjustment for covariates including baseline age, sex, APOE ε4 status, race, education, smoking status, history of diabetes, quartiles of neighborhood median household income, and interaction terms of follow-up time with each covariate. RESULTS: This study included 5646 participants (mean age 76 years, 65% female). On average, each participant had 4 annual visits. When PNC was treated as a continuous variable, there were no statistically or clinically significant changes in annual decline of each cognitive function in relation to an interquartile range elevation in PNC (4026 particles/cm3). Similarly, when PNC was treated as a categorical variable including five exposure groups, there were no linear exposure-response trends in annual decline of each cognitive function across the five exposure groups. CONCLUSIONS: This study found no meaningful associations between residential UFP exposure and cognitive decline in global and domain-specific functions. There is a need for further research that assigns UFP exposure at a finer geographic scale.

NIH funding for vaccine readiness before the COVID-19 pandemic.

Rapid development of vaccines for COVID-19 has relied on the application of existing vaccine technologies. This work examines the maturity of ten technologies employed in candidate vaccines (as of July 2020) and NIH funding for published research on these technologies from 2000-2019. These technologies vary from established platforms, which have been used successfully in approved products, to emerging technologies with no prior clinical validation. A robust body of published research on vaccine technologies was supported by 16,358 fiscal years of NIH funding totaling $17.2 billion from 2000-2019. During this period, NIH funding for published vaccine research against specific pandemic threats such as coronavirus, Zika, Ebola, and dengue was not sustained. NIH funding contributed substantially to the advance of technologies available for rapid development of COVID-19 vaccines, suggesting the importance of sustained public sector funding for foundational technologies in the rapid response to emerging public health threats.

Comparing long-term value creation after biotech and non-biotech IPOs, 1997-2016.

We compared the financial performance of 319 BIOTECH companies focused on developing therapeutics with IPOs from 1997-2016, to that of paired, non-biotech CONTROL companies with concurrent IPO dates. BIOTECH companies had a distinctly different financial structure with high R&D expense, little revenue, and negative profits (losses), but a similar duration of listing on public markets and frequency of acquisitions. Through 2016, BIOTECH and CONTROL companies had equivalent growth in market cap and shareholder value (>$100 billion), but BIOTECH companies had lower net value creation ($93 billion vs $411 billion). Both cohorts exhibited a high-risk/high reward pattern of return, with the majority losing value, but many achieving growth multiples. While investments in biotechnology are often considered to be distinctively risky, we conclude that value creation by biotech companies after IPO resembles that of non-biotech companies at a similar stage and does not present a disproportionate investment risk.

Late-stage Product Development and Approvals by Biotechnology Companies After Initial Public Offering, 1997-2016.

PURPOSE: This work describes the late-stage product portfolios of the biotechnology companies that completed initial public offerings (IPOs) from 1997 to 2016. We asked whether these emerging companies continue to develop innovative, biologic products and produce the innovation promised by the early biotechnology industry. METHODS: We identified therapeutic products that reached Phase III development from 1997 to 2016, the characteristics of the products, the dates of the initiation of Phase III and product approval, proxy indicators of the innovativeness of each product, and the contribution of each biotechnology company. Companies were characterized by IPO window and clinical status of the most advanced product at IPO. Time from IPO to Phase III or approval, and the estimated probability of a company having a product advance to these milestones, were examined using Kaplan-Meier analysis. FINDINGS: A total of 319 biotechnology companies completed IPOs from 1997 to 2016. These companies contributed to the development of 367 products that progressed to Phase III, and of 144 new drug approvals, through 2016. The estimated probability of a company having a product reach Phase III was 78%, and the estimated probability of a company receiving at least 1 product approval was 52%, with most approvals occurring >5 years after IPO. Small-molecule drugs represented 74% of products reaching Phase III and 78% of approvals. Reformulations represented 36% of Phase III products and 46% of approvals. The estimated probability of product approval was significantly higher for reformulations than new molecular entities (NMEs) and slightly higher for small molecules than biologics. The estimated probability of a company receiving product approval varied significantly by IPO window and was greater for companies with Phase III products at IPO (74%). These companies contributed to the development of 78 NMEs, 44% of which were classified as first in class, initiating development of 69% and contributing to the clinical development of 96%. These products represented 16% of all NMEs and 28% of biologics approved between 1997 and 2016. Seven products achieved per-annum sales of >$1 billion during the study period. IMPLICATIONS: The majority of emerging publicly owned biotechnology companies contribute to products that advance to Phase III development and approval, although these companies are no longer distinctively focused on biologic products.

Double trouble? Clinic-specific risk factors for monozygotic twinning.

OBJECTIVE: To investigate clinic-specific risk factors for monozygotic twinning (MZT) using a large, electronic database. DESIGN: Retrospective case-control study. SETTING: Infertility clinics. PATIENT(S): Using an electronic medical record system, viable clinical pregnancy (confirmation of a gestational sac(s) and presence of at least one fetal pole with a heartbeat on first trimester ultrasound), data were obtained from homologous in vitro fertilization (IVF) cycles after single ET from June 1, 2004, to December 31, 2016. Monozygotic twinning was defined as a pregnancy with two fetal heartbeats on ultrasound with sex concordance at birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Risk factors for MZT including cycle type, method of insemination, and method of cryopreservation. RESULT(S): Of the 28,265 IVF cycles that met inclusion criteria over the study period, 8,749 (31.0%) resulted in a viable intrauterine clinical pregnancy. There were 102 (2.7%) MZT in the fresh cycle cohort and 133 (2.7%) in the frozen cycle cohort. Neither cryopreservation nor the method of cryopreservation was a significant risk factor for MZT. However, the use of sequential media was an independent risk factor for MZT in fresh, but not frozen, ETs (odds ratio = 1.72, 95% confidence interval, 1.10-2.68). Significant differences were seen in the incidence of MZT between clinics, and this difference persisted after controlling for known risk factors (clinic 0, reference; clinic 2, odds ratio = 2.22; 95% confidence interval, 1.48-3.32; clinic 3, odds ratio = 1.93; 95% confidence interval, 1.30-2.87). CONCLUSION(S): Differences in MZT rates exist between individual IVF clinics, suggesting that variations in practice patterns may contribute to this event. The present study noted the use of sequential media was an independent risk factor for fresh but not frozen cycles.

Profitability of Large Pharmaceutical Companies Compared With Other Large Public Companies.

Importance: Understanding the profitability of pharmaceutical companies is essential to formulating evidence-based policies to reduce drug costs while maintaining the industry's ability to innovate and provide essential medicines. Objective: To compare the profitability of large pharmaceutical companies with other large companies. Design, Setting, and Participants: This cross-sectional study compared the annual profits of 35 large pharmaceutical companies with 357 companies in the S&P 500 Index from 2000 to 2018 using information from annual financial reports. A statistically significant differential profit margin favoring pharmaceutical companies was evidence of greater profitability. Exposures: Large pharmaceutical vs nonpharmaceutical companies. Main Outcomes and Measures: The main outcomes were revenue and 3 measures of annual profit: gross profit (revenue minus the cost of goods sold); earnings before interest, taxes, depreciation, and amortization (EBITDA; pretax profit from core business activities); and net income, also referred to as earnings (difference between all revenues and expenses). Profit measures are described as cumulative for all companies from 2000 to 2018 or annual profit as a fraction of revenue (margin). Results: From 2000 to 2018, 35 large pharmaceutical companies reported cumulative revenue of $11.5 trillion, gross profit of $8.6 trillion, EBITDA of $3.7 trillion, and net income of $1.9 trillion, while 357 S&P 500 companies reported cumulative revenue of $130.5 trillion, gross profit of $42.1 trillion, EBITDA of $22.8 trillion, and net income of $9.4 trillion. In bivariable regression models, the median annual profit margins of pharmaceutical companies were significantly greater than those of S&P 500 companies (gross profit margin: 76.5% vs 37.4%; difference, 39.1% [95% CI, 32.5%-45.7%]; P < .001; EBITDA margin: 29.4% vs 19%; difference, 10.4% [95% CI, 7.1%-13.7%]; P < .001; net income margin: 13.8% vs 7.7%; difference, 6.1% [95% CI, 2.5%-9.7%]; P < .001). The differences were smaller in regression models controlling for company size and year and when considering only companies reporting research and development expense (gross profit margin: difference, 30.5% [95% CI, 20.9%-40.1%]; P < .001; EBITDA margin: difference, 9.2% [95% CI, 5.2%-13.2%]; P < .001; net income margin: difference, 3.6% [95% CI, 0.011%-7.2%]; P = .05). Conclusions and Relevance: From 2000 to 2018, the profitability of large pharmaceutical companies was significantly greater than other large, public companies, but the difference was less pronounced when considering company size, year, or research and development expense. Data on the profitability of large pharmaceutical companies may be relevant to formulating evidence-based policies to make medicines more affordable.

Visualizing Air Pollution: Communication of Environmental Health Information in a Chinese Immigrant Community.

This study developed and evaluated a visual approach to promoting environmental health literacy about highway pollution. The Interactive Map of Chinatown Traffic Pollution was the centerpiece of a communication approach designed to make complex scientific information about traffic-related air pollution comprehensible to Chinese immigrants with limited English proficiency. The map enabled visualization of the spatial distribution of ultrafine particles (less than 100 nanometers in diameter), a toxic and invisible form of air pollution, in Boston Chinatown. A university-community partnership enabled design of intergenerational training sessions aimed toward empowering community members to take health-promoting actions that reduce exposure to ultrafine particulate pollution. A mixed methods approach was taken to evaluation. Nine high school youth learned to use the map and then tutored adults recruited from English as a Second Language (ESL) classes and from a community workshop. Seventy-three of these adults completed a pre-post survey measuring change in three domains: pollution knowledge, attitudes toward environmental issues, and self-efficacy in using maps. Adult participants demonstrated statistically significant improvements in all three domains (Wilcoxon signed-rank test, all p < 0.01). Seventeen adults and nine youth participated in interviews. Interview participants reported adjusting daily routines to reduce exposure to pollution.

Contribution of NIH funding to new drug approvals 2010-2016.

This work examines the contribution of NIH funding to published research associated with 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010-2016. We identified >2 million publications in PubMed related to the 210 NMEs (n = 131,092) or their 151 known biological targets (n = 1,966,281). Of these, >600,000 (29%) were associated with NIH-funded projects in RePORTER. This funding included >200,000 fiscal years of NIH project support (1985-2016) and project costs >$100 billion (2000-2016), representing ∼20% of the NIH budget over this period. NIH funding contributed to every one of the NMEs approved from 2010-2016 and was focused primarily on the drug targets rather than on the NMEs themselves. There were 84 first-in-class products approved in this interval, associated with >$64 billion of NIH-funded projects. The percentage of fiscal years of project funding identified through target searches, but not drug searches, was greater for NMEs discovered through targeted screening than through phenotypic methods (95% versus 82%). For targeted NMEs, funding related to targets preceded funding related to the NMEs, consistent with the expectation that basic research provides validated targets for targeted screening. This analysis, which captures basic research on biological targets as well as applied research on NMEs, suggests that the NIH contribution to research associated with new drug approvals is greater than previously appreciated and highlights the risk of reducing federal funding for basic biomedical research.

Association of Low-Level Ozone with Cognitive Decline in Older Adults.

Increasing evidence points to an association of airborne pollutant exposure with respiratory, cardiovascular, and neurological pathology. We examined whether or not ground-level ozone or fine particulate matter ≤ 2.5 µm in diameter (PM2.5) was associated with accelerated cognitive decline. Using repeated measures mixed regression modeling, we analyzed cognitive performance of a geographically diverse sampling of individuals from the National Alzheimer's Coordinating Center between 2004-2008. Ambient air concentrations of ozone and PM2.5 were established using a space-time Hierarchical Bayesian Model that statistically merged air monitor data and modeled air quality estimates. We then compared the ambient regional concentrations of ozone and PM2.5 with the rate of cognitive decline in residents within those regions. Increased levels of ozone correlated with an increased rate of cognitive decline, following adjustment for key individual and community-level risk factors. Furthermore, individuals harboring one or more APOE4 alleles exhibited a faster rate of cognitive decline. The deleterious association of ozone was confined to individuals with normal cognition who eventually became cognitively impaired as opposed to those who entered the study with baseline impairment. In contrast to ozone, we did not observe any correlation between ambient PM2.5 and cognitive decline at regulatory limits set by the Environmental Protection Agency. Our findings suggest that prolonged exposure to ground-level ozone may accelerate cognitive decline during the initial stages of dementia development.

Reference Correction to: Making Air Pollution Visible: A Tool for Promoting Environmental Health Literacy.

[This corrects the article DOI: 10.2196/publichealth.7492.].

Making Air Pollution Visible: A Tool for Promoting Environmental Health Literacy.

BACKGROUND: Digital maps are instrumental in conveying information about environmental hazards geographically. For laypersons, computer-based maps can serve as tools to promote environmental health literacy about invisible traffic-related air pollution and ultrafine particles. Concentrations of these pollutants are higher near major roadways and increasingly linked to adverse health effects. Interactive computer maps provide visualizations that can allow users to build mental models of the spatial distribution of ultrafine particles in a community and learn about the risk of exposure in a geographic context. OBJECTIVE: The objective of this work was to develop a new software tool appropriate for educating members of the Boston Chinatown community (Boston, MA, USA) about the nature and potential health risks of traffic-related air pollution. The tool, the Interactive Map of Chinatown Traffic Pollution ("Air Pollution Map" hereafter), is a prototype that can be adapted for the purpose of educating community members across a range of socioeconomic contexts. METHODS: We built the educational visualization tool on the open source Weave software platform. We designed the tool as the centerpiece of a multimodal and intergenerational educational intervention about the health risk of traffic-related air pollution. We used a previously published fine resolution (20 m) hourly land-use regression model of ultrafine particles as the algorithm for predicting pollution levels and applied it to one neighborhood, Boston Chinatown. In designing the map, we consulted community experts to help customize the user interface to communication styles prevalent in the target community. RESULTS: The product is a map that displays ultrafine particulate concentrations averaged across census blocks using a color gradation from white to dark red. The interactive features allow users to explore and learn how changing meteorological conditions and traffic volume influence ultrafine particle concentrations. Users can also select from multiple map layers, such as a street map or satellite view. The map legends and labels are available in both Chinese and English, and are thus accessible to immigrants and residents with proficiency in either language. The map can be either Web or desktop based. CONCLUSIONS: The Air Pollution Map incorporates relevant language and landmarks to make complex scientific information about ultrafine particles accessible to members of the Boston Chinatown community. In future work, we will test the map in an educational intervention that features intergenerational colearning and the use of supplementary multimedia presentations.