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The cohort consisted of 11,178 Mead Corporation employees (9,358 males and 1,820 females) who had worked for at least one year between January 1, 1975 and December 31, 1992 at seven pulp and/or paper mills in the United States. The vital status of the cohort was determined through a variety of sources over an observation period of 17 years (1976-1992). Mortality data were analyzed in terms of cause-specific standardized mortality ratios (SMRs), with expected deaths based on U.S. national mortality rates. Job categories with similar exposures were created based on an historical exposure assessment. Mortality analyses were performed separately for total female and male employees. Among female employees, overall mortality was less than expected, and no significant cause-specific mortality excesses were observed. The small number of deaths among female employees did not permit further detailed analyses. Among male employees, statistically significant deficits from overall mortality (SMR = 69.0) and from all cancers (SMR = 71.3) were reported. In addition, low mortality risks for many specific causes were also observed, including many specific cancer sites, various types of cardiovascular diseases, and different forms of nonmalignant respiratory diseases. In particular, there was no mortality excess from lung cancer (SMR = 77.5), digestive cancer (SMR = 69.4), stomach cancer (SMR = 46.7), laryngeal cancer (no observed death), rectal cancer (SMR = 82.8). Hodgkin's lymphoma (no observed death), non-Hodgkin's lymphoma (SMR = 103.6), leukemia (SMR = 72.2), diabetes mellitus (SMR = 110.4), ischemic heart disease (SMR = 80.0), and nonmalignant respiratory diseases (SMR = 36.7). Furthermore, detailed analyses by length of employment, interval since hire (latency), and job category demonstrated no occupationally related mortality increases from any of the diseases examined. Specifically, based on internal comparisons, no upward trends in cause-specific mortality risk were observed by duration of employment. In conclusion, the results of this epidemiologic investigation demonstrated a favorable mortality experience for employees at the seven pulp and/or paper mills.

Screening programs for pediatric lead (Pb) poisoning routinely collect blood by finger stick onto specially designed filter paper (FP) for subsequent laboratory testing. Here, laser ablation inductively coupled plasma time-of-flight mass spectrometry is evaluated as a novel method for the determination of Pb in blood spotted onto FP cards. The method requires no sample pretreatment and may be particularly suitable for rapidly screening a large number of samples. Signal intensity from the ICP-MS strongly correlated (r (2) = 0.996) with Pb target values for five blood cards from a laboratory proficiency testing program. Better precision was obtained by replicate ablation line scans (<15% rsd) compared to a grid of 25 individual ablation spots (>30% rsd). Because <2% of the sample is consumed in the laser ablation analysis, selected samples can also be analyzed by traditional techniques or archived. Lead isotope ratios determined during the same total-Pb analysis appear to be effective for discerning contamination extraneous to the blood sample. Determining that an elevated result was due to contamination may negate the need for retesting with invasive pediatric venipuncture. Some elements monitored along with Pb exhibited signal profiles conducive to potential quantitation (Ca, V, Fe, Cu Zn), whereas others did not (Cr, Mn, Co, Ni, Cd, Hg, Tl, U). Copper, Ca, and V were inversely correlated with Pb (r = -0.89, -0.90, and -0.92, respectively). Scanning electron microscope images revealed surface modality differences between FP spotted with fresh whole blood and reconstituted freeze-dried blood reference material.

Background: Thyroid nodules are unusual in children, but when present, they carry a higher risk for malignancy, as compared to adults. Several guidelines have been created to address the risk stratification for malignancy of thyroid nodules in adults, but none has been completely validated in children. A few authors have proposed lowering the size threshold to the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS™) management guidelines to decrease missed carcinomas at presentation in children; however, little information is known regarding their accuracy., Objective: To assess the performance of proposed modifications of the ACR TI-RADS™ size criteria to guide management decisions in pediatric thyroid nodules and to assess the associated increase in number of fine needle aspiration (FNA) and follow-up exams., Materials and Methods: This is a retrospective study of children under 18 years old who underwent ultrasound assessment of a thyroid nodule at a tertiary care pediatric institution between January 2006 and August 2021. The largest dimension, maximum ACR TI-RADS™ score, and final thyroid nodules' diagnoses were documented. The course of action based on the adult ACR TI-RADS™ and after modifying the size threshold for management recommendations was documented and compared. Statistics included descriptive analysis, weighted Kappa statistics, sensitivity, specificity, accuracy, and positive/negative predictive values of the ACR TI-RADS™ presented with 95% confidence intervals (CI) using either Clopper-Pearson or standard logit methods., Results: Of 116 nodules, 18 (15.5%) were malignant. Most malignant nodules (94.4%, n = 17) were ACR TI-RADS™ 4 and ACR TI-RADS™ 5 categories. Based on the adult ACR TI-RADS™ criteria, 24 (24.5%) benign and 15 (83.3%) malignant nodules would have undergone FNA; 14 (14.3%) benign and 3 (16.7%) malignant nodules would have been followed up; and 60 (61.2%) benign and none of malignant nodules would have been dismissed. Three (16.7%) malignant nodules would not have been recommended FNA at presentation, delaying their diagnoses. By lowering the size-threshold criteria of the ACR TI-RADS™ guidelines, no malignancy would have been missed at presentation, but this also resulted in a higher number of FNA from 24 (24.5%) to 36 (36.7%) and follow-up ultrasound exams from 14 (14.3%) to 62 (63.3%)., Conclusion: Applying potential modifications to the ACR TI-RADS™ guideline lowering the size threshold criteria of the thyroid nodule to guide management decisions for pediatric thyroid nodules can lead to early detection of malignant nodules in children, but at the cost of a significantly increased number of biopsies or ultrasound exams. Further tailoring of the guideline with larger multicentric studies is needed, before warranting its acceptance and general use in the pediatric population., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

ELEVATE (Study 410; NCT03288129) is the first prospective, multicenter, open-label, Phase IV study of perampanel as monotherapy or first adjunctive therapy in patients aged ≥ 4 years with focal-onset seizures or generalized tonic-clonic seizures in the United States. The study included Screening, Titration (≤ 13 weeks), Maintenance (39 weeks), and Follow-up (4 weeks) Periods. During Titration, perampanel was initiated at 2 mg/day and up-titrated to 4 mg/day at Week 3. Depending on response and tolerability, optional up-titrations to a maximum of 12 mg/day occurred. The primary endpoint was retention rate; additional endpoints included seizure-freedom rate, 50% responder rate, and incidence of treatment-emergent adverse events (TEAEs). At baseline, 10 (18.5%) patients were assigned to the monotherapy group and 44 (81.5%) patients to the first adjunctive therapy group. However, due to the addition of an anti-seizure medication along with perampanel on the first day of treatment, one patient was excluded from the monotherapy subgroup analyses. The mean perampanel exposure duration was 39.8 weeks and 32 (59.3%) patients completed the study. Retention rate at 12 months (or study completion) was 63.0% (monotherapy, 77.8%; first adjunctive therapy, 59.1%). Seizure-freedom rate during the Maintenance Period was 32.7% (monotherapy, 44.4%; first adjunctive therapy, 29.5%) and the 50% responder rate was 78.7% (monotherapy, 85.7%; first adjunctive therapy, 76.9%). TEAEs and serious TEAEs were reported by 88.9% (n = 48/54) and 7.4% (n = 4/54) of patients, respectively. Overall, the efficacy and safety of perampanel as monotherapy or first adjunctive therapy support the use of perampanel as early-line treatment for epilepsy., (© 2024. The Author(s).)

Multiple sclerosis (MS) is characterized by progressive neuroinflammation and neurodegeneration from disease onset that, if left untreated, can result in the accumulation of irreversible neurological disability. Early intervention with high-efficacy therapies (HETs) is increasingly recognized as the best strategy to delay or mitigate disease progression from the earliest stages of the disease and to prevent long-term neurodegeneration. Although there is growing clinical and real-world evidence supporting early HET intervention, foregoing this strategy in favor of a traditional escalation approach prioritizing lower-efficacy disease-modifying therapies remains a common approach in clinical practice. This review explores potential health care professional- and patient-related barriers to the early use of HETs in patients with MS in the United States. Barriers can include regulatory and reimbursement restrictions; knowledge gaps and long-term safety concerns among health care professionals; and various individual, cultural, and societal factors affecting patients. Potential strategies for overcoming these barriers and encouraging early HET use are proposed., (© 2024. The Author(s).)

Background: Identifying the associations between BRAF V600E mutation, the American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) and clinicopathological characteristics could assist in making appropriate treatment strategies for pediatric patients with papillary thyroid carcinoma., Objective: To retrospectively assess the associations between BRAF V600E mutation, TI-RADS, and clinicopathological characteristics in pediatric patients with papillary thyroid carcinoma., Materials and Methods: Between May 2013 and May 2023, pediatric patients with papillary thyroid carcinoma who underwent thyroidectomy were retrospectively evaluated. Univariate and multivariate logistic regression analyses were performed to determine the associations between BRAF V600E mutation, TI-RADS, and clinicopathological characteristics. The diagnostic performance of TI-RADS to predict BRAF V600E mutation was assessed., Results: The BRAF V600E mutation was found in 59.1% (39/66) of pediatric patients with papillary thyroid carcinoma. Multivariate analyses showed that hypoechoic/very hypoechoic [odds ratio (OR) = 8.48; 95% confidence interval (CI) = 1.48-48.74); P-value = 0.02] and punctate echogenic foci (OR = 24.3; 95% CI = 3.80-155.84; P-value = 0.001) were independent factors associated with BRAF V600E mutation. In addition, BRAF V600E mutation was significantly associated with TI-RADS 5 (OR = 12.61; 95% CI = 1.28-124.49; P-value = 0.03). There were no associations between BRAF V600E mutation and nodule size, composition, shape, margin, cervical lymph node metastasis, or Hashimoto's thyroiditis (P-value > 0.05). Combined with hypoechoic/very hypoechoic and punctate echogenic foci, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 89.7%, 85.2%, 89.7%, 85.2%, and 87.9%, respectively., Conclusions: Hypoechoic/very hypoechoic, punctate echogenic foci, and TI-RADS 5 are independently associated with BRAF V600E mutation in pediatric patients with papillary thyroid carcinoma., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To study hiring discrimination against cancer survivors, we conduct a vignette experiment in which American and British professionals recruited via Prolific evaluate fictitious job candidates. Candidates differed by periods of non-employment in their career, including non-employment due to suffering from cancer. We study the effect of cancer experiences on professionals' hirability ratings, as well as its effect on underlying candidate perceptions, related to various potential forms of stigma identified in the literature. We find that employment opportunities are lower for candidates with a history of cancer, compared to candidates without such a gap. This penalty is particularly explained by perceptions that these candidates will have higher sick leave probabilities and create additional costs. However, relative to candidates with a comparable gap due to depression or personal reasons, former cancer patients are less stigmatised, with relatively favourable assessments of their emotional abilities, social abilities, motivation and positive impact on workplace culture., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The Slash (multiple-job holders) become increasingly prevalent in the labor force under the context of fast-developing gig economy and other emerging employment forms active on platforms. However, health outcomes of multiple-job holding have not received sufficient research treatment and is far from reaching consensus. This study provides an empirical investigation on the influence of multiple-job holding on individual health., Method: This study uses data from China Health and Retirement Longitudinal Study (CHARLS-2015 survey) which covers 28 provinces/municipalities in China and tracks work and health status of the population aged over 45 years using stratified random sampling (N = 12,659-16,526 for examinations of different types of health status (i.e., chronic conditions/body aches/depression, in study 1), and from the Survey of Household Economics and Decision-making (SHED-2019) which is conducted by the Federal Reserve Board of the United States and documents economic behavior and related risks of the population aged over 18 years (N = 6603 for baseline model and N = 10,718 for supplementary test, in study 2). To address the potential endogeneity of multiple-job holding, the instrumental variable (IV) regressions are conducted to ensure the validity of results. The implementation of Study 1 and 2 in different national context could help test the generalization of research results., Results: Compared with non-multiple jobs holding, multiple-job holding with only one additional job is associated with better health status (i.e., less chronic conditions and body aches, a lower level of depression shown in study 1, and better self-assessed general health shown in study 2), however, multiple-job holding with at least two additional jobs turns to be associated with worse health status (shown in both study 1 and 2). These results show that the optimal level of multiple-job holding could be featured with one additional job besides the primary job., Conclusion: Multiple-job holding, with different structures, has both bright and dark side for health outcomes. To maintain an optimal level of multiple-job holding could benefit individual health., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Breast cancer treatment includes increasingly complex and expensive treatments. Accordingly, the current estimates of the cost of breast cancer treatment are out of date., Methods: The SEER-Medicare Data Link provided 142,837,978 paid Medicare claims from 398,148 female beneficiaries between the ages of 22 and 110 diagnosed with breast cancer between 2007 and 2016. These claims were compared with 153,071,044 claims from 443,952 Medicare beneficiaries without a cancer diagnosis. The total, fully adjudicated, amounts for each claim were summed to determine total treatment cost for each beneficiary. These costs were then aggregated by year after diagnosis and stage at diagnosis. The actuarial survival of beneficiaries with cancer was calculated using the Kaplan-Meier method., Results: Mean costs for the control group were $8,019 per year. The 10-year cost of cancer treatment in Medicare beneficiaries was directly related to stage at diagnosis and ranged from $103,573 for stage 0 cancers to $376,573 for stage 4 cancers. The highest cost occurred during the first 2 years after diagnosis, the time of the beneficiary's initial treatment. Following the first 2 years, healthcare costs remained elevated for at least 10 years after diagnosis., Conclusions: The 10-year treatment cost of female Medicare beneficiaries with breast cancer increases with increasing stage at diagnosis. Any effective screening technology that reduces stage at diagnosis will result in significant treatment cost savings to the Medicare program., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The priority aim of this study is to investigate the effect of carbon footprint, which is an indicator of environmental degradation, on health expenditures for the USA. In the study, cointegration analysis was performed for the period 1970-2016 by using health expenditures, carbon footprint, gross domestic product per capita and life expectancy at birth variables. According to the results of standard cointegration analysis, only cointegration relationship between health expenditures and income was found. In the models with carbon footprint, no cointegration relationship was discovered between the original values of the variables. This result was approached with suspicion, and it was thought that there might be a hidden cointegration between healthcare expenditures and carbon footprint. For this purpose, the hidden cointegration analysis and crouching error correction model proposed by Granger and Yoon [18] were employed among the positive and negative components of the variables of healthcare expenditures and carbon footprint. The results of the hidden cointegration analysis revealed that there was a hidden cointegration relationship between the positive components of healthcare expenditures and the positive components of carbon footprint. Analysis results show that a 1% increase in carbon footprint will cause a 2.04% increase in healthcare expenditures in the long term in the USA. When the positive components of the variables were considered, it was concluded that there was a one-way long-term asymmetric causality relationship between carbon footprint and healthcare expenditures. As a result of the study, it was proposed that the carbon footprint should be diminished to prevent the increasing burden of the healthcare expenditures on the budget.

During the last 15 years, peer review has been widely incorporated into radiology quality improvement programs. However, current implementations are variable and carry concerns, including subjectivity of numerical scores and a sense of merely satisfying regulatory requirements. The Society for Pediatric Radiology (SPR) Quality and Safety Committee sought to evaluate the state of peer review programs in pediatric radiology practices, including implementation methods, perceived functions, strengths and weaknesses, and opportunities for improvement. We distributed an online 16-question survey to SPR members. Questions pertained to the type of peer review system, the use of numerical scores and comments, how feedback on discordances is given and received, and the use of peer learning conferences. We collected 219 responses (15% of survey invitations), 80% of which were from children's hospitals. Fifty percent of respondents said they use a picture archiving and communication system (PACS)-integrated peer review system. Comment-enhanced feedback for interpretive discordances was either very important or somewhat important to performance improvement in 86% of responses, compared to 48% with a similar perception of numerical scores. Sixty-eight percent of respondents said they either rarely or never check their numerical scores, and 82% either strongly or somewhat agreed that comments are more effective feedback than numerical scores. Ninety-three percent either strongly or somewhat agreed that peer learning conferences would be beneficial to their practice. Forty-eight percent thought that their current peer review system should be modified. Survey results demonstrate that peer review systems in pediatric radiology practices are implemented variably, and nearly half of respondents believe their systems should be modified. Most respondents prefer feedback in the form of comments and peer learning conferences, which are thought to be more beneficial for performance improvement than numerical scores.

This paper introduces a new graphical tool: the mean deviation concentration curve. Using a unified approach, we derive the associated dominance conditions that identify robust rankings of absolute socioeconomic health inequality for all indices obeying Bleichrodt and van Doorslaer's (J Health Econ 25:945-957, 2006) principle of income-related health transfer. We also derive dominance conditions that are compatible with other transfer principles available in the literature. To make the identification of all robust orderings implementable using survey data, we discuss statistical inference for these dominance tests. To illustrate the empirical relevance of the proposed approach, we compare joint distributions of income and health-related behavior in the United States., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: We sought to characterize trends in demographics, comorbidities, and postoperative complications among patients undergoing primary and revision cervical disc replacement (pCDR/rCDR) procedures., Methods: In this retrospective database study, the Premier Healthcare database was queried from 2006 to 2019. Annual proportions or medians were calculated for patient and hospital characteristics, comorbidities, and postoperative complications associated with CDR surgery. Trends were assessed using linear regression analyses with year of service as the sole predictor., Results: A total of 16,178 pCDR and 758 rCDR cases were identified, with a median (IQR) age of 46 (39; 53) and 51 (43; 60) years among patients, respectively. The annual number of both procedures increased between 2006 and 2019, from 135 to 2220 for pCDR (p < 0.001), and from 17 to 49 for rCDR procedures (p < 0.001), with radiculopathy being the main indication for surgery in both groups. Mechanical failure was identified as a major indication for rCDR procedures with an increase over time (p = 0.002). Baseline patient comorbidity burden (p = 0.045) and complication rates (p < 0.001) showed an increase. For both procedures, an increase in outpatient surgeries and procedures performed in rural hospitals was seen (pCDR: p = 0.045; p = 0.006; rCDR: p = 0.028; p = 0.034)., Conclusion: PCDR and rCDR procedures significantly increased from 2006 to 2019. At the same time, comorbidity burden and complication rates increased, while procedures were more often performed in an outpatient and rural setting. The identification of these trends can help guide future practice and lead to further areas of research., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: There is no streamlined approach for sharing radiologic images among medical institutions. Common methods to transfer imaging between facilities include electronic image-sharing platforms and physical media, such as compact discs (CDs). The prompt and secure transfer of imaging is vital for patient safety as demand for imaging increases., Objective: Use a survey-based study to outline the methods and difficulties of image sharing among U.S. children's hospitals., Materials and Methods: A multi-question survey regarding radiologic image sharing was distributed to children's hospital department chairs in the United States in August 2021. Descriptive statistical analyses of the results were performed., Results: Our results reveal 78% of responding U.S. children's hospitals have an electronic image-sharing platform. Twenty-seven percent of surveyed institutions experience daily difficulties with radiologic image sharing. Most of the difficulties are with CDs (67%) and a lack of interoperability among electronic image-sharing platforms (51%)., Conclusion: Our study identified the various methods used by U.S. children's hospitals for radiologic image sharing and quantified the ongoing challenges with these systems., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A recent integrated health care initiative in Belgium supports 12 regional pilot projects scattered across the country and representing 21% of the population. As in shared savings programs, part of the estimated savings in health spending are paid out to the projects to reinvest in new actions. Short-term savings are expected in particular from cost reductions among high-cost patients. We estimate the effect of the projects on spending using a difference-in-difference model. The sensitivity of the results to the right-skewness of spending is commonly addressed by removing or top-coding high-cost cases. However, this leads to an underestimation of realized savings at the top end of the distribution, therefore, lowering incentives for cost reduction. We show that this trade-off can be weakened by an alternative approach in which cost categories that fall out of the scope of the projects' interventions are excluded from the dependent variable. We find that this approach leads to improvements in precision and model fit that are of the same magnitude as excluding high-cost cases altogether. At the same time, it sharpens the incentives for cost reduction because the model better reflects the costs that projects can affect., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Additional occurrence data are needed to better understand human exposure to per- and poly-fluoroalkyl substances (PFAS) from commercially available foods in the United States. The Food and Drug Administration's (FDA) Total Diet Study (TDS) collects foods that are both nationally and regionally distributed. In 2018, 172 processed foods were collected from grocery stores around Lenexa, KS, as part of the TDS national collection. A previously developed method for the analysis of PFAS in foods as part of the TDS regional collection was modified and optimized for these samples. This method was single lab validated using 5 different matrices and method detection limits were calculated. During the analysis of these samples, challenges arose with method blanks and further investigation into statistical methods to distinguish between blank and sample concentrations were done. The confirmation of two short chain PFAS, perfluorobutanoic acid (PFBA) and perfluoropentanoic acid (PFPeA), was not possible using triple quadrupole mass spectrometry and a confirmation method was developed using high-resolution mass spectrometry. This technique was also used to investigate potential detections and interferents that fell within the retention time criteria for positive detections. In the national collection, positive detections of perfluorooctanesulfonic acid (PFOS) and perfluorononanoic acid (PFNA) were found in frozen fish sticks/patties, PFOS and perfluorodecanoic acid (PFDA) in canned tuna, and PFOS in protein powder. Concentrations were all below 150 ppt, and no other detects were confirmed above the method detection limits in any other foods., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Purpose: The primary goal of this study was to assess the growth, most influential articles, countries, journals, authors, and papers published in the field of global oral cancer. Research articles on oral cancer, published between 1989 and 2022, were identified through the Web of Science database to achieve this., Methods: A comprehensive dataset comprising 7,178 documents was meticulously extracted from the Web of Science, forming the basis for scientometric analysis. A refined subset of 4,901 documents was judiciously selected following a rigorous screening process for meticulous, in-depth analysis., Results: The field has witnessed a remarkable publication surge, with the United States taking the lead in productivity. The journal Oral Oncology has become the foremost publication, renowned for its prolific output and widespread citation. This trend highlights the growing importance and interest in this domain, with researchers and experts worldwide contributing to the expanding body of knowledge. The United States' dominance in productivity suggests its strong commitment to advancing research in the field, while Oral Oncology's recognition underscores its influential role in disseminating cutting-edge findings and fostering scientific progress., Conclusion: This scientometric analysis is a valuable resource for researchers, funding agencies, industry, and institutions, offering guidance and insights., Clinical Trial Number: Not Applicable., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The Mouse Metabolic Phenotyping Center (MMPC)Live Program was established in 2023 by the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high quality phenotyping services for mouse models of diabetes and obesity. Emerging as the next iteration of the MMPC Program which served the biomedical research community for 20 years (2001-2021), MMPCLive is designed as an outwardly-facing consortium of service cores that collaborate to provide reduced-cost consultation and metabolic, physiologic, and behavioral phenotyping tests on live mice for U.S. biomedical researchers. Four MMPCLive Centers located at universities around the country perform complex and often unique procedures in vivo on a fee for service basis, typically on mice shipped from the client or directly from a repository or vendor. Current areas of expertise include energy balance and body composition, insulin action and secretion, whole body carbohydrate and lipid metabolism, cardiovascular and renal function, food intake and behavior, microbiome and xenometabolism, and metabolic pathway kinetics. Additionally, an opportunity arose to reduce barriers to access and expand the diversity of the biomedical research workforce by establishing the VIBRANT Program. Directed at researchers historically underrepresented in the biomedical sciences, VIBRANT-eligible investigators have access to testing services, travel and career development awards, expert advice and experimental design consultation, and short internships to learn test technologies. Data derived from experiments run by the Centers belongs to the researchers submitting mice for testing which can be made publicly available and accessible from the MMPCLive database following publication. In addition to services, MMPCLive staff provide expertise and advice to researchers, develop and refine test protocols, engage in outreach activities, publish scientific and technical papers, and conduct educational workshops and training sessions to aid researchers in unraveling the heterogeneity of diabetes and obesity., (© 2024. The Author(s).)

Healthcare knowledge management systems can mitigate hospitals' operational inefficiency. As a healthcare information technology, the electronic health record (EHR) receives much attention from medical institutions due to its considerable impact on operational cost performance. This paper focuses on EHR systems to address operational inefficiency by which patients pay more for health care services, and many U.S. hospitals are filing for bankruptcy. From the theoretical perspective of the practice-based view, this paper introduces a path to implement EHR systems for improving cost performance. The empirical investigation is archival data of 200 hospitals collected from the U.S. healthcare agencies. Findings contribute to prior work by hypothesizing moderating and mediating roles in EHR systems implementation. This paper introduces absorptive capacity and monitoring mechanisms as enablers of implementing EHR systems. The results showed that hospital monitoring strengthens the relationship between absorptive capacity and electronic health record systems implementation, which results in better operational cost performance. Theoretically, this study supports the long-term potential benefits of EHR adoption, and its findings are consistent with optimizing efficiency through data standardization and interoperability. From a practical perspective, this study supports hospitals' investments in evolving healthcare information technology systems through the development of a knowledge-based system employing EHR, particularly when hospitals are merging or need a financial strategic plan to control expenses., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This paper focuses on Medicare's End-Stage Renal Disease Quality Incentive Program (QIP). QIP aims to promote high-quality services in outpatient dialysis facilities by tying their payments to their performance on pre-specified quality measures. In this paper, employing principal-agent theory, we examine the effectiveness of QIP by exploring the changes in various clinical/operational measures when they become a part of the program as a performance measure. We study five QIP quality measures; two are operational: hospitalization and readmission. And three others are clinical: blood transfusion, hypercalcemia, and dialysis adequacy. Overall, we observe a significant improvement in all QIP quality measures after being included in the program, except for readmission. We recommend adjusting the weight and redesigning the readmission measure for Medicare to incentivize providers to reduce readmission. We also discuss establishing care coordination and employing data-driven clinical decision support systems as opportunities for dialysis facilities to improve the care delivery process., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In terms of number of beneficiaries, Medicaid is the single largest health insurance program in the US. Along with the Children's Health Insurance Program (CHIP), Medicaid covers nearly half of all births and provides health insurance to nearly half of the children in the country. This article provides a broad introduction to Medicaid and CHIP for the pediatric radiologist with a special focus on topics relevant to pediatric imaging and population health. This includes an overview of Medicaid's structure and eligibility criteria and how it differs from Medicare. The paper examines the means-tested programs within the context of pediatric radiology, reviewing pertinent topics such as the rise of Medicaid managed care plans, Medicaid expansion, the effects of Medicaid on child health, and COVID-19. Beyond the basics of benefits coverage, pediatric radiologists should understand how Medicaid and CHIP financing and reimbursement affect the ability of pediatric practices, radiology groups, and hospitals to provide services for children in a sustainable manner. The paper concludes with an analysis of future opportunities for Medicaid and CHIP., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Cannabidiol (CBD) products lacking regulatory approval are being used to self-treat a myriad of conditions and for their unsubstantiated health benefits. The scientific evidence supporting these claims largely arises not from controlled clinical trials, but from the recognition that CBD has numerous biological targets. Yet, CBD is commonly consumed and often in over-the-counter products that are unapproved and of unknown composition. Epidiolex® is the only product that has undergone rigorous pharmacokinetic assessment and testing in clinical trials; it was approved as a non-scheduled drug by the U.S. Food and Drug Administration for the treatment of intractable childhood-onset seizures. However, studies investigating CBD for other medical conditions are limited in number and often lack the scientific rigor, controls, or sample sizes required to draw clinically meaningful conclusions. Although Epidiolex® is safe for human consumption, recent changes in regulation of commercially available CBD products have resulted in limited quality control and products marketed with unknown CBD bioavailability. Even scientifically rigorous studies have used different sources of CBD and different suspension vehicles for administration, making it difficult to compare results among studies and resolve mixed outcomes., Objectives: This paper reviews the molecular targets, pharmacokinetics, and safety and abuse liability of CBD; additionally, the extant evidence on its potential therapeutic effects for neurological disorders, pain, inflammation, conditions related to immune function, psychiatric disorders, and substance use are described.

Purpose: Preference-based measures are essential for producing quality-adjusted life years (QALYs) that are widely used for economic evaluations. In the absence of such measures, mapping algorithms can be applied to estimate utilities from disease-specific measures. This paper aims to develop mapping algorithms between the MacNew Heart Disease Quality of Life Questionnaire (MacNew) instrument and the English and the US-based EQ-5D-5L value sets., Methods: Individuals with heart disease were recruited from six countries: Australia, Canada, Germany, Norway, UK and the US in 2011/12. Both parametric and non-parametric statistical techniques were applied to estimate mapping algorithms that predict utilities for MacNew scores from EQ-5D-5L value sets. The optimal algorithm for each country-specific value set was primarily selected based on root mean square error (RMSE), mean absolute error (MAE), concordance correlation coefficient (CCC), and r-squared. Leave-one-out cross-validation was conducted to test the generalizability of each model., Results: For both the English and the US value sets, the one-inflated beta regression model consistently performed best in terms of all criteria. Similar results were observed for the cross-validation results. The preferred model explained 59 and 60% for the English and the US value set, respectively. Linear equating provided predicted values that were equivalent to observed values., Conclusions: The preferred mapping function enables to predict utilities for MacNew data from the EQ-5D-5L value sets recently developed in England and the US with better accuracy. This allows studies, which have included the MacNew to be used in cost-utility analyses and thus, the comparison of services with interventions across the health system.

Purpose: Patients with low back pain (LBP) rarely have serious underlying pathology but frequently undergo inappropriate imaging. A range of guidelines and red flag features are utilised to characterise appropriate imaging. This scoping review explores how LBP imaging appropriateness is determined and calculated in studies of primary care practice., Methods: This scoping review builds upon a previous meta-analysis, incorporating articles identified that were published since 2014, with an updated search to capture articles published since the original search. Electronic databases were searched, and citation lists of included papers were reviewed. Inclusion criteria were studies assessing adult LBP imaging appropriateness in a primary care setting. Twenty-three eligible studies were identified., Results: A range of red flag features were utilised to determine imaging appropriateness. Most studies considered appropriateness in a binary manner, by the presence of any red flag feature. Ten guidelines were referenced, with 7/23 (30%) included studies amending or not referencing any guideline. The method for calculating the proportion of inappropriate imaging varied. Ten per cent of the studies used the total number of patients presenting with LBP as the denominator, suggesting most studies overestimated the rate of inappropriate imaging, and did not capture where imaging is not performed for clinically suspicious LBP., Conclusion: Greater clarity is needed on how we define and measure imaging appropriateness for LBP, which also accounts for the problem of failing to image when indicated. An internationally agreed methodology for imaging appropriateness studies would ultimately lead to an improvement in the care delivered to patients. These slides can be retrieved under Electronic Supplementary Material.

Rationale: As a species, humans are vulnerable to numerous mental disorders, including depression and schizophrenia. This susceptibility may be due to the evolution of our large, complex brains, or perhaps because these illnesses counterintuitively confer some adaptive advantage. Additionally, cultural and biological factors may contribute to susceptibility and variation in mental illness experience and expression. Taking a holistic perspective could strengthen our understanding of these illnesses in diverse cultural contexts., Objectives: This paper reviews some of these potential factors and contextualizes mental disorders within a biocultural framework., Results: There is growing evidence that suggests cultural norms may influence inflammation, neurotransmitters, and neurobiology, as well as the illness experience. Specific examples include variation in schizophrenia delusions between countries, differences in links between inflammation and emotion between the United States and Japan, and differences in brain activity between Caucasian and Asian participants indicating that cultural values may moderate cognitive processes related to social cognition and interoception., Conclusions: Research agendas that are grounded in an appreciation of biocultural diversity as it relates to psychiatric illness represent key areas for truly interdisciplinary research that can result in culturally sensitive treatments and highlight possible biological variation affecting medical treatment.

This paper investigates whether or not suffering a health shock, and becoming eligible for social security, have a joint effect on labor supply. Despite millions of people experiencing both of these events each year, no paper has focused exclusively on the joint effect that these events may have on work outcomes. This is surprising given that experiencing a health shock may impact on how a worker responds to becoming eligible for social security. With data from the Health and Retirement Study, I model weekly hours of work as a function of health shocks, social security eligibility, and their interaction. I find that this interaction leads to a 3-4 h reduction in weekly hours of work for men, but has no effect for women. The results are robust to using different work outcomes, age groups, health shock definitions, subgroups, as well as falsification and placebo tests. The results appear to be driven by men who would have had to return to work with impaired health. Policies that promote a more flexible work situation for older men may alleviate these problems in the future.

This paper analyses whether government ideology and other political- and electoral-related factors influence country-level public healthcare expenditures, focussing on the impact of the Great Recession on that relationship. We test this hypothesis for the OECD countries in 1970-2016. Our results reveal the presence of a partisan effect, left-wing governments being more likely to raise public expenditures in the health sector. We also find that coalitions increase these expenditures, whilst minority governments and those with a high presence in the lower house decrease them. Meanwhile, the opportunistic behaviour of incumbents related to the timing of elections is not supported by our results. The percentage of public expenditures over total health expenditures is also examined, obtaining similar results regarding the partisan effect. However, the onset of the Great Recession has altered these relationships, neutralizing the impact of political factors.

Background and Rationale: Cathinones are amphetamine analogues that produce stimulant effects with rewarding properties. For many decades, synthetic cathinones have been used in the United States (USA) for abuse purposes, leading to concern about public safety by the federal government. Under the Controlled Substances Act (CSA), the federal government may place drugs with high abuse potential but no currently accepted medical use into Schedule I of the CSA. The process of scheduling an abusable drug involves both the Department of Health and Human Services (HHS), through the Food and Drug Administration (FDA) and the National Institute on Drug Abuse (NIDA), and the Department of Justice, through the Drug Enforcement Administration (DEA)., Results: This paper details how numerous synthetic cathinones were placed under CSA control between 1973 and 2018, with an emphasis on 10 cathinones that were placed into Schedule I in 2017 (butylone, naphyrone, pentylone, pentedrone, 3-fluoro-N-methylcathinone (FMC), 4-FMC, 4-methyl-N-ethylcathinone, 4-methyl-pyrrolidinopropiophenone, alpha-pyrrolidinobutiophenone, and α-pyrrolidinopentiophenone). A summary is provided of the scientific and medical analysis performed by HHS, in the form of an Eight-Factor Analysis (8FA), as prescribed by the CSA. This 8FA was then evaluated and signed by the Assistant Secretary for Health at HHS and transmitted to DEA, which permanently placed the 10 cathinones into Schedule I after public notices were published into the Federal Register., Discussion and Conclusions: Understanding the scientific data, analysis, and complex process utilized by the US federal government in the CSA scheduling of cathinones with abuse potential and no accepted medical use is important for transparency in governmental decision-making.

Background: Different countries have different preferences regarding health, and there are different value sets for popular preference-based measures across different countries. However, the cost of collecting data to generate country-specific value sets can be prohibitive for countries with smaller population size or low- and middle-income countries (LMIC). This paper explores whether existing preference weights could be modelled alongside a small own country valuation study to generate representative estimates. This is explored using a case study modelling UK data alongside smaller US samples to generate US estimates., Methods: We analyse EQ-5D valuation data derived from representative samples of the US and UK populations using time trade-off to value 42 health states. A nonparametric Bayesian model was applied to estimate a US value set using the full UK dataset and subsets of the US dataset for 10, 15, 20 and 25 health states. Estimates are compared to a US value set estimated using US values alone using mean predictions and root mean square error., Results: The results suggest that using US data elicited for 20 health states alongside the existing UK data produces similar predicted mean valuations and RMSE as the US value set, while 25 health states produce the exact features., Conclusions: The promising results suggest that existing preference data could be combined with a small valuation study in a new country to generate preference weights, making own country value sets more achievable for LMIC. Further research is encouraged.

Human research with hallucinogens such as lysergic acid diethylamide (LSD) has been ongoing in the USA since 1949. During the 1960s, LSD was investigated for a variety of psychiatric indications, including the following: as an aid in treatment of schizophrenia; as a means of creating a "model psychosis"; as a direct antidepressant; and as an adjunct to psychotherapy. Studies with all drugs, including LSD, have always been conducted under federal regulatory controls, including the 1938 Food Drug and Cosmetic Act (FDCA; which ensured the safety of drugs) and the 1962 Kefauver-Harris Amendments to the FDCA (which described appropriate scientific methodology and ensured drug efficacy). This paper details how the 1962 Amendments introduced numerous safety and efficacy requirements that must be in satisfied during clinical drug research-and how human studies conducted with LSD in the 1960s struggled with their fulfillment. Information is provided from Senate hearings, case law, and interviews with key investigators. Examples are also drawn from scientific papers and symposia published during and since that period, with a focus on information from clinical studies conducted with LSD by psychiatrist Albert Kurland at the Spring Grove State Hospital, near Baltimore, MD. While Kurland largely conformed with these new regulations, other investigators often fell short of complying with scientific standards and federal requirements. Thus, the human hallucinogen studies of the 1960s are best understood as providing pilot data on safety and efficacy, as well as testable hypotheses for current hallucinogen studies conducted under modern scientific and regulatory standards.

Hot springs are natural habitats for thermophilic Archaea and Bacteria. In this paper, we present the metagenomic analysis of eight globally distributed terrestrial hot springs from China, Iceland, Italy, Russia, and the USA with a temperature range between 61 and 92 (∘)C and pH between 1.8 and 7. A comparison of the biodiversity and community composition generally showed a decrease in biodiversity with increasing temperature and decreasing pH. Another important factor shaping microbial diversity of the studied sites was the abundance of organic substrates. Several species of the Crenarchaeal order Thermoprotei were detected, whereas no single bacterial species was found in all samples, suggesting a better adaptation of certain archaeal species to different thermophilic environments. Two hot springs show high abundance of Acidithiobacillus, supporting the idea of a true thermophilic Acidithiobacillus species that can thrive in hyperthermophilic environments. Depending on the sample, up to 58 % of sequencing reads could not be assigned to a known phylum, reinforcing the fact that a large number of microorganisms in nature, including those thriving in hot environments remain to be isolated and characterized.

The NAS Genetics Panel (1956) recommended a switch from a threshold to a linear dose response for radiation risk assessment. To support this recommendation, geneticists on the panel provided individual estimates of the number of children in subsequent generations (one to ten) that would be adversely affected due to transgenerational reproductive cell mutations. It was hoped that there would be close agreement among the individual risk estimates. However, extremely large ranges of variability and uncertainty characterized the wildly divergent expert estimates. The panel members believed that sharing these estimates with the scientific community and general public would strongly undercut their linearity recommendation, as it would have only highlighted their own substantial uncertainties. Essentially, their technical report in the journal Science omitted and misrepresented key adverse reproductive findings in an effort to ensure support for their linearity recommendation. These omissions and misrepresentations not only belie the notion of an impartial and independent appraisal by the NAS Panel, but also amount to falsification and fabrication of the research record at the highest possible level, leading ultimately to the adoption of LNT by governments worldwide. Based on previously unexamined correspondence among panel members and Genetics Panel meeting transcripts, this paper provides the first documentation of these historical developments.

When cases of suspected abusive head trauma are adjudicated in courts of law, several alternative theories of causation are frequently presented. This paper reviews common theories and examines their scientific basis.

CT scans are powerful tools used in the care of pediatric patients daily. Yet the increased use of CT warrants careful monitoring. This article defines diagnostic reference levels and how they can be used to guide practice. Once a facility has adapted its techniques and protocols to fall within diagnostic reference levels or target values, the facility can expand its quality-improvement efforts to include a new concept, diagnostic reference ranges (DRRs). DRRs take into account the subjective image quality of the examination and provide a minimum estimated patient dose, below which accurate interpretation of an image might be difficult, and an upper estimated dose, above which the patient dose may be higher than necessary. This paper also describes how the American College of Radiology Dose Index Registry can be used by a facility as a continuous quality improvement tool to monitor and manage appropriate patient dose.

The management of image quality and radiation dose during pediatric CT scanning is dependent on how well one manages the radiographic techniques as a function of the type of exam, type of CT scanner, and patient size. The CT scanner's display of expected CT dose index volume (CTDIvol) after the projection scan provides the operator with a powerful tool prior to the patient scan to identify and manage appropriate CT techniques, provided the department has established appropriate diagnostic reference levels (DRLs). This paper provides a step-by-step process that allows the development of DRLs as a function of type of exam, of actual patient size and of the individual radiation output of each CT scanner in a department. Abdomen, pelvis, thorax and head scans are addressed. Patient sizes from newborns to large adults are discussed. The method addresses every CT scanner regardless of vendor, model or vintage. We cover adjustments to techniques to manage the impact of iterative reconstruction and provide a method to handle all available voltages other than 120 kV. This level of management of CT techniques is necessary to properly monitor radiation dose and image quality during pediatric CT scans.

This paper describes how cooperation among international organizations, as modeled in Europe, can work to improve imaging safety and standards for children throughout the world. This is demonstrated in the mechanisms employed in a large-scale multi-national study on CT imaging safety practices described elsewhere in this issue of Pediatric Radiology. Here we learn approaches through which CT safety standards have been achieved and the international resources available to help in standardizing safety practices in medical imaging. There are unique strengths of the approach in Europe, which has mandatory requirements on member states to facilitate strengthening of radiation protection. Most countries have national regulatory mechanisms for radiation protection in medicine. International organizations play a significant role in supporting projects in lower-resource countries such that a large proportion of radiologic professionals in low-resource countries are trained through assistance by these organizations. Many of these international organizations make it possible for professionals worldwide to download free training material. Collaboration among international organizations and the Image Gently campaign toward consensus with regard to radiation protection can go further than individual opinions in promoting a higher standard of radiation protection around the world.

When determining a strategy for pediatric CT scanning, clinical staff can either elect to adjust routine adult-protocol parameter settings on a case-by-case basis or rely on pre-set pediatric protocol parameters. The advantages of the latter approach are the topic of this manuscript. This paper outlines specific options to consider, including the need for regular protocol review.

This paper extends a series of historical papers which demonstrated that the linear-no-threshold (LNT) model for cancer risk assessment was founded on ideological-based scientific deceptions by key radiation genetics leaders. Based on an assessment of recently uncovered personal correspondence, it is shown that some members of the United States (US) National Academy of Sciences (NAS) Biological Effects of Atomic Radiation I (BEAR I) Genetics Panel were motivated by self-interest to exaggerate risks to promote their science and personal/professional agenda. Such activities have profound implications for public policy and may have had a significant impact on the adoption of the LNT model for cancer risk assessment.

When the patent of a brand-name, marketed drug expires, new, generic products are usually offered. Small-molecule generic and originator drug products are expected to be chemically identical. Their pharmaceutical similarity can be typically assessed by simple regulatory criteria such as the expectation that the 90% confidence interval for the ratio of geometric means of some pharmacokinetic parameters be between 0.80 and 1.25. When such criteria are satisfied, the drug products are generally considered to exhibit therapeutic equivalence. They are then usually interchanged freely within individual patients. Biological drugs are complex proteins, for instance, because of their large size, intricate structure, sensitivity to environmental conditions, difficult manufacturing procedures, and the possibility of immunogenicity. Generic and brand-name biologic products can be expected to show only similarity but not identity in their various features and clinical effects. Consequently, the determination of biosimilarity is also a complicated process which involves assessment of the totality of the evidence for the close similarity of the two products. Moreover, even when biosimilarity has been established, it may not be assumed that the two biosimilar products can be automatically substituted by pharmacists. This generally requires additional, careful considerations. Without declaring interchangeability, a new product could be prescribed, i.e. it is prescribable. However, two products can be automatically substituted only if they are interchangeable. Interchangeability is a statistical term and it means that products can be used in any order in the same patient without considering the treatment history. The concepts of interchangeability and prescribability have been widely discussed in the past but only in relation to small molecule generics. In this paper we apply these concepts to biosimilars and we discuss: definitions of prescribability and interchangeability and their statistical implementation; the relation between bioequivalence and interchangeability for small-molecule drug products; regulatory requirements and expectations of biosimilar products in various jurisdictions; possible statistical approaches to establish the similarity and interchangeability of biologic drug products; definition of other technical terms such as switchability and automatic substitution. The paper will be concluded with a discussion of the anticipated future use of interchangeability of biological drug products.

This paper extends several recent publications indicating that Hermann J. Muller: (1) Made deceptive statements during his Noble Prize Lecture on December 12, 1946, that were intended to promote the acceptance of the linear dose-response model for risk assessment for ionizing radiation and (2) that such actions of Muller were masked by a series of decisions by Muller's long-time colleague and esteemed radiation geneticist Curt Stern, affecting key publications in the mutation literature. Such actions further enhanced acceptance of the linearity dose-response model while preventing Muller's deceptions from being discovered. This paper provides documentation that Muller reinforced such practices within the scientific literature in the early 1950s, by supporting scientifically questionable actions of Stern. Detailed documentation is provided that demonstrates how these actions affected national and international risk assessment policy for ionizing radiation and chemical carcinogens via the recommendations of the National Academy of Sciences Biological Effects of Atomic Radiation committee in 1956, to adopt the linear dose-response model.

This paper identifies the origin of the linearity at low-dose concept [i.e., linear no threshold (LNT)] for ionizing radiation-induced mutation. After the discovery of X-ray-induced mutations, Olson and Lewis (Nature 121(3052):673-674, 1928) proposed that cosmic/terrestrial radiation-induced mutations provide the principal mechanism for the induction of heritable traits, providing the driving force for evolution. For this concept to be general, a LNT dose relationship was assumed, with genetic damage proportional to the energy absorbed. Subsequent studies suggested a linear dose response for ionizing radiation-induced mutations (Hanson and Heys in Am Nat 63(686):201-213, 1929; Oliver in Science 71:44-46, 1930), supporting the evolutionary hypothesis. Based on an evaluation of spontaneous and ionizing radiation-induced mutation with Drosophila, Muller argued that background radiation had a negligible impact on spontaneous mutation, discrediting the ionizing radiation-based evolutionary hypothesis. Nonetheless, an expanded set of mutation dose-response observations provided a basis for collaboration between theoretical physicists (Max Delbruck and Gunter Zimmer) and the radiation geneticist Nicolai Timoféeff-Ressovsky. They developed interrelated physical science-based genetics perspectives including a biophysical model of the gene, a radiation-induced gene mutation target theory and the single-hit hypothesis of radiation-induced mutation, which, when integrated, provided the theoretical mechanism and mathematical basis for the LNT model. The LNT concept became accepted by radiation geneticists and recommended by national/international advisory committees for risk assessment of ionizing radiation-induced mutational damage/cancer from the mid-1950s to the present. The LNT concept was later generalized to chemical carcinogen risk assessment and used by public health and regulatory agencies worldwide.

The large and growing uninsured population poses an alarming threat to the US health care system, and is a major target of the Obama health reform. This paper investigates analytically and empirically the degree to which the absence of health insurance in the US reflects the availability of the health care safety net, such as the guaranteed or charitable care provided by emergency rooms, community health centers and physicians. Our theoretical model demonstrates that the safety net can be a real alternative to health insurance, thus discouraging private insurance purchase in the market setting. In particular, when the community premium rate fails to reflect the value of such resources, not purchasing insurance becomes a rational decision for a sizeable portion of the population. The calibrated simulation based on US statistics indicates about 15.75% of the uninsured population, or 7.2 million people in US, are attributable to the existing safety net system. Further empirical analysis using nationally representative data shows consistently that the presence of local safety net resources may reduce the probability of individual insurance purchase by as much as 45.9%.

An important health policy issue is the low rate of patient enrollment into clinical trials, which may slow down the process of clinical trials and discourage their supply, leading to delays in innovative life-saving drug treatments reaching the general population. In the US, patients' cost of participating in a clinical trial is considered to be a major barrier to patient enrollment. In order to reduce this barrier, some states in the US have implemented policies requiring health insurers to cover routine care costs for patients enrolled in clinical trials. This paper evaluates empirically how effective these policies were in increasing the supply of clinical trials and speeding up their completion, using data on cancer clinical trials initiated in the US between 2001 and 2007. Our analysis indicates that the policies did not lead to an increased supply in the number of clinical trials conducted in mandate states compared to non-mandate states. However, we find some evidence that once clinical trials are initiated, they are more likely to finish their patient recruitment in a timely manner in mandate states than in non-mandate states. As a result, the overall length to completion was significantly shorter in mandate states than in non-mandate states for cancer clinical trials in certain phases. The findings hint at the possibility that these policies might encourage drug innovation in the long run.

This paper investigates the impact of the introduction of new orphan drugs on premature mortality from rare diseases using longitudinal, disease-level data obtained from a number of major databases. The analysis is performed using data from two countries: the United States (during the period 1999-2006) and France (during the period 2000-2007). For both countries, we estimate models using two alternative definitions of premature mortality, several alternative criteria for inclusion in the set of rare diseases, and several values of the potential lag between new drug approvals and premature mortality reduction. Both the United States and French estimates indicate that, overall, premature mortality from rare diseases is unrelated to the cumulative number of drugs approved 0-2 years earlier but is significantly inversely related to the cumulative number of drugs approved 3-4 years earlier. This delay is not surprising, since most patients probably do not have access to a drug until several years after it has been launched. Although the estimates for the two countries are qualitatively similar, the estimated magnitudes of the US coefficients are about four times as large as the magnitudes of the French coefficients. This may be partly due to greater errors in measuring dates of drug introduction in France. Also, access to new drugs may be more restricted in France than it is in the United States. Our estimates indicate that, in the United States, potential years of life lost to rare diseases before age 65 (PYLL65) declined at an average annual rate of 3.3% and that, in the absence of lagged new drug approvals, PYLL65 would have increased at a rate of 0.9%. Since the US population aged 0-64 was increasing at the rate of 1.0% per year, this means that PYLL65 per person under 65 would have remained approximately constant. The reduction in the US growth rate of PYLL65 attributable to lagged new drug approvals was 4.2%. In France, PYLL65 declined at an average annual rate of 1.8%. The estimates imply that, in the absence of lagged new drug approvals, it would have declined at a rate of 0.6%. The reduction in the French growth rate of PYLL65 attributable to lagged new drug approvals was 1.1%. Earlier access to orphan drugs could result in earlier reductions in premature mortality from rare diseases.