Fitting in? Physician practice style after forced relocation.

OBJECTIVE: This study aims to examine how variation in physicians' treatment decisions for newborn deliveries responds to changes in the hospital-level norms for obstetric clinical decision-making. DATA SOURCES: All hospital-based births in Florida from 2003 through 2017. STUDY DESIGN: Difference-in-differences approach is adopted that leverages obstetric unit closures as the source of identifying variation to exogenously shift obstetricians to a new, nearby hospital with different propensities to approach newborn deliveries less intensively. DATA EXTRACTION: Births attributed to physicians continuously observed 2 years before the closure event and 2 years after the closure event (treatment group physicians) or for identical time periods around a randomly assigned placebo closure date (control group physicians). PRINCIPAL FINDINGS: All of the physicians meeting our inclusion criteria shifted their births to a new hospital less than 20 miles from the hospital shuttering its obstetric unit. The new hospitals approached newborn births more conservatively, and treatment group physicians sharply became less aggressive in their newborn birth clinical management (e.g., use of C-section). The immediate 11-percentage point (33%) increase in delivering newborns without any procedure behavior change is statistically significant (p value <0.01) and persistent after the closure event; however, the physicians' payer and patient mix are unchanged. CONCLUSIONS: Obstetric physician behavior change appears highly malleable and sensitive to the practice patterns of other physicians delivering newborns at the same hospital. Incentives and policies that encourage more appropriate clinical care norms hospital-wide could sharply improve physician treatment decisions, with benefits for maternal and infant outcomes.

Cancer Drug Trastuzumab And Its Biosimilars Compete On Price For Market Share.

Using Medicare claims, we documented US prescribing patterns for originator biologic trastuzumab (Herceptin), a targeted cancer therapy, and five biosimilar entrants since 2019. The first biosimilar captured a dominant share, but over time, average sales prices of all products declined, and later entrants became dominant in some states. Despite strong brand loyalty to the first biosimilar, competitive pressure increased with subsequent entrants.

Disparity in checkpoint inhibitor utilization among commercially insured adult patients with metastatic lung cancer.

BACKGROUND: There is a lack of evidence from nationwide samples on the disparity of initiating immune checkpoint inhibitors (ICIs) after metastatic lung cancer diagnosis. METHODS: We identified metastatic lung cancer patients diagnosed between 2015 and 2020 from a large, nationwide commercial claims database. We analyzed the time from metastatic lung cancer diagnosis to ICI therapy using Cox proportional hazard models. Independent variables included county-level measures (quintiles of percentage of racialized population, quintiles of percentage of population below poverty, urbanity, and density of medical oncologists) and patient characteristics (age, sex, Charlson comorbidity index, Medicare Advantage, and year of diagnosis). All tests were 2-sided. RESULTS: A total of 17 022 patients were included. Counties with a larger proportion of racialized population appeared to be more urban, have a greater percentage of its residents in poverty, and have a higher density of medical oncologists. In Cox analysis, the adjusted hazard ratio of the second, third, fourth, and highest quintile of percentage of racialized population were 0.89 (95% confidence interval [CI] = 0.82 to 0.98), 0.85 (95% CI = 0.78 to 0.93), 0.78 (95% CI = 0.71 to 0.86), and 0.71 (95% CI = 0.62 to 0.81), respectively, compared with counties in the lowest quintile. The slower ICI therapy initiation was driven by counties with the highest percentage of Hispanic population and other non-Black racialized groups. CONCLUSIONS: Commercially insured patients with metastatic lung cancer who lived in counties with greater percentage of racialized population had slower initiation of ICI therapy after lung cancer diagnosis, despite greater density of oncologists in their neighborhood.

Value of Reducing Wait Times for Chimeric Antigen Receptor T-Cell Treatment: Evidence From Randomized Controlled Trial Data on Tisagenlecleucel for Diffuse Large B-Cell Lymphoma.

OBJECTIVES: This study aimed to quantify the value of reducing chimeric antigen receptor T-cell (CAR-T) treatment wait times on patients with refractory and relapsed aggressive blood cancer who can newly gain access to treatment or access treatment earlier in their disease course. METHODS: Using data from the JULIET clinical trial, we first identified the number of additional patients with diffuse large B-cell lymphoma that would have been treated with tisagenlecleucel CAR-T therapy if wait times were shortened. For these patients, we estimated mortality benefits using literature estimates of CAR-T effectiveness. Next, among patients who already received CAR-T, we estimated tumor burden progression over time using a linear probability regression model. The primary outcome variable was an indicator for having above-normal lactate dehydrogenase, and we controlled for time, use of bridging therapy, and time-invariant patient characteristics. The regression results, along with literature estimates relating lactate dehydrogenase to CAR-T effectiveness, were used to compute the survival benefits of earlier CAR-T treatment. RESULTS: Reducing wait times by 2 months increased the number of eligible patients receiving CAR-T by at least 10.7%. For patients already receiving tisagenlecleucel CAR-T, a 2-month reduction in wait times generated a 3.3% increase in survival gains per treated patient. Thus, among patients seeking treatment, the combined treatment efficacy increased by 14%, with approximately one-quarter of survival benefits accruing to existing patients receiving faster treatment. CONCLUSIONS: Delays affected not only access to CAR-T treatments but also treatment effectiveness. Our results highlight the survival benefits of expediting treatment access and may help explain some observed differences in CAR-T effectiveness across countries.

Aortic root repair in a patient with acquired hemophilia A: case report.

BACKGROUND: Patients with acquired hemophilia A (AHA) who require open heart surgery have a life-threatening risk of hemorrhage. Limited data exist to guide perioperative management of these patients. CASE PRESENTATION: A 53-year-old female with rheumatoid arthritis, concomitant aortic valve endocarditis, and severe aortic regurgitation presented to our hospital. Bleeding and abnormal coagulation tests were noted during the initial workup, and she was diagnosed with AHA. The perioperative management plan included the use of pharmaceuticals, porcine recombinant factor VIII, and blood products. Extensive preoperative coagulation data were obtained, and factor VIII levels were continuously monitored to mitigate bleeding complications. The aortic valve replacement and root repair were uneventful. CONCLUSION: Cardiac surgery in patients with AHA is possible as long as complex perioperative hemostatic and hematology management is used.

Spending On Targeted Therapies Reduced Mortality In Patients With Advanced-Stage Breast Cancer.

Costly targeted therapies are playing an increasingly important role in treating cancer. To characterize trends in spending on targeted therapies for breast cancer and to estimate the association of these therapies with cancer mortality, we analyzed cancer diagnoses in the Surveillance, Epidemiology, and End Results Program-Medicare linked database. We categorized total cancer spending into spending on targeted therapies, spending on nontargeted therapies, and spending on other cancer care. Diagnosis-year spending on targeted therapies increased from $1,024 per patient in 2000 to $18,809 per patient in 2015 for patients with advanced-stage cancer and from $82 to $3,289 for patients with early-stage cancer. For patients with advanced-stage cancer, a $1,000 increase in spending on targeted therapies in the diagnosis year was associated with a 0.55-percentage-point decrease in adjusted three-year cancer mortality, whereas for patients with early-stage cancer, there was no association. The other two types of spending (on nontargeted therapies and other cancer care) were not associated with mortality among patients with either advanced- or early-stage cancer. Our results indicate that among various types of cancer treatments, only targeted therapies generated meaningful survival gains for patients with advanced-stage breast cancer.

Provider differences in biosimilar uptake in the filgrastim market.

OBJECTIVES: To identify differences in biosimilar uptake across providers and to examine the association between provider biosimilar uptake and observable practice-level characteristics. STUDY DESIGN: A retrospective analysis of 100% of a commercial medical claims database from June 2015 to June 2018. METHODS: We focused on providers of biologic (Neupogen) and biosimilar (Zarxio) filgrastim. We compared trends in biosimilar uptake across 2 dimensions: provider's place of service and provider's prescribing exclusivity. We then used multivariate regression analysis to estimate the association between any biosimilar uptake and practice-level characteristics, controlling for geography and time fixed effects. RESULTS: Relative to hospital-based providers, office-based providers were earlier and quicker adopters of the biosimilar filgrastim. Across all places of service, providers predominantly prescribed either the biosimilar or biologic, exclusively, for all their patients. Any biosimilar uptake was more common among providers in office-based settings, providers with larger practice sizes, and providers with a higher share of health maintenance organization patients, nonwhite patients, and younger patients. CONCLUSIONS: This study uncovers important associations between provider practice characteristics and biosimilar uptake. Our findings suggest that provider awareness and incentives can be important levers to strengthen US biosimilar market penetration and competition.

Trends in the Price per Median and Mean Life-Year Gained Among Newly Approved Cancer Therapies 1995 to 2017.

BACKGROUND: The prices of newly approved cancer drugs have risen over the past decades. A key policy question is whether the clinical gains offered by these drugs in treating specific cancer indications justify the price increases. OBJECTIVES: To evaluate the price per median and mean life year gained among newly approved cancer therapies from 1995 to 2017. METHODS: We collected data on the price (in 2017 USD) per life-year gained among cancer drug-indication pairs approved by the US Food and Drug Administration (FDA) between 1995 and 2017. We modeled trends using fractional polynomial and linear spline regression models that controlled for route of administration and cancer type fixed effects. RESULTS: We found that between 1995 and 2012, price increases outstripped median survival gains, a finding consistent with previous literature. Nevertheless, price per mean life-year gained increased at a considerably slower rate, suggesting that new drugs have been more effective in achieving longer-term survival. Between 2013 and 2017, price increases reflected equally large gains in median and mean survival, resulting in a flat profile for benefit-adjusted launch prices in recent years. CONCLUSIONS: Although drug costs have been rising more rapidly than median survival gains, they have been rising at about the same rate as mean survival gains. This suggests that when accounting for longer-term survival gains, the benefits of new drugs are roughly keeping pace with their costs, despite rapid cost growth.

Does Spending More Get More? Health Care Delivery and Fiscal Implications From a Medicare Fee Bump.

While salient features of the Affordable Care Act include insurance expansions and private coverage reforms, various other provisions are embedded within the law. We focus on a temporary 10 percent fee increase for primary care visits supplied to publicly insured (Medicare) beneficiaries. Using administrative and survey data, we assess the price shock's impact on service volume, physician labor supply, and quality of care. Primary care physicians (PCPs) in independent practices demonstrate, at most, a marginal 2 percent increase in new patient visits while horizontally and vertically integrated PCPs show no change. Both PCP organizational types witness declines in established patient visits, on average, but there is marked heterogeneity: established patient visits increase by 1 to 2 percent among PCPs with fewer Medicare claims in the pre-period. The Medicare fee bump did not observably impact other labor supply outcomes and quality of care margins. We estimate that the policy introduced a $1.5 billion transfer from taxpayers to providers during the initiative's first three years.

Productivity Benefits of Medical Care: Evidence from US-Based Randomized Clinical Trials.

BACKGROUND: One of the key recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine is to take a societal perspective when evaluating new technologies-including measuring the productivity benefits of new treatments. Yet relatively little is known about the impact that new treatments have on labor productivity. OBJECTIVES: To examine the relationship between new drug treatments and gains in labor productivity across conditions in the United States and to evaluate which randomized clinical trials (RCTs) collected labor productivity data. METHODS: We collected data on US-based RCTs with work-ability surveys from searches of Google Scholar, PubMed, Scopus, the Cochrane Central Registry of Clinical Trials, and ClinicalTrails.gov. Combining RCT data with survey data from the Medical Expenditure Panel Survey, we assessed productivity changes from new drug treatments. RESULTS: During the last decade, some disease conditions have seen treatments that improve ability to work by as much as 60%. The annual increase in productivity gains attributable to new drug treatments was modest 1.1% (P = 0.53). Of the 5092 RCTs reviewed, ability-to-work measures were collected in 2% of trials. Work productivity surveys were more likely among prevalent medical conditions that affected individuals who worked, earned higher wages, and experienced larger reductions in hours worked as a consequence of disease diagnosis. CONCLUSIONS: From our data, we estimated that drug innovation increased productivity by 4.8 million work days per year and $221 billion in wages per year. These labor-sector benefits should be taken into account when assessing the socially optimal cost for new drug innovation.

Therapeutic Plasma Exchange for Urgent Rivaroxaban Reversal.

Direct oral anticoagulants, which include the factor Xa inhibitor rivaroxaban, have some advantages over vitamin K antagonists in regard to stroke prevention in patients with atrial fibrillation. However, no antidotes to reverse the effect of oral anticoagulants are commercially available, which can complicate treating patients in whom reversal is urgent. We faced this challenge in a kidney transplant candidate, a 65-year-old man with end-stage renal disease who had been taking rivaroxaban for paroxysmal atrial fibrillation. When a deceased-donor kidney became available, we needed to rapidly reduce the patient's bleeding risk, while minimizing the cold ischemic time of the donor kidney. Therefore, we decided to take an experimental approach and perform therapeutic plasma exchange. The patient's plasma anti-factor Xa level decreased from 0.4 IU/mL immediately before treatment to 0.21 IU/mL afterward, indicating that rivaroxaban had been actively removed from circulation. Waste fluid showed significant anti-Xa activity, indicating that the risk of rebound anticoagulation had been mitigated. The patient subsequently underwent successful kidney transplantation. To our knowledge, this is the first report of therapeutic plasma exchange to reverse the effects of rivaroxaban in a patient undergoing urgent surgery. This treatment may also be suitable for patients who have life-threatening, large-volume bleeding, especially in the presence of substantial kidney or liver dysfunction.

Use of an Intravascular Warming Catheter during Off-Pump Coronary Artery Bypass Surgery in a Patient with Severe Cold Hemagglutinin Disease.

Cold hemagglutinin disease with broad thermal amplitude and high titers presents challenges in treating cardiac-surgery patients. Careful planning is needed to prevent the activation of cold agglutinins and the agglutination of red blood cells as the patient's temperature drops during surgery. We describe our approach to mitigating cold agglutinin formation in a 77-year-old man with severe cold hemagglutinin disease who underwent off-pump coronary artery bypass surgery without the use of preoperative plasmapheresis. This experience shows that the use of an intravascular warming catheter can maintain normothermia and prevent the activation and subsequent formation of cold agglutinins. To our knowledge, this is the first reported use of this technique in a patient with cold hemagglutinin disease. The chief feature in this approach is the use of optimal thermal maintenance-rather than the more usual decrease in cold-agglutinin content by means of therapeutic plasma exchange.

The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck.

JNK pathway-associated phosphatase (JKAP, also known as DUSP22 or JSP-1) is a JNK activator. The in vivo role of JKAP in immune regulation remains unclear. Here we report that JKAP directly inactivates Lck by dephosphorylating tyrosine-394 residue during T-cell receptor (TCR) signalling. JKAP-knockout T cells display enhanced cell proliferation and cytokine production. JKAP-knockout mice show enhanced T-cell-mediated immune responses and are more susceptible to experimental autoimmune encephalomyelitis (EAE). In addition, the recipient mice that are adoptively transferred with JKAP-knockout T cells show exacerbated EAE symptoms. Aged JKAP-knockout mice spontaneously develop inflammation and autoimmunity. Thus, our results indicate that JKAP is an important phosphatase that inactivates Lck in the TCR signalling turn-off stage, leading to suppression of T-cell-mediated immunity and autoimmunity.

When does weight matter most?

Past empirical work establishes a wage penalty from being overweight. In this paper, I exploit variation in an individual's weight over time to determine the age when weight has the largest impact on labor market outcomes. For white men, controlling for weight at younger ages does not eliminate the effect of older adult weight on wage: being overweight as a young adult only adds an additional penalty to adult wages. However, for white women, what they weigh in their early twenties solely determines the existence of an adult wage penalty. The female early-twenties weight penalty has a persistent effect on wages, and differences in marital characteristics, occupation status, or education cannot explain it. It also is not a proxy for intergenerational unobservables.

Chk1 haploinsufficiency results in anemia and defective erythropoiesis.

BACKGROUND: Erythropoiesis is a highly regulated and well-characterized developmental process responsible for providing the oxygen transport system of the body. However, few of the mechanisms involved in this process have been elucidated. Checkpoint Kinase 1 (Chk1) is best known for its role in the cell cycle and DNA damage pathways, and it has been shown to play a part in several pathways which when disrupted can lead to anemia. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that haploinsufficiency of Chk1 results in 30% of mice developing anemia within the first year of life. The anemic Chk1+/- mice exhibit distorted spleen and bone marrow architecture, and abnormal erythroid progenitors. Furthermore, Chk1+/- erythroid progenitors exhibit an increase in spontaneous DNA damage foci and improper contractile actin ring formation resulting in aberrant enucleation during erythropoiesis. A decrease in Chk1 RNA has also been observed in patients with refractory anemia with excess blasts, further supporting a role for Chk1 in clinical anemia. CONCLUSIONS/SIGNIFICANCE: Clinical trials of Chk1 inhibitors are currently underway to treat cancer, and thus it will be important to track the effects of these drugs on red blood cell development over an extended period. Our results support a role for Chk1 in maintaining the balance between erythroid progenitors and enucleated erythroid cells during differentiation. We show disruptions in Chk1 levels can lead to anemia.

Hematopoietic fingerprints: an expression database of stem cells and their progeny.

Hematopoietic stem cells (HSCs) continuously regenerate the hematologic system, yet few genes regulating this process have been defined. To identify candidate factors involved in differentiation and self-renewal, we have generated an expression database of hematopoietic stem cells and their differentiated progeny, including erythrocytes, granulocytes, monocytes, NK cells, activated and naive T cells, and B cells. Bioinformatic analysis revealed HSCs were more transcriptionally active than their progeny and shared a common activation mechanism with T cells. Each cell type also displayed unique biases in the regulation of particular genetic pathways, with Wnt signaling particularly enhanced in HSCs. We identified approximately 100-400 genes uniquely expressed in each cell type, termed lineage "fingerprints." In overexpression studies, two of these genes, Zfp 105 from the NK cell lineage, and Ets2 from the monocyte lineage, were able to significantly influence differentiation toward their respective lineages, demonstrating the utility of the fingerprints for identifying genes that regulate differentiation.