A transcriptional rheostat couples past activity to future sensory responses.

Animals traversing different environments encounter both stable background stimuli and novel cues, which are thought to be detected by primary sensory neurons and then distinguished by downstream brain circuits. Here, we show that each of the ∼1,000 olfactory sensory neuron (OSN) subtypes in the mouse harbors a distinct transcriptome whose content is precisely determined by interactions between its odorant receptor and the environment. This transcriptional variation is systematically organized to support sensory adaptation: expression levels of more than 70 genes relevant to transforming odors into spikes continuously vary across OSN subtypes, dynamically adjust to new environments over hours, and accurately predict acute OSN-specific odor responses. The sensory periphery therefore separates salient signals from predictable background via a transcriptional rheostat whose moment-to-moment state reflects the past and constrains the future; these findings suggest a general model in which structured transcriptional variation within a cell type reflects individual experience.

An autonomous activation of interleukin-17 receptor signaling sustains inflammation and promotes disease progression.

Anti-interleukin-17 (IL-17) therapy has been used in various autoimmune diseases. However, the efficacy is unexpectedly limited in several IL-17-associated diseases, and the mechanism of limited efficacy remains unclear. Here, we show that a molecular complex containing the adaptor molecule Act1 and tyrosine phosphatase SHP2 mediated autonomous IL-17R signaling that accelerated and sustained inflammation. SHP2, aberrantly augmented in various autoimmune diseases, was induced by IL-17A itself in astrocytes and keratinocytes, sustaining chemokine production even upon anti-IL-17 therapies. Mechanistically, SHP2 directly interacted with and dephosphorylated Act1, which replaced Act1-TRAF5 complexes and induced IL-17-independent activation of IL-17R signaling. Genetic or pharmacologic inactivation of SHP2, or blocking Act1-SHP2 interaction, paralyzed both IL-17-induced and IL-17-independent signaling and attenuated primary or relapsing experimental autoimmune encephalomyelitis. Therefore, Act1-SHP2 complexes mediate an alternative pathway for autonomous activation of IL-17R signaling, targeting which could be a therapeutic option for IL-17-related diseases in addition to current antibody therapies.

The Affordable Care Act and access to care across the cancer control continuum: A review at 10 years.

Lack of health insurance coverage is strongly associated with poor cancer outcomes in the United States. The uninsured are less likely to have access to timely and effective cancer prevention, screening, diagnosis, treatment, survivorship, and end-of-life care than their counterparts with health insurance coverage. On March 23, 2010, the Patient Protection and Affordable Care Act (ACA) was signed into law, representing the largest change to health care delivery in the United States since the introduction of the Medicare and Medicaid programs in 1965. The primary goals of the ACA are to improve health insurance coverage, the quality of care, and patient outcomes, and to maintain or lower costs by catalyzing changes in the health care delivery system. In this review, we describe the main components of the ACA, including health insurance expansions, coverage reforms, and delivery system reforms, provisions within these components, and their relevance to cancer screening and early detection, care, and outcomes. We then highlight selected, well-designed studies examining the effects of the ACA provisions on coverage, access to cancer care, and disparities throughout the cancer control continuum. Finally, we identify research gaps to inform evaluation of current and emerging health policies related to cancer outcomes.

Democratizing social scientists' impact on federal policy: Using the evidence act to help government and ourselves.

It is common for social scientists to discuss the implications of our research for policy. However, what actions can we take to inform policy in more immediate and impactful ways, regardless of our existing institutional affiliations or personal connections? Focusing on federal policy, I suggest that the answer requires understanding a basic coordination problem. On the government side, the Foundations of Evidence-based Policymaking Act (2018) requires that large federal agencies pose, communicate, and answer research questions related to their effects on people and communities. This advancement has opened the black box of federal agency policy priorities, but it has not addressed capacity challenges: These agencies often do not have the financial resources or staff to answer the research questions they pose. On the higher education side, we have more than 150,000 academic social scientists who are knowledge producers and educators by training and vocation. However, especially among those in disciplinary departments, or those without existing institutional or personal connections to federal agencies, we often feel locked out of federal policymaking processes. In this article, I define the coordination problem and offer concrete actions that the academic and federal government communities can take to address it. I also offer leading examples of how academics and universities are making public policy impact possible in multiple governmental spheres. I conclude by arguing that both higher education institutions and all levels of government can do more to help academic social scientists put our knowledge to work in service of the public good.

Inter-chromosomal Contact Properties in Live-Cell Imaging and in Hi-C.

Imaging (fluorescence in situ hybridization [FISH]) and genome-wide chromosome conformation capture (Hi-C) are two major approaches to the study of higher-order genome organization in the nucleus. Intra-chromosomal and inter-chromosomal interactions (referred to as non-homologous chromosomal contacts [NHCCs]) have been observed by several FISH-based studies, but locus-specific NHCCs have not been detected by Hi-C. Due to crosslinking, neither of these approaches assesses spatiotemporal properties. Toward resolving the discrepancies between imaging and Hi-C, we sought to understand the spatiotemporal properties of NHCCs in living cells by CRISPR/Cas9 live-cell imaging (CLING). In mammalian cells, we find that NHCCs are stable and occur as frequently as intra-chromosomal interactions, but NHCCs occur at farther spatial distance that could explain their lack of detection in Hi-C. By revealing the spatiotemporal properties in living cells, our study provides fundamental insights into the biology of NHCCs.

Valuing improvements in the ecological integrity of local and regional waters using the biological condition gradient.

Scientific knowledge related to quantifying the monetized benefits for landscape-wide water quality improvements does not meet current regulatory and benefit-cost analysis needs in the United States. In this study we addressed this knowledge gap by incorporating the Biological Condition Gradient (BCG) as a water quality metric into a stated preference survey capable of estimating the total economic value (use and nonuse) for aquatic ecosystem improvements. The BCG is grounded in ecological principles and generalizable and transferable across space. Moreover, as the BCG translates available data on biological condition into a score on a 6-point scale, it provides a simple metric that can be readily communicated to the public. We applied our BCG-based survey instrument to households across the Upper Mississippi, Ohio, and Tennessee river basins and report values for a range of potential improvements that vary by location, spatial scale, and the scope of the water quality change. We found that people are willing to pay twice as much for an improvement policy that targets their home watershed (defined as a four-digit hydrologic unit) versus a more distant one. We also found that extending the spatial scale of a local policy beyond the home watershed does not generate additional benefits to the household. Finally, our results suggest that nonuse sources of value (e.g., bequest value, intrinsic aesthetic value) are an important component of overall benefits.

Overcoming barriers and stigma: new frontiers in solid organ transplantation for people with HIV.

There is a growing need for solid organ transplantation (SOT) for people living with human immunodeficiency virus (HIV). With the advent of antiretroviral therapy, people living with HIV are experiencing increased life expectancies and are, therefore, developing more comorbidities, including end-stage organ disease. In cases of advanced organ failure, SOT is often the best therapeutic option to improve quality of life and overall survival. As organ shortages persist, transplantation of organs from donors with HIV to recipients with HIV has become a potential therapeutic option. This article first reviews the current state of organ transplantation from donors without HIV to recipients with HIV (HIV D-/R+) by organ and discusses key lessons learned from these transplant trials, including those about drug-drug interactions, rejection, and opportunistic infections. It then explores transplantation from donors with HIV to recipients with HIV (HIV D+/R+), a new frontier. Finally, it investigates challenges of implementation, including public awareness and regulatory requirements, and explores future directions for SOT in people living with HIV.

Intragenic suppressors unravel the role of the SCREAM ACT-like domain for bHLH partner selectivity in stomatal development.

Multicellular organisms develop specialized cell types to achieve complex functions of tissues and organs. The basic helix-loop-helix (bHLH) proteins act as master regulatory transcription factors of such specialized cell types. Plant stomata are cellular valves in the aerial epidermis for efficient gas exchange and water control. Stomatal differentiation is governed by sequential actions of three lineage-specific bHLH proteins, SPEECHLESS (SPCH), MUTE, and FAMA, specifying initiation and proliferation, commitment, and terminal differentiation, respectively. A broadly expressed bHLH, SCREAM (SCRM), heterodimerizes with SPCH/MUTE/FAMA and drives stomatal differentiation via switching its partners. Yet nothing is known about its heterodimerization properties or partner preference. Here, we report the role of the SCRM C-terminal ACT-like (ACTL) domain for heterodimerization selectivity. Our intragenic suppressor screen of a dominant scrm-D mutant identified the ACTL domain as a mutation hotspot. Removal of this domain or loss of its structural integrity abolishes heterodimerization with MUTE, but not with SPCH or FAMA, and selectively abrogates the MUTE direct target gene expression. Consequently, the scrm-D ACTL mutants confer massive clusters of arrested stomatal precursor cells that cannot commit to differentiation when redundancy is removed. Structural and biophysical studies further show that SPCH, MUTE, and FAMA also possess the C-terminal ACTL domain, and that ACTL•ACTL heterodimerization is sufficient for partner selectivity. Our work elucidates a role for the SCRM ACTL domain in the MUTE-governed proliferation-differentiation switch and suggests mechanistic insight into the biological function of the ACTL domain, a module uniquely associated with plant bHLH proteins, as a heterodimeric partner selectivity interface.

Assessing Per-Sex-Act HIV-1 Risk Reduction Among Women Using the Dapivirine Vaginal Ring.

BACKGROUND: Confounding introduced by individuals' sexual risk behavior is potentially a significant source of bias in HIV-1 prevention intervention studies. To more completely account for sexual behaviors when assessing the efficacy of the monthly dapivirine ring, a new longer-acting HIV-1 prevention option for women, we estimated per-sex-act risk reduction associated with product use. METHODS: We conducted a secondary analysis of data from MTN-020/ASPIRE, a phase 3, randomized, placebo-controlled efficacy trial of the dapivirine ring that recruited HIV-uninfected, African women aged 18-45 years. With cumulative sex acts as the time scale, we used multivariable Cox regression with inverse probability of censoring weights to estimate HIV-1 risk reduction associated with a rate of dapivirine release indicative of consistent product use. RESULTS: Women in the dapivirine ring group (n = 1187) had an estimated incidence rate of 2.3 (95% confidence interval [CI], 1.8-3.1) HIV-1 acquisition events per 10 000 sex acts versus 3.6 (95% CI, 2.9-4.4) per 10 000 acts in the placebo group (n = 1187). Dapivirine release indicative of consistent ring use was associated with a 63% (95% CI, 33%-80%) per-sex-act HIV-1 risk reduction. CONCLUSIONS: These results support the efficacy of the dapivirine vaginal ring for HIV-1 prevention and help to inform decision-making for women, providers, and policymakers regarding product use. CLINICAL TRIALS REGISTRATION: NCT01617096.

Long-term PM2.5 exposure and peak expiratory flow in middle-aged and older people in China: A quasi-experimental study.

China's Clean Air Act (CCAA) has been demonstrated to reduce the public health burden of ambient air pollution. Few studies have assessed the health effects of CCAA on lung function. We aimed to investigate the effects of CCAA and PM2.5 exposures on peak expiratory flow (PEF) in middle-aged and older people in China. Three waves (2011, 2013, and 2015) of the China Health and Retirement Longitudinal Study (CHARLS) were included in this study. We performed a difference-in-difference (DID) model and mixed effect method to assess the association between CCAA, PM2.5, and PEF. To increase the reliability, multiple environmental factors were considered, and spline function was utilized to fit the spatial autocorrelations. We found that the risk of decreased PEF in the policy intervention group was reduced by 46% (95% CI: 23%~62%). The estimate showed a 10µg/m3 increase in PM2.5 would increase the risk of decreased PEF by 10% (95% CI: 3%~18%). The results of the mixed effect model showed a 10 µg/m3 increase in PM2.5 concentration was associated with a 2.23% (95% CI: 1.35%~3.06%) decrease in the PEF. These results contributed to the limited epidemiology evidence on demonstrating the effect of PM2.5 on lung function.

Identification of critical mitochondrial hub gene for facial nerve regeneration.

Mitochondria play a critical role in nerve regeneration, yet the impact of gene expression changes related to mitochondria in facial nerve regeneration remains unknown. To address this knowledge gap, we analyzed the expression profile of the facial motor nucleus (FMN) using data obtained from the Gene Expression Omnibus (GEO) database (GSE162977). By comparing different time points in the data, we identified differentially expressed genes (DEGs). Additionally, we collected mitochondria-related genes from the Gene Ontology (GO) database and intersected them with the DEGs, resulting in the identification of mitochondria-related DEGs (MIT-DEGs). To gain further insights, we performed functional enrichment and pathway analysis of the MIT-DEGs. To explore the interactions among these MIT-DEGs, we constructed a protein-protein interaction (PPI) network using the STRING database and identified hub genes using the Degree algorithm of Cytoscape software. To validate the relevance of these genes to nerve regeneration, we established a rat facial nerve injury (FNI) model and conducted a series of experiments. Through these experiments, we confirmed three MIT-DEGs (Myc, Lyn, and Cdk1) associated with facial nerve regeneration. Our findings provide valuable insights into the transcriptional changes of mitochondria-related genes in the FMN following FNI, which can contribute to the development of new treatment strategies for FNI.

HiC-ACT: improved detection of chromatin interactions from Hi-C data via aggregated Cauchy test.

Genome-wide chromatin conformation capture technologies such as Hi-C are commonly employed to study chromatin spatial organization. In particular, to identify statistically significant long-range chromatin interactions from Hi-C data, most existing methods such as Fit-Hi-C/FitHiC2 and HiCCUPS assume that all chromatin interactions are statistically independent. Such an independence assumption is reasonable at low resolution (e.g., 40 kb bin) but is invalid at high resolution (e.g., 5 or 10 kb bins) because spatial dependency of neighboring chromatin interactions is non-negligible at high resolution. Our previous hidden Markov random field-based methods accommodate spatial dependency but are computationally intensive. It is urgent to develop approaches that can model spatial dependence in a computationally efficient and scalable manner. Here, we develop HiC-ACT, an aggregated Cauchy test (ACT)-based approach, to improve the detection of chromatin interactions by post-processing results from methods assuming independence. To benchmark the performance of HiC-ACT, we re-analyzed deeply sequenced Hi-C data from a human lymphoblastoid cell line, GM12878, and mouse embryonic stem cells (mESCs). Our results demonstrate advantages of HiC-ACT in improving sensitivity with controlled type I error. By leveraging information from neighboring chromatin interactions, HiC-ACT enhances the power to detect interactions with lower signal-to-noise ratio and similar (if not stronger) epigenetic signatures that suggest regulatory roles. We further demonstrate that HiC-ACT peaks show higher overlap with known enhancers than Fit-Hi-C/FitHiC2 peaks in both GM12878 and mESCs. HiC-ACT, effectively a summary statistics-based approach, is computationally efficient (∼6 min and ∼2 GB memory to process 25,000 pairwise interactions).

Efficacy of TIL Therapy in Advanced Cutaneous Melanoma in the Current Immuno-oncology Era: Updated Systematic Review and Meta-analysis.

BACKGROUND: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL-ACT) has consistently shown efficacy in advanced melanoma. New results in the field provide now the opportunity to assess overall survival (OS) after TIL-ACT and to examine the effect of prior anti-PD-(L)1 therapy on its efficacy. METHODS: A comprehensive search was conducted in PubMed up to 29 February 2024. Ιn this meta-analysis we focused on studies including high-dose interleukin-2 (HD IL-2), doubling the patient numbers from our previous meta-analysis conducted up to December 20181 and using OS as the primary endpoint. Objective response rate (ORR), complete response rate (CRR) and duration of response (DOR) were secondary endpoints. Findings are synthesized using tables, Kaplan-Meier plots and forest plots. Pooled estimates for ORR and CRR were derived from fixed or random effect models. RESULTS: A total of 13 HD IL-2 studies were included in this updated meta-analysis, with OS information available for 617 patients. No difference was found in median OS between studies with prior anti-PD-(L)1 treatment [n=238; 17.5 months (95% confidence interval (CI):13.8-20.5)] and without [n=379; 16.3 months (95%CI:14.2-20.6)] (log-rank p=0.53). ORR was estimated to be 34% (95%CI:16%-52%) and 44% (95%CI:37%-51%), for the studies with and without prior anti-PD-(L)1, respectively. The pooled estimate for CRR was 10% for both groups. No statistically significant difference was observed between the two groups, either for ORR (p=0.15) or CRR (p=0.45). CONCLUSIONS: Prior anti-PD-(L)1 treatment has no effect on the clinical response or survival benefit from TIL-ACT in advanced cutaneous melanoma. The benefit of TIL therapy in the second-line setting is also present post anti-PD-(L)1 treatment. Our data reinforce the evidence that TIL-ACT should be considered as a treatment of choice in second-line for metastatic melanoma patients failing anti-PD-(L)1 therapy.

Is the price right? Paying for value today to get more value tomorrow.

BACKGROUND: Contemporary debates about drug pricing feature several widely held misconceptions, including the relationship between incentives and innovation, the proportion of total healthcare spending on pharmaceuticals, and whether the economic evaluation of a medicine can be influenced by things other than clinical efficacy. MAIN BODY: All citizens should have access to timely, equitable, and cost-effective care covered by public funds, private insurance, or a combination of both. Better managing the collective burden of diseases borne by today's and future generations depends in part on developing better technologies, including better medicines. As in any innovative industry, the expectation of adequate financial returns incentivizes innovators and their investors to develop new medicines. Estimating expected returns requires that they forecast revenues, based on the future price trajectory and volume of use over time. How market participants decide what price to set or accept can be complicated, and some observers and stakeholders want to confirm whether the net prices society pays for novel medicines, whether as a reward for past innovation or an incentive for future innovation, are commensurate with those medicines' incremental value. But we must also ask "value to whom?"; medicines not only bring immediate clinical benefits to patients treated today, but also can provide a broad spectrum of short- and long-term benefits to patients, their families, and society. Spending across all facets of healthcare has grown over the last 25 years, but both inpatient and outpatient spending has outpaced drug spending growth even as our drug armamentarium is constantly improving with safer and more effective medicines. In large part, this is because, unlike hospitals, drugs typically go generic, thus making room in our budgets for new and better ones, even as they often keep patients out of hospitals, driving further savings. CONCLUSION: A thorough evaluation of drug spending and value can help to promote a better allocation of healthcare resources for both the healthy and the sick, both of whom must pay for healthcare. Taking a holistic approach to assessing drug value makes it clear that a branded drug's value to a patient is often only a small fraction of the drug's total value to society. Societal value merits consideration when determining whether and how to make a medicine affordable and accessible to patients: a drug that is worth its price to society should not be rendered inaccessible to ill patients by imposing high out-of-pocket costs or restricting coverage based on narrow health technology assessments (HTAs). Furthermore, recognizing the total societal cost of un- or undertreated conditions is crucial to gaining a thorough understanding of what guides the biomedical innovation ecosystem to create value for society. It would be unwise to discourage the development of new solutions without first appreciating the cost of leaving the problems unsolved.

Medicaid expansion in California and breast cancer incidence across neighborhoods with varying social vulnerabilities.

PURPOSE: To investigate changes in breast cancer incidence rates associated with Medicaid expansion in California. METHODS: We extracted yearly census tract-level population counts and cases of breast cancer diagnosed among women aged between 20 and 64 years in California during years 2010-2017. Census tracts were classified into low, medium and high groups according to their social vulnerability index (SVI). Using a difference-in-difference (DID) approach with Poisson regression models, we estimated the incidence rate, incidence rate ratio (IRR) during the pre- (2010-2013) and post-expansion periods (2014-2017), and the relative IRR (DID estimates) across three groups of neighborhoods. RESULTS: Prior to the Medicaid expansion, the overall incidence rate was 93.61, 122.03, and 151.12 cases per 100,000 persons among tracts with high, medium, and low-SVI, respectively; and was 96.49, 122.07, and 151.66 cases per 100,000 persons during the post-expansion period, respectively. The IRR between high and low vulnerability neighborhoods was 0.62 and 0.64 in the pre- and post-expansion period, respectively, and the relative IRR was 1.03 (95% CI 1.00 to 1.06, p = 0.026). In addition, significant DID estimate was only found for localized breast cancer (relative IRR = 1.05; 95% CI, 1.01 to 1.09, p = 0.049) between high and low-SVI neighborhoods, not for regional and distant cancer stage. CONCLUSIONS: The Medicaid expansion had differential impact on breast cancer incidence across neighborhoods in California, with the most pronounced increase found for localized cancer stage in high-SVI neighborhoods. Significant pre-post change was only found for localized breast cancer between high and low-SVI neighborhoods.

Comparison of the Efficacy of Omalizumab and Mepolizumab in Non-Steroidal Anti-Inflammatory Drug-Exacerbated Respiratory Disease.

INTRODUCTION: Non-steroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is heterogeneous in both phenotypes and endotypes. Due to insufficient head-to-head comparison studies, it is hard to decide which biological to initiate. This study aimed to compare the efficacy of omalizumab and mepolizumab which can be used in the treatment of patients with severe eosinophilic asthma diagnosed with N-ERD. METHODS: The population of this observational, cross-sectional study comprised of N-ERD patients who received omalizumab or mepolizumab for at least 6 months for severe asthma. Outcomes included the asthma control test (ACT), and sino-nasal outcome test scores (SNOT-22), blood eosinophil counts at initiation of biological treatment (T0, baseline) and at the end of 6th months (T6). Adverse effects related to biological treatment and changes of oral corticosteroids dose was recorded. RESULTS: The study included a total of 22 patients, of whom 11 received mepolizumab and 11 received omalizumab. The change in ACT, SNOT-22, eosinophil counts, and adverse effects related to biologicals were similar at T6 (p = 0.606, p = 0.168, p = 0.05, p = 0.053, respectively). However, when examining the SNOT-22 and ACT based on the cumulative distribution curve (SUCRA), mepolizumab (SUCRA value: 0.61, 0.72, respectively) demonstrated greater efficacy compared to omalizumab (SUCRA value: 0.19, 0.35, respectively). The oral corticosteroids discontinuation rate was similar between the two groups (p = 0.05). CONCLUSION: We found both omalizumab and mepolizumab to be effective in treatment; however, we determined that mepolizumab may have a potential superiority in efficacy.

Precision breeding in agriculture and food systems in the United Kingdom.

In recent years there have been major advances in precision breeding technologies, such as gene editing, that offer promising solutions to revolutionise global crop production and tackle the pressing issues in food systems. The UK has leading expertise in genomics, and research is already taking place to develop crops with improved resilience to climate change, resistance to disease and less reliance on chemical inputs. In March 2023, the Genetic Technology (Precision Breeding) Act received Royal Assent and passed into UK law. It provides a framework from which to build more proportionate regulations for plants and animals made using genetic technologies which contain genetic changes that could also arise through traditional breeding-known as 'Precision Bred Organisms'. New legislation and the utilization of UK world-leading research could help to enhance the efficiency of breeding systems and enable the development of plants and animals that are healthier, better for the environment and more resilient to climate change.

Imbalance in the vWF - ADAMTS13 axis exists early in acute pancreatitis and predicts persistent organ failure and pancreatic necrosis-a prospective study.

BACKGROUND: The pathophysiology of Acute Pancreatitis (AP) may be complicated by endothelial activation. von Willebrand Factor (vWF)- ADAMTS13 axis is a marker of endothelial activation. The study aimed to investigate the axis in AP, comparing it in patients with and without persistent organ failure (OF), with and without pancreatic necrosis, and correlating it with the standard severity scores (CRP, APACHE II, BISAP, SOFA, and qSOFA) METHODS: vWF-Antigen (vWF:Ag), vWF-Collagen-Binding-Assay (vWF:CBA), and ADAMTS13 activity (ADAMTS13:act) levels were measured within 5 days of symptom onset in consecutive patients (n = 98), who were admitted with a first episode of AP (Dec 2021-May 2023). RESULTS: Of the 98 patients admitted with AP, 78(79.6 %) had no or transient OF; 20(20.4 %) had persistent OF. Age was comparable (43.73 ± 15.36 vs 38.65 ± 13.69) [mean ± SD](years), and males were predominant in both groups (70.5 % vs 80 %). Patientswith persistent OF had higher vWF:CBA(%)[323(279-486.5) vs 199.5(159.1-295.75)] and lower ADAMTS13:act(%)[35.4(23.8-56.85) vs 56.35(44.1-71.9)][median (25th - 75th percentile)](P = 0.001) than those with no or transient OF. Patients with pancreatic necrosis (n = 19) had lower ADAMTS13:act(%)[42.79 ± 18.69] than those without pancreatic necrosis (n = 18) [62.49 ± 22.64] (P < 0.01). ADAMTS13:act had a negative correlation(r = -0.2), whereas vWF:Ag and vWF:CBA had a positive correlation (r = 0.2) with the standard severity scores (P < 0.05). ADAMTS13:act could predict pancreatic necrosis [AUROC-0.737, P < 0.05] and persistent OF [AUROC-0.746, P < 0.001], while vWF:CBA could predict persistent OF [AUROC- 0.73, P < 0.001]. CONCLUSION: vWF-ADAMTS13 axis helps to predict severe disease and is associated with poor outcomes in acute pancreatitis.

Associations between pharmaceutical industry payments to physicians and prescription of PARP inhibitors in the United States.

PURPOSE: To evaluate the association between industry payments to physicians related to poly (ADP-ribose) polymerase inhibitors (PARPis) and physicians' prescribing behaviors for PARPis. METHODS: This panel-data analysis used the publicly accessible Open Payments Database and Medicare Part D database between 2017 and 2021. All physicians who reported >10 claims for either olaparib, rucaparib, or niraparib were included in this study. Non-research payments for the PARPis to the physicians from the PARPi manufacturers were extracted from the Open Payments Database. Associations between the physicians' receipt of payments and likelihood of prescribing PARPis were assessed with logistic generalized estimating equations (GEEs). Dose-response associations between the number of payments and prescription volumes and Medicare expenditures were evaluated with linear GEEs. RESULTS: Of the 1686 eligible physician prescribers, 68.7% received one or more non-research payments related to any of the three PARPis from the manufacturers between 2017 and 2021. Median annual payments per physician were $57 for olaparib, $39 for rucaparib, and $62 for niraparib. Receipt of payments for each PARPi was associated with higher odds of prescribing olaparib (odds ratio [OR]: 1.30 [95% CI: 1.14-1.48], p < 0.001), rucaparib (OR: 2.07 [95% CI: 1.58-2.72], p < 0.001), and niraparib (OR: 1.49 [95% CI: 1.22-1.81], p < 0.001). Dose-response effects were observed between the number of annual payments and the number of prescriptions and/or Medicare expenditures for olaparib and rucaparib. CONCLUSION: Non-research payments to physician prescribers of PARP inhibitors from the manufacturers were significantly associated with increased prescriptions and Medicare expenditures for olaparib and rucaparib in the United States.

Cost in the United States of FDA-approved small molecule protein kinase inhibitors used in the treatment of neoplastic and non-neoplastic diseases.

Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis of many illnesses, this enzyme family is the target of many drug discovery programs worldwide. The FDA has approved 80 small molecule protein kinase inhibitors with 77 drugs orally bioavailable. The data indicate that 69 of these medicinals are approved for the management of neoplasms including solid tumors such as breast and lung cancer as well as non-solid tumors such as leukemia. Moreover, the remaining 11 drugs target non-neoplastic diseases including psoriasis, rheumatoid arthritis, and ulcerative colitis. The cost of drugs was obtained from www.pharmacychecker.com using the FDA label to determine the dosage and number of tablets required per day. This methodology excludes any private or governmental insurance coverage, which would cover the entire cost or more likely a fraction of the stated price. The average monthly cost for the treatment of neoplastic diseases was $17,900 with a price of $44,000 for futibatinib (used to treat cholangiocarcinomas with FGFR2 fusions) and minimum of $5100 for binimetinib (melanoma). The average monthly cost for the treatment of non-neoplastic diseases was $6800 with a maximum of $17,000 for belumosudil (graft vs. host disease) and a minimum of $200 for netarsudil eye drops (glaucoma). There is a negative correlation of the cost of the drugs and the incidence of the targeted disease. Many of these agents are or were designated as orphan drugs meaning that there are fewer than 200,000 potential patients in the United States.