The impact of cannabis access laws on opioid prescribing.

While recent research has shown that cannabis access laws can reduce the use of prescription opioids, the effect of these laws on opioid use is not well understood for all dimensions of use and for the general United States population. Analyzing a dataset of over 1.5 billion individual opioid prescriptions between 2011 and 2018, which were aggregated to the individual provider-year level, we find that recreational and medical cannabis access laws reduce the number of morphine milligram equivalents prescribed each year by 11.8 and 4.2 percent, respectively. These laws also reduce the total days' supply of opioids prescribed, the total number of patients receiving opioids, and the probability a provider prescribes any opioids net of any offsetting effects. Additionally, we find consistent evidence that cannabis access laws have different effects across types of providers, physician specialties, and payers.

"Sorry" Is Never Enough: How State Apology Laws Fail to Reduce Medical Malpractice Liability Risk.

Based on case studies indicating that apologies from physicians to patients can promote healing, understanding, and dispute resolution, thirty-nine states (and the District of Columbia) have sought to reduce litigation and medical malpractice liability by enacting apology laws. Apology laws facilitate apologies by making them inadmissible as evidence in subsequent malpractice trials. The underlying assumption of these laws is that after receiving an apology, patients will be less likely to pursue malpractice claims and will be more likely to settle claims that are filed. However, once a patient has been made aware that the physician has committed a medical error, the patient's incentive to pursue a claim may increase even though the apology itself cannot be introduced as evidence. Thus, apology laws could lead to either increases or decreases in overall medical malpractice liability risk. Despite apology laws' status as one of the most widespread tort reforms in the country, there is little evidence that they achieve their goal of reducing litigation. This Article provides critical new evidence on the role of apology laws by examining a dataset of malpractice claims obtained directly from a large national malpractice insurer. This dataset includes substantially more information than is publicly available, and thus presents a unique opportunity to understand the effect of apology laws on the entire litigation landscape in ways that are not possible using only publicly available data. Decomposing medical malpractice liability risk into the frequency of claims and the magnitude of those claims, we examine the malpractice claims against 90% of physicians in the country who practice within a particular specialty over an eight-year period.

RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4/6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1.

KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer. In this study, we found that combinatory treatment with LY3009120 and abemaciclib synergistically inhibited proliferation of tumor cells in vitro and led to tumor growth regression in xenograft models with a KRAS, NRAS or BRAF mutation at the doses of two drugs that were well tolerated in combination. Further in vitro screen in 328 tumor cell lines revealed that tumor cells with KRAS, NRAS or BRAF mutation, or cyclin D activation are more sensitive, whereas tumor cells with PTEN, PIK3CA, PIK3R1 or retinoblastoma (Rb) mutation are more resistant to this combination treatment. Molecular analysis revealed that abemaciclib alone inhibited Rb phosphorylation partially and caused an increase of cyclin D1. The combinatory treatment cooperatively demonstrated more complete inhibition of Rb phosphorylation, and LY3009120 suppressed the cyclin D1 upregulation mediated by abemaciclib. These results were further verified by CDK4/6 siRNA knockdown. Importantly, the more complete phospho-Rb inhibition and cyclin D1 suppression by LY3009120 and abemaciclib combination led to more significant cell cycle G0/G1 arrest of tumor cells. These preclinical findings suggest that combined inhibition of RAF and d-cyclin-dependent kinases might provide an effective approach to treat patients with tumors harboring mutations in RAS or RAF genes.

Anticipating the Unintended Consequences of Closing the Door on Physician Self-Referral.

PURPOSE: While physician self-referral has been associated with increased health care use, the downstream effects of the practice remain poorly characterized. Accordingly we identified the relationship between urologist self-referral and downstream health care use in patients with urinary stone disease. MATERIALS AND METHODS: With urologist self-referral status as the exposure of interest, we performed a retrospective cohort study of Medicare beneficiaries from 2008 to 2010 to evaluate the relationship between self-referral and imaging intensity, risk of surgical treatment and time to surgical treatment for urinary stone disease. RESULTS: We identified dose dependent increases in computerized tomography use with increasing stratum of urologist self-referral. Compared to nonself-referring urologists, computerized tomography use was 1.19 times higher (95% CI 1.07-1.34) in episodes ascribed to intermediate frequency (5 to 9) and 1.32 times higher (95% CI 1.16-1.50) in episodes ascribed to high frequency (10+) self-referring urologists. Self-referral was inversely associated with risk of surgical treatment for stone disease. Specifically, patients treated by intermediate and high frequency self-referring urologists were less likely to undergo surgical treatment than those treated by nonself-referring urologists, with HR 0.84 (95% CI 0.71-0.99) and HR 0.81 (95% CI 0.66-0.99), respectively. We identified no statistically significant between-group differences in time to surgical treatment. CONCLUSIONS: Self-referral is associated with increased use of computerized tomography and with decreased use of surgery for stone disease. While policy efforts to further restrict physician self-referral may reduce the use of computerized tomography, they may also result in unintended consequences with respect to patterns of surgical care.

Long-term functional outcomes after treatment for localized prostate cancer.

BACKGROUND: The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy. METHODS: The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment. RESULTS: Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence was noted at 15 years. Similarly, although patients undergoing prostatectomy were more likely to have erectile dysfunction at 2 years (odds ratio, 3.46; 95% CI, 1.93 to 6.17) and 5 years (odds ratio, 1.96; 95% CI, 1.05 to 3.63), no significant between-group difference was noted at 15 years. Patients undergoing prostatectomy were less likely to have bowel urgency at 2 years (odds ratio, 0.39; 95% CI, 0.22 to 0.68) and 5 years (odds ratio, 0.47; 95% CI, 0.26 to 0.84), again with no significant between-group difference in the odds of bowel urgency at 15 years. CONCLUSIONS: At 15 years, no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy. Nonetheless, men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up. (Funded by the National Cancer Institute.).

Antialiasing procedural shaders with reduction maps.

Both image textures and procedural textures suffer from minification aliasing, however, unlike image textures, there is no good automatic method to anti-alias procedural textures. Given a procedural texture on a surface, we present a method that automatically creates an anti-aliased version of the procedural texture. The new procedural texture maintains the original texture's details, but reduces minification aliasing artifacts. This new algorithm creates a pyramid similar to MIP-Maps to represent the texture. Instead of storing per-texel color, our texture hierarchy stores weighted sums of reflectance functions, allowing a wider range of effects to be anti-aliased. The stored reflectance functions are automatically selected based on an analysis of the different reflectances found over the surface. When the texture is viewed at close range, the original texture is used, but as the texture footprint grows, the algorithm gradually replaces the texture's result with an anti-aliased one.

Paternal effects on offspring fitness in a multimale primate society.

When females mate with multiple males, paternal care is generally expected to be negligible, because it may be difficult or impossible for males to discriminate their own offspring from those of other males, and because engaging in paternal care may reduce male mating opportunities. Consequently, males in multimale societies are not predicted to provide direct benefits to their offspring. We have recently demonstrated, however, that males in a typical multimale primate society (yellow baboons, Papio cynocephalus) discriminate their own offspring from those of other males and provide care to them in the form of repeated support during agonistic encounters. This observation raises the question of whether fathers enhance offspring fitness in this species. Here we use 30 years of data on age at maturity for 118 yellow baboons with known fathers. We show that the father's presence in the offspring's social group during the offspring's immature period accelerated the timing of physiological maturation in daughters. Sons also experienced accelerated maturation if their father was present during their immature period, but only if the father was high ranking at the time of their birth. Because age at reproductive maturity has a large impact on lifetime reproductive success, our results indicate a direct effect of paternal presence on offspring fitness. This relationship in turn suggests that the multiple roles that males play in multimale animal societies have not been sufficiently examined or appreciated and that paternal effects may be more pervasive than previously appreciated.

Valuing hospital investment in information technology: does governance make a difference?

This article examines the investment of patient care information technology (IT) systems by a nationwide sample of U.S. short-term acute care hospitals and the resulting impact these systems have in the productivity of institutions from 1990-1998. Of particular interest is the extent to which for-profit and not-for-profit hospitals obtain different results from the adoption of lT systems. We find that the marginal effect of IT on for-profit hospital productivity is to reduce the number of days supplied, while in not-for-profit hospitals the marginal effect of IT is to increase the quantity of services supplied. This resulting effect is consistent with the differing objectives of not-for-profit and for-profit hospitals and demonstrates the positive marginal value of IT as a sustainable and prudent investment.

How do nonprofit hospitals manage earnings?

We hypothesize that, unlike for-profit firms, nonprofit hospitals have incentives to manage earnings to a range just above zero. We consider two ways managers can achieve this. They can adjust discretionary spending [Hoerger, T.J., 1991. 'Profit' variability in for-profit and not-for-profit hospitals. Journal of Health Economics 10, 259-289.] and/or they can adjust accounting accruals using the flexibility inherent in Generally Accepted Accounting Principles (GAAP). To test our hypothesis we use regressions as well as tests of the distribution of earnings by Burgstahler and Dichev [Burgstahler, D., Dichev, I., 1997. Earnings management to avoid earnings decreases and losses. Journal of Accounting and Economics 24, 99-126.] on a sample of 1,204 hospitals and 8,179 hospital-year observations. Our tests support the use of discretionary spending and accounting accrual management. Like Hoerger (1991), we find evidence that nonprofit hospitals adjust discretionary spending to manage earnings. However, we also find significant use of discretionary accruals (e.g., adjustments to the third-party-allowance, and allowance for doubtful accounts) to meet earnings objectives. These findings have two important implications. First, the previous evidence by Hoerger that nonprofit hospitals show less variation in income may at least partly be explained by an accounting phenomenon. Second, our findings provide guidance to users of these financial statements in predicting the direction of likely bias in reported earnings.

Abnormal returns and the regulation of nonprofit hospital sales and conversions.

During the 1990s, concerns that nonprofit (NP) hospitals were being sold at below-market prices to investor-owned (IO) chains helped to prompt the widespread adoption of state laws regulating the sale and conversion of nonprofits. In this paper, we provide a simple test of under-pricing using the IO acquirer's abnormal stock market returns at the time of the acquisition. Prior to regulation, we find that IO chains did not earn abnormal returns from their acquisitions of NPs and earned greater returns from purchasing other IO and privately owned hospitals. In states that subsequently adopted regulations, acquisition activity slowed significantly and acquirer returns became negative. Efficient markets theory suggests that, absent regulation, expected merger synergies were already being transferred to the NP target and that regulation may have reduced expected synergies or increased the costs of acquiring NP hospitals.

Mycobacteria induces pleural mesothelial permeability by down-regulating beta-catenin expression.

Patients with pulmonary tuberculosis develop pleural effusions with a high protein content. Pleural mesothelial adherens junctions promote mesothelial cell-cell adhesion and contribute to pleural integrity. In the present study we have investigated the effect of mycobacterium (BCG) on mesothelial cell adherens junction proteins and pleural permeability. BCG enhanced pleural mesothelial cell (PMC) release of vascular endothelial growth factor (VEGF), and decreased electrical resistance across the PMC monolayer. Neutralizing antibodies to VEGF significantly restored the drop in PMC electrical resistance caused by BCG. BCG infection down regulated beta-catenin (adherens junction protein) expression and caused increased permeability across confluent mesothelial monolayer. Our results suggest that in TB pleurisy, mycobacteria cause VEGF release from mesothelial cells and leads to protein exudation by altering mesothelial adherens junction proteins.

Longitudinal studies of Sin Nombre virus in deer mouse-dominated ecosystems of Montana.

Sin Nombre virus (SNV), hosted by the deer mouse (Peromyscus maniculatus), is the primary etiologic agent of Hantavirus pulmonary syndrome (HPS) in North America. To improve our understanding of the epidemiology of HPS in the western United States, we conducted studies of population dynamics and SNV antibody prevalence in deer mouse populations for 6 years on 12 mark-recapture grids in Montana. Monthly numbers of deer mice ranged from zero to over 170 on 1-hectare grids. SNV antibody prevalence was higher than observed in studies in other parts of the United States, averaging 13% (0% to 50%), and peaking in May or June each year. Antibody-positive mice were older (heavier) (78% of positives were adults versus 52% of negatives) and more likely to be males (61% of positives versus 53.4% of negatives). A higher proportion of antibody-positive deer mice of all age-mass classes had scars than did antibody-negative mice. Month-to-month survivorship of antibody-positive adult mice was similar to that of antibody-negative mice, but survival of young antibody-positive deer mice was lower than antibody-negative deer mice. This is the first study to clearly suggest a detrimental effect of SNV infection on deer mice.

Polar production of interleukin-8 by mesothelial cells promotes the transmesothelial migration of neutrophils: role of intercellular adhesion molecule-1.

Migration of polymorphonuclear neutrophils (PMNL) from the vascular compartment into the pleural space occurs rapidly during the development of parapneumonic effusions. This study investigated the polarized secretion of interleukin (IL)-8 in activated pleural mesothelial cells (PMC) and the migration of PMNL across resting, activated PMC monolayers. Results show that PMC produce IL-8 in a polar manner. When PMC were stimulated with Staphylococcus aureus or IL-1beta at the basal or at the apical surface, significantly (P< .05) more IL-8 was released toward the apical surface. This polarized production of IL-8 was confirmed by in situ hybridization. PMNL migration was higher from the basilar to apical than from the apical to basilar surface of PMC. Neutralizing antibodies against IL-8 and intercellular adhesion molecule (ICAM)-1 significantly (P< .001) blocked PMNL migration across activated monolayers. Thus, during pleural inflammation, PMC regulate the influx of PMNL into the pleural space by polar production of IL-8 and expression of ICAM-1.

Noninvasive blood pressure performance: a reproducible method for quantifying motion artifact tolerance in oscillometry.

Motion artifact tends to degrade oscillometric noninvasive blood pressure measurement (NIBP) accuracy and other aspects of performance (measurement time, patient comfort, false-positive readings). Medical personnel generally have not fully appreciated the extent of these degradations, in part because NIBP provides no waveform display to allow visualization of artifact disruption (unlike the electrocardiography (ECG) and pulse oximetry (SpO2) patient channels). More importantly, the magnitude and frequency of NIBP errors has also gone unappreciated because the auditory noise produced by transport vibration prevents accurate quantification of NIBP accuracy by the traditional auscultatory method. To overcome these problems, a commercially available NIBP simulator was modified to permit the superimposition of repeatable motion artifact waveforms from a function generator onto known patient blood pressure profiles available in the NIBP simulator. The superimposed artifact waveforms had been collected under transport conditions. This methodology enabled comparisons between artifact-free NIBP readings, on the one hand, and artifact-contaminated readings on the other. Monitors under test were subjected to multiple combinations of patient and artifact profiles. Measurement errors were expressed as a percent deviation of the artifact-contaminated readings from the expected (artifact-free) readings. Statistical analyses of the data compared the performance of the different monitor types with nonparametric tests of inference (Kruskal-Wallis H test, Mann-Whitney U test, and chi-squared test). These analyses demonstrated statistically significant differences in performance including accuracy, yield (incidence of values within various error categories), retries, measurement time, and false-positive readings under artifact-only conditions. The method further demonstrated that the monitor using ECG synchronization to filter motion artifact achieved statistically and clinically significant improvements in accuracy without compromising clinical expectations for measurement time. This approach provided a reproducible and quantifiable method by which to assess and differentiate the artifact tolerance of different NIBP technologies.

Health maintenance organizations and hospital quality for coronary artery bypass surgery.

This study uses hospital discharge data for 1992-1994 to assess differences between HMO and insured non-HMO patients in California and Florida with regard to the quality of the hospitals used for coronary artery bypass graft (CABG) surgery. The authors found that commercially insured HMO patients in California used higher quality hospitals than commercially insured non-HMO patients, controlling for patient distance to the hospital. In contrast, commercially insured HMO and non-HMO patients in Florida were similarly distributed across hospitals of different quality levels, whereas Medicare HMO patients in Florida used lower quality hospitals than patients in the standard Medicare program. The authors conclude that the association between HMO coverage and hospital quality may differ across geographic areas and patient populations, possibly related to the maturity and structure of managed care markets.

The impact of physician involvement in managed care on efficient use of hospital resources.

OBJECTIVES: This research assesses the impact of managed care on the physician's efficient use of hospital resources. It examines three questions. (1) Does a higher percentage and volume of managed care patients in the physician's hospital practice lead to more efficient utilization? (2) Do physicians shift cost to nonmanaged care patients in an effort to compensate for lower reimbursement for managed care patients? (3) Are there threshold effects in the percentage and volume of managed care patients treated by physicians? METHODS: The study combines patient discharge data from the state of Arizona with physician and hospital data for a 2-year period. Random effects maximum likelihood (REML) regressions were performed for four different diagnosis classifications to examine the effect of the physician's managed care caseload on mean-adjusted charges and length of stay. RESULTS: The findings suggest that physicians with high percentages and volumes of managed care patients in their hospital practice are more efficient in using hospital resources. The findings also suggest that physicians may compensate for the lower reimbursement from managed care patients by increasing their resource use among non-health maintenance organization patients. CONCLUSIONS: Finally, there appears to be a threshold effect of managed care activity on the physician's hospital utilization in one of the conditions studied.

Hantavirus in Montana deer mouse populations: preliminary results.

Dynamics of small mammal populations and the prevalence of antibodies for hantavirus were determined in six locations in central and western Montana (USA). Eighteen live-trapping grids were trapped monthly from June through September 1994. Deer mouse (Peromyscus maniculatus) populations ranged from 0 to over 90 on one-hectare grids. Our bleeding technique had no apparent effect on survival of deer mice. Deer mice, meadow voles (Microtus pennsylvanicus), and sagebrush voles (Lagurus curtatus) were seropositive. Thirty-eight (8%) (range, 0% to 30%) of 471 deer mice were seropositive for hantavirus antibodies. Seropositive mice were older and had lower monthly survival rates than seronegative deer mice. We found no relationship between prevalence of hantavirus antibodies and population density.

Characterization of the metabolites of the peptidomimetic human immunodeficiency virus type 1 protease inhibitor SK&F 107461 in rats using liquid chromatography/mass spectrometry.

The metabolic fate of SK&F 107461 [Cbz-Ala-Ala-Phe psi [CHOHCH2] Gly-Val-Val-OMe], a potent and specific inhibitor of the protease encoded by human immunodeficiency virus type 1, in male Sprague-Dawley rats is described. SK&F 107461 is a hexapeptide analog containing a hydroxyethylene linkage in place of one of the peptide bonds, and in which the amino terminus is blocked with a carbobenzyloxy group and the carboxy terminus is modified to a methyl ester. The major metabolites of SK&F 107461 found in bile and urine after intravenous administration of 3H-labeled compound were characterized by LC/MS using either thermospray or continuous flow/FAB models of ionization. Approximately 80% of the administered radioactivity was recovered in the bile of bile duct-exteriorized rats following an intravenous dose. Radiochromatographic profiling indicated that SK&F 107461 was subject to extensive biotransformation. Structures were determined for three major biliary and five major urinary metabolites. Two of the major circulating plasma metabolites observed after intravenous bolus administration had similar retention times to metabolites that were observed in both bile and urine. A pathway for the biotransformation of SK&F 107461 in the rat is proposed. The parent molecule underwent two primary modes of metabolism. Hydrolysis of the carboxy-terminal ester or hydrolysis of the Ala-Ala peptide bond near the amino terminus were the primary metabolic events. All of the other metabolites characterized can be accounted for by exopeptidase activity subsequent to one or both of these primary events. There were no major metabolites observed resulting from anything other than hydrolysis of the ester or peptide bonds in the parent molecule.

Health and the welfare of U.S. business.

Business leaders continue to blame the skyrocketing cost of health care for jeopardizing the global competitiveness of U.S. industries, and they continue to turn to Washington for the solution. Yet after a study of 16 countries, Wharton researchers David Brailer and R. Lawrence Van Horn have discovered that health care costs do not directly hinder U.S. competitiveness. Their conclusion: there is indeed a health care crisis in the United States as well as a competitiveness crisis. But the two are unrelated, and confusing them makes it difficult to solve either one. The real problem, according to the authors, is the hands-off approach that employers typically adopt when it comes to health care. No matter how Washington responds to the health care crisis, employers must explore their own role in ensuring the health of their work force. And they must realize that their role can be a strategic one. Instead of containing costs by fine-tuning benefits packages, companies can control costs and improve health care delivery by treating health care like any other crucial component of production. Brailer and Van Horn propose three strategies for managing health care delivery: First, companies must intervene in the supply side of the health care market. This may mean creating a clinic alone or with other companies, or joining with other companies to procure health care. Second, companies need to translate corporate health benefits into the most cost-effective set of services at the local level. Finally, companies must encourage and educate employees to participate in decisions regarding health care delivery.(ABSTRACT TRUNCATED AT 250 WORDS)