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Localized stress concentrations at fiber ends in short fiber-reinforced polymer composites (SFRCs) significantly affect their mechanical properties. Our research targets these stress concentrations by embedding nitro-spiropyran (SPN) mechanophores into the polymer matrix. SPN mechanophores change color under mechanical stress, allowing us to visualize and quantify stress distributions at the fiber ends. We utilize glass fibers as the reinforcing material and employ confocal fluorescence microscopy to detect color changes in the SPN mechanophores, providing real-time insights into the stress distribution. By combining this mechanophore-based stress sensing with finite element analysis (FEA), we evaluate localized stresses that develop during a single fiber pull-out test near different fiber end geometries-flat, cone, round, and sharp. This method precisely quantifies stress distributions for each fiber end geometry. The mechanophore activation intensity varies with fiber end geometry and pull-out displacement. Our results indicate that round fiber ends exhibit more gradual stress transfer into the matrix, promoting effective stress distribution. Also, different fiber end geometries lead to distinct failure mechanisms. These findings demonstrate that fiber end geometry plays a crucial role in stress distribution management, critical for optimizing composite design and enhancing the reliability of SFRCs in practical applications. By integrating mechanophores for real-time stress visualization, we can accurately map quantified stress distributions that arise during loading and identify failure mechanisms in polymer composites, offering a comprehensive approach to enhancing their durability and performance.

Objective: Opioid overdose is a public health epidemic adversely impacting individuals and communities. To combat this, California passed a law mandating that prescribers offer a naloxone prescription in certain circumstances. Our objective was to evaluate associations with California's naloxone prescription mandate and emergency department (ED) overdose visits/hospitalizations, opioid and naloxone prescribing, and 30-day mortality., Methods: This retrospective cohort study included data from January 1, 2018, to December 31, 2019, and included all Kaiser Permanente Southern California (KPSC) members aged >10 years across 15 KPSC EDs. Exposure was defined as presentation to the ED within the study period. The primary outcome was ED visits for opioid overdose pre- and post-implementation of California's naloxone prescription mandate., Results: A total of 1.1 million ED visits (534K pre/576K post) were included in the study population. ED opioid overdose visits were 344 (6.4/10,000) pre-policy and 351 (6.1/10,000) post-policy implementation, while non-opioid overdose visits were 309 (5.8/10,000) pre-implementation and 411 (7.1/10,000) post-implementation. The unadjusted rate of visits with opioid prescriptions decreased significantly (14.9% pre to 13.5% post) after implementation. ED naloxone prescriptions increased substantially (104 pre vs. 6031 post). Primary adjusted interrupted time series analysis found no statistical difference between monthly opioid overdose visits pre versus post (odds ratio 1.02, 95% confidence interval [CI] 0.98‒1.07). Difference-in-differences analysis revealed no significant changes in hospitalization (coefficient [CE] = ‒0.05, 95% CI = ‒0.11 to 0.02) or 30-day mortality (CE = ‒0.01, 95% CI = ‒0.03 to 0.01)., Conclusion: This study revealed that the implementation of California's naloxone prescription mandate was associated with significantly increased naloxone prescribing and decreased opioid prescribing, but no significant change in ED opioid overdose visits, hospitalizations, or 30-day mortality. This indicates that increasing naloxone prescribing alone may not be sufficient to lower opioid overdose rates., Competing Interests: The authors declare they have no conflicts of interest., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Background: U.S. state electronic prescription drug monitoring programs (PDMPs) are associated with reduced opioid dispensing among people with chronic pain and may impact use of other chronic pain treatments. In states with medical cannabis laws (MCLs), patients can use cannabis for chronic pain management, reducing their need for chronic-pain related treatment visits and moderating effects of PDMP laws., Objective: Given high rates of chronic pain among Medicaid enrollees, we examined associations between PDMP enactment in the presence or absence of MCL on chronic pain-related outpatient and emergency department (ED) visits., Design: We created annual cohorts of Medicaid enrollees with chronic pain diagnoses using national Medicaid claims data from 2002-2013 and 2016. Negative binomial hurdle models produced adjusted odds ratios (aOR) for the likelihood of any chronic pain-related outpatient or ED visit and incident rate ratios (IRR) for the rate of visits among patients with ≥ 1 visit., Participants: Medicaid enrollees aged 18-64 years with chronic pain (N = 4,878,462)., Main Measures: A 3-level state-year variable with the following categories: 1) no PDMP, 2) PDMP enactment in the absence of MCL, or 3) PDMP enactment in the presence of MCL. Healthcare codes for chronic pain-related outpatient and ED visits each year., Key Results: The sample was primarily female (67.2%), non-Hispanic White (51.2%), and ages 40-55 years (37.2%). Compared to no-PDMP states, PDMP enactment in the absence of MCL was not associated with chronic pain-related outpatient visits but PDMP enactment in the presence of MCL was associated with lower odds of chronic pain-related outpatient visits (aOR = 0.81, 95% CI:0.71-0.92). PDMP enactment was not associated with ED visits, irrespective of MCL., Conclusions: During a period of PDMP and MCL expansion, our findings suggest treatment shifts for persons with chronic pain away from outpatient settings, potentially related to increased use of cannabis for chronic pain management., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Despite efforts to expand naloxone access, opioid-related overdoses remain a significant contributor to mortality. We study state efforts to expand naloxone distribution through pharmacies by reducing the non-monetary costs to prescribers, dispensers, and/or potential recipients of naloxone. We find that laws that only address liability costs have small and insignificant effects on the volume of naloxone dispensed through pharmacies. In contrast, we estimate large effects of laws removing the need for patients to obtain prescriptions from traditional prescribers (e.g., primary care physicians): laws authorizing non-patient-specific prescription distribution and laws granting pharmacists prescriptive authority. We test whether areas designated as primary care shortage areas-where it would be costlier to obtain a prescription-were disproportionately impacted. Shortage areas experienced sharper growth in pharmacy naloxone dispensing in states adopting prescriptive authority policies. These gains were primarily due to those facing low out-of-pocket costs, suggesting that price barriers also must be addressed to increase naloxone purchases., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 RAND Corporation. Published by Elsevier B.V. All rights reserved.)

Mandatory prescription drug monitoring programs and cannabis legalization have been hypothesized to reduce overdose deaths. We examined associations between prescription monitoring programs with access mandates ("must-query PDMPs"), legalization of medical and recreational cannabis supply, and opioid overdose deaths in United States counties in 2013-2020. Using data on overdose deaths from the National Vital Statistics System, we fit Bayesian spatiotemporal models to estimate risk differences and 95% credible intervals (CrI) in county-level opioid overdose deaths associated with enactment of these state policies. Must-query PDMPs were independently associated with on average 0.8 (95% CrI: 0.5, 1.0) additional opioid-involved overdose deaths per 100,000 person-years. Legal cannabis supply was not independently associated with opioid overdose deaths in this time period. Must-query PDMPs enacted in the presence of legal (medical or recreational) cannabis supply were associated with 0.7 (95% CrI: 0.4, 0.9) more opioid-involved deaths, relative to must-query PDMPs without any legal cannabis supply. In a time when overdoses are driven mostly by non-prescribed opioids, stricter opioid prescribing policies and more expansive cannabis legalization were not associated with reduced overdose death rates., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pulmonary disorders affect 40%-80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragm muscle weakness. Increased intradiaphragmatic adiposity and extracellular matrix (ECM) content correlate with reductions in contractile force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein linked with muscular damage in genetic myopathies. THBS1 induces proliferation of fibro-adipogenic progenitors (FAPs) - mesenchymal cells that differentiate into adipocytes and fibroblasts. We hypothesized that THBS1 drives FAP-mediated diaphragm remodeling and contractile dysfunction in DIO. We tested this by comparing the effects of dietary challenge on diaphragms of wild-type (WT) and Thbs1-knockout (Thbs1-/-) mice. Bulk and single-cell transcriptomics demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs displayed upregulation of ECM and TGF-β-related expression signatures and augmentation of a Thy1-expressing subpopulation previously linked to type 2 diabetes. Despite similar weight gain, Thbs1-/- mice were protected from these transcriptomic changes and from obesity-induced increases in diaphragm adiposity and ECM deposition. Unlike WT controls, Thbs1-/- diaphragms maintained normal contractile force and motion after DIO challenge. THBS1 is therefore a necessary mediator of diaphragm stromal remodeling and contractile dysfunction in overnutrition and a potential therapeutic target in obesity-associated respiratory dysfunction.

Introduction: The crisis of drug-related harm in the United States continues to worsen. While prescription-related overdoses have fallen dramatically, they are still far above pre-2010 levels. Physicians can reduce the risk of overdose and other drug-related harms by improving opioid prescribing practices and ensuring that patients are able to easily access medications for substance use disorder treatment. Most physicians received little or no training in those subjects in medical school. It is possible that continuing medical education can improve physician knowledge of appropriate prescribing and substance use disorder treatment and patient outcomes., Methods: Descriptive legal review. Laws in all 50 states and the District of Columbia were searched for provisions that require all or most physicians to receive either one-time or continuing medical education regarding controlled substance prescribing, pain management, or substance use disorder treatment., Results: There has been a rapid increase in the number of states with relevant requirements, from three states at the end of 2010 to 42 at the end of 2020. The frequency and duration of required education varied substantially across states. In all states, the number of hours required in relevant topics is a small fraction of overall required continuing education, an average of 1 h per year. Despite recent shifts in the substances driving overdose, most requirements remain focused on opioids., Conclusion: While most states have now adopted continuing education requirements regarding controlled substance prescribing, pain management, or substance use disorder treatment, these requirements comprise a small component of the required post-training education requirements. Research is needed to determine whether this training translates into reductions in drug-related harm., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self-administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. PLAIN LANGUAGE SUMMARY: Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The United States (US) opioid epidemic is a persistent and pervasive public health emergency that claims the lives of over 80,000 Americans per year as of 2021. There have been sustained efforts to reverse this crisis over the past decade, including a number of measures designed to decrease the use of prescription opioids for the treatment of pain. This study analyzed the changes in federal production quotas for prescription opioids and the distribution of prescription opioids for pain and identified state-level differences between 2010 and 2019. Data (in grams) on opioid production quotas and distribution (from manufacturer to hospitals, retail pharmacies, practitioners, and teaching institutions) of 10 prescription opioids (codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, and tapentadol) for 2010 to 2019 were obtained from the US Drug Enforcement Administration. Amounts of each opioid were converted from grams to morphine milligram equivalent (MME), and the per capita distribution by state was calculated using population estimates. Total opioid production quotas increased substantially from 2010 to 2013 before decreasing by 41.5% from 2013 (87.6 MME metric tons) to 2019 (51.3). The peak year for distribution of all 10 prescription opioids was between 2010 and 2013, except for codeine (2015). The largest quantities of opioid distribution were observed in Tennessee (520.70 MME per person) and Delaware (251.45) in 2011 and 2019. There was a 52.0% overall decrease in opioid distribution per capita from 2010 to 2019, with the largest decrease in Florida (-61.6%) and the smallest in Texas (-18.6%). Southern states had the highest per capita distribution for eight of the ten opioids in 2019. The highest to lowest state ratio of total opioid distribution, corrected for population, decreased from 5.25 in 2011 to 2.78 in 2019. The mean 95th/5th ratio was relatively consistent in 2011 (4.78 ± 0.70) relative to 2019 (5.64 ± 0.98). This study found a sustained decline in the distribution of ten prescription opioids during the last five years. Distribution was non-homogeneous at the state level. Analysis of state-level differences revealed a fivefold difference in the 95th:5th percentile ratio between states, which has remained unchanged over the past decade. Production quotas did not correspond with the distribution, particularly in the 2010-2016 period. Future research, focused on identifying factors contributing to the observed regional variability in opioid distribution, could prove valuable to understanding and potentially remediating the pronounced disparities in prescription opioid-related harms in the US.

For acute treatment of seizure clusters in patients with epilepsy, intranasal administration of acute seizure therapies has been shown to provide accessibility and ease of use to care partners as well as the potential for self-administration by patients. Diazepam nasal spray (Valtoco®) was approved by the US Food and Drug Administration for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Self-administration consistent with the prescribing information is feasible and was reported by a subgroup of patients (n = 27 of 163) in a long-term phase 3 safety study. Data regarding self-administration among these patients with seizure clusters are examined here to explore the safety profiles and measures of effectiveness, as well as the quality of life of those who self-treated. In addition, this focused look at patients who self-administered diazepam nasal spray may offer some insights into the characteristics of patients who may be appropriate for self-administration., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Misra was an employee of Neurelis, Inc., at the time of the development of this manuscript and has received stock options from Neurelis, Inc. Dr Sperling has received compensation for speaking at continuing medical education programs from Medscape, Projects for Knowledge, International Medical Press, and UCB Pharma. He has consulted for Medtronic; Neurelis, Inc.; and Johnson & Johnson. He has received research support from Eisai; Medtronic; Neurelis, Inc.; SK Life Science; Takeda; Xenon; Cerevel; UCB Pharma; Janssen; and Engage Pharmaceuticals. He receives royalties from Oxford University Press and Cambridge University Press. Dr Rao has served as a consultant for NeuroPace, Inc., manufacturer of the RNS® System. Dr Peters has served as a speaker and consultant for Neurelis, Inc.; SK Life Science; and Jazz Pharmaceuticals. Dr Penovich has served on speakers bureaus for Jazz Pharmaceuticals; Neurelis, Inc.; and UCB Pharma, and is an advisor to LVIS Corporation and Neurelis, Inc. Dr Wheless has served as an advisor or consultant for CombiMatrix; Eisai Inc.; GW Pharmaceuticals; Lundbeck, Inc.; Neurelis, Inc.; NeuroPace, Inc.; Supernus Pharmaceuticals, Inc.; and Upsher-Smith Laboratories, Inc. Dr. Wheless has served as a speaker or a member of a speakers bureau for: Cyberonics, Inc.; Eisai Inc.; Lundbeck, Inc.; Mallinckrodt; Neurelis, Inc.; Supernus Pharmaceuticals, Inc.; Upsher-Smith Laboratories, Inc., and has received grants for clinical research from Acorda Therapeutics; GW Pharmaceuticals; and INSYS. Dr Hogan has received research support from UCB Pharmaceuticals, Neurelis, Inc; and Biogen Inc, and is an advisor for Neurelis, Inc. Dr Davis is a consultant to Neurelis, Inc. Dr Carrazana is an employee of and received stock and stock options from Neurelis, Inc. Dr Rabinowicz is an employee of and has received stock options from Neurelis, Inc., (© 2024 The Authors. Published by Elsevier Inc.)

Importance: Two states modified laws to remove or substantially reduce criminal penalties for any drug possession. The hypothesis was that removing criminal penalties for drug possession may reduce fatal drug overdoses due to reduced incarceration and increased calls for help at the scene of an overdose., Objective: To evaluate whether decriminalization of drug possession in Oregon and Washington was associated with changes in either direction in fatal drug overdose rates., Design, Setting, and Participants: This cohort study used a synthetic control method approach to examine whether there were changes in drug possession laws and fatal drug overdose rates in Oregon and Washington in the postpolicy period (February 1, 2021, to March 31, 2022, in Oregon and March 1, 2021, to March 31, 2022, in Washington). A counterfactual comparison group (synthetic controls) was created for Oregon and Washington, using 48 states and the District of Columbia, that did not implement similar policies during the study period (January 1, 2018, to March 31, 2022). For 2018-2021, final multiple cause-of-death data from the National Vital Statistics System (NVSS) were used. For 2022, provisional NVSS data were used. Drug overdose deaths were identified using International Statistical Classification of Diseases and Related Health Problems, 10th Revision underlying cause-of-death codes X40-X44, X60-X64, X85, and Y10-Y14., Exposures: In Oregon, Measure 110 went into effect on February 1, 2021. In Washington, the Washington Supreme Court decision in State v Blake occurred on February 25, 2021., Main Outcome: Monthly fatal drug overdose rates., Results: Following the implementation of Measure 110, absolute monthly rate differences between Oregon and its synthetic control were not statistically significant (probability = 0.26). The average rate difference post Measure 110 was 0.268 fatal drug overdoses per 100 000 state population. Following the implementation of the policy change in Washington, the absolute monthly rate differences between Washington and synthetic Washington were not statistically significant (probability = 0.06). The average rate difference post Blake was 0.112 fatal drug overdoses per 100 000 state population., Conclusions and Relevance: This study found no evidence of an association between legal changes that removed or substantially reduced criminal penalties for drug possession in Oregon and Washington and fatal drug overdose rates. Additional research could examine potential other outcomes as well as longer-term associations with fatal drug overdose overall and across racial and ethnic groups.

Background: In the United States, methadone treatment for opioid use disorder is only available at opioid treatment programs (OTPs). In addition to federal regulations, states can enact laws which shape access to OTPs. We aimed to define classes of states according to restrictiveness of state OTP laws and examine population characteristics associated with class membership., Methods: A set of laws was extracted from a database of statutes and regulations governing OTPs in 49 states and the District of Columbia as of June 2021. Latent class analysis of laws was used to estimate the probability of class membership for each state. Class-weighted multinomial logistic regression analysis assessed state-level correlates of class membership and adjusted Relative Risk Ratio (aRRR) and 95% confidence intervals (95%CI) were generated., Results: States (n = 50) were assigned to three classes; Class 1) High restrictiveness on patient experience, low restrictiveness on access to service (n = 13); Class 2) Medium restrictiveness on patient experience, high restrictiveness on access to service (n = 14); Class 3) Low restrictiveness on patient experience, low restrictiveness on access to service (n = 23). States with a higher probability of membership in Classes with higher restrictiveness had higher rates of unemployment (Class 1 vs Class 3, aRRR:1.24; 95%CI:1.06-1.45), and Black residents (Class 2 vs Class 3, aRRR:1.10; 95%CI:1.04-1.15), and lower likelihood of Medicaid coverage of methadone (Class 1 vs Class 3, aRRR:0.25; 95%CI:0.07-0.88). States with a higher probability of membership in Classes with higher restrictiveness also had higher rates of potential indicators for opioid use disorder treatment need, including rates of opioid dispensing (Class 1 vs Class 3, aRRR:1.06; 95%CI:1.02-1.10, Class 2 vs Class 3, aRRR:1.07; 95%CI:1.03-1.11) and HIV diagnoses attributed to injection (Class 1 vs Class 3, aRRR:3.92; 95%CI:1.25-12.22)., Conclusions: States with indicators of greater potential need for opioid use disorder treatment have the most restrictions, raising concerns about unmet treatment need., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CT has received speaker fees from Abbvie and Gilead and has received a research grant from Merck outside the submitted work. JG is a consultant/advisor and has received research grants from Abbvie, bioLytical, Camurus, Cepheid, Gilead Sciences, Hologic, and Indivior. NK provides testimony for ongoing opioid litigation. AC, FM, SD, VB, ADM, CSD, SC and MC have nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Despite evidence that the U.S. "War on Drugs" is associated with increases in drug-related harm and other negative outcomes, all U.S. states have long criminalized most drug possession. In early 2021, both Oregon and Washington became exceptions to this rule when they fully (Oregon) or partially (Washington) decriminalized possession of small amounts of all drugs., Methods: We obtained arrest data for 2019 to 2021 for intervention states (Oregon and Washington) and control states (Colorado, Idaho, Montana, and Nevada). We calculated monthly rates for arrests overall and for violent crimes, drug possession, equipment possession, non-drug crimes, and a set of low-level crimes termed displaced arrests. Using an interrupted time series analysis, we examined changes in monthly arrest rates after the implementation of policy change in Oregon and Washington compared to control states., Results: In Oregon, there were 3 fewer drug possession arrests per 100,000 in the month after the policy change; the rate decreased throughout the post-implementation period. In Washington, there were almost 5 fewer drug possession arrests per 100,000 in the month following policy change, and the rate remained stable thereafter. Both declines were significantly greater than in comparison states. There were also statistically significant reductions in arrests for possession of drug equipment in Washington and a significant increase in displaced arrests in Oregon. There were no significant changes in overall arrests, non-drug arrests or arrests for violent crime in either state, relative to controls., Conclusion: This analysis demonstrates that it is possible for state drug decriminalization policies to dramatically reduce arrests for drug possession without increasing arrests for violent crimes, potentially reducing harm to people who use drugs and their communities. Additional research is needed to determine whether these legal reforms were associated with changes in overdose rates and other drug-related harms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Recent advances in biomaterials and 3D printing/culture methods enable various tissue-engineered tumor models. However, it is still challenging to achieve native tumor-like characteristics due to lower cell density than native tissues and prolonged culture duration for maturation. Here, we report a new method to create tumoroids with a mechanically active tumor-stroma interface at extremely high cell density. This method, named "inkjet-printed morphogenesis" (iPM) of the tumor-stroma interface, is based on a hypothesis that cellular contractile force can significantly remodel the cell-laden polymer matrix to form densely-packed tissue-like constructs. Thus, differential cell-derived compaction of tumor cells and cancer-associated fibroblasts (CAFs) can be used to build a mechanically active tumor-stroma interface. In this methods, two kinds of bioinks are prepared, in which tumor cells and CAFs are suspended respectively in the mixture of collagen and poly (N-isopropyl acrylamide-co-methyl methacrylate) solution. These two cellular inks are inkjet-printed in multi-line or multi-layer patterns. As a result of cell-derived compaction, the resulting structure forms tumoroids with mechanically active tumor-stroma interface at extremely high cell density. We further test our working hypothesis that the morphogenesis can be controlled by manipulating the force balance between cellular contractile force and matrix stiffness. Furthermore, this new concept of "morphogenetic printing" is demonstrated to create more complex structures beyond current 3D bioprinting techniques., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Drug overdose deaths continue to rise, and considerable racial inequities have emerged. Overdose Good Samaritan laws (GSLs) are intended to encourage overdose witnesses to seek emergency assistance. However, evidence of their effectiveness is mixed, and little is known regarding racial disparities in their implementation. This study examined GSL impact by assessing racial differences in awareness of and trust in New York state's GSL., Methods: Using a sequential mixed methods design, Black and white participants were recruited from an existing longitudinal cohort study of people who use illicit opioids in New York City to participate in a quantitative survey and qualitative interviews. Racially stratified survey responses were analyzed using chi-squared tests, Fisher exact tests, or t-tests. Qualitative interviews were analyzed using a hybrid inductive-deductive approach., Results: Participants (n=128) were 56% male and predominantly aged 50 years or older. Most met criteria for severe opioid use disorder (81%). Fifty-seven percent reported that the New York GSL makes them more likely to call 911 even though 42% reported not trusting law enforcement to abide by the GSL; neither differed by race. Black people were less likely to have heard of the GSL (36.1% vs 60%) and were less likely to have accurate information regarding its protections (40.4% vs 49.6%)., Conclusions: Though GSLs may reduce negative impacts of the criminalization of people who use drugs, their implementation may exacerbate existing racial disparities. Resources should be directed towards harm reduction strategies that do not rely on trust in law enforcement., Competing Interests: Declaration of Competing Interest No conflicts declared., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: As the average level of medical education indebtedness rises, physicians look to programs such as Public Service Loan Forgiveness (PSLF) and National Health Service Corps (NHSC) to manage debt burden. Both represent service-dependent loan repayment programs, but the requirements and program outcomes diverge, and assessing the relative uptake of each program may help to inform health workforce policy decisions. We sought to describe variation in the composition of repayment program participant groups and measure relative impact on patient access to care., Methods: In this bivariate analysis, we analyzed data from 10,677 respondents to the American Board of Family Medicine's National Graduate Survey to study differences in loan repayment program uptake as well as the unique participant demographics, scope of practice, and likelihood of practicing with a medically underserved or rural population in each program cohort., Results: The rate of PSLF uptake tripled between 2016 and 2020, from 7% to 22% of early career family physicians, while NHSC uptake remained static at 4% to 5%. Family physicians reporting NHSC assistance were more likely than those reporting PSLF assistance to come from underrepresented groups, demonstrated a broader scope of practice, and were more likely to practice in rural areas (23.3% vs 10.8%) or whole-county Health Professional Shortage Areas (12.5% vs 3.7%) and with medically underserved populations (82.2% vs 24.2%)., Conclusions: Although PSLF supports family physicians intending to work in public service, their peers who choose NHSC are much more likely to work in underserved settings. Our findings may prompt a review of the goals of service loan forgiveness programs with potential to better serve health workforce needs., (© 2023 Annals of Family Medicine, Inc.)

Background: The United States continues to experience unprecedented rates of overdose mortality. Addressing the overdose epidemic has been challenging for policy makers given the lack of effectiveness of existing drug control policy measures. More recently, the implementation of harm reduction-based policies such as Good Samaritan Laws has led to increasing scholarly attention aimed at evaluating their effectiveness at reducing the likelihood of criminal justice-related sanctions for individuals following an overdose incident. The results of these studies, however, have been mixed., Methods: This study utilizes data from a nationally representative survey of law enforcement agencies designed to provide national information on services, policies, practices, operations, and resources of law enforcement drug response around overdoses to assess whether state Good Samaritan Laws reduce the likelihood of overdose victims being cited or being jailed following an overdose incident., Results: In general, findings indicate that although most agencies reported that overdose victims were not incarcerated or cited following an overdose incident, that this did not vary by whether agencies were in a state that had a GSL arrest protection for possession of controlled substances., Conclusions: GSLs are often written in complex and confusing language that officers and people who use drugs do not fully understand, which may deter their being used for their intended purpose. Although GSLs are well-intentioned, these findings highlight the need for training and education for law enforcement and people who use drugs around the scope of these laws., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Prior work suggests opioid prescribing cap laws are not associated with changes in opioid prescribing among patients with chronic pain. It is unknown how these effects differ by provider specialty, provider opioid prescribing volume, or patient insurer. This study assessed effects of state opioid prescribing cap laws on opioid prescribing among providers of patients with chronic non-cancer pain, by high volume prescribing, provider specialty, and patient insurer. We identified 224,290 providers of patients with low back pain, fibromyalgia, or headache from the IQVIA administrative database. Using a difference-in-differences approach, we examined impacts of opioid prescribing cap laws implemented between 2016 and 2018 on the annual proportion of a provider's patient panel who received any opioid prescription, as well as on dose and duration of opioid prescriptions. For providers overall, high volume prescribers, all specialties, and patient insurance categories, prescribing cap laws were associated with non-significant changes of <1.0, 1.5, and 3.5 percentage points in the proportion of chronic non-cancer patients receiving any opioid prescription, a prescription with 7 days' supply, or with >50 morphine milligram equivalents (MME)/day, per year, respectively. There were two exceptions with high dose prescribing: prescribing cap laws were associated with a 1.5 percentage point increase in the proportion of high-volume prescribers' patient panel receiving an opioid prescription with ≥50 MME/day, and a 3.0 percentage point decrease in the same measure among surgeons. Among nearly all measured subgroups of providers and patient insurers, opioid prescribing cap laws were not associated with changes in opioid prescribing., Competing Interests: Declaration of Competing Interest Drs. Tormohlen, White, Bandara, McCourt, Davis, and McGinty have no financial disclosures. Dr. Bicket reports past service as a consultant for Axial Healthcare, unrelated to the submitted work., (Copyright © 2023. Published by Elsevier Inc.)

Progressive muscle atrophy and loss of muscle strength associated with old age have been well documented. Although age-associated impairments in skeletal muscle regeneration following injury have been demonstrated, less is known about whether aging impacts the regenerative response of neuromuscular junctions (NMJ) following contraction-induced injury. Reduced ability of NMJs to regenerate could lead to increased numbers of denervated muscle fibers and therefore play a contributing role to age-related sarcopenia. To investigate the relationship between age and NMJ regeneration following injury, extensor digitorum longus (EDL) muscles of middle-aged (18-19 months) and old mice (27-28 months) were subjected to a protocol of lengthening contractions (LC) that resulted in an acute force deficit of ~55% as well as functional and histological evidence of a similar magnitude of injury 3 days post LCs that was not different between age groups. After 28 days, the architecture and innervation of the NMJs were evaluated. The numbers of fragmented endplates increased and of fully innervated NMJs decreased post-injury for the muscle of both middle-aged and old mice and for contralateral uninjured muscles of old compared with uninjured muscles of middle-aged controls. Thus, the diminished ability of the skeletal muscle of old mice to recover following injury may be due in part to an age-related decrease in the ability to regenerate NMJs in injured muscles. The impaired ability to regenerate NMJs may be a triggering factor for degenerative changes at the NMJ contributing to muscle fiber weakness and loss in old age., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Importance: Expanding the use of buprenorphine for treating opioid use disorder is a critical component of the US response to the opioid crisis, but few studies have examined how state policies are associated with buprenorphine dispensing., Objective: To examine the association of 6 selected state policies with the rate of individuals receiving buprenorphine per 1000 county residents., Design, Setting, and Participants: This cross-sectional study used 2006 to 2018 US retail pharmacy claims data for individuals dispensed buprenorphine formulations indicated for treating opioid use disorder., Exposures: State implementation of policies requiring additional education for buprenorphine prescribers beyond waiver training, continuing medical education related to substance misuse and addiction, Medicaid coverage of buprenorphine, Medicaid expansion, mandatory prescriber use of prescription drug monitoring programs, and pain management clinic laws were examined., Main Outcomes and Measures: The main outcome was buprenorphine treatment months per 1000 county residents as measured using multivariable longitudinal models. Statistical analyses were conducted from September 1, 2021, through April 30, 2022, with revised analyses conducted through February 28, 2023., Results: The mean (SD) number of months of buprenorphine treatment per 1000 persons nationally increased steadily from 1.47 (0.04) in 2006 to 22.80 (0.55) in 2018. Requiring that buprenorphine prescribers receive additional education beyond that required to obtain the federal X-waiver was associated with significant increases in the number of months of buprenorphine treatment per 1000 population in the 5 years following implementation of the requirement (from 8.51 [95% CI, 2.36-14.64] months in year 1 to 14.43 [95% CI, 2.61-26.26] months in year 5). Requiring continuing medical education for physician licensure related to substance misuse or addiction was associated with significant increases in buprenorphine treatment per 1000 population in each of the 5 years following policy implementation (from 7.01 [95% CI, 3.17-10.86] months in the first year to 11.43 [95% CI, 0.61-22.25] months in the fifth year). None of the other policies examined was associated with a significant change in buprenorphine months of treatment per 1000 county residents., Conclusions and Relevance: In this cross-sectional study of US pharmacy claims, state-mandated educational requirements beyond the initial training required to prescribe buprenorphine were associated with increased buprenorphine use over time. The findings suggest requiring education for buprenorphine prescribers and training in substance use disorder treatment for all controlled substance prescribers as an actionable proposal for increasing buprenorphine use, ultimately serving more patients. No single policy lever can ensure adequate buprenorphine supply; however, policy maker attention to the benefits of enhancing clinician education and knowledge may help to expand buprenorphine access.

Background: Naloxone distribution is central to ongoing efforts to address the opioid overdose crisis. Some critics contend that naloxone expansion may inadvertently promote high-risk substance use behaviors among adolescents, but this question has not been directly investigated., Methods: We examined relationships between naloxone access laws and pharmacy naloxone distribution with lifetime heroin and injection drug use (IDU), 2007-2019. Models generating adjusted odds ratios (aOR) and 95% confidence intervals (CI) included year and state fixed effects, controlled for demographics and sources of variation in opioid environments (e.g., fentanyl penetration), as well as additional policies expected to impact substance use (e.g., prescription drug monitoring). Exploratory and sensitivity analyses further examined naloxone law provisions (e.g., third-party prescribing) and applied e-value testing to assess vulnerability to unmeasured confounding., Results: Adoption of any naloxone law was not associated with changes in adolescent lifetime heroin or IDU. For pharmacy dispensing, we observed a small decrease in heroin use (aOR: 0.95 [CI: 0.92, 0.99]) and a small increase in IDU (aOR: 1.07 [CI: 1.02, 1.11]). Exploratory analyses of law provisions suggested that third-party prescribing (aOR: 0.80, [CI: 0.66, 0.96]) and non-patient-specific dispensing models (aOR: 0.78, [CI: 0.61, 0.99]) were associated with decreased heroin use but not decreased IDU. Small e-values associated with the pharmacy dispensing and provision estimates indicate that unmeasured confounding may explain observed findings., Conclusion: Naloxone access laws and pharmacy naloxone distribution were more consistently associated with decreases rather than increases in lifetime heroin and IDU among adolescents. Our findings therefore do not support concerns that naloxone access promotes high-risk adolescent substance use behaviors. As of 2019, all US states have adopted legislation to improve naloxone access and facilitate use. However, further removal of adolescent naloxone access barriers is an important priority given that the opioid epidemic continues to affect people of all ages., Competing Interests: Declarations of Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D. Hasin has received funding from Syneos Health for an unrelated project. K. Keyes has received personal fees related to expert work in litigation. H. Samples has received consulting fees from the American Society of Addiction Medicine., (Copyright © 2023. Published by Elsevier B.V.)

In 2017, Rhode Island responded to rising overdose deaths by establishing statewide emergency department (ED) treatment standards for opioid overdose and opioid use disorder. One requirement of the policy is that providers prescribe or provide take-home naloxone to anyone presenting to EDs with opioid overdose. Among adults presenting to EDs with opioid overdose from 2018 to 2019, approximately half received take-home naloxone. Receipt of naloxone was associated with administration of naloxone before ED presentation, ED policy certification level, and regional overdose frequency. ( Am J Public Health . 2023;113(4):372-377. https://doi.org/10.2105/AJPH.2022.307213).

Whole-body knock-out of Cu,Zn superoxide dismutase (Sod1KO) results in accelerated, age-related loss of muscle mass and function associated with neuromuscular junction (NMJ) breakdown similar to sarcopenia. In order to determine whether altered redox in motor neurons underlies this phenotype, an inducible neuron-specific deletion of Sod1 (i-mnSod1KO) was compared with wild-type (WT) mice of different ages (adult, mid-age, and old) and whole-body Sod1KO mice. Nerve oxidative damage, motor neuron numbers and structural changes to neurons and NMJ were examined. Tamoxifen-induced deletion of neuronal Sod1 from two months of age. No specific effect of a lack of neuronal Sod1 was seen on markers of nerve oxidation (electron paramagnetic resonance of an in vivo spin probe, protein carbonyl, or protein 3-nitrotyrosine contents). i-mnSod1KO mice showed increased denervated NMJ, reduced numbers of large axons and increased number of small axons compared with old WT mice. A large proportion of the innervated NMJs in old i-mnSod1KO mice displayed a simpler structure than that seen in adult or old WT mice. Thus, previous work showed that neuronal deletion of Sod1 induced exaggerated loss of muscle in old mice, and we report that this deletion leads to a specific nerve phenotype including reduced axonal area, increased proportion of denervated NMJ, and reduced acetyl choline receptor complexity. Other changes in nerve and NMJ structure seen in the old i-mnSod1KO mice reflect aging of the mice., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Pollock et al.)

Control over the surface chemistry of elastomers such as polydimethylsiloxane (PDMS) is important for many applications. However, achieving nanostructured chemical control on amorphous material interfaces below the length scale of substrate heterogeneity is not straightforward, and can be particularly difficult to decouple from changes in network structure that are required for certain applications (e.g., variation of elastic modulus for cell culture). We have recently reported a new method for precisely structured surface functionalization of PDMS and other soft materials, which displays high densities of ligands directly on the material surface, maximizing steric accessibility. Here, we systematically examine structural factors in the PDMS components (e.g., base and cross-linker structures) that impact efficiency of the interfacial reaction that leads to surface functionalization. Applying this understanding, we demonstrate routes for generating equivalent nanometer-scale functional patterns on PDMS with elastic moduli from 0.013 to 1.4 MPa, establishing a foundation for use in applications such as cell culture.

Objectives: Before the coronavirus disease 2019 pandemic, federal law required in-person evaluation before buprenorphine initiation. Regulatory changes during the pandemic allow for buprenorphine initiation by audio-only or audiovisual telehealth. Little is known about treatment engagement after buprenorphine initiation conducted via audio-only telehealth., Methods: A retrospective cohort study of 94 individuals who received initial treatment through an audio-only encounter between April 2020 and February 2021 was performed. Participant demographics, substance use history, withdrawal symptoms, 30-day treatment engagement, and adverse outcomes were determined by an electronic chart and REDcap database review. Subsequent buprenorphine prescriptions filled within 30 days of the initial encounter were tracked through the Rhode Island Prescription Drug Monitoring Program., Results: Buprenorphine was prescribed for 94 individuals. Most (92 of 94 [97.9%]) filled their prescription within 30 days. Most had previously taken buprenorphine, including prescribed (42 of 92 [45.7%]) and nonprescribed (58 of 92 [63.0%]). Two thirds were in opioid withdrawal at the time of the call (61 of 92 [66.3%]) with a mean Subjective Opioid Withdrawal Scale of 26.8 (range, 4-57). Four individuals experienced precipitated withdrawal (4 of 94 [4.3%]), and 2 reported persistent withdrawal at their follow-up visit (2 of 94 [2.1%]). More than 70% filled a subsequent prescription for buprenorphine within 30 days of the end of their hotline prescription (65 of 92 [70.7%]), on average of 5.88 days (range, 0-28) after completion of their telehealth prescription., Conclusions: Expanding telehealth-delivered buprenorphine care has the potential to address treatment gaps and facilitate delivery of on-demand services during peak motivation. This evaluation of audio-only buprenorphine initiation found high rates of unobserved buprenorphine initiation and treatment continuation with low rates of complications., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)

Background: Many states have adopted laws that limit the amount or duration of opioid prescriptions. These limits often focus on prescriptions for acute pain, but there may be unintended consequences for those diagnosed with chronic pain, including reduced opioid prescribing without substitution of appropriate non-opioid treatments., Objective: To evaluate the effects of state opioid prescribing cap laws on opioid and non-opioid treatment among those diagnosed with chronic pain., Design: We used a difference-in-differences approach that accounts for staggered policy adoption. Treated states included 32 states that implemented a prescribing cap law between 2017 and 2019., Population: A total of 480,856 adults in the USA who were continuously enrolled in medical and pharmacy coverage from 2013 to 2019 and diagnosed with a chronic pain condition between 2013 and 2016., Main Measures: Among individuals with chronic pain in each state: proportion with at least one opioid prescription and with prescriptions of a specific duration or dose, average number of opioid prescriptions, average opioid prescription duration and dose, proportion with at least one non-opioid chronic pain prescription, average number of such prescriptions, proportion with at least one chronic pain procedure, and average number of such procedures., Key Results: State laws limiting opioid prescriptions were not associated with changes in opioid prescribing, non-opioid medication prescribing, or non-opioid chronic pain procedures among patients with chronic pain diagnoses., Conclusions: These findings do not support an association between state opioid prescribing cap laws and changes in the treatment of chronic non-cancer pain., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Inbreeding depression can reduce the viability of wild populations. Detecting inbreeding depression in the wild is difficult; developing accurate estimates of inbreeding can be time and labor intensive. In this study, we used a two-step modeling procedure to incorporate uncertainty inherent in estimating individual inbreeding coefficients from multilocus genotypes into estimates of inbreeding depression in a population of Weddell seals ( Leptonychotes weddellii ). The two-step modeling procedure presented in this paper provides a method for estimating the magnitude of a known source of error, which is assumed absent in classic regression models, and incorporating this error into inferences about inbreeding depression. The method is essentially an errors-in-variables regression with non-normal errors in both the dependent and independent variables. These models, therefore, allow for a better evaluation of the uncertainty surrounding the biological importance of inbreeding depression in non-pedigreed wild populations. For this study we genotyped 154 adult female seals from the population in Erebus Bay, Antarctica, at 29 microsatellite loci, 12 of which are novel. We used a statistical evidence approach to inference rather than hypothesis testing because the discovery of both low and high levels of inbreeding are of scientific interest. We found evidence for an absence of inbreeding depression in lifetime reproductive success, adult survival, age at maturity, and the reproductive interval of female seals in this population., Competing Interests: The authors declare no conflict of interest.

Control of adhesion is important in a host of applications including soft robotics, pick-and-place manufacturing, wearable devices, and transfer printing. While there are adhesive systems with discrete switchability between states of high and low adhesion, achieving continuously variable adhesion strength remains a challenge. In this work, a pressure-tunable adhesive (PTA) that is based on the self-assembly of stiff microscale asperities on an elastomeric substrate is presented. It is demonstrated that the adhesion strength of the PTA increases with the applied compressive preload due to the unique contact formation mechanism caused by the asperities. Additionally, a contact mechanics model is developed to explain the resulting trends. For a specific PTA design, the critical pull-off force can be increased from 0.4 to 30 mN by increasing the applied preload from 1 to 30 mN. Finally, the applicability of precision control of adhesion strength is demonstrated by utilizing the PTA for pick-and-place material handling. The approach in pressure-tunable adhesive design based on self-assembly of asperities presents a scalable and versatile approach that is applicable to a variety of material systems having different mechanical or surface properties., (© 2022 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

The US overdose crisis continues to worsen and is disproportionately harming Black and Hispanic/Latino people. Although the "War on Drugs" continues to shape drug policy-at the disproportionate expense of Black and Hispanic/Latino people-states have taken some steps to reduce War on Drugs-related harms and adopt a public health-centered approach. However, the rhetoric regarding these changes has, in many cases, outstripped reality. Using overdose Good Samaritan Laws (GSLs) as a case study, we argue that public health-oriented policy changes made in some states are undercut by the broader enduring environment of a structurally racist drug criminalization agenda that continues to permeate and constrict most attempts at change. Drawing from our collective experiences in public health research and practice, we describe 3 key barriers to GSL effectiveness: the narrow parameters within which they apply, the fact that they are subject to police discretion, and the passage of competing laws that further criminalize people who use illicit drugs. All reveal a persisting climate of drug criminalization that may reduce policy effectiveness and explain why current reforms may be destined for failure and further disadvantage Black and Hispanic/Latino people who use drugs. ( Am J Public Health . 2023;113(S1):S43-S48. https://doi.org/10.2105/AJPH.2022.307037).

Rationale: Pulmonary exacerbation (PEx) events contribute to lung function decline in people with cystic fibrosis (CF). CF Foundation PEx guidelines note that a short course of systemic corticosteroids may offer benefit without contributing to long-term adverse effects. However, insufficient evidence exists to recommend systemic corticosteroids for PEx treatment. Objectives: To determine if systemic corticosteroids for the treatment of in-hospital pediatric PEx are associated with improved clinical outcomes compared with treatment without systemic corticosteroids. Methods: We conducted a retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System linked database. People with CF were included if hospitalized for a PEx between 2006 and 2018 and were 6-21 years of age. Time to next PEx was assessed by Cox proportional hazards regression. Lung function outcomes were assessed by linear mixed-effect modeling and generalized estimating equations. To address confounding by indication, inverse probability treatment weighting was used. Results: A total of 3,471 people with CF contributed 9,787 PEx for analysis. Systemic corticosteroids were used in 15% of all PEx. In our primary analysis, systemic corticosteroids were not associated with better pre- to post-PEx percent predicted forced expiratory volume in 1 second responses (mean difference, -0.36; 95% confidence interval [CI], -1.14, 0.42; P  = 0.4) or a higher odds of returning to lung function baseline (odds ratio, 0.97; 95% CI, 0.84-1.12; P  = 0.7) but were associated with a reduced chance of future PEx requiring intravenous antibiotics (hazard ratio, 0.91; 95% CI, 0.85-0.96; P  = 0.002). When restricting the analysis to one PEx per person, lung function outcomes remained no different among PEx treated with or without systemic corticosteroids, but, in contrast to our primary analysis, the use of systemic corticosteroids was no longer associated with a reduced chance of having a future PEx requiring intravenous antibiotics (hazard ratio, 0.96; 95% CI, 0.86, 1.07; P  = 0.42). Conclusions: Systemic corticosteroid treatment for in-hospital pediatric PEx was not associated with improved lung function outcomes. Prospective trials are needed to better evaluate the risks and benefits of systemic corticosteroid use for PEx treatment in children with CF.

Background: Since 2011, the Teaching Health Center Graduate Medical Education (THC GME) program has sought to expand access to care by training residents in safety net settings., Objective: To examine impact on physician scope, location, and patient population served using a unique data set., Methods: Using 2017-2020 data from the American Board of Family Medicine National Graduate Survey, we compared demographics, practice location, populations served, and scope of practice between graduates of THC GME programs and graduates of other family medicine programs., Results: Our sample comprised 8608 (out of 13 465) eligible family medicine graduates 3 years after completion of residency training, for a response rate of 63.9%. THC graduates were significantly more likely than other graduates to practice in a rural location (17.9% to 11.8%), within 5 miles of their residency program (18.9% to 12.9%), and to care for medically underserved populations (35.2% to 18.6%). Their scope of practice was wider than other graduates and more likely to comprise services like buprenorphine prescribing, behavioral health care, and outpatient gynecological procedures. Regression results suggest that THC training is independently correlated with a broader scope of practice., Conclusions: Graduates of THC programs were significantly more likely than graduates of other programs to practice close to their training sites and in rural areas, and to care for underserved patients while maintaining a broader scope of practice than other graduates., Competing Interests: Conflict of interest: The authors declare they have no competing interests.

Background: States have enacted multiple types of laws, with a variety of constituent provisions, in response to the opioid epidemic, often simultaneously. This temporal proximity and variation in state-to-state operationalization has resulted in significant challenges for empirical research on their effects. Thus, expert consensus can be helpful to classify laws and their provisions by their degree of helpfulness and impact., Methods: We conducted a four-stage modified policy Delphi process to identify the top 10 most helpful and 5 most harmful provisions from eight opioid-related laws. This iterative consultation with six types of opioid experts included a preliminary focus group (n=12), two consecutive surveys (n=56 and n=40, respectively), and a final focus group feedback session (n=5)., Results: On a scale of very harmful (0) to very helpful (4), overdose Good Samaritan laws received the highest average helpfulness rating (3.62, 95% CI: 3.48-3.75), followed by naloxone access laws (3.37, 95% CI: 3.22-3.51), and pain management clinic laws (3.08, 95% CI: 2.89-3.26). Drug-induced homicide (DIH) laws were rated the most harmful (0.88, 95% CI: 0.66-1.11). Impact ratings aligned similarly, although Medicaid laws received the second highest overall impact rating (3.71, 95% CI: 3.45, 3.97). The two most helpful provisions were naloxone standing orders (3.94, 95% CI: 3.86-4.02) and Medicaid coverage of medications for opioid use disorder (MOUD) (3.89, 95% CI: 3.82). Mandatory minimum DIH laws were the most harmful provision (0.73, 95% CI 0.53-0.93); followed by requiring prior authorization for Medicaid coverage of MOUD (1.00 95% CI: 0.72-1.27)., Conclusion: Overall, experts rated laws and provisions that facilitated harm reduction efforts and access to MOUD as most helpful. Laws and provisions rated as most harmful criminalized substance use and placed restrictions on access to MOUD. These ratings provide a foundation for evaluating the overall overdose policy environment for each state., Competing Interests: Declarations of Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Samples has received consulting fees from the American Society of Addiction Medicine., (Copyright © 2022. Published by Elsevier B.V.)

Objective: To evaluate the effects of state opioid prescribing cap laws on opioid prescribing after surgery., Data Sources: OptumLabs Data Warehouse administrative claims data covering all 50 states from July 2012 through June 2019., Study Design: We included individuals from 20 states that had implemented prescribing cap laws without exemptions for postsurgical pain by June 2019 and individuals from 16 control states plus the District of Columbia. We used a difference-in-differences approach accounting for differential timing in law implementation across states to estimate the effects of state prescribing cap laws on postsurgical prescribing of opioids. Outcome measures included filling an opioid prescription within 30 days after surgery; filling opioid prescriptions of specific doses or durations; and the number, days' supply, daily dose, and pill quantity of opioid prescriptions. To assess the validity of the parallel counterfactual trends assumption, we examined differences in outcome trends between law-implementing and control states in the years preceding law implementation using an equivalence testing framework., Data Collection/extraction Methods: We included the first surgery in the study period for opioid-naïve individuals undergoing one of eight common surgical procedures., Principal Findings: State prescribing cap laws were associated with 0.109 lower days' supply of postsurgical opioids on the log scale (95% Confidence Interval [CI]: -0.139, -0.080) but were not associated with the number (Average treatment effect on the treated [ATT]: -0.011; 95% CI: -0.043, 0.021) or daily dose of postsurgical opioid prescriptions (ATT: -0.013; 95% CI: -0.030, 0.005). The negative association observed between prescribing cap laws and the probability of filling a postsurgical opioid prescription (ATT: -0.041; 95% CI: -0.054, -0.028) was likely spurious, given differences between law-implementing and control states in the pre-law period., Conclusions: Prescribing cap laws appear to have minimal effects on postsurgical opioid prescribing., (© 2022 Health Research and Educational Trust.)

Overdose Good Samaritan laws (GSLs) aim to reduce mortality by providing limited legal protections when a bystander to a possible drug overdose summons help. Most research into the impact of these laws is dated or potentially confounded by coenacted naloxone access laws. Lack of awareness and trust in GSL protections, as well as fear of police involvement and legal repercussions, remain key deterrents to help-seeking. These barriers may be unequally distributed by race/ethnicity due to racist policing and drug policies, potentially producing racial/ethnic disparities in the effectiveness of GSLs for reducing overdose mortality. We used 2015-2019 vital statistics data to estimate the effect of recent GSLs on overdose mortality, overall (8 states) and by Black/White race/ethnicity (4 states). Given GSLs' near ubiquity, few unexposed states were available for comparison. Therefore, we generated an "inverted" synthetic control method (SCM) to compare overdose mortality in new-GSL states with that in states that had GSLs throughout the analytical period. The estimated relationships between GSLs and overdose mortality, both overall and stratified by Black/White race/ethnicity, were consistent with chance. An absence of effect could result from insufficient protection provided by the laws, insufficient awareness of them, and/or reticence to summon help not addressable by legal protections. The inverted SCM may be useful for evaluating other widespread policies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Given the continued rise in opioid-related overdoses, many states have expanded access to the opioid antagonist naloxone. We sought to provide comprehensive data on one such strategy: the authority of providers at different emergency medical services (EMS) licensure levels to administer naloxone., Methods: We conducted a systematic legal review of state laws and protocols governing the authority of different EMS licensure levels to administer naloxone. We used Westlaw, state government websites and scope of practice protocols. We coded relevant policies regarding which, if any, administration routes and dosages of naloxone are permitted for each licensure level: emergency medical responder (EMR), emergency medical technician (EMT), advanced emergency medical technician (AEMT), and paramedic., Results: As of July 2020, all states with relevant laws or protocols authorize paramedics, AEMTs, and EMTs to administer naloxone. Thirty-nine states with an EMR licensure level and statewide protocol authorize naloxone administration by EMRs, up from only two in 2013. Permissible routes of administration have increased across all EMS provider levels, providing advanced life support providers (i.e., paramedics and AEMTs) with expanded discretion; however, authorization for intravenous and intramuscular administration remains relatively uncommon for basic life support (BLS) providers. When specified, maximum doses authorized ranged widely, from 2.0 to 12.0 milligrams., Conclusions: Naloxone administration authority is now widely granted to EMS providers. Most states allow all licensed EMS provider levels to administer naloxone, a substantial increase for EMRs and EMTs since 2013. Paramedics and AEMTs have the greatest authority to select the dosage and route of administration., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Surgery resident mental health, burnout, and overall well-being are constantly scrutinized, and improving surgery resident well-being programs continuously requires refinement. We sought to evaluate the effectiveness of human-centered design (HCD) sprints to enhance our surgery resident well-being program., Methods: An HCD sprint was conducted with 34 surgery residents in a single session using seven separate domains, including Mental Health/Reflection and Therapy; Mentoring or Faculty Engagement; Physical Well-being; Retreats; Scheduled Breaks or Free Time; Social Connection; and Well-being Lectures, Emails, or Curriculum. Responses were characterized as: "How might we", Suggestions, Useful, and Not Useful., Results: Well-being Lectures, Emails, or Curriculum were overwhelmingly viewed, as Not Useful (77%), as was Mental Health/Reflection and Therapy (42%). Scheduled Breaks or Free Time was viewed as the most Useful (42%). This category also had the most suggestions and "How might we" ideas for improvement (41%). Lastly, Suggestions and "How might we" ideas were also common for improving Mentoring or Faculty Engagement (31% and 29%, respectively). These results were incorporated into multiple strategies to improve surgery resident well-being and also shared in a Department of Surgery Grand Rounds., Conclusions: Surgery resident well-being and a targeted approach by a well-being program are critical to a residency program, particularly with the arduous nature of surgical training during the pandemic resulting in periods of prolonged social isolation. HCD sprints are an effective means to refine a surgery resident well-being program and to involve the residents themselves in that process., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Violations of the positivity assumption (also called the common support condition) challenge health policy research and can result in significant bias, large variance, and invalid inference. We define positivity in the single- and multiple-timepoint (i.e., longitudinal) health policy evaluation setting, and discuss real-world threats to positivity. We show empirical evidence of the practical positivity violations that can result when attempting to estimate the effects of health policies (in this case, Naloxone Access Laws). In such scenarios, an alternative is to estimate the effect of a shift in law enactment (e.g., the effect if enactment had been delayed by some number of years). Such an effect corresponds to what is called a modified treatment policy, and dramatically weakens the required positivity assumption, thereby offering a means to estimate policy effects even in scenarios with serious positivity problems. We apply the approach to define and estimate the longitudinal effects of Naloxone Access Laws on opioid overdose rates., Competing Interests: Disclosure: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: High-dose and long-duration opioid prescriptions remain relatively common among children and adolescents, but there is insufficient research on the association of state laws limiting the dose and/or duration of opioid prescriptions (referred to as opioid prescribing cap laws) with opioid prescribing for this group., Objective: To examine the association between state opioid prescribing cap laws and the receipt of opioid prescriptions among children and adolescents., Design Setting and Participants: This repeated cross-sectional study used a difference-in-differences approach accounting for staggered policy adoption to assess the association of state opioid prescribing cap laws in the US from January 1, 2013, to December 31, 2019, with receipt of opioid prescriptions among children and adolescents. Analyses were conducted between March 22 and December 15, 2021. Data were obtained from the OptumLabs Data Warehouse, a national commercial insurance claims database. The analysis included 482 118 commercially insured children and adolescents aged 0 to 17 years with full calendar-year continuous insurance enrollment between 2013 and 2019. Individuals were included for every year in which they were continuously enrolled; they did not need to be enrolled for the entire 7-year study period. Those with any cancer diagnosis were excluded from analysis., Exposure: Implementation of a state opioid prescribing cap law between January 1, 2017, and July 1, 2019. This date range allowed analysis of the same number years for both pre-cap and post-cap data., Main Outcomes and Measures: Outcomes of interest included receipt of any opioid prescription and, among those with at least 1 opioid prescription, the mean number of opioid prescriptions, mean morphine milligram equivalents (MMEs) per day, and mean days' supply., Results: Among 482 118 children and adolescents (754 368 person-years of data aggregated to the state-year level), 245 178 (50.9%) were male, with a mean (SD) age of 9.8 (4.8) years at the first year included in the sample (data on race and ethnicity were not collected as part of this data set, which was obtained from insurance billing claims). Overall, 10 659 children and adolescents (2.2%) received at least 1 opioid prescription during the study period. Among those with at least 1 prescription, the mean (SD) number of filled opioid prescriptions was 1.2 (0.8) per person per year. No statistically significant association was found between state opioid prescribing cap laws and any outcome. After opioid prescribing cap laws were implemented, a -0.001 (95% CI, -0.005 to 0.002) percentage point decrease in the proportion of youths receiving any opioid prescription was observed. In addition, percentage point decreases of -0.01 (95% CI, -0.10 to 0.09) in high-dose opioid prescriptions (>50 MMEs per day) and -0.02 (95% CI, -0.12 to 0.08) in long-duration opioid prescriptions (>7 days' supply) were found after cap laws were implemented., Conclusions and Relevance: In this cross-sectional study, no association was observed between state opioid prescribing cap laws and the receipt of opioid prescriptions among children and adolescents. Alternative strategies, such as opioid prescribing guidelines tailored to youths, are needed., Competing Interests: Conflict of Interest Disclosures: Dr Bicket reported receiving grants from the Centers for Disease Control and Prevention, the Michigan Department of Health and Human Services, and the National Institutes of Health and personal fees from Alosa Health and axialHealthcare outside the submitted work. No other disclosures were reported., (Copyright 2022 Stone EM et al. JAMA Health Forum.)

Purpose: Trauma is the leading cause of death before the age of 45 in the United States. Precision medicine (PM) is the most advanced scientific form of medical practice and seeks to gather data from the genome, environmental interactions, and lifestyles. Relating to trauma, PM promises to significantly advance our understanding of the factors that contribute to the physiologic response to injury., Methods: We review the status of PM-driven trauma care. Semantic-based methods were used to gather data on genetic/epigenetic variability previously linked to the principal causes of trauma-related outcomes. Data were curated to include human investigations involving genomics/epigenomics with clinical relevance identifiable early after injury., Results: Most studies relevant to genomic/epigenomic differences in trauma are specific to traumatic brain injury and injury-related sepsis. Genomic/epigenomic differences rarely encompass other relevant factors, such as coagulability and pharmacogenomics. Few studies describe clinical use of genomics/epigenomics for therapeutic intervention in trauma care, and even fewer attempt to incorporate real-time genomic/epigenomic information to precisely guide clinical decision-making., Conclusion: Considering that genomics/epigenomics, environmental exposures, and lifestyles are most likely to be of significant medical relevance in advancing the field of trauma, the lack of application of concepts and methodologies from PM to trauma education, research, practice, and community wellness is underwhelming. We suggest that significant effort be given to incorporate the tools of what is becoming the "new medicine"., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Fentanyl and fentanyl analogs are increasingly prevalent in the nation's illicit drug supply. While fentanyl-related deaths were previously confined largely to states east of the Mississippi, they are now increasing rapidly throughout much of the United States. Contaminants other than fentanyl are also present in illicitly obtained drugs. Using drug checking equipment to determine the contaminants that may be present in these drugs is a promising avenue for reducing overdose-related harm., Methods: Systematic legal review in which three trained legal researchers collected, reviewed, and coded all US state laws that specify whether the possession and distribution of drug checking equipment is generally legal, whether is it legal in the context of syringe services programs, and, where possession or distribution of drug checking equipment is not clearly legal, the potential penalties for violation., Results: We find that it is clearly legal to possess some or all drug checking equipment in 22 states, and clearly legal to distribute it to adults in 19 states. In 14 states where distribution of drug checking equipment is not clearly legal generally, it is legal when that equipment is obtained from a syringe services program. Potential penalties for violations range from small civil fines to multi-year jail sentences., Conclusions: There are currently great variations between states regarding the legality of drug checking equipment. Clarifying, modifying, or repealing drug paraphernalia laws would likely improve access to these promising technologies, potentially reducing overdose deaths., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: To determine if state laws that forbid substance use disorder treatment providers from refusing services based on pregnancy are associated with improved ability to secure an initial appointment for opioid use disorder treatment with methadone and buprenorphine., Methods: Ten states in which a "secret shopper" study was conducted were stratified based on whether they have a law that forbids substance use disorder treatment providers from refusing to treat individuals because of pregnancy. We tested for differences in percent of pregnant versus nonpregnant callers offered an initial appointment for medication for opioid use disorder treatment between states with a law and those without. We also tested for differences in acceptance based on caller insurance type., Results: Four states with 1461 callers had relevant laws; 6 states with 2495 callers did not. None of the laws apply to all providers. In both groups of states, nonpregnant callers were significantly more likely to obtain a buprenorphine appointment (75.1% vs 60.1% in states with a law, P < 0.01; 73.1% vs 62.3% in states without, P < 0.01). No significant differences were found in methadone appointment access either between pregnant and nonpregnant callers or between pregnant callers in states with a law compared to those without., Conclusions: Laws that forbid providers from refusing to treat potential patients because they are pregnant were not associated with success in obtaining an initial appointment for medication for opioid use disorder treatment. States should consider expanding those laws to apply to all treatment providers and ensure that currently covered providers are in compliance., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)