Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms.

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.

Contextual modifiers of healthspan, lifespan, and epigenome in mice under chronic social stress.

Sustained life stress and low socioeconomic status are among the major causes of aging-related diseases and decreased life expectancy. Experimental rodent models can help to identify the underlying mechanisms, yet very few studies address the long-term consequences of social stress on aging. We conducted a randomized study involving more than 300 male mice of commonly used laboratory strains (C57BL/6J, CD1, and Sv129Ev) chosen for the spontaneous aggression gradient and stress-vulnerability. Mice were exposed to a lifelong chronic psychosocial stress protocol to model social gradients in aging and disease vulnerability. Low social rank, inferred based on a discretized aggression index, was found to negatively impact lifespan in our study population. However, social rank interacted with genetic background in that low-ranking C57BL/6J, high-ranking Sv129Ev, and middle-ranking CD1 mice had lower survival, respectively, implying a cost of maintaining a given social rank that varies across strains. Machine learning linear discriminant analysis identified baseline fat-free mass as the most important predictor of mouse genetic background and social rank in the present dataset. Finally, strain and social rank differences were significantly associated with epigenetic changes, most significantly in Sv129Ev mice and in high-ranking compared to lower ranking subjects. Overall, we identified genetic background and social rank as critical contextual modifiers of aging and lifespan in an ethologically relevant rodent model of social stress, thereby providing a preclinical experimental paradigm to study the impact of social determinants of health disparities and accelerated aging.

Proteome-wide association study using cis and trans variants and applied to blood cell and lipid-related traits in the Women's Health Initiative study.

In most Proteome-Wide Association Studies (PWAS), variants near the protein-coding gene (±1 Mb), also known as cis single nucleotide polymorphisms (SNPs), are used to predict protein levels, which are then tested for association with phenotypes. However, proteins can be regulated through variants outside of the cis region. An intermediate GWAS step to identify protein quantitative trait loci (pQTL) allows for the inclusion of trans SNPs outside the cis region in protein-level prediction models. Here, we assess the prediction of 540 proteins in 1002 individuals from the Women's Health Initiative (WHI), split equally into a GWAS set, an elastic net training set, and a testing set. We compared the testing r2 between measured and predicted protein levels using this proposed approach, to the testing r2 using only cis SNPs. The two methods usually resulted in similar testing r2, but some proteins showed a significant increase in testing r2 with our method. For example, for cartilage acidic protein 1, the testing r2 increased from 0.101 to 0.351. We also demonstrate reproducible findings for predicted protein association with lipid and blood cell traits in WHI participants without proteomics data and in UK Biobank utilizing our PWAS weights.

mLiftOver: harmonizing data across Infinium DNA methylation platforms.

MOTIVATION: Infinium DNA methylation BeadChips are widely used for genome-wide DNA methylation profiling at the population scale. Recent updates to probe content and naming conventions in the EPIC version 2 (EPICv2) arrays have complicated integrating new data with previous Infinium array platforms, such as the MethylationEPIC (EPIC) and the HumanMethylation450 (HM450) BeadChip. RESULTS: We present mLiftOver, a user-friendly tool that harmonizes probe ID, methylation level, and signal intensity data across different Infinium platforms. It manages probe replicates, missing data imputation, and platform-specific bias for accurate data conversion. We validated the tool by applying HM450-based cancer classifiers to EPICv2 cancer data, achieving high accuracy. Additionally, we successfully integrated EPICv2 healthy tissue data with legacy HM450 data for tissue identity analysis and produced consistent copy number profiles in cancer cells. AVAILABILITY AND IMPLEMENTATION: mLiftOver is implemented R and available in the Bioconductor package SeSAMe (version 1.21.13+): https://bioconductor.org/packages/release/bioc/html/sesame.html. Analysis of EPIC and EPICv2 platform-specific bias and high-confidence mapping is available at https://github.com/zhou-lab/InfiniumAnnotationV1/raw/main/Anno/EPICv2/EPICv2ToEPIC_conversion.tsv.gz. The source code is available at https://github.com/zwdzwd/sesame/blob/devel/R/mLiftOver.R under the MIT license.

Assessing the properties of patient-specific treatment effect estimates from causal forest algorithms under essential heterogeneity.

BACKGROUND: Treatment variation from observational data has been used to estimate patient-specific treatment effects. Causal Forest Algorithms (CFAs) developed for this task have unknown properties when treatment effect heterogeneity from unmeasured patient factors influences treatment choice - essential heterogeneity. METHODS: We simulated eleven populations with identical treatment effect distributions based on patient factors. The populations varied in the extent that treatment effect heterogeneity influenced treatment choice. We used the generalized random forest application (CFA-GRF) to estimate patient-specific treatment effects for each population. Average differences between true and estimated effects for patient subsets were evaluated. RESULTS: CFA-GRF performed well across the population when treatment effect heterogeneity did not influence treatment choice. Under essential heterogeneity, however, CFA-GRF yielded treatment effect estimates that reflected true treatment effects only for treated patients and were on average greater than true treatment effects for untreated patients. CONCLUSIONS: Patient-specific estimates produced by CFAs are sensitive to why patients in real-world practice make different treatment choices. Researchers using CFAs should develop conceptual frameworks of treatment choice prior to estimation to guide estimate interpretation ex post.

Smoking Dependence, Time-Discounting, and Sustained Cessation Behavior: A Longitudinal Study of Predominantly Light Smokers.

INTRODUCTION: This study aimed to assess whether two established psychosocial predictors of smoking abstinence, nicotine dependence and time-discounting, also apply to a population of predominantly cigarette light smokers, which is the dominant pattern of smoking in countries like Mexico. Relatively infrequent smoking is increasingly prevalent, yet still harmful, making it important to understand the predictors of cessation in this population. AIMS AND METHODS: Mexican adult smokers recruited from an online consumer panel were surveyed every 4 months between November 2018 and July 2020. We considered respondents who reported a quit attempt in between surveys (n = 1288). Dependence was measured with a 10-item version of the Wisconsin Inventory of Smoking Dependence Motives (WISDM). Time-discounting was assessed with five branching questions about hypothetical reward scenarios. Logistic models regressed sustained quit attempts (≥30 days of abstinence) at time t + 1 on study variables at time t. RESULTS: We found strong interitem reliability (α = 0.92) and intraindividual consistency of our brief WISDM (ρ = 0.68), but moderate intraindividual consistency of the time-discounting measure (ρ = 0.48). Forty-eight percent of the sample reported sustained quit attempts, and 79% were non-daily or light daily smokers (≤5 cigarettes per day). Smokers with higher WISDM-10 had lower odds of sustained quitting and this result remained when controlling for smoking frequency and the Heaviness of Smoking Index (adjusted odds ratio [AOR] = 0.768). Time-discounting was unassociated with sustained quitting. CONCLUSIONS: Our findings suggest that a brief, 10-item multidimensional measure of dependence is useful for predicting sustained quitting in a context of relatively light smoking; time-discounting appears less relevant, although our results are not conclusive because of the low test-retest reliability of our measure. IMPLICATIONS: Given the increase in non-daily and light daily cigarette smoking in many countries, including in Mexico, and the health risks this still poses, it is important to understand the predictors of cessation among relatively light smokers. The WISDM-10 multidimensional measure seems to be a good instrument to assess dependence and predict successful quitting in this population, and possibly more appropriate than physical dependence measures. As such, it could help design and target more suitable cessation treatments for non-daily and daily light cigarette smokers. While this study did not find time-discounting to be a relevant predictor of smoking abstinence, future studies should explore other measures.

The impact of sodium-glucose cotransporter-2 inhibitors on outcome of patients with diabetes mellitus and colorectal cancer.

BACKGROUND AND AIM: Patients with type 2 diabetes mellitus (T2DM) have a higher risk of colorectal cancer (CRC), and those with diagnosed CRC have a poorer prognosis compared with individuals with normal glucose levels. The inhibition of sodium-glucose cotransporter 2 (SGLT2) channels has been associated with a reduction in tumor proliferation in preclinical studies. We aimed to investigate the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the outcome of T2DM patients with colorectal cancer. METHODS: We performed a retrospective cohort study comprising adult patients with T2DM and colorectal adenocarcinoma. SGLT2i recipients were matched to non-SGLT2i recipients in a 1:1 ratio based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were previously reported serious adverse events associated with SGLT2i. RESULTS: We identified 1347 patients with T2DM and colorectal adenocarcinoma, from which 92 patients in the SGLT2i cohort were matched to the non-SGLT2i cohort. Compared to non-SGLT2i recipients, SGLT2i recipients had a higher rate of 5-year OS (86.2% [95% CI: 72.0-93.5] vs 62.3% [95% CI: 50.9-71.8], P = 0.013) and 5-year PFS (76.6% [95% CI: 60.7-86.7] vs 57.0% [95% CI: 46.2-66.4], P = 0.021). In Cox proportional hazard analyses, SGLT2i were associated with a 50-70% reduction in all-cause mortality and disease progression. SGLT2i were not associated with an increased risk of serious adverse events. CONCLUSION: SGLT2i were associated with a higher rate of survival in T2DM patients with colorectal cancer.

ColocQuiaL: a QTL-GWAS colocalization pipeline.

SUMMARY: Identifying genomic features responsible for genome-wide association study (GWAS) signals has proven to be a difficult challenge; many researchers have turned to colocalization analysis of GWAS signals with expression quantitative trait loci (eQTL) and splicing quantitative trait loci (sQTL) to connect GWAS signals to candidate causal genes. The ColocQuiaL pipeline provides a framework to perform these colocalization analyses at scale across the genome and returns summary files and locus visualization plots to allow for detailed review of the results. As an example, we used ColocQuiaL to perform colocalization between a recent type 2 diabetes GWAS and Genotype-Tissue Expression (GTEx) v8 single-tissue eQTL and sQTL data. AVAILABILITY AND IMPLEMENTATION: ColocQuiaL is primarily written in R and is freely available on GitHub: https://github.com/bvoightlab/ColocQuiaL.

Deep Eutectic Solvents: A Review of Fundamentals and Applications.

Deep eutectic solvents (DESs) are an emerging class of mixtures characterized by significant depressions in melting points compared to those of the neat constituent components. These materials are promising for applications as inexpensive "designer" solvents exhibiting a host of tunable physicochemical properties. A detailed review of the current literature reveals the lack of predictive understanding of the microscopic mechanisms that govern the structure-property relationships in this class of solvents. Complex hydrogen bonding is postulated as the root cause of their melting point depressions and physicochemical properties; to understand these hydrogen bonded networks, it is imperative to study these systems as dynamic entities using both simulations and experiments. This review emphasizes recent research efforts in order to elucidate the next steps needed to develop a fundamental framework needed for a deeper understanding of DESs. It covers recent developments in DES research, frames outstanding scientific questions, and identifies promising research thrusts aligned with the advancement of the field toward predictive models and fundamental understanding of these solvents.

Prediction of Surgical Outcomes of Radial Polydactyly From the Wassel-Flatt Type and Symmetry of Duplication.

BACKGROUND: The Wassel classification is commonly used for cases of radial polydactyly but has not been used to predict surgical outcomes. This study aimed to investigate the predictive factors of surgical outcomes using the Wassel type and symmetry of duplication. METHODS: Forty-five patients with 47 radial polydactylies were reviewed using the Japanese Society for Surgery of the Hand (JSSH) scores 4.6 years after minor thumb excision and reconstructive surgery. The symmetry index was defined as the metaphyseal width ratio of the minor thumb to the dominant thumb. The relationships between the JSSH scores and operation age, sex, side, follow-up duration, Wassel type, symmetric index, divergent angle, and joint angulation were analyzed by linear regression. RESULTS: The mean JSSH score of the 47 thumbs was 18.3 points (range, 15-20). Five thumbs had fair or poor outcomes (scores <17), all of which were Wassel type IV. The hypoplastic type had a better JSSH score (19.4) than other Wassel types. The symmetric index had a negative relationship with JSSH scores, especially for Wassel type IV (r=-0.68, P =0.001). Linear regression revealed that the symmetric index was the only independent factor significantly associated with JSSH scores among Wassel type IV polydactylies ( P <0.05). The receiver operating characteristic curve suggested a symmetric index <0.74 could predict good or excellent outcomes. CONCLUSION: The symmetry of the 2 duplicated thumbs is an important factor for surgical outcomes. The Wassel type IV polydactylies with a symmetric index >0.74 are at greater risk of fair or poor outcomes after excision and reconstruction, and further studies are warranted to confirm whether the Bilhaut-Cloquet procedure is a good choice. LEVEL OF EVIDENCE: Level IV-Case-control study.

Recurrent hip instability after hip reconstruction in cerebral palsy children with spastic hip disease.

BACKGROUND: Migration percentage (MP) is widely used to evaluate hip stability in children with spastic cerebral palsy (CP). Orthopedic surgeons need more objective information to make a proper hip reconstruction surgical plan and predict the outcome. METHODS: Medical records and plain radiographs of children with CP who underwent the hip reconstruction procedure for dysplasia were reviewed retrospectively. RESULTS: In total, 253 operated hips (140 patients; 11.7 ± 3.3 years old) were included in this study. MP at pre-operative (Tpre) was 35.3 ± 22.5%; at immediate follow-up (Tpost) was 5.9 ± 9.5%; at last follow-up (Tfinal) was 9.8 ± 10.8% (4.5 ± 2.3 years post-operative at age 16.3 ± 2.8 years). In hips with Melbourne Cerebral Palsy Hip Classification Scale (MCPHCS) grade 3 (n = 78), around 30-45% had an unsatisfactory outcome at Tpost and Tfinal. However, hips categorized as other grades showed only 2.1-9.1% of unsatisfactory outcome. In less affected hips (pre-operative MP<30%, n = 122), 109 hips (89.3%) had varus derotation osteotomy only, the other 13 hips (10.7%) were combined with a pelvic osteotomy. In more severely affected hips (pre-operative MP ≥ 30%, n = 131), 26 hips (19.8%) had varus derotation osteotomy only, the other 105 hips (80.2%) were combined with a pelvic osteotomy. CONCLUSIONS: Hips with pre-operative MP between 15 and 29% (MCPHCS grades 3) can be a higher risk group of recurrent hip instability after hip reconstruction surgery. Multiple indications beyond MP should be considered when indicating pelvic osteotomy or hip muscle release as combined procedures with varus femoral osteotomy for hip reconstruction in this milder group to achieve a consistent long-term satisfactory outcome.

A Sonography-based Decision Model for Use in Treatment of Developmental Dysplasia of the Hip.

The objective of this study was to delineate a model for management of developmental dysplasia of the hip (DDH) treatment that incorporates hip ultrasound with objective/predicative parameters at key decision-making times. Hip sonograms of 74 infants (59 females, 15 males; 141 hips) with DDH were retrospectively reviewed. Hip sonographic score (HSS; ranges 0-10) was developed to reflect hip status based on sonographic position, stability, and morphology. Analysis on different management groups (i.e., no treatment, successful treatment, and failed treatment) showed that the trend of HSS is helpful in predicting course of the disease and determining effectiveness of treatment. A model for the management of DDH that utilizes an HSS and frequency schedule for hip sonography that is aligned with times of critical treatment decisions is proposed. This model illustrates how hip sonography can bring added value when timed to guide critical treatment decisions. (Journal of Surgical Orthopaedic Advances 32(1):047-054, 2023).

Favorable Mortality-to-Incidence Ratio Trends of Lung Cancer in Countries with High Computed Tomography Density.

Background and Objectives: The prognoses of lung cancer deteriorate dramatically as the cancer progresses through its stages. Therefore, early screening using techniques such as low-dose computed tomography (LDCT) is critical. However, the epidemiology of the association between the popularization of CT and the prognosis for lung cancer is not known. Materials and Methods: Data were obtained from GLOBOCAN and the health data and statistics of the World Health Organization. Mortality-to-incidence ratios (MIRs) and the changes in MIR over time (δMIR; calculated as the difference between MIRs in 2018 and 2012) were used to evaluate the correlation with CT density disparities via Spearman's rank correlation coefficient. Results: Countries with zero CT density presented a relatively low incidence crude rate and a relatively high MIR in 2018 and a negative δMIR. Conversely, countries with a CT density over 30 had a positive δMIR. The CT density was significantly associated with the HDI score and MIR in 2018, whereas it demonstrated no association with MIR in 2012. The CT density and δMIR also showed a significant linear correlation. Conclusions: CT density was significantly associated with lung cancer MIR in 2018 and with δMIR, indicating favorable clinical outcomes in countries in which CT has become popularized.

Epigenetic moderators of naltrexone efficacy in reducing heavy drinking in Alcohol Use Disorder: a randomized trial.

Polymorphisms in genes associated with opioid signaling and dopamine reuptake and inactivation may moderate naltrexone efficacy in Alcohol Use Disorder (AUD), but the effects of epigenetic modification of these genes on naltrexone response are largely unexplored. This study tested interactions between methylation in the µ-opioid receptor (OPRM1), dopamine transporter (SLC6A3), and catechol-O-methyltransferase (COMT) genes as predictors of naltrexone effects on heavy drinking in a 16-week randomized, placebo-controlled trial among 145 treatment-seeking AUD patients. OPRM1 methylation interacted with both SLC6A3 and COMT methylation to moderate naltrexone efficacy, such that naltrexone-treated individuals with lower methylation of the OPRM1 promoter and the SLC6A3 promoter (p = 0.006), COMT promoter (p = 0.005), or SLC6A3 3' untranslated region (p = 0.004), relative to placebo and to those with higher OPRM1 and SLC6A3 or COMT methylation, had significantly fewer heavy drinking days. Epigenetic modification of opioid- and dopamine-related genes may represent a novel pharmacoepigenetic predictor of naltrexone efficacy in AUD.

The Cost-Effectiveness of Nicotine Replacement Therapy Sampling in Primary Care: a Markov Cohort Simulation Model.

BACKGROUND: Pharmacotherapies remain a central focus of successful tobacco control, but uptake remains very low. OBJECTIVE: To estimate the cost effectiveness of a primary care nicotine replacement therapy (NRT) sampling intervention. DESIGN: A Markov cohort simulation model was constructed to conduct cost-effectiveness analyses. Clinical trial results were used to initialize the Markov model. All other model parameters were derived from the literature. The study was conducted over a lifetime horizon, from the payers' budgetary perspective. PARTICIPANTS: Smokers with a primary care visit. INTERVENTION: Medication sampling, which provided short, starter packets of NRT (nicotine patch and lozenge) to smokers in the primary care setting. MAIN MEASURES: Lifetime healthcare expenditures, quality-adjusted life years, and life years. KEY RESULTS: Medication sampling was the dominant strategy compared to standard care. Our intervention cost $75, yielding a discounted lifetime savings of $1065 in healthcare expenditures, and increased both discounted quality-adjusted life years and discounted life years by 0.01. One-way sensitivity analyses showed that medication sampling remained dominant in plausible ranges except when it failed to increase cessation relative to standard care. Probabilistic sensitivity analyses confirmed that medication sampling was dominant in 94.1% of the simulated cases, with an implementation cost of $74 (95% CI $73-$76) and discounted lifetime savings in health expenditures of $1061 (- $1106 to - $1,017), increasing quality-adjusted life years by 0.008 (0.0085-0.0093) and life years by 0.008 (0.0081-0.0089). CONCLUSION: Medication sampling, an easily implementable, scalable and low-cost intervention to encourage smoking cessation, is cost saving and improves quality of life.

Policing of Drug Safety Information Dissemination Under the False Claims Act.

On July 25, 2017, the second largest multi-million dollar settlement was pursued with the assistance of the Department of Justice and alleging inappropriate marketing strategies utilized by the pharmaceutical industry came to an end.

Assessing the ability of an instrumental variable causal forest algorithm to personalize treatment evidence using observational data: the case of early surgery for shoulder fracture.

BACKGROUND: Comparative effectiveness research (CER) using observational databases has been suggested to obtain personalized evidence of treatment effectiveness. Inferential difficulties remain using traditional CER approaches especially related to designating patients to reference classes a priori. A novel Instrumental Variable Causal Forest Algorithm (IV-CFA) has the potential to provide personalized evidence using observational data without designating reference classes a priori, but the consistency of the evidence when varying key algorithm parameters remains unclear. We investigated the consistency of IV-CFA estimates through application to a database of Medicare beneficiaries with proximal humerus fractures (PHFs) that previously revealed heterogeneity in the effects of early surgery using instrumental variable estimators. METHODS: IV-CFA was used to estimate patient-specific early surgery effects on both beneficial and detrimental outcomes using different combinations of algorithm parameters and estimate variation was assessed for a population of 72,751 fee-for-service Medicare beneficiaries with PHFs in 2011. Classification and regression trees (CART) were applied to these estimates to create ex-post reference classes and the consistency of these classes were assessed. Two-stage least squares (2SLS) estimators were applied to representative ex-post reference classes to scrutinize the estimates relative to known 2SLS properties. RESULTS: IV-CFA uncovered substantial early surgery effect heterogeneity across PHF patients, but estimates for individual patients varied with algorithm parameters. CART applied to these estimates revealed ex-post reference classes consistent across algorithm parameters. 2SLS estimates showed that ex-post reference classes containing older, frailer patients with more comorbidities, and lower utilizers of healthcare were less likely to benefit and more likely to have detriments from higher rates of early surgery. CONCLUSIONS: IV-CFA provides an illuminating method to uncover ex-post reference classes of patients based on treatment effects using observational data with a strong instrumental variable. Interpretation of treatment effect estimates within each ex-post reference class using traditional CER methods remains conditional on the extent of measured information in the data.

Development of a core outcome set for basal cell carcinoma.

BACKGROUND: There is variation in the outcomes reported in clinical studies of basal cell carcinoma. This can prevent effective meta-analyses from answering important clinical questions. OBJECTIVE: To identify a recommended minimum set of core outcomes for basal cell carcinoma clinical trials. METHODS: Patient and professional Delphi process to cull a long list, culminating in a consensus meeting. To be provisionally accepted, outcomes needed to be deemed important (score, 7-9, with 9 being the maximum) by 70% of each stakeholder group. RESULTS: Two hundred thirty-five candidate outcomes identified via a systematic literature review and survey of key stakeholders were reduced to 74 that were rated by 100 health care professionals and patients in 2 Delphi rounds. Twenty-seven outcomes were provisionally accepted. The final core set of 5 agreed-upon outcomes after the consensus meeting included complete response; persistent or serious adverse events; recurrence-free survival; quality of life; and patient satisfaction, including cosmetic outcome. LIMITATIONS: English-speaking patients and professionals rated outcomes extracted from English language studies. CONCLUSION: A core outcome set for basal cell carcinoma has been developed. The use of relevant measures may improve the utility of clinical research and the quality of therapeutic guidance available to clinicians.

Long-term effects of spasticity treatment, including selective dorsal rhizotomy, for individuals with cerebral palsy.

AIM: To understand the long-term effects of comprehensive spasticity treatment, including selective dorsal rhizotomy (SDR), on individuals with spastic cerebral palsy. METHOD: This was a pre-registered, multicenter, retrospectively matched cohort study. Children were matched on age range and spasticity at baseline. Children at one center underwent spasticity treatment including SDR (Yes-SDR, n=35) and antispastic injections. Children at two other centers had no SDR (No-SDR, n=40 total) and limited antispastic injections. All underwent subsequent orthopedic treatment. Participants returned for comprehensive long-term assessment (age ≥21y, follow-up ≥10y). Assessment included spasticity, contracture, bony alignment, strength, gait, walking energy, function, pain, stiffness, participation, and quality of life. RESULTS: Spasticity was effectively reduced at long-term assessment in the Yes-SDR group and was unchanged in the No-SDR group. There were no meaningful differences between the groups in any measure except the Gait Deviation Index (Yes-SDR + 11 vs No-SDR + 5) and walking speed (Yes-SDR unchanged, No-SDR declined 25%). The Yes-SDR group underwent more subsequent orthopedic surgery (11.9 vs 9.7 per individual) and antispastic injections to the lower limbs (14.4 vs <3, by design). INTERPRETATION: Untreated spasticity does not cause meaningful impairments in young adulthood at the level of pathophysiology, function, or quality of life.

What are the health consequences associated with differences in medical malpractice liability laws? An instrumental variable analysis of surgery effects on health outcomes for proximal humeral facture across states with different liability rules.

BACKGROUND: States enacted tort reforms to lower medical malpractice liability, which are associated with higher surgery rates among Medicare patients with shoulder conditions. Surgery in this group often entails tradeoffs between improved health and increased risk of morbidity and mortality. We assessed whether differences in surgery rates across states with different liability rules are associated with surgical outcomes among Medicare patients with proximal humeral fracture. METHODS: We obtained data for 67,966 Medicare beneficiaries with a diagnosis of proximal humeral fracture in 2011. Outcome measures included adverse events, mortality, and treatment success rates, defined as surviving the treatment period with < $300 in shoulder-related expenditures. We used existing state-level tort reform rules as instruments for surgical treatment and separately as predictors to answer our research question, both for the full cohort and for stratified subgroups based on age and general health status measured by Charlson Comorbidity Index and Function-Related Indicators. RESULTS: We found a 0.32 percentage-point increase (p < 0.05) in treatment success and a 0.21 percentage-point increase (p < 0.01) in mortality for every 1 percentage-point increase in surgery rates among patients in states with lower liability risk. In subgroup analyses, mortality increased among more vulnerable patients, by 0.29 percentage-point (p < 0.01) for patients with Charlson Comorbidity Index > = 2 and by 0.45 percentage-point (p < 0.01) among those patients with Function-Related Indicator scores > = 2. On the other hand, treatment success increased in patients with lower Function-Related Index scores (< 2) by 0.54 percentage-point (p < 0.001). However, younger Medicare patients (< 80 years) experienced an increase in both mortality (0.28 percentage-point, p < 0.01) and treatment success (0.89 percentage-point, p < 0.01). The reduced-form estimates are consistent with our instrumental variable results. CONCLUSIONS: A tradeoff exists between increased mortality risk and increased treatment success across states with different malpractice risk levels. These results varied across patient subgroups, with more vulnerable patients generally bearing the brunt of the increased mortality and less vulnerable patients enjoying increased success rates. These findings highlight the important risk-reward scenario associated with different liability environments, especially among patients with different health status.