Recreational Marijuana Laws and Teen Marijuana Use, 1993-2021.

This cross-sectional study uses data from the Youth Risk Behavior surveys to assess the association of state-level recreational marijuana laws and youth marijuana use.

Measuring the burden of hundreds of BioBricks defines an evolutionary limit on constructability in synthetic biology.

Engineered DNA will slow the growth of a host cell if it redirects limiting resources or otherwise interferes with homeostasis. Populations of engineered cells can rapidly become dominated by "escape mutants" that evolve to alleviate this burden by inactivating the intended function. Synthetic biologists working with bacteria rely on genetic parts and devices encoded on plasmids, but the burden of different engineered DNA sequences is rarely characterized. We measured how 301 BioBricks on high-copy plasmids affected the growth rate of Escherichia coli. Of these, 59 (19.6%) negatively impacted growth. The burden imposed by engineered DNA is commonly associated with diverting ribosomes or other gene expression factors away from producing endogenous genes that are essential for cellular replication. In line with this expectation, BioBricks exhibiting burden were more likely to contain highly active constitutive promoters and strong ribosome binding sites. By monitoring how much each BioBrick reduced expression of a chromosomal GFP reporter, we found that the burden of most, but not all, BioBricks could be wholly explained by diversion of gene expression resources. Overall, no BioBricks reduced the growth rate of E. coli by >45%, which agreed with a population genetic model that predicts such plasmids should be "unclonable" because escape mutants will take over during growth of a bacterial colony or small laboratory culture from a transformed cell. We made this model available as an interactive web tool for synthetic biology education and added our burden measurements to the iGEM Registry descriptions of each BioBrick.

Staphylococcus aureus skin colonization is mediated by SasG lectin variation.

Staphylococcus aureus causes the majority of skin and soft tissue infections, but this pathogen only transiently colonizes healthy skin. However, this transient skin exposure enables S. aureus to transition to infection. The initial adhesion of S. aureus to skin corneocytes is mediated by surface protein G (SasG). Here, phylogenetic analyses reveal the presence of two major divergent SasG alleles in S. aureus: SasG-I and SasG-II. Structural analyses of SasG-II identify a nonaromatic arginine in the binding pocket of the lectin subdomain that mediates adhesion to corneocytes. Atomic force microscopy and corneocyte adhesion assays indicate that SasG-II can bind to a broader variety of ligands than SasG-I. Glycosidase treatment results in different binding profiles between SasG-I and SasG-II on skin cells. In addition, SasG-mediated adhesion is recapitulated using differentiated N/TERT keratinocytes. Our findings indicate that SasG-II has evolved to adhere to multiple ligands, conferring a distinct advantage to S. aureus during skin colonization.

An autoantibody signature predictive for multiple sclerosis.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.

Three-Dimensional Instrumented Gait Analysis for Children With Cerebral Palsy: An Evidence-Based Clinical Practice Guideline.

BACKGROUND: Children with cerebral palsy (CP) who walk have complex gait patterns and deviations often requiring physical therapy (PT)/medical/surgical interventions. Walking in children with CP can be assessed with 3-dimensional instrumented gait analysis (3D-IGA) providing kinematics (joint angles), kinetics (joint moments/powers), and muscle activity. PURPOSE: This clinical practice guideline provides PTs, physicians, and associated clinicians involved in the care of children with CP, with 7 action statements on when and how 3D-IGA can inform clinical assessments and potential interventions. It links the action statement grades with specific levels of evidence based on a critical appraisal of the literature. CONCLUSIONS: This clinical practice guideline addresses 3D-IGA's utility to inform surgical and non-surgical interventions, to identify gait deviations among segments/joints and planes and to evaluate the effectiveness of interventions. Best practice statements provide guidance for clinicians about the preferred characteristics of 3D-IGA laboratories including instrumentation, staffing, and reporting practices.Video Abstract: Supplemental digital content available at http://links.lww.com/PPT/A524.

Hormonal Control of Blood Viscosity.

The hemodynamic milieu differs throughout the vascular tree because of varying vascular geometry and blood velocities. Accordingly, the risk of turbulence, which is dictated by the Reynolds and Dean numbers, also varies. Relatively high blood viscosity is needed to prevent turbulence in the left ventricle and aorta, where high-velocity blood changes direction several times. Low blood viscosity is needed in the capillaries, where erythrocytes pass through vessels with a diameter smaller than their own. In addition, higher blood viscosity is necessary when the cardiac output and peak blood velocity increase as a part of a sympathetic response or anemia, which occurs following significant hemorrhage. Blood viscosity, as reflected in systemic vascular resistance and vascular wall shear stress, is sensed, respectively, by cardiomyocyte stretching in the left ventricle and mechanoreceptors for wall shear stress in the carotid sinus. By controlling blood volume and red blood cell mass, the renin-aldosterone-angiotensin system and the systemic vascular resistance response control the hematocrit, the strongest intrinsic determinant of blood viscosity. These responses provide gross control of blood viscosity. Fine-tuning of blood viscosity in transient conditions is provided by hormonal control of erythrocyte deformability. The short half-life of some of these hormones limits their activity to specific vascular beds. Hormones that modulate blood viscosity include erythropoietin, angiotensin II, brain natriuretic factor, epinephrine, prostacyclin E2, antidiuretic hormone, and nitric oxide.

Chatbot Reliability in Managing Thoracic Surgical Clinical Scenarios.

BACKGROUND: Chatbot use in medicine is growing, and concerns have been raised regarding their accuracy. We assessed the performance of four different chatbots in managing thoracic surgical clinical scenarios. METHODS: Topic domains were identified and clinical scenarios were developed within each domain. Each scenario included three stems utilizing Key Feature methods related to diagnosis, evaluation, and treatment. Twelve scenarios were presented to ChatGPT-4, Bard, Perplexity, and Claude 2 in three separate runs. Up to 1 point was awarded for each stem, yielding a potential of 3 points per scenario. Critical failures were identified prior to scoring; if they occurred, the stem and overall scenario scores were adjusted to 0. We arbitrarily established a threshold of ≥2 points mean adjusted score per scenario as a passing grade and established a critical fail rate of ≥30% as failure to pass. RESULTS: The bot performances varied considerably within each run and their overall performance was a fail on all runs (critical mean scenario fails of 83%, 71%, and 71%). The bots trended towards "learning" from the first to the second run, but without improvement in overall raw (1.24 ± 0.47 vs 1.63 ± 0.76 vs 1.51 ± 0.60; p=0.29) and adjusted scenario scores (0.44 ± 0.54 vs 0.80 ± 0.94 vs 0.76 ± 0.81; p=0.48) after all runs. CONCLUSIONS: Chatbot performance in managing clinical scenarios was insufficient to provide reliable assistance. This is a cautionary note against reliance on the current accuracy of chatbots in complex Thoracic Surgery medical decision making.

Pediatric mental health emergency department visits from 2017 to 2022: A multicenter study.

BACKGROUND: The COVID-19 pandemic adversely affected children's mental health (MH) and changed patterns of MH emergency department (ED) utilization. Our objective was to assess how pediatric MH ED visits during the COVID-19 pandemic differed from expected prepandemic trends. METHODS: We retrospectively studied MH ED visits by children 5 to <18 years old at nine U.S. hospitals participating in the Pediatric Emergency Care Applied Research Network Registry from 2017 to 2022. We described visit length by time period: prepandemic (January 2017-February 2020), early pandemic (March 2020-December 2020), midpandemic (2021), and late pandemic (2022). We estimated expected visit rates from prepandemic data using multivariable Poisson regression models. We calculated rate ratios (RRs) of observed to expected visits per 30 days during each pandemic time period, overall and by sociodemographic and clinical characteristics. RESULTS: We identified 175,979 pediatric MH ED visits. Visit length exceeded 12 h for 7.3% prepandemic, 8.4% early pandemic, 15.0% midpandemic, and 19.2% late pandemic visits. During the early pandemic, observed visits per 30 days decreased relative to expected rates (RR 0.80, 95% confidence interval [CI] 0.78-0.84), were similar to expected rates during the midpandemic (RR 1.01, 95% CI 0.96-1.07), and then decreased below expected rates during the late pandemic (RR 0.92, 95% CI 0.86-0.98). During the late pandemic, visit rates were higher than expected for females (RR 1.10, 95% CI 1.02-1.20) and for bipolar disorders (RR 1.83, 95% CI 1.38-2.75), schizophrenia spectrum disorders (RR 1.55, 95% CI 1.10-2.59), and substance-related and addictive disorders (RR 1.50, 95% CI 1.18-2.05). CONCLUSIONS: During the late pandemic, pediatric MH ED visits decreased below expected rates; however, visits by females and for specific conditions remained elevated, indicating a need for increased attention to these groups. Prolonged ED visit lengths may reflect inadequate availability of MH services.

Dermatologic manifestations of hematologic disorders.

Distinguishing key morphologic features and understanding the pathophysiology of common cutaneous manifestations of hematologic disorders is essential to ensure prompt and appropriate treatment. In fact, classic cutaneous signs may provide the first clue to the diagnosis of an underlying hematologic disease. Disorders of coagulation, vascular abnormalities, or cutaneous infiltration and deposition are responsible for the underlying pathophysiology of cutaneous manifestations in the majority of cases. Hematologists often feel ill-equipped in identifying morphologic changes in the skin. Thus, the purpose of this review is to provide a comprehensive overview of classic cutaneous manifestations and diagnostic considerations of the associated hematologic conditions. Though there is a specific focus on non-malignant disorders, those straddling the spectrum of malignancy are also discussed. In many disease states, the skin may serve as an important marker of an emerging hematologic disorder, so close collaboration and multidisciplinary input remain essential to provide optimal and timely care for these patients.

Reported Outcome Measures in Complex Fracture Elbow Dislocations: A Systematic Review.

BACKGROUND: Complex elbow fracture dislocations, dislocation with fracture of one or several surrounding bony stabilizers, are difficult to manage and associated with poor outcomes. While many studies have explored treatment strategies but a lack of standardization of patient-reported outcome measures (PROMs) makes cross-study comparison difficult. In this systematic review, we aim to describe what injury patterns, measured outcomes, and associated complications are reported in the complex elbow fracture dislocation literature to provide outcome reporting recommendations that will facilitate improved future cross-study comparison. METHODS: A systematic review was performed per PRISMA guidelines. We queried PubMed/MEDLINE, Embase, Web of Science, and Cochrane databases to identify articles published between 2010 and 2022 reporting on adult patients who had a complex elbow fracture dislocation. Pathologic fractures were excluded. A bias assessment using the methodological index for non-randomized studies criteria was conducted. For each article, patient demographics, injury pattern, outcome measures, and complications were recorded. RESULTS: Ninety-one studies reporting on 3664 elbows (3654 patients) with an elbow fracture and dislocation (weighted mean age 44 years, follow-up of 30 months, 41% female) were evaluated. Of these, the injury pattern was described in 3378 elbows and included 2951 (87%) terrible triad injuries and 72 (2%) transolecranon fracture-dislocations. The three most commonly reported classification systems were: Mason classification for radial head fractures, Regan and Morrey coronoid classification for coronoid fractures, and O'Driscoll classification for coronoid fractures. Range of motion was reported in 87 (96%) studies with most reporting flexion (n=70), extension (n=62), pronation (n=68), or supination (n=67). Strength was reported in 11 (12%) studies. PROMs were reported in 83 (91%) studies with an average of 2.6 outcomes per study. There were 14 outcome scores including the Mayo Elbow Performance Score (MEPS) (n=69 [83%]), the Disabilities of Arm, Shoulder and Hand (DASH) score (n=28 [34%]), the visual analog scale for pain (VAS) (n=27 [33%]), QuickDASH score (n=13 [15.7%]), and Oxford Elbow score (n=5 [6.0%]). No significance was found between the number of PROMs used per article and the year of publication (P=.313), study type (P=.689), complex fracture pattern (P=.211), or number of elbows included (P=.152). CONCLUSION: There is great heterogeneity in reported PROMs in the complex elbow fracture dislocation literature. Although there is no gold standard PROM for assessing complex elbow fracture dislocations, we recommend the use of at least the MEPS and DASH outcomes measures as well as VAS pain rating scale in future studies to facilitate cross-study comparisons.

Achieving the Fundamental Quantum Limit of Linear Waveform Estimation.

Sensing a classical signal using a linear quantum device is a pervasive application of quantum-enhanced measurement. The fundamental precision limits of linear waveform estimation, however, are not fully understood. In certain cases, there is an unexplained gap between the known waveform-estimation quantum Cramér-Rao bound and the optimal sensitivity from quadrature measurement of the outgoing mode from the device. We resolve this gap by establishing the fundamental precision limit, the waveform-estimation Holevo Cramér-Rao bound, and how to achieve it using a nonstationary measurement. We apply our results to detuned gravitational-wave interferometry to accelerate the search for postmerger remnants from binary neutron-star mergers. If we have an unequal weighting between estimating the signal's power and phase, then we propose how to further improve the signal-to-noise ratio by a factor of sqrt[2] using this nonstationary measurement.

Higher odds of periodontitis in systemic lupus erythematosus compared to controls and rheumatoid arthritis: a systematic review, meta-analysis and network meta-analysis.

Introduction: Periodontitis as a comorbidity in systemic lupus erythematosus (SLE) is still not well recognized in the dental and rheumatology communities. A meta-analysis and network meta-analysis were thus performed to compare the (i) prevalence of periodontitis in SLE patients compared to those with rheumatoid arthritis (RA) and (ii) odds of developing periodontitis in controls, RA, and SLE. Methods: Pooled prevalence of and odds ratio (OR) for periodontitis were compared using meta-analysis and network meta-analysis (NMA). Results: Forty-three observational studies involving 7,800 SLE patients, 49,388 RA patients, and 766,323 controls were included in this meta-analysis. The pooled prevalence of periodontitis in SLE patients (67.0%, 95% confidence interval [CI] 57.0-77.0%) was comparable to that of RA (65%, 95% CI 55.0-75.0%) (p>0.05). Compared to controls, patients with SLE (OR=2.64, 95% CI 1.24-5.62, p<0.01) and RA (OR=1.81, 95% CI 1.25-2.64, p<0.01) were more likely to have periodontitis. Indirect comparisons through the NMA demonstrated that the odds of having periodontitis in SLE was 1.49 times higher compared to RA (OR=1.49, 95% CI 1.09-2.05, p<0.05). Discussion: Given that RA is the autoimmune disease classically associated with periodontal disease, the higher odds of having periodontitis in SLE are striking. These results highlight the importance of addressing the dental health needs of patients with SLE. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42021272876.

Longitudinal changes in adverse effects reporting in multiple dietary supplement classifications: The US military dietary supplement use study.

Over 70% of United States military service members (SMs) regularly use dietary supplements (DSs) and about 18% have reported adverse effects (AEs) associated with use. This investigation examined longitudinal changes in AEs reporting among DS users. On two separate occasions 1.3 ± 0.2 years apart (mean ± standard deviation), 5778 SMs completed identical questionnaires on DS use and associated AEs. Among SMs reporting DS use ≥1 time/week, ≥1 AE was reported by 19% and 15% in the baseline and follow-up phases, respectively. The risk of reporting DS use at follow-up was similar among those reporting and not reporting AEs at baseline for most DS categories including prohormones, proteins/amino acids, individual vitamins and minerals, multivitamin/multiminerals, herbals, fish oils, joint health products, and other DSs. An exception was combination products where those reporting AEs at baseline had an increased risk of use at follow-up (risk ratio = 1.13, 95% confidence interval = 1.06-1.09). Those reporting AEs at baseline and continuing DS use in the follow-up were more likely to report AEs at follow-up compared to those not reporting baseline AEs. In conclusion, AEs reported at baseline did not deter many participants from using DSs in the follow-up period, and many SMs reporting AEs at baseline continued reporting them at follow-up.

The Association between Race and Extended Length of Stay in Low-energy Proximal Humerus Fractures in Elderly Patients.

INTRODUCTION: Proximal humerus fractures (PHFs) are one of the most common fractures among patients aged 65 years and older, commonly due to low-energy mechanisms. It is essential to identify drivers of increased healthcare utilization in geriatric PHF patients and bring awareness to any disparities in care. Here, we identify factors associated with the likelihood of inpatient admission and prolonged hospital stay among patients aged 65 years and older who sustain PHF due to falls. METHODS: A national database was used to identify patients aged 65 years and older who suffered proximal humeral fractures due to a fall. Patient factors were analyzed for association with the likelihood of admission and odds of prolonged stay (≥5 days). RESULTS: In the study period, 75,385 PHF patients who met our inclusion criteria presented to the emergency department and 14,118 (18.7%) were admitted. Black race was significantly associated with decreased odds of admission (P < 0.001) and increased likelihood of prolonged stay (P = 0.007) compared with White patients. Patients aged 75 to 84 and 85+ were both more likely to be admitted (P < 0.001) and experienced a prolonged hospital stay (P = 0.015). Patients undergoing surgical intervention with reverse total shoulder arthroplasty were associated with admission and prolonged length of stay (P < 0.001). Hospitals in Midwestern (P < 0.001) and Western (P < 0.001) regions exhibited lower rates of admission and Northeastern hospitals were associated with prolonged stays (P = 0.001). Finally, trauma and nonmetropolitan (P < 0.001) centers were associated with admission. CONCLUSION: Our study highlights the notable influence of age and race on the likelihood of hospital admission and prolonged hospital stay. Specifically, Black patients exhibited prolonged hospital stay, which has been associated with lower-quality care, warranting additional exploration. Understanding these demographic and hospital-related factors is essential for optimizing resource allocation and reducing healthcare disparities in the care of PHF patients, especially as the population ages and the incidence of PHF continues to rise.

Repeat Next-Generation Sequencing Testing on Progression in Men With Metastatic Prostate Cancer Can Identify New Actionable Alterations.

PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB. RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients. CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.

Timing of Radiotherapy (RT) After Radical Prostatectomy (RP): Long-term outcomes in the RADICALS-RT trial [NCT00541047].

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for PSA failure. METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, pre-op PSA≥10ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ("Adjuvant-RT") or an observation policy with salvage RT for PSA failure ("Salvage-RT") defined as PSA≥0.1ng/ml or 3 consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5Gy/20 fractions or 66Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant metastasis, designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10yr with Adjuvant-RT. Secondary outcome measures were bPFS, freedom-from-non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; HR<1 favours Adjuvant-RT. FINDINGS: Between Oct-2007 and Dec-2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with median age 65yr. 93% (649/697) Adjuvant-RT reported RT within 6m after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10yr FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 (95%CI 0·43-1·07, p=0·095). Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95%CI 0.667-1.440, p=0.917). Adjuvant-RT reported worse urinary and faecal incontinence one year after randomisation (p=0.001); faecal incontinence remained significant after ten years (p=0.017). INTERPRETATION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy.

Lipoprotein insulin resistance score and mortality risk stratification in heart failure.

BACKGROUND: Higher total serum cholesterol is associated with lower mortality in heart failure. Evaluating associations between lipoprotein subfractions and mortality among people with heart failure may provide insights into this observation. METHODS: We prospectively enrolled a community cohort of people with heart failure from 2003 to 2012 and assessed vital status through 2021. Plasma collected at enrollment was used to measure lipoprotein subfractions via nuclear magnetic resonance spectroscopy. A composite score of six lipoprotein subfractions was generated using the lipoprotein insulin resistance index (LP-IR) algorithm. Using covariate-adjusted proportional hazards regression models, we evaluated associations between LP-IR score and all-cause mortality. RESULTS: Among 1,382 patients with heart failure (median follow-up 13.9 years), a one standard deviation (SD) increment in LP-IR score was associated with lower mortality (hazard ratio [HR]= 0.93, 95% CI: 0.97, 0.99). Among LP-IR parameters, mean high density lipoprotein (HDL) particle size was significantly associated with lower mortality (HR per 1-SD decrement in mean HDL particle size = 0.83, 95% CI: 0.78, 0.89), suggesting the inverse association between LP-IR score and mortality may be driven by smaller mean HDL particle size. CONCLUSIONS: LP-IR score was inversely associated with mortality among patients with heart failure and may be driven by smaller HDL particle size.