Factors Associated with Venous Thromboembolism Pharmacoprophylaxis Initiation in Hospitalized Medical Patients: The Medical Inpatients Thrombosis and Hemostasis (MITH) Study.

BACKGROUND: Although guidelines recommend risk assessment for hospital-acquired venous thromboembolism (HA-VTE) to inform prophylaxis decisions, studies demonstrate inappropriate utilization of pharmacoprophylaxis in hospitalized medical patients. Predictors of pharmacoprophylaxis initiation in medical inpatients remain largely unknown. OBJECTIVE: To determine factors associated with HA-VTE pharmacoprophylaxis initiation in adults hospitalized on medical services. DESIGN: Cohort study using electronic health record data from adult patients hospitalized on medical services at four academic medical centers between 2016 and 2019. PARTICIPANTS: Among 111,550 admissions not on intermediate or full-dose anticoagulation, 48,520 (43.5%) received HA-VTE pharmacoprophylaxis on the day of or the day after admission. MAIN MEASURES: Candidate predictors of HA-VTE pharmacoprophylaxis initiation, including known HA-VTE risk factors, predicted HA-VTE risk, and bleeding diagnoses present on admission. KEY RESULTS: After adjustment for age, sex, race/ethnicity, and study site, the strongest clinical predictors of HA-VTE pharmacoprophylaxis initiation were malnutrition and chronic obstructive pulmonary disease. Thrombocytopenia and history of gastrointestinal bleeding were associated with decreased odds of HA-VTE pharmacoprophylaxis initiation. Patients in the highest two tertiles of predicted HA-VTE risk were less likely to receive HA-VTE pharmacoprophylaxis than patients in the lowest (1st) tertile (OR 0.84, 95% CI [0.81, 0.86] for 2nd tertile, OR 0.95, 95% CI [0.92, 0.98] for 3rd tertile). CONCLUSIONS: Among patients not already receiving anticoagulants, HA-VTE pharmacoprophylaxis initiation during the first two hospital days was lower in patients with higher predicted HA-VTE risk and those with risk factors for bleeding. Reasons for not initiating pharmacoprophylaxis in those with higher predicted risk could not be assessed.

Early 3D Growth in Uncomplicated Type B Aortic Dissection is Associated with Long-Term Outcomes.

OBJECTIVE: Late adverse events (LAE) are common among initially uncomplicated type B aortic dissection (uTBAD), however, identifying those patients at highest risk of LAE remains a significant challenge. Early false lumen (FL) growth has been suggested to increase risk, but confident determination of growth is often hampered by error in 2D clinical measurements. Semi-automated 3D mapping of aortic growth, such as by vascular deformation mapping (VDM), can potentially overcome this limitation using CT angiograms (CTA). We hypothesized that FL growth in the early pre-dissection phase by VDM can accurately predict LAEs. METHODS: We performed a two-centre retrospective study of uTBAD patients, with paired CTAs in the acute (1-14 days) and subacute/early chronic (1-6 months) periods. VDM analysis was used to map 3D growth. Standard clinical CT measures (i.e., aortic diameters, tear characteristics) were also collected. Multivariate analysis was conducted using a decision tree and Cox proportional hazards model. LAEs were defined as aneurysmal FL (>55mm); rapid growth (>5mm within 6 months); aorta-specific mortality, rupture, or re-dissection. RESULTS: 107 (69% male) initially uTBAD patients met inclusion criteria with a median follow-up of 7.3 (IQR 4.7-9.9) years. LAEs occurred in 72 patients (67%) at 2.5 (IQR 0.7-4.8) years after the initial event. A multivariate decision tree model identified VDM growth (>2.1 mm) and baseline diameter (>42.7 mm) as optimal predictors of LAEs (AUC-ROC = 0.94), achieving an 87% accuracy (sensitivity of 93%, specificity of 76%) after leave-one-out validation. Guideline reported high-risk features were not significantly different between groups. CONCLUSION: Early growth of the FL in uTBAD was the best tested indicator for LAEs and improves upon the current gold-standard of baseline diameter in selecting patients for early prophylactic TEVAR.

Do 3-dimensional Spinopelvic Characteristics Normalize After THA? A Prospective, Comparative Study Using Motion Capture Analysis.

BACKGROUND: Spinopelvic stiffness (primarily in the sagittal plane) has been identified as a factor associated with inferior patient-reported outcomes (PROs) and increased dislocation risk after THA. Incorporating preoperative spinopelvic characteristics into surgical planning has been suggested to determine a patient-specific cup orientation that minimizes dislocation risk. Sagittal plane radiographic analysis of static postures indicates that patients exhibit a degree of normalization in their spinopelvic characteristics after THA. It is not yet known whether normalization is also evident during dynamic movement patterns, nor whether it occurs in the coronal and axial planes as well. QUESTIONS/PURPOSES: (1) Does motion capture analysis of sagittal spinopelvic motion provide evidence of normalization after THA? (2) Do changes in coronal and axial plane motion accompany those in the sagittal plane? METHODS: Between April 2019 and February 2020, 25 patients agreed to undergo motion capture movement analysis before THA for the treatment of hip osteoarthritis (OA). Of those, 20 underwent the same assessment between 8 and 31 months after THA. Five patients were excluded because of revision surgery (n = 1), contralateral hip OA (n = 1), and technical issues with a force plate during post-THA assessment (n = 3), leaving a cohort total of 15 (median age [IQR] 65 years [10]; seven male and eight female patients). A convenience sample of nine asymptomatic volunteers, who were free of hip and spinal pathology, was also assessed (median age 51 years [34]; four male and five female patients). Although the patients in the control group were younger than those in the patient group, this set a high bar for our threshold of spinopelvic normalization, reducing the possibility of false positive results. Three-dimensional motion capture was performed to measure spinal, pelvic, and hip motion while participants completed three tasks: seated bend and reach, seated trunk rotation, and gait on a level surface. ROM during each task was assessed and compared between pre- and post-THA conditions and between patients and controls. Statistical parametric mapping (SPM) was used to assess the timing of differences in motion during gait, and spatiotemporal gait parameters were also measured. RESULTS: After THA, patients demonstrated improvements in sagittal spinal (median [IQR] 32° [18°] versus 41° [14°]; difference of medians 9°; p = 0.004), pelvis (25° [21°] versus 30° [8°]; difference of medians 5°; p = 0.02), and hip ROM (21° [18°] versus 27° [10°]; difference of medians 6°; p = 0.02) during seated bend and reach as well in sagittal hip ROM during gait (30° [11°] versus 44° [7°]; difference of medians 14°; p < 0.001) compared with their pre-THA results, and they showed a high degree of normalization overall. These sagittal plane changes were accompanied by post-THA increases in coronal hip ROM (12° [9°] versus 18° [8°]; difference of medians 6°; p = 0.01) during seated trunk rotation, by both coronal (6° [4°] versus 9° [3°]; difference of medians 3°; p = 0.01) and axial (10° [8°] versus 16° [7°]; difference of medians 6°; p = 0.003) spinal ROM, as well as coronal (8° [3°] versus 13° [4°]; difference of medians 5°; p < 0.001) and axial hip ROM (21° [11°] versus 34° [24°]; difference of medians 13°; p = 0.01) during gait compared with before THA. The SPM analysis showed these improvements occurred during the late swing and early stance phases of gait. CONCLUSION: When restricted preoperatively, spinopelvic characteristics during daily tasks show normalization after THA, concurring with previous radiographic findings in the sagittal plane. Thus, spinopelvic characteristics change dynamically, and incorporating them into surgical planning would require predictive models on post-THA improvements to be of use. LEVEL OF EVIDENCE: Level II, prognostic study.

Testing the combined effects of the PAX Good Behavior Game and MyTeachingPartner™ coaching for early career teachers: Impacts on teacher-student interaction quality and teachers' occupational health.

Early career teachers experience exceptionally high rates of attrition from the profession, often due in part to elevated concerns about student behavior and poor occupational health. This study reports findings from a randomized controlled trial testing the combined effect of the PAX Good Behavior Game and MyTeachingPartner™ for 188 early career, early elementary teachers (Grades K-3). Of primary focus were observations of the quality of teachers' interactions with students and their self-reported occupational health over 2 consecutive school years. Results indicated that relative to comparison teachers, those in the intervention condition reported lower distress at follow-up (d = -0.23) and less decline in teacher affiliation across the 2-year period (d = 0.50). In addition, the intervention teachers who were highly distressed at baseline and who experienced high levels of disruptive behavior had higher quality interactions with students around emotional support (d = 0.27), classroom organization (d = 0.32), and instructional support (d = 0.69) at the end of 2 years than comparison teachers. This subgroup of intervention teachers also experienced more favorable changes over time in distress (d = -2.47) and teacher affiliation (d = 3.00) over the course of the study. Professional development focused on classroom management with coaching support may be particularly impactful for early career teachers experiencing higher levels of distress and in classrooms with higher rates of behavior problems.

Mental Health Care Use among Adolescent Sexual Minority Males Before and During COVID-19.

Adolescent (cisgender) sexual minority males (ASMM) face multiple mental health disparities. Yet surprisingly little is known about use of mental health care among ASMM. The current study examined mental health care use among ASMM, both lifetime use and during the COVID-19 pandemic. ASMM (N=154, ages 14-17 years) enrolled in Spring 2020 for a pilot randomized controlled trial of an online sexual health intervention. Participants were assessed at baseline and 3-month follow-up. Participants reported lifetime (at baseline) and recent (at follow-up) mental health care use. Anxiety and depressive symptoms were assessed at both timepoints. Differences in care use by sociodemographics, healthcare access, and mental health symptoms were established. More than half of participants reported clinically significant anxiety and depressive symptoms at baseline and at follow-up. Of those youth, fifty-three percent reported lifetime mental health care use, while only 28% reported recent care at follow-up. Being out to an accepting guardian (aOR=4.0, 95% CI: 1.9-8.4), having a primary care physician (aOR=2.6, 95% CI: 1.0-6.7), and having clinically significant symptoms (aOR=3.1, 95% CI: 1.5-6.5) were each independently associated with a greater odds of having received lifetime mental health care. Findings indicate that many ASMM in the sample received mental health care in their lifetimes. However, more participants endorsed clinically significant anxiety/depressive symptoms than received care at both timepoints. This disparity was even more pronounced approximately five months into the COVID-19 pandemic. Research and practice efforts must reduce care barriers and augment facilitators for all ASMM, with particular urgency during COVID-19 and its aftermath.

Vision Impairment and the Population Attributable Fraction of Dementia in Older Adults.

Importance: Vision impairment is a potentially modifiable risk factor for dementia. Although few prior studies have estimated the contribution of vision impairments to dementia, none have reported on multiple objectively measured vision impairments (eg, distance and near visual acuity and contrast sensitivity) in a nationally representative sample of older adults. Objective: To quantify population attributable fractions of dementia from objective vision impairments in older adults, stratified by age, self-reported sex, self-reported race and ethnicity, and educational attainment. Design, Setting, and Participants: This was a population-based cross-sectional analysis in the National Health and Aging Trends Study, which gathers nationally representative information on Medicare beneficiaries aged 65 years and older in the US. A total of 2767 community-dwelling adults eligible for vision and cognitive testing in 2021 were included. Data were analyzed from April to August 2023. Exposures: Near and distance visual acuity impairments were each defined as >0.30 logMAR. Contrast sensitivity impairment was defined as <1.55 logCS. At least 1 vision impairment was defined as impairment to either near acuity, distance acuity, or contrast sensitivity. Main Outcomes and Measures: Adjusted population attributable fractions of prevalent dementia, defined using a standardized algorithmic diagnosis (≥1.5 SDs below mean on 1 or more cognitive domains, self- or proxy-reported dementia diagnosis, or the Ascertain Dementia-8 Dementia Screening Interview Score of probable dementia). Results: The survey-weighted prevalence of vision impairment among participants aged 71 and older (1575 [54.7%] female and 1192 [45.3%] male; 570 [8.0%] non-Hispanic Black, 132 [81.7%] Hispanic, 2004 [81.7%] non-Hispanic White, and 61 [3.3%] non-Hispanic other) was 32.2% (95% CI, 29.7-34.6). The population attributable fraction of prevalent dementia from at least 1 vision impairment was 19.0% (95% CI, 8.2-29.7). Contrast sensitivity impairment yielded the strongest attributable fraction among all impairments (15.0%; 95% CI, 6.6-23.6), followed by near acuity (9.7%; 95% CI, 2.6-17.0) and distance acuity (4.9%; 95% CI, 0.1-9.9). Population attributable fractions from at least 1 impairment were highest among participants aged 71 to 79 years (24.3%; 95% CI, 6.6-41.8), female (26.8%; 95% CI, 12.2-39.9), and non-Hispanic White (22.3%; 95% CI, 9.6-34.5) subpopulations, with estimates consistent across educational strata. Conclusions and Relevance: The population attributable fraction of dementia from vision impairments ranged from 4.9%-19.0%. While not proving a cause-and-effect relationship, these findings support inclusion of multiple objective measures of vision impairments, including contrast sensitivity and visual acuity, to capture the total potential impact of addressing vision impairment on dementia.

Airway tryptase levels inform the lack of clinical efficacy of the tryptase inhibitor MTPS9579A in asthma.

BACKGROUND: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract. METHODS: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid. RESULTS: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline. CONCLUSIONS: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.

Effect of hearing intervention on communicative function: A secondary analysis of the ACHIEVE randomized controlled trial.

BACKGROUND: The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Study was designed to determine the effects of a best-practice hearing intervention on cognitive decline among community-dwelling older adults. Here, we conducted a secondary analysis of the ACHIEVE Study to investigate the effect of hearing intervention on self-reported communicative function. METHODS: The ACHIEVE Study is a parallel-group, unmasked, randomized controlled trial of adults aged 70-84 years with untreated mild-to-moderate hearing loss and without substantial cognitive impairment. Participants were randomly assigned (1:1) to a hearing intervention (audiological counseling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed semiannually for 3 years. Self-reported communicative function was measured with the Hearing Handicap Inventory-Elderly Screening version (HHIE-S, range 0-40, higher scores indicate greater impairment). Effect of hearing intervention versus control on HHIE-S was analyzed through an intention-to-treat model controlling for known covariates. RESULTS: HHIE-S improved after 6-months with hearing intervention compared to control, and continued to be better through 3-year follow-up. We estimated a difference of -8.9 (95% CI: -10.4, -7.5) points between intervention and control groups in change in HHIE-S score from baseline to 6 months, -9.3 (95% CI: -10.8, -7.9) to Year 1, -8.4 (95% CI: -9.8, -6.9) to Year 2, and - 9.5 (95% CI: -11.0, -8.0) to Year 3. Other prespecified sensitivity analyses that varied analytical parameters did not change the observed results. CONCLUSIONS: Hearing intervention improved self-reported communicative function compared to a control intervention within 6 months and with effects sustained through 3 years. These findings suggest that clinical recommendations for older adults with hearing loss should encourage hearing intervention that could benefit communicative function and potentially have positive downstream effects on other aspects of health.

"Synthetic" DSC perfusion MRI with adjustable acquisition parameters in brain tumors using dynamic spin-and-gradient-echo echoplanar imaging.

BACKGROUND AND PURPOSE: Normalized relative cerebral blood volume (nrCBV) and percentage of signal recovery (PSR) computed from dynamic susceptibility contrast (DSC) perfusion imaging are useful biomarkers for differential diagnosis and treatment response assessment in brain tumors. However, their measurements are dependent on DSC acquisition factors, and CBV-optimized protocols technically differ from PSR-optimized protocols. This study aimed to generate "synthetic" DSC data with adjustable synthetic acquisition parameters using dual-echo gradient-echo (GE) DSC datasets extracted from dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI). Synthetic DSC was aimed at: 1) simultaneously create nrCBV and PSR maps using optimal sequence parameters, 2) compare DSC datasets with heterogeneous external cohorts, and 3) assess the impact of acquisition factors on DSC metrics. MATERIALS AND METHODS: Thirty-eight patients with contrast-enhancing brain tumors were prospectively imaged with dynamic SAGE-EPI during a non-preloaded single-dose contrast injection and included in this cross-sectional study. Multiple synthetic DSC curves with desired pulse sequence parameters were generated using the Bloch equations applied to the dual-echo GE data extracted from dynamic SAGE-EPI datasets, with or without optional preload simulation. RESULTS: Dynamic SAGE-EPI allowed for simultaneous generation of CBV-optimized and PSR-optimized DSC datasets with a single contrast injection, while PSR computation from guideline-compliant CBV-optimized protocols resulted in rank variations within the cohort (Spearman's ρ=0.83-0.89, i.e. 31%-21% rank variation). Treatment-naïve glioblastoma exhibited lower parameter-matched PSR compared to the external cohorts of treatment-naïve primary CNS lymphomas (PCNSL) (p<0.0001), supporting a role of synthetic DSC for multicenter comparisons. Acquisition factors highly impacted PSR, and nrCBV without leakage correction also showed parameter-dependence, although less pronounced. However, this dependence was remarkably mitigated by post-hoc leakage correction. CONCLUSIONS: Dynamic SAGE-EPI allows for simultaneous generation of CBV-optimized and PSR-optimized DSC data with one acquisition and a single contrast injection, facilitating the use of a single perfusion protocol for all DSC applications. This approach may also be useful for comparisons of perfusion metrics across heterogeneous multicenter datasets, as it facilitates post-hoc harmonization. ABBREVIATIONS: DSC = dynamic susceptibility contrast; FA = flip angle; GBCA = gadolinium-based contrast agent; GBM = glioblastoma; GE = gradient echo; IDH = isocitrate dehydrogenase; IDHm = IDH-mutant; IDHwt = IDH-wild-type; 1p19qcod = 1p19q codeleted; 1p19qint = 1p19q intact; MRI = magnetic resonance imaging; PCNSL = primary CNS lymphoma; PSR = percentage of signal recovery; Rec = recurrent; SAGE-EPI = spin-and-gradient-echo echoplanar imaging; CBV = cerebral blood volume; nrCBV = normalized relative CBV; ROI = region of interest; TE = echo time; TN = treatment-naïve; TR = repetition time.

An instantaneous voice synthesis neuroprosthesis.

Brain computer interfaces (BCIs) have the potential to restore communication to people who have lost the ability to speak due to neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text1-3. However, text communication fails to capture the nuances of human speech such as prosody, intonation and immediately hearing one's own voice. Here, we demonstrate a "brain-to-voice" neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real-time to change intonation, emphasize words, and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.

A Case Report of a Mysterious Mycetoma.

Mycetoma, a chronic subcutaneous infection caused by bacterial or fungal species from soil and water, presents a diagnostic challenge due to its rarity and diverse clinical manifestations. Predominantly affecting male workers in endemic regions, mycetoma typically manifests as painless swelling evolving into purulent lesions with draining sinuses in the extremities. Although historically uncommon in regions like North America, rising immigration and international travel have led to an increased prevalence, necessitating heightened clinical suspicion. Early diagnosis is crucial to prevent severe complications such as limb loss and septicemia. This case report details the diagnosis and management of chronic actinomycetoma due to Nocardia spp. in a Guatemalan immigrant landscaper and emphasizes the importance of comprehensive understanding and timely intervention in mycetoma cases.

An Accurate and Rapidly Calibrating Speech Neuroprosthesis.

BACKGROUND: Brain-computer interfaces can enable communication for people with paralysis by transforming cortical activity associated with attempted speech into text on a computer screen. Communication with brain-computer interfaces has been restricted by extensive training requirements and limited accuracy. METHODS: A 45-year-old man with amyotrophic lateral sclerosis (ALS) with tetraparesis and severe dysarthria underwent surgical implantation of four microelectrode arrays into his left ventral precentral gyrus 5 years after the onset of the illness; these arrays recorded neural activity from 256 intracortical electrodes. We report the results of decoding his cortical neural activity as he attempted to speak in both prompted and unstructured conversational contexts. Decoded words were displayed on a screen and then vocalized with the use of text-to-speech software designed to sound like his pre-ALS voice. RESULTS: On the first day of use (25 days after surgery), the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. Calibration of the neuroprosthesis required 30 minutes of cortical recordings while the participant attempted to speak, followed by subsequent processing. On the second day, after 1.4 additional hours of system training, the neuroprosthesis achieved 90.2% accuracy using a 125,000-word vocabulary. With further training data, the neuroprosthesis sustained 97.5% accuracy over a period of 8.4 months after surgical implantation, and the participant used it to communicate in self-paced conversations at a rate of approximately 32 words per minute for more than 248 cumulative hours. CONCLUSIONS: In a person with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore conversational communication after brief training. (Funded by the Office of the Assistant Secretary of Defense for Health Affairs and others; BrainGate2 ClinicalTrials.gov number, NCT00912041.).

Folate Deficiency and Medication-Induced Severe Pancytopenia in a Bilateral Lung Transplantee.

Folate is a water-soluble vitamin that is essential to DNA synthesis and replication. Its deficiency is a leading cause of megaloblastic anemia, which is often asymptomatic but can present with nonspecific symptoms, such as fatigue and lightheadedness. Folate deficiency can rarely present with pancytopenia, which has been described in past case reports but even more scarcely in transplant recipients. We present a 74-year-old bilateral lung transplantee who presented with presyncope and was found to have severe pancytopenia with folate deficiency during the initial workup. Some medications, including mycophenolate mofetil, valganciclovir, and posaconazole were held. Peripheral blood smear showed blastoid cells, but follow-up imaging and flow cytometry negated any concern for a malignant process. Bone marrow biopsy showed an extremely hypocellular marrow with marked trilineage hypoplasia. He required blood product transfusions, but his admission was overall uneventful with no life-threatening sequelae. His blood counts improved with folate replacement and discontinuation of offending medications. He was discharged after nine days in stable condition. Two months later, he experienced a milder and self-limited recurrence of pancytopenia with normal folate and cobalamin levels.

Firearm injury hospitalizations and handgun purchaser licensing laws: longitudinal evaluation of state-level purchaser licensure requirements on firearm violence, 2000-2016.

BACKGROUND: Handgun purchaser licensing (HPL) laws mandate individuals to obtain a license from law enforcement before buying a firearm. Research indicates these laws effectively reduce various forms of fatal firearm violence, including homicides, suicides, and mass shootings. Our study sought to assess the impact of HPL laws on non-fatal firearm violence. METHODS: Utilizing the augmented synthetic control method (ASCM), we estimated the average treatment effect on the treated (ATT) resulting from a full repeal of an HPL law in Missouri (2007), a partial repeal in Michigan (2012), and an adoption on HPL law in Maryland (2013) on firearm injury hospitalizations. We utilized RAND's healthcare cost and utilization project-based dataset from 2000 to 2016 for our outcome variable. We conducted in-time placebo testing and leave-one-out donor pool testing as sensitivity analyses. RESULTS: Maryland's adoption was associated with a statistically significant 32.3% reduction in firearm-related injury hospitalization (FIH) rates (ATT = - 0.497, standard error (SE) = 0.123); Missouri's repeal was associated with a statistically significant 35.7% increase in FIH rates (ASCM = 0.456, SE = 0.155); and Michigan's partial repeal showed no statistically significant associations with FIH rates (ATT = - 0.074, SE = 0.129). Sensitivity analyses confirm the robustness of the estimated HPL effects. DISCUSSION: HPL laws appear to be protective against hospitalizations for nonfatal firearm injuries. These findings align with prior research indicating that HPL laws are effective in reducing fatal firearm violence. States without such licensing systems ought to consider these robust policies as a means to address firearm violence.

Exon 1-targeting miRNA reduces the pathogenic exon 1 HTT protein in Huntington disease models.

Huntington disease (HD) is a fatal neurodegenerative disease caused by a trinucleotide repeat expansion in exon 1 of the huntingtin gene (HTT) resulting in toxic gain-of-function and cell death. Despite its monogenic cause, the pathogenesis of HD is highly complex and increasing evidence indicates that, in addition to the full-length (FL) mutant HTT protein, the expanded exon 1 HTT (HTTexon1) protein that is translated from the HTT1a transcript generated by aberrant splicing is prone to aggregate and may contribute to HD pathology. This finding suggests that reducing the expression of HTT1a may achieve a greater therapeutic benefit than targeting only FL mutant HTT. Conversely, strategies that exclusively target FL HTT may not fully prevent the pathogenesis of HD. We have developed an engineered microRNA targeting the HTT exon 1 sequence (miHTT), delivered via adeno-associated virus serotype 5 (AAV5). The target sequence of miHTT is present in both FL HTT and HTT1a transcripts. Preclinical studies with AAV5-miHTT have demonstrated efficacy in several rodent and large animal models by reducing FL HTT mRNA and protein and rescuing HD-like phenotypes, and have been the rationale for phase I/II clinical studies now ongoing in the US and Europe. In the present study, we evaluated the ability of AAV5-miHTT to reduce the levels of aberrantly spliced HTT1a mRNA and the HTTexon1 protein in the brain of two mouse models of HD (heterozygous zQ175 knock-in mice and humanized Hu128/21 mice). Polyadenylated HTT1a mRNA and HTTexon1 protein were detected in the striatum and cortex of heterozygous zQ175 knock-in mice, but not in wild-type, littermate control mice. Intrastriatal administration of AAV5-miHTT resulted in dose-dependent expression of mature miHTT microRNA in cortical brain regions, accompanied by significant lowering of both FL HTT and HTT1a mRNA expression at two months post-injection. Mutant HTT and HTTexon1 protein levels were also significantly reduced in the striatum and cortex of heterozygous zQ175 knock-in at 2 months after AAV5-miHTT treatment and in humanized Hu128/21 mice 7 months post-treatment. The effects were confirmed in primary Hu128/21 neuronal cultures. These results demonstrate that AAV5-miHTT gene therapy is an effective approach to lower both FL HTT and the pathogenic HTTexon1 levels, which could potentially have an additive therapeutic benefit compared to other HTT-targeting modalities.

Intersystem Crossing Control of the Nb+ + CO2 → NbO+ + CO Reaction.

The transfer of an oxygen atom from carbon dioxide (CO2) to a transition metal cation in the gas phase offers atomic level insights into single-atom catalysis for CO2 activation. Given that these reactions often involve open-shell transition metals, they may proceed through intersystem crossing between different spin manifolds. However, a definitive understanding of such spin-forbidden reaction requires dynamical calculations on multiple global potential energy surfaces (PESs) coupled by spin-orbit couplings. In this work, we report global PESs and spin-orbit couplings for three low-lying spin (quintet, triplet, and singlet) states for the reaction between the niobium cation (Nb+) and CO2, which are used to investigate the nonadiabatic reaction dynamics and kinetics. Comparison with experimental data of kinetics and collision dynamics shows satisfactory agreement. This reaction is found to be very similar to that between Ta+ + CO2. Specifically, our theoretical findings suggest that the rate-limiting step in this reaction is intersystem crossing, rather than potential barriers.