A phase 2 single-arm trial of high-dose precision targeted radiotherapy added to immunotherapy for patients with metastatic non-small cell lung cancer.

HYPOTHESIS: For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS). METHODS: In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%. RESULTS: Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis. CONCLUSIONS: The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease.

Association between state minimum wage and firearm suicides in the USA, 2000-2020.

BACKGROUND: Firearm suicides constitute a major public health issue. Policies that enhance economic security and decrease community-level poverty may be effective strategies for reducing risk of firearm suicide. This study examined the association between state minimum wage and firearm suicide. METHODS: State minimum wage, obtained from Temple's Law Atlas and augmented by legal research, was conceptualised using the modified Kaitz Index and a continuous variable centred on the federal minimum wage. State-level suicide counts were obtained from 2000 to 2020 multiple-cause-of-death mortality data from the National Vital Statistics System. Log-linear regressions were conducted to model the associations between state minimum wage and firearm suicides, stratifying by demographic groups. Analyses were conducted in 2023. RESULTS: A one percentage point increase in a state's modified Kaitz Index was associated with a 0.3% (95% CI -0.6% to -0.0%) decrease in firearm suicides within a state. A US$1.00 increase in a state's minimum wage above the federal minimum wage was associated with a 1.4% (95% CI -2.1% to -0.6%) decrease in firearm suicides. When stratified by quartile of firearm ownership, the modified Kaitz Index was associated with decreases in firearm suicides most consistently in the two lowest quartiles. CONCLUSION: Increasing a state's minimum wage may be a policy option to consider as part of a comprehensive approach to reducing firearm suicides. These findings expand the evidence base for how economic policies may be leveraged to reduce firearm suicides.

Synthesis and Characterization of Sol-Gelled Barium Zirconate as Novel MTA Radiopacifiers.

Barium zirconate (BaZrO3, BZO), which exhibits superior mechanical, thermal, and chemical stability, has been widely used in many applications. In dentistry, BZO is used as a radiopacifier in mineral trioxide aggregates (MTAs) for endodontic filling applications. In the present study, BZO was prepared using the sol-gel process, followed by calcination at 700-1000 °C. The calcined BZO powders were investigated using X-ray diffraction and scanning electron microscopy. Thereafter, MTA-like cements with the addition of calcined BZO powder were evaluated to determine the optimal composition based on radiopacity, diametral tensile strength (DTS), and setting times. The experimental results showed that calcined BZO exhibited a majority BZO phase with minor zirconia crystals. The crystallinity, the percentage, and the average crystalline size of BZO increased with the increasing calcination temperature. The optimal MTA-like cement was obtained by adding 20% of the 700 °C-calcined BZO powder. The initial and final setting times were 25 and 32 min, respectively. They were significantly shorter than those (70 and 56 min, respectively) prepared with commercial BZO powder. It exhibited a radiopacity of 3.60 ± 0.22 mmAl and a DTS of 3.02 ± 0.18 MPa. After 28 days of simulated oral environment storage, the radiopacity and DTS decreased to 3.36 ± 0.53 mmAl and 2.84 ± 0.27 MPa, respectively. This suggests that 700 °C-calcined BZO powder has potential as a novel radiopacifier for MTAs.

Effects of Calcination Temperature on the Synthesis of One-Pot Sol-Gelled Barium Titanate Powder and Its Performance as an Endodontic Radiopacifier.

Barium titanate (BaTiO3, BTO), conventionally used for dielectric and ferroelectric applications, has been assessed for biomedical applications, such as its utilization as a radiopacifier in mineral trioxide aggregates (MTA) for endodontic treatment. In the present study, BTO powders were prepared using the sol-gel process, followed by calcination at 400-1100 °C. The X-ray diffraction technique was then used to examine the as-prepared powders to elucidate the effect of calcination on the phase composition and crystalline size of BTO. Calcined BTO powders were then used as radiopacifiers for MTA. MTA-like cements were investigated to determine the optimal calcination temperature based on the radiopacity and diametral tensile strength (DTS). The experimental results showed that the formation of BTO phase was observed after calcination at temperatures of 600 °C and above. The calcined powders were a mixture of BaTiO3 phase with residual BaCO3 and/or Ba2TiO4 phases. The performance of MTA-like cements with BTO addition increased with increasing calcination temperature up to 1000 °C. The radiopacity, however, decreased after 7 days of simulated oral environmental storage, whereas an increase in DTS was observed. Optimal MTA-like cement was obtained by adding 40 wt.% 1000 °C-calcined BTO powder, with its resulting radiopacity and DTS at 4.83 ± 0.61 mmAl and 2.86 ± 0.33 MPa, respectively. After 7 days, the radiopacity decreased slightly to 4.69 ± 0.51 mmAl, accompanied by an increase in DTS to 3.13 ± 0.70 MPa. The optimal cement was biocompatible and verified using MG 63 and L929 cell lines, which exhibited cell viability higher than 95%.

Understanding forms of childhood adversities and associations with adult health outcomes: A regression tree analysis.

BACKGROUND: Empirical studies have demonstrated associations between ten original adverse childhood experiences (ACEs) and multiple health outcomes. Identifying expanded ACEs can capture the burden of other childhood adversities that may have important health implications. OBJECTIVE: We sought to identify childhood adversities that warrant consideration as expanded ACEs. We hypothesized that experiencing expanded and original ACEs would be associated with poorer adult health outcomes compared to experiencing original ACEs alone. PARTICIPANTS: The 11,545 respondents of the National Longitudinal Surveys (NLS) and Child and Young Adult Survey were 48.9 % female, 22.7 % Black, 15.8 % Hispanic, 36.1 % White, 1.7 % Asian/Native Hawaiian/Pacific Islander/Native American/Native Alaskan, and 7.5 % Other. METHODS: This study used regression trees and generalized linear models to identify if/which expanded ACEs interacted with original ACEs in association with six health outcomes. RESULTS: Four expanded ACEs-basic needs instability, lack of parental love and affection, community stressors, and mother's experience with physical abuse during childhood -significantly interacted with general health, depressive symptom severity, anxiety symptom severity, and violent crime victimization in adulthood (all p-values <0.005). Basic needs instability and/or lack of parental love and affection emerged as correlates across multiple outcomes. Experiencing lack of parental love and affection and original ACEs was associated with greater anxiety symptoms (p = 0.022). CONCLUSIONS: This is the first study to use supervised machine learning to investigate interaction effects among original ACEs and expanded ACEs. Two expanded ACEs emerged as predictors for three adult health outcomes and warrant further consideration in ACEs assessments.

Fracture characteristics and translucency of multilayer monolithic zirconia crowns of various thicknesses.

OBJECTIVES: Multilayer monolithic zirconia (M-Zr) crowns can be engineered to achieve gradational translucency and color intensity. However, this modification may compromise the mechanical strength, raising concerns regarding the ability of M-Zr crowns to withstand occlusal stresses. The effects of M-Zr crown thickness on translucency and ability to endure occlusal forces were investigated at different tooth positions (incisors, premolars, and molars). The objective was to determine the minimal thickness of M-Zr crowns used in tooth preparation to meet aesthetic and functional demands. METHODS: M-Zr samples (Vita A1) with four thicknesses (0.5, 1.0, 1.5, and 2.0 mm) were prepared and subjected to translucency testing using a digital colorimeter by 3-third and 9-square division methods. Crown-shaped M-Zr samples with three thicknesses (1.0, 1.5, and 2.0 mm) and three tooth positions (incisor, premolar, and molar) were digitally designed, and 2.0 mm metal abutments were fabricated. The samples were bonded to the abutments; their fracture characteristics were evaluated using a universal testing machine, and their fracture surfaces examined using an optical microscope. Statistical analyses included the Shapiro-Wilk test, Pearson correlation, and one-way and two-way ANOVA with a post hoc Tukey HSD test (α = 0.05). RESULTS: Color analysis results revealed a significant negative correlation between thickness and translucency (r < -0.96, P < 0.01), with the highest values in the incisal region. Cross-sectional profiles confirmed the uniform thickness and morphology of the digitally designed M-Zr crowns. The results of fracture strength analysis showed position-dependent variability, a strong positive correlation with thickness (r > 0.96, P < 0.01), and fracture strengths consistently exceeding 1200 N across all tooth positions. Fracture patterns indicated that thinner crowns at the incisors and molars were more prone to cracking, whereas those at the premolars demonstrated significantly higher strength (4872.51 N, P < 0.05), only with crack or even no fracture occurring at 2.0 mm. CONCLUSIONS: Thickness significantly influenced both the translucency and fracture strength of M-Zr, with the tooth position playing an additional role, albeit to a lesser extent. Although thinner crowns exhibited lower strength at each tooth position, even at a thickness of 1.0 mm, fracture strength exceeding 1200 N was maintained, surpassing the typical occlusal forces. Thus, it can be asserted that M-Zr crowns with a minimum thickness of 1.0 mm can meet both aesthetic and functional requirements.

Proteasome localization and activity in pig brain and in vivo small molecule screening for activators.

Introduction: Loss of proteasome function, proteinopathy, and proteotoxicity may cause neurodegeneration across the human lifespan in several forms of brain injury and disease. Drugs that activate brain proteasomes in vivo could thus have a broad therapeutic impact in neurology. Methods: Using pigs, a clinically relevant large animal with a functionally compartmental gyrencephalic cerebral cortex, we evaluated the localization and biochemical activity of brain proteasomes and tested the ability of small molecules to activate brain proteasomes. Results: By Western blotting, proteasome protein subunit PSMB5 and PSMA3 levels were similar in different pig brain regions. Immunohistochemistry for PSMB5 showed localization in the cytoplasm (diffuse and particulate) and nucleus (cytoplasm < nucleus). Some PSMB5 immunoreactivity was colocalized with mitochondrial (voltage-gated anion channel and cyclophilin D) and cell death (Aven) proteins in the neuronal soma and neuropil in the neocortex of pig and human brains. In the nucleus, PSMB5 immunoreactivity was diffuse, particulate, and clustered, including perinucleolar decorations. By fluorogenic assay, proteasome chymotrypsin-like activities (CTL) in crude tissue soluble fractions were generally similar within eight different pig brain regions. Proteasome CTL activity in the hippocampus was correlated with activity in nasal mucosa biopsies. In pilot analyses of subcellular fractions of pig cerebral cortex, proteasome CTL activity was highest in the cytosol and then ~50% lower in nuclear fractions; ~15-20% of total CTL activity was in pure mitochondrial fractions. With in-gel activity assay, 26S-singly and -doubly capped proteasomes were the dominant forms in the pig cerebral cortex. With a novel in situ histochemical activity assay, MG132-inhibitable proteasome CTL activity was localized to the neuropil, as a mosaic, and to cell bodies, nuclei, and centrosome-like perinuclear satellites. In piglets treated intravenously with pyrazolone derivative and chlorpromazine over 24 h, brain proteasome CTL activity was modestly increased. Discussion: This study shows that the proteasome in the pig brain has relative regional uniformity, prominent nuclear and perinuclear presence with catalytic activity, a mitochondrial association with activity, 26S-single cap dominance, and indications from small molecule systemic administration of pyrazolone derivative and chlorpromazine that brain proteasome function appears safely activable.

The Association Between State Minimum Wage and Firearm Homicides, 2000-2020.

INTRODUCTION: Recent research has indicated an association between both poverty and income inequality and firearm homicides. Increased minimum wages may serve as a strategy for reducing firearm violence by increasing economic security among workers earning low wages and reducing the number of families living in poverty. This study aimed to examine the association between state minimum wage and firearm homicides in the U.S. between 2000 and 2020. METHODS: State minimum wage, obtained from Temple's Law Atlas and augmented by legal research, was conceptualized using the Kaitz Index. State-level homicide counts were obtained from 2000 to 2020 multiple-cause-of death mortality data from the National Vital Statistics System. Log-linear regressions were conducted to model the associations between state minimum wage and firearm homicides, stratifying by demographic groups. Analyses were conducted in 2023. RESULTS: A 1% point increase in a state's Kaitz Index was associated with a 1.3% (95% CI: -2.1% to -0.5%) decrease in a state's firearm homicide rate. When interacted with quartile of firearm ownership, the Kaitz Index was associated with decreases in firearm homicide in all except the lowest quartile. These findings were largely consistent across stratifications. CONCLUSIONS: Changing a state's minimum wage, whereby a full-time minimum wage worker's salary is closer to a state's median income, may be an option for reducing firearm homicides.

Advanced child tax credit payments and national child abuse hotline contacts, 2019-2022.

BACKGROUND: Children in households experiencing poverty are disproportionately exposed to maltreatment. Income support policies have been associated with reductions in child abuse and neglect. The advance child tax credit (CTC) payments may reduce child maltreatment by improving the economic security of some families. No national studies have examined the association between advance CTC payments and child abuse and neglect. This study examines the association between the advance CTC payments and child abuse and neglect-related contacts to the Childhelp National Child Abuse Hotline. METHODS: A time series study of contacts to the Childhelp National Child Abuse Hotline between January 2019 and December 2022 was used to examine the association between the payments and hotline contacts. An interrupted time series (ITS) exploiting the variation in the advance CTC payments was estimated using fixed effects. RESULTS: The CTC advance payments were associated with an immediate 13.8% (95% CI -17.5% to -10.0%) decrease in contacts to the hotline in the ITS model. Following the expiration of the advance CTC payments, there was a significant and gradual 0.1% (95% CI +0.0% to +0.2%) daily increase in contacts. Sensitivity analyses found significant reductions in contacts following each payment, however, the reductions were associated with the last three of the six total payments. CONCLUSION: These findings suggest the advance CTC payments may reduce child abuse and neglect-related hotline contacts and continue to build the evidence base for associations between income-support policies and reductions in child abuse and neglect.

In vitro study of optimal removable partial denture clasp design made from novel high-performance polyetherketoneketone.

PURPOSE: This study aimed to investigate the retentive force and deformation of double Akers' polyetherketoneketone (PEKK) clasps on removable partial dentures (RPDs) with varying designs and undercut depths. METHODS: Thirty double Akers' PEKK clasps with two different widths and heights (Groups I and II) were fabricated using computer-aided design and computer-aided manufacturing (CAD/CAM). Each design was further subdivided (n = 5) into three undercut depths (0.25, 0.50, and 0.75 mm). The retentive force of the clasps was measured after 10 years of clinical use (15,000 insertion/removal cycles), and the deformation of the clasp tips was analyzed before and after cycling. RESULTS: Clasps with 0.50-mm and 0.75-mm undercut depths exhibited greater initial retentive forces (3.15-3.51 N) compared to those in the 0.25-mm undercut group (2.40-2.80 N). Group I maintained consistent retentive forces over the cycles (P = 0.345), whereas Group II showed declining forces after the initial use (P < 0.003). In both groups, the 0.50-mm undercut exhibited a greater retentive force than the 0.25-mm (P < 0.001 and P < 0.004, respectively), with no significant differences between the 0.50-mm and 0.75-mm undercut depths. Despite a lower initial retentive force, the 0.25-mm undercut showed less deformation and clasp tip wear. CONCLUSIONS: The PEKK clasps did not exhibit significantly reduced retentive forces or permanent deformations after 15,000 fatigue cycles. These results suggest that the PEKK polymer displays superior mechanical properties as an esthetic clasp material, and clasps with 0.50-mm and 0.75-mm undercut depths are recommended for long-term clinical use.

Comparative analysis of the retention force and deformation of PEEK and PEKK removable partial denture clasps with different thicknesses and undercut depths.

STATEMENT OF PROBLEM: The retentive force and deformation of milled polyetheretherketone (PEEK) and polyetherketoneketone (PEKK) removable partial denture (RPD) frameworks are not well understood. PURPOSE: The purpose of this in vitro study was to assess the retentive force and deformation of PEEK and PEKK Akers clasps with different designs and undercut depths. MATERIAL AND METHODS: A master model containing the first and second molar abutments was used to design Akers clasps of different cross-sectional dimensions, undercut depths (0.5 and 0.75 mm), and materials. The components of the removable partial denture framework also included an occlusal rest and were manufactured using a milling machine (n=5). The fatigue resistance of the Akers clasps was measured before and after deformation regarding the retentive forces. RESULTS: The PEEK2-U50 clasp had the largest retentive force with no significant difference among all groups before and after the insertion and removal cycle. In addition, the increased cross-sectional dimensions of the design resulted in significant differences in retentive forces between the PEEK1 and PEEK2 groups and between the PEEK and PEKK materials. CONCLUSIONS: Increasing the clasp's cross-sectional dimensions significantly impacted retentive forces, especially between different PEEK groups and between PEEK and PEKK materials.

Endodontic Radiopacifying Application of Barium Titanate Prepared through a Combination of Mechanical Milling and Heat Treatment.

Mineral trioxide aggregates (MTA) are commonly used as endodontic filling materials but suffer from a long setting time and tooth discoloration. In the present study, the feasibility of using barium titanate (BTO) for discoloration and a calcium chloride (CaCl2) solution to shorten the setting time was investigated. BTO powder was prepared using high-energy ball milling for 3 h, followed by sintering at 700-1300 °C for 2 h. X-ray diffraction was used to examine the crystallinity and crystalline size of the as-milled and heat-treated powders. MTA-like cements were then prepared using 20-40 wt.% BTO as a radiopacifier and solidified using a 0-30% CaCl2 solution. The corresponding radiopacity, diametral tensile strength (DTS), initial and final setting times, and discoloration performance were examined. The experimental results showed that for the BTO powder prepared using a combination of mechanical milling and heat treatment, the crystallinity and crystalline size increased with the increasing sintering temperature. The BTO sintered at 1300 °C (i.e., BTO-13) exhibited the best radiopacity and DTS. The MTA-like cement supplemented with 30% BTO-13 and solidified with a 10% CaCl2 solution exhibited a radiopacity of 3.68 ± 0.24 mmAl and a DTS of 2.54 ± 0.28 MPa, respectively. In the accelerated discoloration examination using UV irradiation, the color difference was less than 1.6 and significantly lower than the clinically perceptible level (3.7). This novel MTA exhibiting a superior color stability, shortened setting time, and excellent biocompatibility has potential for use in endodontic applications.

RECONSTRUCTIVE THERAPY OF PERI­IMPLANTITIS, COMPARED TO RESECTIVE INTERVENTION, MAY RESULT IN LESS PERI­IMPLANT MUCOSAL RECESSION.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Sanz-Martín I, Cha J-K, Sanz-Sánchez I, Figuero E, Herrera D, Sanz M. Changes in peri­implant soft tissue levels following surgical treatment of peri­implantitis: a systematic review and meta-analysis. Clin Oral Implants Res. 2021;32(suppl 21):230-244. https://doi.org/10.1111/clr.13840. SOURCE OF FUNDING: No financial support. TYPE OF STUDY/DESIGN: Systematic review with meta-analysis.

Hypothermic Protection in Neocortex Is Topographic and Laminar, Seizure Unmitigating, and Partially Rescues Neurons Depleted of RNA Splicing Protein Rbfox3/NeuN in Neonatal Hypoxic-Ischemic Male Piglets.

The effects of hypothermia on neonatal encephalopathy may vary topographically and cytopathologically in the neocortex with manifestations potentially influenced by seizures that alter the severity, distribution, and type of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia (HT) with continuous electroencephalography (cEEG) for seizures. Neonatal male piglets received HI-normothermia (NT), HI-HT, sham-NT, or sham-HT treatments. Randomized unmedicated sham and HI piglets underwent cEEG during recovery. Survival was 2-7 days. Normal and pathological neurons were counted in different neocortical areas, identified by cytoarchitecture and connectomics, using hematoxylin and eosin staining and immunohistochemistry for RNA-binding FOX-1 homolog 3 (Rbfox3/NeuN). Seizure burden was determined. HI-NT piglets had a reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to sham-NT and sham-HT piglets with differing severities in the anterior and posterior motor, somatosensory, and frontal cortices. Neocortical neuropathology was attenuated by HT. HT protection was prominent in layer III of the inferior parietal cortex. Rbfox3 immunoreactivity distinguished cortical neurons as: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had an increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT piglets. Neuronal Rbfox3 depletion was partly rescued by HT. Seizure burdens in HI-NT and HI-HT piglets were similar. We conclude that the neonatal HI piglet neocortex has: (1) suprasylvian vulnerability to HI and seizures; (2) a limited neuronal cytopathological repertoire in functionally different regions that engages protective mechanisms with HT; (3) higher seizure burden, insensitive to HT, that is correlated with more panlaminar ischemic-necrotic neurons in the somatosensory cortex; and (4) pathological RNA splicing protein nuclear depletion that is sensitive to HT. This work demonstrates that HT protection of the neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores neuronal depletion of RNA splicing factor.

Emergency Department Visits for Firearm Injuries Before and During the COVID-19 Pandemic - United States, January 2019-December 2022.

During the COVID-19 pandemic, the U.S. firearm homicide rate increased by nearly 35%, and the firearm suicide rate remained high during 2019-2020 (1). Provisional mortality data from the National Vital Statistics System indicate that rates continued to increase in 2021: the rates of firearm homicide and firearm suicide in 2021 were the highest recorded since 1993 and 1990, respectively (2). Firearm injuries treated in emergency departments (EDs), the primary setting for the immediate medical treatment of such injuries, gradually increased during 2018-2019 (3); however, more recent patterns of ED visits for firearm injuries, particularly during the COVID-19 pandemic, are unknown. Using data from the National Syndromic Surveillance Program (NSSP),* CDC examined changes in ED visits for initial firearm injury encounters during January 2019-December 2022, by year, patient sex, and age group. Increases in the overall weekly number of firearm injury ED visits were detected at certain periods during the COVID-19 pandemic. One such period during which there was a gradual increase was March 2020, which coincided with both the declaration of COVID-19 as a national emergency† and a pronounced decrease in the total number of ED visits. Another increase in firearm injury ED visits occurred in late May 2020, concurrent with a period marked by public outcry related to social injustice and structural racism (4), changes in state-level COVID-19-specific prevention strategies,§ decreased engagement in COVID-19 mitigation behaviors (5), and reported increases in some types of crime (4). Compared with 2019, the average number of weekly ED visits for firearm injury was 37% higher in 2020, 36% higher in 2021, and 20% higher in 2022. A comprehensive approach is needed to prevent and respond to firearm injuries in communities, including strategies that engage community and street outreach programs, implement hospital-based violence prevention programs, improve community physical environments, enhance secure storage of firearms, and strengthen social and economic supports.

Development of a Machine Learning Model to Estimate US Firearm Homicides in Near Real Time.

Importance: Firearm homicides are a major public health concern; lack of timely mortality data presents considerable challenges to effective response. Near real-time data sources offer potential for more timely estimation of firearm homicides. Objective: To estimate near real-time burden of weekly and annual firearm homicides in the US. Design, Setting, and Participants: In this prognostic study, anonymous, longitudinal time series data were obtained from multiple data sources, including Google and YouTube search trends related to firearms (2014-2019), emergency department visits for firearm injuries (National Syndromic Surveillance Program, 2014-2019), emergency medical service activations for firearm-related injuries (biospatial, 2014-2019), and National Domestic Violence Hotline contacts flagged with the keyword firearm (2016-2019). Data analysis was performed from September 2021 to September 2022. Main Outcomes and Measures: Weekly estimates of US firearm homicides were calculated using a 2-phase pipeline, first fitting optimal machine learning models for each data stream and then combining the best individual models into a stacked ensemble model. Model accuracy was assessed by comparing predictions of firearm homicides in 2019 to actual firearm homicides identified by National Vital Statistics System death certificates. Results were also compared with a SARIMA (seasonal autoregressive integrated moving average) model, a common method to forecast injury mortality. Results: Both individual and ensemble models yielded highly accurate estimates of firearm homicides. Individual models' mean error for weekly estimates of firearm homicides (root mean square error) varied from 24.95 for emergency department visits to 31.29 for SARIMA forecasting. Ensemble models combining data sources had lower weekly mean error and higher annual accuracy than individual data sources: the all-source ensemble model had a weekly root mean square error of 24.46 deaths and full-year accuracy of 99.74%, predicting the total number of firearm homicides in 2019 within 38 deaths for the entire year (compared with 95.48% accuracy and 652 deaths for the SARIMA model). The model decreased the time lag of reporting weekly firearm homicides from 7 to 8 months to approximately 6 weeks. Conclusions and Relevance: In this prognostic study of diverse secondary data on machine learning, ensemble modeling produced accurate near real-time estimates of weekly and annual firearm homicides and substantially decreased data source time lags. Ensemble model forecasts can accelerate public health practitioners' and policy makers' ability to respond to unanticipated shifts in firearm homicides.

Plasma Biomarkers of Evolving Encephalopathy and Brain Injury in Neonates with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: The objective of the study was to evaluate the relationship between a panel of candidate plasma biomarkers and (1) death or severe brain injury on magnetic resonance imaging (MRI) and (2) dysfunctional cerebral pressure autoregulation as a measure of evolving encephalopathy. STUDY DESIGN: Neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) at 2 level IV neonatal intensive care units were enrolled into this observational study. Patients were treated with therapeutic hypothermia (TH) and monitored with continuous blood pressure monitoring and near-infrared spectroscopy. Cerebral pressure autoregulation was measured by the hemoglobin volume phase (HVP) index; a higher HVP index indicates poorer autoregulation. Serial blood samples were collected during TH and assayed for Tau, glial fibrillary acidic protein, and neurogranin. MRIs were assessed using National Institutes of Child Health and Human Development scores. The relationships between the candidate biomarkers and (1) death or severe brain injury on MRI (defined as a National Institutes of Child Health and Human Development score of ≥ 2B) and (2) autoregulation were evaluated using bivariate and adjusted logistic regression models. RESULTS: Sixty-two patients were included. Elevated Tau levels on days 2-3 of TH were associated with death or severe injury on MRI (aOR: 1.06, 95% CI: 1.03-1.09; aOR: 1.04, 95% CI: 1.01-1.06, respectively). Higher Tau was also associated with poorer autoregulation (higher HVP index) on the same day (P = .022). CONCLUSIONS: Elevated plasma levels of Tau are associated with death or severe brain injury by MRI and dysfunctional cerebral autoregulation in neonates with HIE. Larger-scale validation of Tau as a biomarker of brain injury in neonates with HIE is warranted.