ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion.

Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.

An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway.

Animals sense and respond to nutrient availability in their environments, a task coordinated in part by the mTOR complex 1 (mTORC1) pathway. mTORC1 regulates growth in response to nutrients and, in mammals, senses specific amino acids through specialized sensors that bind the GATOR1/2 signaling hub. Given that animals can occupy diverse niches, we hypothesized that the pathway might evolve distinct sensors in different metazoan phyla. Whether such customization occurs, and how the mTORC1 pathway might capture new inputs, is unknown. Here, we identify the Drosophila melanogaster protein Unmet expectations (CG11596) as a species-restricted methionine sensor that directly binds the fly GATOR2 complex in a fashion antagonized by S-adenosylmethionine (SAM). We find that in Dipterans GATOR2 rapidly evolved the capacity to bind Unmet and to thereby repurpose a previously independent methyltransferase as a SAM sensor. Thus, the modular architecture of the mTORC1 pathway allows it to co-opt preexisting enzymes to expand its nutrient sensing capabilities, revealing a mechanism for conferring evolvability on an otherwise conserved system.

Initial Imaging of Pregnant Patients in the Trauma Bay-Discussion and Review of Presentations at a Level-1 Trauma Centre.

Trauma is the leading non-obstetric cause of maternal and fetal mortality and affects an estimated 5-7% of all pregnancies. Pregnant women, thankfully, are a small subset of patients presenting in the trauma bay, but they do have distinctive physiologic and anatomic changes. These increase the risk of certain traumatic injuries, and the gravid uterus can both be the primary site of injury and mask other injuries. The primary focus of the initial management of the pregnant trauma patient should be that of maternal stabilization and treatment since it directly affects the fetal outcome. Diagnostic imaging plays a pivotal role in initial traumatic injury assessment and should not deviate from normal routine in the pregnant patient. Radiographs and focused assessment with sonography in the trauma bay will direct the use of contrast-enhanced computed tomography (CT), which remains the cornerstone to evaluate the potential presence of further management-altering injuries. A thorough understanding of its risks and benefits is paramount, especially in the pregnant patient. However, like any other trauma patient, if evaluation for injury with CT is indicated, it should not be denied to a pregnant trauma patient due to fear of radiation exposure.

Evaluation of Real and Perceived Risk to Health Care Workers Caring for Patients With the Omicron Variant of the SARS-CoV-2 Virus in Surgery and Obstetrics.

OBJECTIVES: The Omicron variant of the SARS-CoV-2 virus is described as more contagious than previous variants. We sought to assess risk to health care workers (HCWs) caring for patients with COVID-19 in surgical/obstetrical settings, and the perception of risk among this group. METHODS: From January to April 2022, reverse transcription polymerase chain reaction was used to detect the presence of SARS-CoV-2 viral ribonucleic acid in patient, environmental (floor, equipment, passive air) samples, and HCWs' masks (inside surface) during urgent surgery or obstetrical delivery for patients with SARS-CoV-2 infection. The primary outcome was the proportion of HCWs' masks testing positive. Results were compared with our previous cross-sectional study involving obstetrical/surgical patients with earlier variants (2020-2021). HCWs completed a risk perception electronic questionnaire. RESULTS: Eleven patients were included: 3 vaginal births and 8 surgeries. In total, 5/108 samples (5%) tested positive (SARS-CoV-2 Omicron) viral ribonucleic acid: 2/5 endotracheal tubes, 1/22 floor samples, 1/4 patient masks, and 1 nasal probe. No samples from the HCWs' masks (0/35), surgical equipment (0/10), and air (0/11) tested positive. No significant differences were found between the Omicron and 2020/21 patient groups' positivity rates (Mann-Whitney U test, P = 0.838) or the level of viral load from the nasopharyngeal swabs (P = 0.405). Nurses had a higher risk perception than physicians (P = 0.038). CONCLUSION: No significant difference in contamination rates was found between SARS-CoV-2 Omicron BA.1 and previous variants in surgical/obstetrical settings. This is reassuring as no HCW mask was positive and no HCW tested positive for COVID-19 post-exposure.

Comparison of pharmaceutical properties and biological activities of prednisolone, deflazacort, and vamorolone in DMD disease models.

Duchenne muscular dystrophy (DMD) is a progressive disabling X-linked recessive disorder that causes gradual and irreversible loss of muscle, resulting in early death. The corticosteroids prednisone/prednisolone and deflazacort are used to treat DMD as the standard of care; however, only deflazacort is FDA approved for DMD. The novel atypical corticosteroid vamorolone is being investigated for treatment of DMD. We compared the pharmaceutical properties as well as the efficacy and safety of the three corticosteroids across multiple doses in the B10-mdx DMD mouse model. Pharmacokinetic studies in the mouse and evaluation of p-glycoprotein (P-gP) efflux in a cellular system demonstrated that vamorolone is not a strong P-gp substrate resulting in measurable central nervous system (CNS) exposure in the mouse. In contrast, deflazacort and prednisolone are strong P-gp substrates. All three corticosteroids showed efficacy, but also side effects at efficacious doses. After dosing mdx mice for two weeks, all three corticosteroids induced changes in gene expression in the liver and the muscle, but prednisolone and vamorolone induced more changes in the brain than did deflazacort. Both prednisolone and vamorolone induced depression-like behavior. All three corticosteroids reduced endogenous corticosterone levels, increased glucose levels, and reduced osteocalcin levels. Using micro-computed tomography, femur bone density was decreased, reaching significance with prednisolone. The results of these studies indicate that efficacious doses of vamorolone, are associated with similar side effects as seen with other corticosteroids. Further, because vamorolone is not a strong P-gp substrate, vamorolone distributes into the CNS increasing the potential CNS side-effects.

Nephron progenitors rhythmically alternate between renewal and differentiation phases that synchronize with kidney branching morphogenesis.

The mammalian kidney achieves massive parallelization of function by exponentially duplicating nephron-forming niches during development. Each niche caps a tip of the ureteric bud epithelium (the future urinary collecting duct tree) as it undergoes branching morphogenesis, while nephron progenitors within niches balance self-renewal and differentiation to early nephron cells. Nephron formation rate approximately matches branching rate over a large fraction of mouse gestation, yet the nature of this apparent pace-maker is unknown. Here we correlate spatial transcriptomics data with branching 'life-cycle' to discover rhythmically alternating signatures of nephron progenitor differentiation and renewal across Wnt, Hippo-Yap, retinoic acid (RA), and other pathways. We then find in human stem-cell derived nephron progenitor organoids that Wnt/ß-catenin-induced differentiation is converted to a renewal signal when it temporally overlaps with YAP activation. Similar experiments using RA activation indicate a role in setting nephron progenitor exit from the naive state, the spatial extent of differentiation, and nephron segment bias. Together the data suggest that nephron progenitor interpretation of consistent Wnt/ß-catenin differentiation signaling in the niche may be modified by rhythmic activity in ancillary pathways to set the pace of nephron formation. This would synchronize nephron formation with ureteric bud branching, which creates new sites for nephron condensation. Our data bring temporal resolution to the renewal vs. differentiation balance in the nephrogenic niche and inform new strategies to achieve self-sustaining nephron formation in synthetic human kidney tissues.

Spontaneous, idiopathic granulomatous mastitis in a pregnant patient: A case report and review of the literature.

Idiopathic granulomatous mastitis is a rare breast condition of unclear etiology. Its course is often rapidly progressive, slow to resolve, and can have a high rate of recurrence. Clinical presentation can mimic breast abscess, infectious mastitis, and carcinoma of the breast, generating a diagnostic challenge. Histopathological analysis is required to make the diagnosis after common conditions are excluded. There is no standard treatment, however surgical excision, steroid treatment, and observation are commonly reported approaches. Here, we describe a complex case of a multiparous patient presenting with idiopathic granulomatous mastitis at 32 weeks gestation. In this review, we highlight the importance of collaboration amongst a multidisciplinary team for effective diagnosis and treatment. We discuss the use of oral corticosteroids in the antenatal period and illustrate the patient support required to both facilitate successful breastfeeding in the postpartum period and promote recovery.

Network Analysis for Formative Evaluation of Collaborative, Team Science Research Partnerships.

Cancer health disparities persist across the cancer care continuum despite decades of effort to eliminate them. Among the strategies currently used to address these disparities are multi-institution research initiatives that engage multiple stakeholders and change efforts. Endemic to the theory of change of such programs is the idea that collaboration-across institutions, research disciplines, and academic ranks-is necessary to improve outcomes. Despite this emphasis on collaboration, however, it is not often a focus of evaluation for these programs and others like them. In this paper we describe a method for evaluating collaboration within the Meharry-Vanderbilt-Tennessee State University Cancer Partnership using network analysis. Specifically, we used network analysis of co-authorship on academic publications to visualize the growth and patterns of scientific collaboration across partnership institutions, research disciplines, and academic ranks over time. We presented the results of the network analysis to internal and external advisory groups, creating the opportunity to discuss partnership collaboration, celebrate successes, and identify opportunities for improvement. We propose that basic network analysis of existing data along with network visualizations can foster conversation and feedback and are simple and effective ways to evaluate collaboration initiatives.

An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway.

Animals must sense and respond to nutrient availability in their local niche. This task is coordinated in part by the mTOR complex 1 (mTORC1) pathway, which regulates growth and metabolism in response to nutrients1-5. In mammals, mTORC1 senses specific amino acids through specialized sensors that act through the upstream GATOR1/2 signaling hub6-8. To reconcile the conserved architecture of the mTORC1 pathway with the diversity of environments that animals can occupy, we hypothesized that the pathway might maintain plasticity by evolving distinct nutrient sensors in different metazoan phyla1,9,10. Whether such customization occurs-and how the mTORC1 pathway might capture new nutrient inputs-is not known. Here, we identify the Drosophila melanogaster protein Unmet expectations (Unmet, formerly CG11596) as a species-restricted nutrient sensor and trace its incorporation into the mTORC1 pathway. Upon methionine starvation, Unmet binds to the fly GATOR2 complex to inhibit dTORC1. S-adenosylmethionine (SAM), a proxy for methionine availability, directly relieves this inhibition. Unmet expression is elevated in the ovary, a methionine-sensitive niche11, and flies lacking Unmet fail to maintain the integrity of the female germline under methionine restriction. By monitoring the evolutionary history of the Unmet-GATOR2 interaction, we show that the GATOR2 complex evolved rapidly in Dipterans to recruit and repurpose an independent methyltransferase as a SAM sensor. Thus, the modular architecture of the mTORC1 pathway allows it to co-opt preexisting enzymes and expand its nutrient sensing capabilities, revealing a mechanism for conferring evolvability on an otherwise highly conserved system.

Surveillance for Violent Deaths - National Violent Death Reporting System, 48 States, the District of Columbia, and Puerto Rico, 2020.

Problem/Condition: In 2020, approximately 71,000 persons died of violence-related injuries in the United States. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) on violent deaths that occurred in 48 states, the District of Columbia, and Puerto Rico in 2020. Results are reported by sex, age group, race and ethnicity, method of injury, type of location where the injury occurred, circumstances of injury, and other selected characteristics. Period Covered: 2020. Description of System: NVDRS collects data regarding violent deaths obtained from death certificates, coroner and medical examiner records, and law enforcement reports. This report includes data collected for violent deaths that occurred in 2020. Data were collected from 48 states (all states with exception of Florida and Hawaii), the District of Columbia, and Puerto Rico. Forty-six states had statewide data, two additional states had data from counties representing a subset of their population (35 California counties, representing 71% of its population, and four Texas counties, representing 39% of its population), and the District of Columbia and Puerto Rico had jurisdiction-wide data. NVDRS collates information for each violent death and links deaths that are related (e.g., multiple homicides, homicide followed by suicide, or multiple suicides) into a single incident. Results: For 2020, NVDRS collected information on 64,388 fatal incidents involving 66,017 deaths that occurred in 48 states (46 states collecting statewide data, 35 California counties, and four Texas counties), and the District of Columbia. In addition, information was collected for 729 fatal incidents involving 790 deaths in Puerto Rico. Data for Puerto Rico were analyzed separately. Of the 66,017 deaths, the majority (58.4%) were suicides, followed by homicides (31.3%), deaths of undetermined intent (8.2%), legal intervention deaths (1.3%) (i.e., deaths caused by law enforcement and other persons with legal authority to use deadly force acting in the line of duty, excluding legal executions), and unintentional firearm deaths (<1.0%). The term "legal intervention" is a classification incorporated into the International Classification of Diseases, Tenth Revision, and does not denote the lawfulness or legality of the circumstances surrounding a death caused by law enforcement.Demographic patterns and circumstances varied by manner of death. The suicide rate was higher for males than for females. Across all age groups, the suicide rate was highest among adults aged ≥85 years. In addition, non-Hispanic American Indian or Alaska Native (AI/AN) persons had the highest suicide rates among all racial and ethnic groups. Among both males and females, the most common method of injury for suicide was a firearm. Among all suicide victims, when circumstances were known, suicide was most often preceded by a mental health, intimate partner, or physical health problem or by a recent or impending crisis during the previous or upcoming 2 weeks. The homicide rate was higher for males than for females. Among all homicide victims, the homicide rate was highest among persons aged 20-24 years compared with other age groups. Non-Hispanic Black (Black) males experienced the highest homicide rate of any racial or ethnic group. Among all homicide victims, the most common method of injury was a firearm. When the relationship between a homicide victim and a suspect was known, the suspect was most frequently an acquaintance or friend for male victims and a current or former intimate partner for female victims. Homicide most often was precipitated by an argument or conflict, occurred in conjunction with another crime, or, for female victims, was related to intimate partner violence. Nearly all victims of legal intervention deaths were male, and the legal intervention death rate was highest among men aged 35-44 years. The legal intervention death rate was highest among AI/AN males, followed by Black males. A firearm was used in the majority of legal intervention deaths. When a specific type of crime was known to have precipitated a legal intervention death, the type of crime was most frequently assault or homicide. When circumstances were known, the three most frequent circumstances reported for legal intervention deaths were as follows: the victim's death was precipitated by another crime, the victim used a weapon in the incident, and the victim had a substance use problem (other than alcohol use).Other causes of death included unintentional firearm deaths and deaths of undetermined intent. Unintentional firearm deaths were most frequently experienced by males, non-Hispanic White (White) persons, and persons aged 15-24 years. These deaths most frequently occurred while the shooter was playing with a firearm and were precipitated by a person unintentionally pulling the trigger. The rate of deaths of undetermined intent was highest among males, particularly among AI/AN and Black males, and among adults aged 30-54 years. Poisoning was the most common method of injury in deaths of undetermined intent, and opioids were detected in nearly 80% of decedents tested for those substances. Interpretation: This report provides a detailed summary of data from NVDRS on violent deaths that occurred in 2020. The suicide rate was highest among AI/AN and White males, whereas the homicide rate was highest among Black male victims. Intimate partner violence precipitated a large proportion of homicides for females. Mental health problems, intimate partner problems, interpersonal conflicts, and acute life stressors were primary circumstances for multiple types of violent death. Public Health Action: Violence is preventable, and states and communities can use data to guide public health action. NVDRS data are used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in developing, implementing, and evaluating programs, policies, and practices to reduce and prevent violent deaths. For example, the Colorado Violent Death Reporting System (VDRS), Kentucky VDRS, and Oregon VDRS have used their VDRS data to guide suicide prevention efforts and generate reports highlighting where additional focus is needed. In Colorado, VDRS data were used to examine the increased risk for suicide among first and last responders in the state. Kentucky VDRS used local data to highlight how psychological and social effects of the COVID-19 pandemic might increase risk for suicide, particularly among vulnerable populations. Oregon VDRS used their data to develop a publicly available data dashboard displaying firearm mortality trends and rates in support of the state's firearm safety campaign. Similarly, states participating in NVDRS have used their VDRS data to examine homicide in their state. Illinois VDRS, for example, found that state budget cuts were associated with notable increases in homicides among youths in Chicago. With an increase of participating states and jurisdictions, this report marks progress toward providing nationally representative data.

Deep Learning Model to Denoise Luminescence Images of Silicon Solar Cells.

Luminescence imaging is widely used to identify spatial defects and extract key electrical parameters of photovoltaic devices. To reliably identify defects, high-quality images are desirable; however, acquiring such images implies a higher cost or lower throughput as they require better imaging systems or longer exposure times. This study proposes a deep learning-based method to effectively diminish the noise in luminescence images, thereby enhancing their quality for inspection and analysis. The proposed method eliminates the requirement for extra hardware expenses or longer exposure times, making it a cost-effective solution for image enhancement. This approach significantly improves image quality by >30% and >39% in terms of the peak signal-to-noise ratio and the structural similarity index, respectively, outperforming state-of-the-art classical denoising algorithms.

High-Energy, Whole-Body Proton Irradiation Differentially Alters Long-Term Brain Pathology and Behavior Dependent on Sex and Alzheimer's Disease Mutations.

Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer's-like and wildtype littermate mice 7-8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer's model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state.

Surgical Outcomes between Routes of Hysterectomy in Patients with a Previous Cesarean Section.

STUDY OBJECTIVE: To determine the difference in surgical complications for patients with a previous cesarean section (CS) undergoing abdominal, vaginal, or laparoscopic hysterectomy. DESIGN: A population-based retrospective cohort study. SETTING: Province of Ontario, Canada. PATIENTS: 10 300 patients with at least 1 CS between July 1, 1991, and February 17, 2018. INTERVENTIONS: Benign, nongravid hysterectomy between Apr 1, 2002, and March 31, 2018. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite of all surgical complications within 30 days of surgery. Secondary outcomes were rate of genitourinary complications, readmission to hospital, and emergency department visit occurring within 30 days of surgery. Of 10 300 patients who had at least one previous CS, who underwent subsequent hysterectomy for a benign indication, 7370 underwent an abdominal hysterectomy (71.55%), 813 (7.9%) had a vaginal hysterectomy, and 2117 (20.55%) underwent a laparoscopic hysterectomy. The adjusted odds of any surgical complication from hysterectomy was significantly lower when performed by the vaginal approach than the laparoscopic approach (odds ratio, 0.32; 95% confidence interval, 0.20-0.51; p <.0001). There was no difference in the odds of surgical complication between abdominal and laparoscopic approaches (odds ratio, 1.09; 95% confidence interval, 0.87-1.37; p = .45). CONCLUSION: Our retrospective population-based study demonstrates that, after previous CS, patients selected to undergo vaginal hysterectomy experienced lower risk than either abdominal or laparoscopic approaches. This suggests that CS alone should not be a contraindication to vaginal hysterectomy.

Interpersonal Violence Victimization Experiences of Middle School Youth: An Exploration by Gender and Sexual/Romantic Attraction.

Sexual minority youth (SMY) are at increased risk for interpersonal violence victimization compared to heterosexual youth. The current study examined how self-reported victimization (i.e., bullying, sexual harassment and dating violence) among middle school youth varied as a function of sexual/romantic attraction as well as gender identity. Cross-sectional data were gathered from students at seven middle schools in New England (n = 2245). Mean comparisons with post-hoc Tukey tests determined differences in rates of past 6-month and lifetime interpersonal violence victimization by sexual/romantic attraction and the intersection of gender and attraction. As hypothesized, interpersonal violence victimization among middle school youth differed as a function of sexual/romantic attraction as well as gender. To date, most research has focused on older samples, particularly high-school youth and young adults. These data are consistent with these prior studies documenting increased risk for interpersonal violence victimization among youth who indicate same-gender attraction but add to the literature in demonstrating the expansive forms of peer victimization that same-gender-attracted youth already experience by early adolescence. Given that victimization is associated acutely and longitudinally with many deleterious outcomes, including poorer mental health and increased risk for subsequent victimization, greater structural supports are needed for early adolescent SMY.

Drawn-on-Skin Sensors from Fully Biocompatible Inks toward High-Quality Electrophysiology.

The need to develop wearable devices for personal health monitoring, diagnostics, and therapy has inspired the production of innovative on-demand, customizable technologies. Several of these technologies enable printing of raw electronic materials directly onto biological organs and tissues. However, few of them have been thoroughly investigated for biocompatibility of the raw materials on the cellular, tissue, and organ levels or with different cell types. In addition, highly accurate multiday in vivo monitoring using such on-demand, in situ fabricated devices has yet to be done. Presented herein is the first fully biocompatible, on-skin fabricated electronics for multiple cell types and tissues that can capture electrophysiological signals with high fidelity. While also demonstrating improved mechanical and electrical properties, the drawn-on-skin ink retains its properties under various writing conditions, which minimizes the variation in electrical performance. Furthermore, the drawn-on-skin ink shows excellent biocompatibility with cardiomyocytes, neurons, mice skin tissue, and human skin. The high signal-to-noise ratios of the electrophysiological signals recorded with the DoS sensor over multiple days demonstrate its potential for personalized, long-term, and accurate electrophysiological health monitoring.

Violence perpetration prevalence among Colorado (United States) high school students across gender, racial/ethnic, and sexual identities.

Adolescent violence, including sexual violence, homophobic name-calling, and teen dating violence, are public health problems that cause harm to many adolescents in the United States. Although research on the perpetration of these forms of adolescent violence has increased in recent years, little is known about perpetration rates across gender, race/ethnicity, and sexual orientation. To address this gap, the current study descriptively examined perpetration rates between and across different identities, including self-identified race/ethnicity, sexual identity, and gender identity. In Fall 2017, 9th - 11th grade students (N = 4782) at 20 high schools in Colorado (United States) completed a survey that assessed demographics (e.g., race/ethnicity, sexual identity, and gender identity) and various forms of violence perpetration. Compared to female adolescents, male adolescents reported significantly higher perpetration rates for: any sexual violence (27% vs. 17%); sexual harassment (26% vs. 15%); unwanted sexual contact (8% vs. 4%); and homophobic name-calling (61% vs. 38%). Differences in perpetration rates were also observed among various racial/ethnic, sexual, and gender minority students compared to non-minority students. This emphasizes a need for more research on how minority stress that results from the dynamics of intersecting identities and societal systems of power-including racism, sexism, homophobia, and transphobia-contributes to violence perpetration. Evidence-based violence prevention approaches, particularly strategies targeted at changing social norms about violence, gender, and sexuality, need to be tailored and evaluated for students with diverse cultural and social identities to ensure safe school climates for all students.

Precise control of microtubule disassembly in living cells.

Microtubules tightly regulate various cellular activities. Our understanding of microtubules is largely based on experiments using microtubule-targeting agents, which, however, are insufficient to dissect the dynamic mechanisms of specific microtubule populations, due to their slow effects on the entire pool of microtubules. To overcome this technological limitation, we have used chemo and optogenetics to disassemble specific microtubule subtypes, including tyrosinated microtubules, primary cilia, mitotic spindles, and intercellular bridges, by rapidly recruiting engineered microtubule-cleaving enzymes onto target microtubules in a reversible manner. Using this approach, we show that acute microtubule disassembly swiftly halts vesicular trafficking and lysosomal dynamics. It also immediately triggers Golgi and ER reorganization and slows the fusion/fission of mitochondria without affecting mitochondrial membrane potential. In addition, cell rigidity is increased after microtubule disruption owing to increased contractile stress fibers. Microtubule disruption furthermore prevents cell division, but does not cause cell death during interphase. Overall, the reported tools facilitate detailed analysis of how microtubules precisely regulate cellular architecture and functions.

Quantitative CT and machine learning classification of fibrotic interstitial lung diseases.

OBJECTIVES: To evaluate quantitative computed tomography (QCT) features and QCT feature-based machine learning (ML) models in classifying interstitial lung diseases (ILDs). To compare QCT-ML and deep learning (DL) models' performance. METHODS: We retrospectively identified 1085 patients with pathologically proven usual interstitial pneumonitis (UIP), nonspecific interstitial pneumonitis (NSIP), and chronic hypersensitivity pneumonitis (CHP) who underwent peri-biopsy chest CT. Kruskal-Wallis test evaluated QCT feature associations with each ILD. QCT features, patient demographics, and pulmonary function test (PFT) results trained eXtreme Gradient Boosting (training/validation set n = 911) yielding 3 models: M1 = QCT features only; M2 = M1 plus age and sex; M3 = M2 plus PFT results. A DL model was also developed. ML and DL model areas under the receiver operating characteristic curve (AUC) and 95% confidence intervals (CIs) were compared for multiclass (UIP vs. NSIP vs. CHP) and binary (UIP vs. non-UIP) classification performances. RESULTS: The majority (69/78 [88%]) of QCT features successfully differentiated the 3 ILDs (adjusted p ≤ 0.05). All QCT-ML models achieved higher AUC than the DL model (multiclass AUC micro-averages 0.910, 0.910, 0.925, and 0.798 and macro-averages 0.895, 0.893, 0.925, and 0.779 for M1, M2, M3, and DL respectively; binary AUC 0.880, 0.899, 0.898, and 0.869 for M1, M2, M3, and DL respectively). M3 demonstrated statistically significant better performance compared to M2 (∆AUC: 0.015, CI: [0.002, 0.029]) for multiclass prediction. CONCLUSIONS: QCT features successfully differentiated pathologically proven UIP, NSIP, and CHP. While QCT-based ML models outperformed a DL model for classifying ILDs, further investigations are warranted to determine if QCT-ML, DL, or a combination will be superior in ILD classification. KEY POINTS: • Quantitative CT features successfully differentiated pathologically proven UIP, NSIP, and CHP. • Our quantitative CT-based machine learning models demonstrated high performance in classifying UIP, NSIP, and CHP histopathology, outperforming a deep learning model. • While our quantitative CT-based machine learning models performed better than a DL model, additional investigations are needed to determine whether either or a combination of both approaches delivers superior diagnostic performance.

Detection of SARS-CoV-2 contamination in the operating room and birthing room setting: a cross-sectional study.

BACKGROUND: The exposure risks to front-line health care workers caring for patients with SARS-CoV-2 infection undergoing surgery or obstetric delivery are unclear, and an understanding of sample types that may harbour virus is important for evaluating risk. We sought to determine whether SARS-CoV-2 viral RNA from patients with SARS-CoV-2 infection undergoing surgery or obstetric delivery was present in the peritoneal cavity of male and female patients, in the female reproductive tract, in the environment of the surgery or delivery suite (surgical instruments or equipment used, air or floors), and inside the masks of the attending health care workers. METHODS: We conducted a cross-sectional study from November 2020 to May 2021 at 2 tertiary academic Toronto hospitals, during urgent surgeries or obstetric deliveries for patients with SARS-CoV-2 infection. The presence of SARS-CoV-2 viral RNA in patient, environmental and air samples was identified by real-time reverse transcription polymerase chain reaction (RT-PCR). Air samples were collected using both active and passive sampling techniques. The primary outcome was the proportion of health care workers' masks positive for SARS-CoV-2 RNA. We included adult patients with positive RT-PCR nasal swab undergoing obstetric delivery or urgent surgery (from across all surgical specialties). RESULTS: A total of 32 patients (age 20-88 yr) were included. Nine patients had obstetric deliveries (6 cesarean deliveries), and 23 patients (14 male) required urgent surgery from the orthopedic or trauma, general surgery, burn, plastic surgery, cardiac surgery, neurosurgery, vascular surgery, gastroenterology and gynecologic oncology divisions. SARS-CoV-2 RNA was detected in 20 of 332 (6%) patient and environmental samples collected: 4 of 24 (17%) patient samples, 5 of 60 (8%) floor samples, 1 of 54 (2%) air samples, 10 of 23 (43%) surgical instrument or equipment samples, 0 of 24 cautery filter samples and 0 of 143 (95% confidence interval 0-0.026) inner surface of mask samples. INTERPRETATION: During the study period of November 2020 to May 2021, we found evidence of SARS-CoV-2 RNA in a small but important number of samples obtained in the surgical and obstetric operative environment. The finding of no detectable virus inside the masks worn by the health care teams would suggest a low risk of infection for health care workers using appropriate personal protective equipment.

Surveillance for Violent Deaths - National Violent Death Reporting System, 42 States, the District of Columbia, and Puerto Rico, 2019.

PROBLEM/CONDITION: In 2019, approximately 67,000 persons died of violence-related injuries in the United States. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) on violent deaths that occurred in 42 states, the District of Columbia, and Puerto Rico in 2019. Results are reported by sex, age group, race and ethnicity, method of injury, type of location where the injury occurred, circumstances of injury, and other selected characteristics. PERIOD COVERED: 2019. DESCRIPTION OF SYSTEM: NVDRS collects data regarding violent deaths obtained from death certificates, coroner and medical examiner records, and law enforcement reports. This report includes data collected for violent deaths that occurred in 2019. Data were collected from 39 states with statewide data (Alabama, Alaska, Arizona, Colorado, Connecticut, Delaware, Georgia, Hawaii, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Minnesota, Missouri, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Rhode Island, South Carolina, Utah, Vermont, Virginia, Washington, West Virginia, Wisconsin, and Wyoming), three states with data from counties representing a subset of their population (30 California counties, representing 57% of its population, and 47 Illinois counties and 40 Pennsylvania counties, representing at least 80% of their populations), the District of Columbia, and Puerto Rico. NVDRS collates information for each violent death and links deaths that are related (e.g., multiple homicides, homicide followed by suicide, or multiple suicides) into a single incident. RESULTS: For 2019, NVDRS collected information on 50,374 fatal incidents involving 51,627 deaths that occurred in 42 states (39 states collecting statewide data, 30 California counties, 47 Illinois counties, and 40 Pennsylvania counties), and the District of Columbia. In addition, information was collected for 831 fatal incidents involving 897 deaths in Puerto Rico. Data for Puerto Rico were analyzed separately. Of the 51,627 deaths, the majority (64.1%) were suicides, followed by homicides (25.1%), deaths of undetermined intent (8.7%), legal intervention deaths (1.4%) (i.e., deaths caused by law enforcement and other persons with legal authority to use deadly force acting in the line of duty, excluding legal executions), and unintentional firearm deaths (<1.0%). The term "legal intervention" is a classification incorporated into the International Classification of Diseases, Tenth Revision, and does not denote the lawfulness or legality of the circumstances surrounding a death caused by law enforcement. Demographic patterns and circumstances varied by manner of death. The suicide rate was higher for males than for females. Across all age groups, the suicide rate was highest among adults aged 45-54 years. In addition, non-Hispanic American Indian or Alaska Native (AI/AN) and non-Hispanic White (White) persons had the highest suicide rates among all racial and ethnic groups. Among males, the most common method of injury for suicide was a firearm, whereas poisoning was the most common method of injury among females. Among all suicide victims, suicide was most often preceded by a mental health, intimate partner, or physical health problem or by a recent or impending crisis during the previous or upcoming 2 weeks. The homicide rate was higher for males than for females. Among all homicide victims, the homicide rate was highest among persons aged 20-24 years compared with other age groups. Non-Hispanic Black (Black) males experienced the highest homicide rate of any racial or ethnic group. Among all homicide victims, the most common method of injury was a firearm. When the relationship between a homicide victim and a suspect was known, the suspect was most frequently an acquaintance or friend for male victims and a current or former intimate partner for female victims. Homicide most often was precipitated by an argument or conflict, occurred in conjunction with another crime, or, for female victims, was related to intimate partner violence. Nearly all victims of legal intervention deaths were male, and the legal intervention death rate was highest among men aged 25-29 years. The legal intervention death rate was highest among AI/AN males, followed by Black males. A firearm was used in the majority of legal intervention deaths. When a specific type of crime was known to have precipitated a legal intervention death, the type of crime was most frequently assault or homicide. The three most frequent circumstances reported for legal intervention deaths were as follows: the victim's death was precipitated by another crime, the victim used a weapon in the incident, and the victim had a mental health or substance use problem (other than alcohol use). Unintentional firearm deaths were most frequently experienced by males, White persons, and persons aged 15-24 years. These deaths most frequently occurred while the shooter was playing with a firearm and were precipitated by a person unintentionally pulling the trigger or mistakenly thinking the firearm was unloaded. The rate of deaths of undetermined intent was highest among males, particularly among Black and AI/AN males, and among adults aged 30-44 years. Poisoning was the most common method of injury in deaths of undetermined intent, and opioids were detected in nearly 80% of decedents tested for those substances. INTERPRETATION: This report provides a detailed summary of data from NVDRS on violent deaths that occurred in 2019. The suicide rate was highest among AI/AN and White males, whereas the homicide rate was highest among Black males. Mental health problems, intimate partner problems, interpersonal conflicts, and acute life stressors were primary circumstances for multiple types of violent death. PUBLIC HEALTH ACTION: Violence is preventable, and data can guide public health action. NVDRS data are used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in developing, implementing, and evaluating programs, policies, and practices to reduce and prevent violent deaths. For example, the New Hampshire Violent Death Reporting System (VDRS), Indiana VDRS, and Colorado VDRS have used their VDRS data to guide suicide prevention efforts and generate reports highlighting where additional focus is needed. In New Hampshire, VDRS data have been used to monitor the increase in suicide rates during 2014-2018 and guide statewide collaborative prevention efforts. Indiana VDRS used local data to demonstrate differences in suicide and other related mental health problems among Black persons and highlight a need for improved suicide awareness and culturally competent mental health care. The Colorado VDRS conducted geospatial and demographic analysis, considering local VDRS data with existing suicide prevention efforts and resources, to identify regions with high suicide rates regions and populations at high risk for suicide. Similarly, states participating in NVDRS have used their VDRS data to examine related to homicide in their state. In North Carolina for example, where homicide rates among AI/AN and Black persons were approximately 2.5 times higher than the statewide homicide rate, the North Carolina VDRS program aims to partner with historically Black colleges and universities in the state to train researchers to use VDRS data to address health equity issues in and around their immediate community.