Early oxidative stress and DNA damage in Aß-burdened hippocampal neurons in an Alzheimer's-like transgenic rat model.

Oxidative stress is a key contributor to AD pathology. However, the earliest role of pre-plaque neuronal oxidative stress, remains elusive. Using laser microdissected hippocampal neurons extracted from McGill-R-Thy1-APP transgenic rats we found that intraneuronal amyloid beta (iAß)-burdened neurons had increased expression of genes related to oxidative stress and DNA damage responses including Ercc2, Fancc, Sod2, Gsr, and Idh1. DNA damage was further evidenced by increased neuronal levels of XPD (Ercc2) and γH2AX foci, indicative of DNA double stranded breaks (DSBs), and by increased expression of Ercc6, Rad51, and Fen1, and decreased Sirt6 in hippocampal homogenates. We also found increased expression of synaptic plasticity genes (Grin2b (NR2B), CamkIIα, Bdnf, c-fos, and Homer1A) and increased protein levels of TOP2ß. Our findings indicate that early accumulation of iAß, prior to Aß plaques, is accompanied by incipient oxidative stress and DSBs that may arise directly from oxidative stress or from maladaptive synaptic plasticity.

Barriers to Participation in a Structured Quality Improvement Initiative to Reduce Avoidable Emergency Department Visits-A Qualitative Study.

INTRODUCTION: Barriers to quality improvement (QI) initiatives in multi-institutional hospital settings are understudied. Here we describe a qualitative investigation of factors negatively affecting a QI initiative focused on reducing avoidable emergency department (ED) visits after bariatric surgery across 17 hospitals. Our goal was to explore participant perspectives and identify themes describing why the program was not effectively implemented or why the program may have been ineffective when correctly implemented. METHODS: We performed semistructured group interviews with 17 sites (42 interviews) participating in a statewide bariatric QI program. We used descriptive content analysis to identify challenges, facilitators, and barriers to implementation of the QI program. All analyses were conducted using MAXQDA software. RESULTS: Results revealed barriers across hospitals related to four themes: buy-in, provider accessibility, resources at participating hospitals, and patient barriers to care. In particular, the initiative faced difficulty if it was not well-matched to the factors driving increasing ED visits at a particular site, such as lack of patient access to outpatient or primary care. Additional challenges occurred if the initiative was not adapted and customized to the working systems in place at each site, involving employees, surgeons, support staff, and leadership. CONCLUSIONS: Overall, findings can direct future focused efforts aimed at site-specific interventions to reduce unnecessary postoperative ED visits. Results demonstrated a need for a nuanced approach that can be adapted based on facility needs and resources.

Right-sided Morgagni diaphragmatic hernia presenting as isolated left shoulder pain.

A woman in her 60s presented to the emergency department with excruciating, deep left shoulder pain and was found to have a right-sided Morgagni hernia, a rare type of congenital diaphragmatic hernia (CDH). She did not have chest pain, palpitations, shortness of breath, cough, abdominal pain, constipation, diarrhoea, nausea, vomiting or other symptoms classically associated with CDHs in adults. Laparoscopic robotic-assisted repair with mesh placement was performed, and the patient's recovery was uncomplicated, with no recurrence of shoulder pain. Our patient's presentation was unusual due to the absence of symptoms typically seen with CDHs in adults, and the presence of contralateral, left-sided shoulder pain with a right-sided Morgagni hernia.

Prehospital Assaults Against Asian Americans, Native Hawaiians, and Pacific Islanders During COVID-19.

INTRODUCTION: Anti-Asian sentiment increased when the SARS-CoV-2 virus reached the United States in 2020. Trends in national assaults occurring during the COVID-19 pandemic in the Asian American, Native Hawaiian, and Pacific Islander (AANHPI) community were evaluated. METHODS: Patients treated for assaults by emergency medical services between January 2019 and December 2021 were extracted from ImageTrend Collaborate, a national database. Multivariable logistic regression models, adjusting for age, sex, and urbanicity, were used to compare assault rates overall and in the AANHPI population. RESULTS: There were 84,825 assaults (8.5% of injury incidents) in 2019; 96,314 (9.2%) in 2020; and 97,841 (8.4%) in 2021. Assaults against AANHPI increased from 870 (7.1 assaults per 100 injuries) to 987 (8.3) and 1150 (7.9) between 2019 and 2021, respectively. Compared to 2019, risk of assaults in 2020 in all races increased (OR 1.08; 1.07, 1.10) but decreased in 2021 (OR 0.97; 0.96, 0.98). However, among AANHPI, risk of assaults increased in both 2020 (OR 1.22; 1.10, 1.35) and 2021 (OR 1.13; 1.03, 1.25). Most AANHPI assault victims were between 25 and 34 y old (11.8% in 2019) with an increase in 2020 (15.6%) and 2021 (14.4%). Assaults against AANHPI with blunt and sharp objects increased annually from 2019 to 2021. CONCLUSIONS: Despite national decreases of assaults in 2021 to pre-COVID baseline, the rate of assaults treated by emergency medical services for the AANHPI population remained elevated. Further studies analyzing in-hospital assault trends will allow for better understanding and will quantify the impact the pandemic and surrounding social influences had on minorities across the United States.

Elevated Electron Temperature Coincident with Observed Fusion Reactions in a Sheared-Flow-Stabilized Z Pinch.

The sheared-flow-stabilized Z pinch concept has been studied extensively and is able to produce fusion-relevant plasma parameters along with neutron production over several microseconds. We present here elevated electron temperature results spatially and temporally coincident with the plasma neutron source. An optical Thomson scattering apparatus designed for the FuZE device measures temperatures in the range of 1-3 keV on the axis of the device, 20 cm downstream of the nose cone. The 17-fiber system measures the radial profiles of the electron temperature. Scanning the laser time with respect to the neutron pulse time over a series of discharges allows the reconstruction of the T_{e} temporal response, confirming that the electron temperature peaks simultaneously with the neutron output, as well as the pinch current and inductive voltage generated within the plasma. Comparison to spectroscopic ion temperature measurements suggests a plasma in thermal equilibrium. The elevated T_{e} confirms the presence of a plasma assembled on axis, and indicates limited radiative losses, demonstrating a basis for scaling this device toward net gain fusion conditions.

Carbapenem use in extended-spectrum cephalosporin-resistant Enterobacterales infections in US hospitals and influence of IDSA guidance: a retrospective cohort study.

BACKGROUND: Disparate and rapidly changing practice recommendations from major professional infectious diseases societies for managing non-severe infections caused by extended-spectrum ß-lactamase-producing Enterobacterales might hamper carbapenem stewardship. We aimed to understand the real-world management of extended-spectrum cephalosporin-resistant (ECR) Enterobacterales infections in US hospitals and factors influencing preference for carbapenems over alternative treatments. METHODS: This retrospective cohort study included adults (aged ≥18 years) admitted to hospital with ECR Enterobacterales infections in the PINC AI database. Antibiotic regimens were assessed during empirical and targeted treatment periods and by infection severity and site. Likelihood of receiving targeted carbapenems over time and before or after initial release of the Infectious Diseases Society of America (IDSA) guidance on Sept 8, 2020, was established with generalised estimating equations controlling for patient, hospital, and temporal confounders. FINDINGS: Between Jan 1, 2018, and Dec 31, 2021, 30 041 inpatient encounters with ECR Enterobacterales infections were identified at 168 US hospitals, of which 16 006 (53·3%) encounters were in women and 14 035 (46·7%) were in men, with a mean age of 67·3 years (SD 15·1). Although few patients received carbapenems empirically (5324 [17·7%] of 30 041), many did so as targeted treatment (17 518 [58·3%] of 30 041), including subgroups of patients without septic shock (3031 [45·6%] of 6651) and patients with urinary tract infections without septic shock (1845 [46·8%] of 3943) in whom specific narrower-spectrum alternatives were active. Transitions from non-carbapenem to carbapenem antibiotics occurred most often on the day that the ECR phenotype was reported, regardless of illness severity. Carbapenems were the predominant choice to treat ECR Enterobacterales infections over time (adjusted odds ratio 1·00 [95% CI 1·00-1·00]), with no additional immediate change (1·07 [0·95-1·20]) or sustained change (0·99 [0·98-1·00]) after IDSA guidance release. INTERPRETATION: High carbapenem use in targeting non-severe ECR Enterobacterales infections in US hospitals predates 2020 IDSA guidance and has persisted thereafter. Efforts to increase awareness and implementation of recommendations among clinicians to use carbapenem-sparing alternatives in ECR Enterobacterales infections might decrease global carbapenem selective pressure. FUNDING: US National Institutes of Health Intramural Research Program, National Institute of Allergy and Infectious Diseases, and US Food and Drug Administration.

mARC1 in MASLD: Modulation of lipid accumulation in human hepatocytes and adipocytes.

BACKGROUND: Mutations in the gene MTARC1 (mitochondrial amidoxime-reducing component 1) protect carriers from metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MTARC1 encodes the mARC1 enzyme, which is localized to the mitochondria and has no known MASH-relevant molecular function. Our studies aimed to expand on the published human genetic mARC1 data and to observe the molecular effects of mARC1 modulation in preclinical MASH models. METHODS AND RESULTS: We identified a novel human structural variant deletion in MTARC1, which is associated with various biomarkers of liver health, including alanine aminotransferase levels. Phenome-wide Mendelian Randomization analyses additionally identified novel putatively causal associations between MTARC1 expression, and esophageal varices and cardiorespiratory traits. We observed that protective MTARC1 variants decreased protein accumulation in in vitro overexpression systems and used genetic tools to study mARC1 depletion in relevant human and mouse systems. Hepatocyte mARC1 knockdown in murine MASH models reduced body weight, liver steatosis, oxidative stress, cell death, and fibrogenesis markers. mARC1 siRNA treatment and overexpression modulated lipid accumulation and cell death consistently in primary human hepatocytes, hepatocyte cell lines, and primary human adipocytes. mARC1 depletion affected the accumulation of distinct lipid species and the expression of inflammatory and mitochondrial pathway genes/proteins in both in vitro and in vivo models. CONCLUSIONS: Depleting hepatocyte mARC1 improved metabolic dysfunction-associated steatotic liver disease-related outcomes. Given the functional role of mARC1 in human adipocyte lipid accumulation, systemic targeting of mARC1 should be considered when designing mARC1 therapies. Our data point to plasma lipid biomarkers predictive of mARC1 abundance, such as Ceramide 22:1. We propose future areas of study to describe the precise molecular function of mARC1, including lipid trafficking and subcellular location within or around the mitochondria and endoplasmic reticulum.

Scenario-Based Messages on Social Media Motivate COVID-19 Information Seeking.

Communicating information about health risks empowers individuals to make informed decisions. To identify effective communication strategies, we manipulated the specificity, self-relevance, and emotional framing of messages designed to motivate information seeking about COVID-19 exposure risk. In Study 1 (N=221,829), we conducted a large-scale social media field study. Using Facebook advertisements, we targeted users by age and political attitudes. Episodic specificity drove engagement: Advertisements that contextualized risk in specific scenarios produced the highest click-through rates, across all demographic groups. In Study 2, we replicated and extended our findings in an online experiment (N=4,233). Message specificity (but not self-relevance or emotional valence) drove interest in learning about COVID-19 risks. Across both studies, we found that older adults and liberals were more interested in learning about COVID-19 risks. However, message specificity increased engagement across demographic groups. Overall, evoking specific scenarios motivated information seeking about COVID-19, facilitating risk communication to a broad audience.

Impaired autophagy following ex vivo cooling of simulated hypothermic temperatures in peripheral blood mononuclear cells from young and older adults.

Hypothermia is a critical consequence of extreme cold exposure that increases the risk of cold-related injury and death in humans. While the initiation of cytoprotective mechanisms including the process of autophagy and the heat shock response (HSR) is crucial to cellular survival during periods of stress, age-related decrements in these systems may underlie cold-induced cellular vulnerability in older adults. Moreover, whether potential sex-related differences in autophagic regulation influence the human cold stress response remain unknown. We evaluated the effect of age and sex on mechanisms of cytoprotection (autophagy and the HSR) and cellular stress (apoptotic signaling and the acute inflammatory response) during ex vivo hypothermic cooling. Venous blood samples from 20 healthy young (10 females; mean [SD]: 22 [2] years) and 20 healthy older (10 females; 66 [5] years) adults were either isolated immediately (baseline) for peripheral blood mononuclear cells (PBMCs) or exposed to water bath temperatures maintained at 37, 35, 33, 31, or 4 °C for 90 min before PBMC isolation. Proteins associated with autophagy, apoptosis, the HSR, and inflammation were analyzed via Western blotting. Indicators of autophagic initiation and signaling (LC3, ULK1, and beclin-2) and the HSR (HSP90 and HSP70) increased when exposed to hypothermic temperatures in young and older adults (all p ≤ 0.007). Sex-related differences were only observed with autophagic initiation (ULK1; p = 0.015). However, despite increases in autophagic initiators ULK1 and beclin-2 (all p < 0.001), this was paralleled by autophagic dysfunction (increased p62) in all groups (all p < 0.001). Further, apoptotic (cleaved-caspase-3) and inflammatory (IL-6 and TNF-α) signaling increased in all groups (all p < 0.001). We demonstrated that exposure to hypothermic conditions is associated with autophagic dysfunction, irrespective of age or sex, although there may exist innate sex-related differences in cytoprotection in response to cold exposure as evidenced through altered autophagic initiation.

Parous women perform less moderate to vigorous physical activity than their nulliparous peers: a population-based study in Denmark.

OBJECTIVES: The World Health Organization (WHO) highlights parous women as a key population for monitoring trends of physical activity (PA). We aimed to estimate the proportion of Danish women non-adhering to WHO PA guidelines in parous women compared with nulliparous women and to describe leisure-time PA intensity in each of these groups. STUDY DESIGN: Cross-sectional study. METHODS: This population-based study builds on a sample of 27,668 women aged 16-40 years from the Danish National Health Survey 2021. These data were linked with childbirth data from the Danish National Birth Registry. The primary outcome was self-reported weekly hours of moderate to vigorous leisure-time PA (MVPA) dichotomized into: (i) adhering to WHO guidelines for MVPA or (ii) not adhering to WHO guidelines for MVPA. Binomial regression analysis was used to calculate prevalence proportions (PP) and prevalence proportion ratios (PPR). RESULTS: Of the 27,668 women, a total of 20,022 were included; 9338 (46.6%) parous women and 10,684 (53.4%) nulliparous women. The PP of women non-adhering to WHO PA guidelines was 63.8% (95% CI 62.9-64.8) for parous and 51.3% (95% CI 50.4-52.3) for nulliparous women, corresponding to a PPR of 1.24 (95% CI 1.21; 1.27). CONCLUSIONS: The proportion of parous women who did not adhere to WHO PA guidelines for MVPA was 24% higher than that of nulliparous women. This highlights parous women as a subgroup of the adult population at increased risk of non-adherence to WHO PA guidelines. These findings call for future research to inform new strategies aiming to promote PA in parous women.

Validation of a Novel, Rapid Sepsis Diagnostic for Emergency Department Use.

OBJECTIVES: To assess the in vitro IntelliSep test, a microfluidic assay that quantifies the state of immune activation by evaluating the biophysical properties of leukocytes, as a rapid diagnostic for sepsis. DESIGN: Prospective cohort study. SETTING: Five emergency departments (EDs) in Louisiana, Missouri, North Carolina, and Washington. PATIENTS: Adult patients presenting to the ED with signs (two of four Systemic Inflammatory Response Syndrome criteria, where one must be temperature or WBC count) or suspicion (provider-ordered culture) of infection. INTERVENTIONS: All patients underwent testing with the IntelliSep using ethylene diamine tetraacetic acid-anticoagulated whole blood followed by retrospective adjudication for sepsis by sepsis-3 criteria by a blinded panel of physicians. MEASUREMENTS AND MAIN RESULTS: Of 599 patients enrolled, 572 patients were included in the final analysis. The result of the IntelliSep test is reported as the IntelliSep Index (ISI), ranging from 0.1 to 10.0, divided into three interpretation bands for the risk of sepsis: band 1 (low) to band 3 (high). The median turnaround time for ISI results was 7.2 minutes. The ISI resulted band 1 in 252 (44.1%), band 2 in 160 (28.0%), and band 3 in 160 (28.0%). Sepsis occurred in 26.6% (152 of 572 patients). Sepsis prevalence was 11.1% (95% CI, 7.5-15.7%) in band 1, 28.1% (95% CI, 21.3-35.8%) in band 2, and 49.4% (95% CI, 41.4-57.4%) in band 3. The Positive Percent Agreement of band 1 was 81.6% and the Negative Percent Agreement of band 3 was 80.7%, with an area under the receiver operating characteristic curve of 0.74. Compared with band 1, band 3 correlated with adverse clinical outcomes, including mortality, and resource utilization. CONCLUSIONS: Increasing ISI interpretation band is associated with increasing probability of sepsis in patients presenting to the ED with suspected infection.

Does Neoadjuvant Chemotherapy in Clinical T1-T2 N0 Triple-Negative Breast Cancer Increase the Extent of Axillary Surgery?

BACKGROUND: Current management strategies for early-stage triple-negative breast cancer (TNBC) include upfront surgery to determine pathologic stage to guide chemotherapy recommendations, or neoadjuvant chemotherapy (NAC) to de-escalate surgery, elucidate tumor response, and determine the role of adjuvant chemotherapy. However, patients who receive NAC with residual pathological nodal (pN) involvement require axillary lymph node dissection (ALND) as they are Z11/AMAROS ineligible. We aimed to evaluate the impact of NAC compared with upfront surgery on pN status and ALND rates in cT1-2N0 TNBC. METHODS: The National Cancer Database (NCDB) was queried for women with operable cT1-2N0 TNBC from 2014 to 2019. Demographic, clinicopathologic, and treatment data were collected. Multivariable linear regression analysis was performed to assess the odds of pN+ disease and undergoing ALND. RESULTS: Overall, 55,624 women were included: 26.9% (n = 14,942) underwent NAC and 73.1% (n = 40,682) underwent upfront surgery. The NAC cohort was younger (mean age 52.9 vs. 61.3 years; p < 0.001) with more cT2 tumors (71.6% vs. 31.0%; p < 0.001), and had lower ALND rates (4.3% vs. 5.5%; p < 0.001). The upfront surgery cohort was more likely to have one to three pathologically positive nodes (12.1% vs. 6.5%; odds ratio [OR] 2.37, 95% confidence interval (CI) 2.17-2.58; p < 0.001) but there was no difference in the likelihood of ALND (OR 1.1, 95% CI 0.99-1.24; p = 0.08). CONCLUSION: Patients who underwent upfront surgery were more likely to be pN+; however, ALND rates were similar between the two cohorts. Thus, the use of NAC does not result in a higher odds of ALND and the decision for NAC should be individualized and based on modern guidelines and systemic therapy benefits.

A Parallel Process Growth Curve Analysis of Teacher-Student Relationships and Academic Achievement.

Teacher-student relationships (TSR) have been a key focus of study for developmental and educational psychology researchers interested in improving proximal and distal academic outcomes for children and youth. Although prior empirical work suggests some degree of association between TSR and achievement, the co-development of TSR and achievement during elementary grades remains unclear with most findings limited to reading and mathematics achievement. The current study used parallel process growth curve models (PPGCMs) to examine the longitudinal growth trajectories of teacher-student closeness and conflict, and science, reading, and mathematics achievement simultaneously for children followed from kindergarten to third grade in the Early Childhood Longitudinal Study, Kindergarten Class of 2010-2011 (N = 13,490). Findings from the final PPGCM showed teacher-student closeness in kindergarten was positively associated with science, reading and mathematics achievement in kindergarten (r = 0.234 to 0.277) and the linear growth of achievement through third grade (r = 0.068 to 0.156). Teacher-student conflict in kindergarten was negatively associated with science, reading, and mathematics achievement in kindergarten (r = -0.099 to -0.203) and the linear growth of achievement through third grade (r = -0.081 to -0.135). Child biological sex, family socioeconomic status, and child racial and ethnic identity predicted TSR and achievement developmental trends. Implications of the findings and future directions for research are discussed.

National trends in neoadjuvant chemotherapy utilization in patients with early-stage node-negative triple-negative breast cancer: the impact of the CREATE-X trial.

PURPOSE: Neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) allows for assessment of tumor pathological response and has survival implications. In 2017, the CREATE-X trial demonstrated survival benefit with adjuvant capecitabine in patients TNBC and residual disease after NAC. We aimed to assess national rates of NAC for cT1-2N0M0 TNBC before and after CREATE-X and examine factors associated with receiving NAC vs adjuvant chemotherapy (AC). METHODS: A retrospective cohort study of women with cT1-2N0M0 TNBC diagnosed from 2014 to 2019 in the National Cancer Database (NCDB) was performed. Variables were analyzed via ANOVA, Chi-squared, Fisher Exact tests, and a multivariate linear regression model was created. RESULTS: 55,633 women were included: 26.9% received NAC, 52.4% AC, and 20.7% received no chemotherapy (median ages 53, 59, and 71 years, p < 0.01). NAC utilization significantly increased over time: 19.5% in 2014-15 (n = 3,465 of 17,777), 27.1% in 2016-17 (n = 5,140 of 18,985), and 33.6% in 2018-19 (n = 6,337 of 18,871, p < 0.001). On multivariate analysis, increased NAC was associated with younger age (< 50), non-Hispanic white race/ethnicity, lack of comorbidities, cT2 tumors, care at an academic or integrated-network cancer program, and diagnosis post-2017 (p < 0.05 for all). Patients with government-provided insurance were less likely to receive NAC (p < 0.01). Women who traveled > 60 miles for treatment were more likely to receive NAC (p < 0.01). CONCLUSION: From 2014 to 2019, NAC utilization increased for patients with cT1-2N0M0 TNBC. Racial, socioeconomic, and access disparities were observed in who received NAC vs AC and warrants interventions to ensure equitable care.

Human biology and the study of precarity: How the intersection of uncertainty and inequality is taking us to new extremes.

Inequality represents an extreme environment to which humans must respond. One phenomenon that contributes to this growing extreme is precarity or the intersection of uncertainty and some form of inequality. While precarity has an important intellectual history in the fields of sociology and sociocultural anthropology, it has not been well studied in the field of human biology. Rather human biologists have engaged with the study of closely related concepts such as uncertainty and resource insecurity. In this article, we propose that human biology take on the study of precarity as a novel way of investigating inequality. We first provide a brief intellectual history of precarity which is followed by a review of research on uncertainty and resource security in human biology which, while not exhaustive, illustrates some key gaps that precarity may aid us in addressing. We then review some of the pathways through which precarity comes to affect human biology and health and some of the evidence for why the unpredictable nature of precarity may make it a unique physiological stress. A case study based on research in Nuñoa, Peru provides an important example of how precarity can elucidate the influences of health in an extreme setting, albeit with insights that apply more broadly. We conclude that precarity holds important potential for the study of human biology, including helping us more effectively operationalize and study uncertainty, encouraging us to explore the predictability of resources and stressors, and reminding us to think about the intersectional nature of stressors.