A Phase 0 Study to Assess the Biodistribution and Pharmacokinetics of a Radiolabeled Antibody Targeting Human Kallikrein 2 in Participants with Metastatic Castration-Resistant Prostate Cancer.

Despite the inclusion of multiple agents within the prostate cancer treatment landscape, new treatment options are needed to address the unmet need for patients with metastatic castration-resistant prostate cancer (mCRPC). Although prostate-specific membrane antigen is the only cell-surface target to yield clinical benefit in men with advanced prostate cancer, additional targets may further advance targeted immune, cytotoxic, radiopharmaceutical, and other tumor-directed therapies for these patients. Human kallikrein 2 (hK2) is a novel prostate-specific target with little to no expression in nonprostate tissues. This first-in-human phase 0 trial uses an 111In-radiolabeled anti-hK2 monoclonal antibody, [111In]-DOTA-h11B6, to credential hK2 as a potential target for prostate cancer treatment. Methods: Participants with progressive mCRPC received a single infusion of 2 mg of [111In]-DOTA-h11B6 (185 MBq of 111In), with or without 8 mg of unlabeled h11B6 to assess antibody mass effects. Sequential imaging and serial blood samples were collected to determine [111In]-DOTA-h11B6 biodistribution, dosimetry, serum radioactivity, and pharmacokinetics. Safety was assessed within a 2-wk follow-up period from the time of [111In]-DOTA-h11B6 administration. Results: Twenty-two participants received [111In]-DOTA-h11B6 and are included in this analysis. Within 6-8 d of administration, [111In]-DOTA-h11B6 visibly accumulated in known mCRPC lesions, with limited uptake in other organs. Two treatment-emergent adverse events unrelated to treatment occurred, including tumor-related bleeding in 1 patient, which led to early study discontinuation. Serum clearance, biodistribution, and tumor targeting were independent of total antibody mass (2 or 10 mg). Conclusion: This first-in-human study demonstrates that tumor-associated hK2 can be identified and targeted using h11B6 as a platform as the h11B6 antibody selectively accumulated in mCRPC metastases with mass-independent clearance kinetics. These data support the feasibility of hK2 as a target for imaging and hK2-directed agents as potential therapies in patients with mCRPC.

The Winding Road from Origin to Emergence (of Life).

Humanity's strive to understand why and how life appeared on planet Earth dates back to prehistoric times. At the beginning of the 19th century, empirical biology started to tackle this question yielding both Charles Darwin's Theory of Evolution and the paradigm that the crucial trigger putting life on its tracks was the appearance of organic molecules. In parallel to these developments in the biological sciences, physics and physical chemistry saw the fundamental laws of thermodynamics being unraveled. Towards the end of the 19th century and during the first half of the 20th century, the tensions between thermodynamics and the "organic-molecules-paradigm" became increasingly difficult to ignore, culminating in Erwin Schrödinger's 1944 formulation of a thermodynamics-compliant vision of life and, consequently, the prerequisites for its appearance. We will first review the major milestones over the last 200 years in the biological and the physical sciences, relevant to making sense of life and its origins and then discuss the more recent reappraisal of the relative importance of metal ions vs. organic molecules in performing the essential processes of a living cell. Based on this reassessment and the modern understanding of biological free energy conversion (aka bioenergetics), we consider that scenarios wherein life emerges from an abiotic chemiosmotic process are both thermodynamics-compliant and the most parsimonious proposed so far.

Transdermal alcohol concentration features predict alcohol-induced blackouts in college students.

BACKGROUND: Alcohol-induced blackouts (AIBs) are common in college students. Individuals with AIBs also experience acute and chronic alcohol-related consequences. Research suggests that how students drink is an important predictor of AIBs. We used transdermal alcohol concentration (TAC) sensors to measure biomarkers of increasing alcohol intoxication (rise rate, peak, and rise duration) in a sample of college students. We hypothesized that the TAC biomarkers would be positively associated with AIBs. METHODS: Students were eligible to participate if they were aged 18-22 years, in their second or third year of college, reported drinking 4+ drinks on a typical Friday or Saturday, experienced ≥1 AIB in the past semester, owned an iPhone, and were willing to wear a sensor for 3 days each weekend. Students (N = 79, 55.7% female, 86.1% White, Mage = 20.1) wore TAC sensors and completed daily diaries over four consecutive weekends (89.9% completion rate). AIBs were assessed using the Alcohol-Induced Blackout Measure-2. Logistic multilevel models were conducted to test for main effects. RESULTS: Days with faster TAC rise rates (OR = 2.69, 95% CI: 1.56, 5.90), higher peak TACs (OR = 2.93, 95% CI: 1.64, 7.11), and longer rise TAC durations (OR = 4.16, 95% CI: 2.08, 10.62) were associated with greater odds of experiencing an AIB. CONCLUSIONS: In a sample of "risky" drinking college students, three TAC drinking features identified as being related to rising intoxication independently predicted the risk for daily AIBs. Our findings suggest that considering how an individual drinks (assessed using TAC biomarkers), rather than quantity alone, is important for assessing risk and has implications for efforts to reduce risk. Not only is speed of intoxication important for predicting AIBs, but the height of the peak intoxication and the time spent reaching the peak are important predictors, each with different implications for prevention.

Cardiovascular risk, social vigilance, and stress profiles of male law enforcement officers versus civilians.

This study examined the cardiovascular disease (CVD) risk profiles of male law enforcement officers (LEOs) and civilians. CVD risk profiles were based on data collected using traditional objective (e.g., resting BP, cholesterol), novel objective (e.g., ambulatory BP) and self-report measures (e.g., EMA social vigilance). A subset of male LEOs (n = 30, M age = 41.47, SD = 8.03) and male civilians (n = 120, M age = 40.73, SD = 13.52) from a larger study were included in analyses. Results indicated LEOs had significantly higher body mass index [BMI], 31.17 kg/m2 versus 28.87 kg/m2, and exhibited significantly higher trait and state social vigilance across multiple measures, whereas perceived stress was higher among civilians. Findings highlight the need for future research examining CVD risk associated with occupational health disparities, including attributes of individuals entering certain professions as well as experiential and environmental demands of the work.

Comparison of SARS-CoV-2 spike-specific IgA and IgG in nasal secretions, saliva and serum.

Introduction: Several novel vaccine platforms aim at mucosal immunity in the respiratory tract to block SARS-CoV-2 transmission. Standardized methods for mucosal sample collection and quantification of mucosal antibodies are therefore urgently needed for harmonized comparisons and interpretations across mucosal vaccine trials and real-world data. Methods: Using commercial electrochemiluminescence antibody panels, we compared SARS-CoV-2 spike-specific IgA and IgG in paired saliva, nasal secretions, and serum from 1048 healthcare workers with and without prior infection. Results: Spike-specific IgA correlated well in nasal secretions and saliva (r>0.65, p<0.0001), but the levels were more than three-fold higher in nasal secretions as compared to in saliva (p<0.01). Correlations between the total population of spike-specific IgA and spike-specific secretory IgA (SIgA) were significantly stronger (p<0.0001) in nasal secretions (r=0.96, p<0.0001) as opposed to in saliva (r=0.77, p<0.0001), and spike-specific IgA correlated stronger (p<0.0001) between serum and saliva (r=0.73, p<0.001) as opposed to between serum and nasal secretions (r=0.54, p<0.001), suggesting transudation of monomeric spike specific IgA from the circulation to saliva. Notably, spike-specific SIgA had a markedly higher SARS-CoV-2 variant cross-binding capacity as compared to the total population of spike specific IgA and IgG in both nasal secretions, saliva and serum, (all p<0.0001), which emphasizes the importance of taking potential serum derived monomeric IgA into consideration when investigating mucosal immune responses. Discussion: Taken together, although spike-specific IgA can be reliably measured in both nasal secretions and saliva, our findings imply an advantage of higher levels and likely also a larger proportion of SIgA in nasal secretions as compared to in saliva. We further corroborate the superior variant cross-binding capacity of SIgA in mucosal secretions, highlighting the potential protective benefits of a vaccine targeting the upper respiratory tract.

Repeated Hyposalinity Pulses Immediately And Persistently Impair The Sea Urchin Adhesive System.

Climate change will increase the frequency and intensity of extreme climatic events (e.g., storms) that result in repeated pulses of hyposalinity in nearshore ecosystems. Sea urchins inhabit these ecosystems and are stenohaline (restricted to salinity levels ∼ 32 ‰), thus are particularly susceptible to hyposalinity events. As key benthic omnivores, sea urchins use hydrostatic adhesive tube feet for numerous functions, including attachment to and locomotion on the substratum as they graze for food. Hyposalinity severely impacts sea urchin locomotor and adhesive performance but several ecologically-relevant and climate change-related questions remain. First, does sea urchin locomotion and adhesion acclimate to repeated pulses of hyposalinity? Second, how do tube feet respond to tensile forces during single and repeated hyposalinity events? Third, do the negative effects of hyposalinity exposure persist following return to normal salinity levels? To answer these questions, we repeatedly exposed green sea urchins (Strongylocentrotus droebachiensis) to pulses of three different salinities (control: 32 ‰, moderate hyposalinity: 22 ‰, severe hyposalinity: 16 ‰) over the course of two months and measured locomotor performance, adhesive performance, and tube foot tensile behavior. We also measured these parameters 20 hours after sea urchins returned to normal salinity levels. We found no evidence that tube feet performance and properties acclimate to repeated pulses of hyposalinity, at least over the timescale examined in this study. In contrast, hyposalinity has severe consequences on locomotion, adhesion, and tube foot tensile behavior and these impacts are not limited to the hyposalinity exposure. Our results suggest both moderate and severe hyposalinity events have the potential to increase sea urchin dislodgment and reduce movement, which may impact sea urchin distribution and their role in marine communities.

Subjective intoxication predicts alcohol-related consequences at equivalent alcohol concentrations in young adults using ecological momentary assessment and alcohol sensors.

OBJECTIVE: Subjective intoxication (SI) when drinking may serve as an internal barometer of whether to continue drinking or engage in potentially unsafe behavior. Mobile assessments offer the potential to use SI as a prospective risk indicator during drinking episodes; little evidence exists for the validity of real-time SI measures. We test the correspondence of SI with estimated blood alcohol concentration and transdermal alcohol concentration (TAC) in young adults' natural settings. We provide a novel test of whether SI features (peak and mean SI) uniquely predict consequences adjusting for alcohol concentration. METHOD: Two hundred twenty-two heavy-drinking young adults (Mage = 22.3, 64% female, 79% non-Hispanic White, 84% undergraduates) participated in a 6-day study that used ecological momentary assessment of drinking and TAC sensors. SI was assessed every 30 min during drinking episodes. Multilevel modeling was used to test hypotheses. RESULTS: Momentary SI and estimated blood alcohol concentration had moderate associations at the moment and day levels (standardized ßs = 0.5-0.6); SI was moderately associated with TAC at the day level (ßs = 0.5). Associations between SI and alcohol concentration varied widely between persons and across days. Day-level SI features predicted consequences when adjusting for alcohol concentration (incidence rate ratios, IRRs = 1.29-1.70). CONCLUSIONS: Our two-item SI measure shows evidence of validity in real-world settings with heavy-drinking young adults. SI was significantly correlated with alcohol concentration and was a unique predictor of consequences. The strength of these associations varied greatly across persons and days. Real-time SI measurement may be useful in preventive interventions, but continued research is needed into when and for whom momentary SI is most predictive of risk. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

College Students' Day-to-Day Maladaptive Drinking Responses to Stress Severity and Stressor-Related Guilt and Anger.

BACKGROUND: Stress is a common part of college students' daily lives that may influence their physical activity (PA) and alcohol use. Understanding features of daily stress processes that predict health behaviors could help identify targets for just-in-time interventions. PURPOSE: This study used intensive longitudinal data to examine whether prior day stress processes predict current day PA or alcohol use. METHODS: Participants (N=58, Mage=20.5, 59% women, 70% White) were 18-to-25-year-old students who engaged in binge drinking at least twice monthly and used cannabis or tobacco in the past year. They wore activity (activPAL4) and alcohol (Secure Continuous Remote Alcohol Monitor) monitors for 11 days to assess daily PA (e.g., step counts) and alcohol use (e.g., drinking day), and completed daily surveys about yesterday's stress, including number of stressors (i.e., frequency), stressor intensity (i.e., severity), and frequency of affective states (e.g., guilt). Multilevel models examined prior day stress predicting current day PA or alcohol use. RESULTS: Participants had higher odds of current day drinking (odds ratio=1.21) and greater area under the curve (B=0.08) when they experienced greater than usual stress severity the prior day. Participants had higher current day peak transdermal alcohol concentration (B=0.12) and area under the curve (B=0.11) when they more frequently experienced guilt due to stressors the prior day. CONCLUSIONS: College students' unhealthy response of increasing alcohol use due to stress could adversely impact health outcomes. There is a critical need for interventions addressing students' ability to effectively manage and respond to the stress-inducing, daily demands of student life.

College students experience stress regularly, which may influence their physical activity (PA) and drinking behaviors. Understanding how daily stress predicts health behaviors could be useful for stress-reduction interventions. This study examined whether prior day stress predicted current day PA or alcohol use. Participants (N = 58) were 18- to 25-year-old college students who binge drank at least twice per month and used cannabis or tobacco in the past year. They wore PA and alcohol sensors for 11 days to assess daily PA and alcohol use, and completed daily surveys about yesterday's stress, including the number of stressors experienced (i.e., frequency), stressor intensity (i.e., severity), and mood responses related to stress (anger, anxiety, guilt, sadness). Participants were 21% more likely to drink and drank at higher intensity when they experienced greater than usual stress severity the prior day. Participants had higher current day alcohol use intensity when they more frequently experienced guilt due to stressors the prior day. College students' unhealthy response of increasing alcohol use due to stress could negatively impact short- and long-term health outcomes. There is a critical need for interventions addressing students' ability to effectively manage and respond to the stress-inducing, daily demands of student life.

Young Adult Depression and Cannabis Use: Associations Before and After Recreational Legalization.

INTRODUCTION: The co-occurrence of depression with cannabis use worsens both mood and substance use disorder outcomes, with young adults particularly at risk of co-occurrence. This research investigates whether the association of state-level prevalence rates of young adult (age 18-25) depression and cannabis use in the U.S. changed following enactment of recreational (adult use) cannabis legalization between 2008 and 2019. METHODS: Annual, state prevalence data on past-year major depressive episode (hereafter, depression) and past-month cannabis use were extracted from the National Survey on Drug Use and Health (N=600 state-year observations). Moderated regression models tested whether the association of depression with cannabis use differed before versus after recreational legalization by comparing prevalence rates of depression and cannabis use in states that enacted recreational legalization to those that did not, while fixing state, year, and medical legalization effects. Data were accessed and analyzed in 2023. RESULTS: Prevalence rates of both depression and cannabis use increased throughout the study period. The positive statistical effect of depression on cannabis use more than doubled in magnitude after legalization (ß=0.564, 95% CI=0.291, 0.838) as compared to before (ß=0.229, 95% CI=0.049, 0.409), representing a significant change (ß=0.335, 95% CI=0.093, 0.577). CONCLUSIONS: These results suggest that the association between prevalence rates of young adult depression and cannabis use strengthened following recreational legalization in the U.S. This is potentially due to increases in cannabis accessibility and the acceptance of the health benefits of cannabis, which may enhance the use of cannabis as a coping mechanism among young adults with depression.

A Dual-Process Decision-Making Model Examining the Longitudinal Associations Between Alcohol-Induced Blackouts and Alcohol Use Disorder Risk Among College Student Drinkers.

OBJECTIVE: The purpose of this study was to use a dual-process decision-making model to examine the longitudinal associations between alcohol-induced blackouts (blackouts) and alcohol use disorder (AUD) risk symptoms among college student drinkers. METHOD: Undergraduate drinkers (N = 2,024; 56% female; 87% White; 5% Hispanic) at a large northeastern university completed online surveys each semester during their first (Time [T] 1, T2), second (T3, T4), third (T5, T6), and fourth (T7, T8) years of college (87% retention across the study). Path analyses were examined testing the longitudinal associations between T1 willingness to experience a blackout, T1 intentions to avoid a blackout, T2-T8 drinking, T2-T8 blackouts, and T8 AUD risk symptoms. Hypotheses 1 and 2 tested the associations between T1 willingness, T1 intentions, T2-T8 drinking, and T2-T8 blackouts. Hypothesis 3 tested the associations between T2-T8 drinking, T2-T8 blackouts, and T8 AUD risk symptoms. RESULTS: Students experienced an average of 8 (SD = 8) blackouts during college. Approximately 1,514 (88.8%) participants reported experiencing 1 of 8 AUD risk symptoms. T1 willingness was positively associated with T2-T8 blackouts. T2-T8 drinking and T2-T8 blackouts were positively associated with T8 AUD risk symptoms. T1 willingness significantly indirectly affected T8 AUD risk symptoms through its association with T2-T8 blackouts. CONCLUSIONS: Results estimated that, on average, college student drinkers experienced eight blackouts across 4 years of college, and 88% of participants reported experiencing at least one symptom of AUD in the last semester of college. Willingness to experience a blackout influenced students' AUD risk symptoms through the number of blackouts they experienced throughout college.

Chiropractic spinal manipulative therapy for acute neck pain: A 4-arm clinical placebo randomized controlled trial. A prospective study protocol.

INTRODUCTION: Neck pain poses enormous individual and societal costs worldwide. Spinal manipulative therapy and Non-Steroidal Anti-Inflammatory Drug treatment are frequently used despite a lack of compelling efficacy data. This protocol describes a multicentre 4-arm, clinical placebo randomized controlled trial (RCT), investigating the efficacy of chiropractic spinal manipulative therapy (CSMT) versus sham CSMT, ibuprofen, and placebo medicine for acute neck pain. This superiority study will employ parallel groups, featuring a 1:1:1:1 allocation ratio. MATERIAL AND METHODS: We will randomize 320 participants equally into four groups: CSMT, sham CSMT, ibuprofen, or placebo medicine. CSMT groups are single-blinded, while the medicine groups are double-blinded. Data will be collected at baseline (Day 0), during treatment and post-treatment. The primary endpoint will assess the difference in mean pain intensity from Day 0 to Day 14 on a numeric rating scale 0-10; the CSMT group is compared to sham CSMT, ibuprofen, and placebo medicine groups, respectively. Secondary endpoints will assess mean pain intensity and mean duration at different time points, and adverse events, blinding success, and treatment satisfaction, including comparison between ibuprofen and placebo medicine. Power calculation is based on a mean neck pain rating of 5 at Day 0, with standard deviation of 1 in all groups. Mean pain reduction at Day 14 is expected to be 60% in the CSMT group, 40% in sham CSMT and ibuprofen groups, and 20% in the placebo medicine group. A linear mixed model will compare the mean values for groups with corresponding 95% confidence intervals. P values below 0.017 will be considered statistically significant. All analyses will be conducted blinded from group allocation. DISCUSSION: This RCT aims towards the highest research standards possible for manual-therapy RCTs owing to its two placebo arms. If CSMT and/or ibuprofen proves to be effective, it will provide evidence-based support for CSMT and/or ibuprofen for acute neck pain. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05374057. EU Clinical Trials Register: EudraCT number: 2021-005483-21.

SARS-CoV-2 Infection is Associated with an Increase in New Diagnoses of Schizophrenia Spectrum and Psychotic Disorder: A Study Using the US National COVID Cohort Collaborative (N3C).

Amid the ongoing global repercussions of SARS-CoV-2, it's crucial to comprehend its potential long-term psychiatric effects. Several recent studies have suggested a link between COVID-19 and subsequent mental health disorders. Our investigation joins this exploration, concentrating on Schizophrenia Spectrum and Psychotic Disorders (SSPD). Different from other studies, we took acute respiratory distress syndrome (ARDS) and COVID-19 lab negative cohorts as control groups to accurately gauge the impact of COVID-19 on SSPD. Data from 19,344,698 patients, sourced from the N3C Data Enclave platform, were methodically filtered to create propensity matched cohorts: ARDS (n = 222,337), COVID-positive (n = 219,264), and COVID-negative (n = 213,183). We systematically analyzed the hazard rate of new-onset SSPD across three distinct time intervals: 0-21 days, 22-90 days, and beyond 90 days post-infection. COVID-19 positive patients consistently exhibited a heightened hazard ratio (HR) across all intervals [0-21 days (HR: 4.6; CI: 3.7-5.7), 22-90 days (HR: 2.9; CI: 2.3 -3.8), beyond 90 days (HR: 1.7; CI: 1.5-1.)]. These are notably higher than both ARDS and COVID-19 lab-negative patients. Validations using various tests, including the Cochran Mantel Haenszel Test, Wald Test, and Log-rank Test confirmed these associations. Intriguingly, our data indicated that younger individuals face a heightened risk of SSPD after contracting COVID-19, a trend not observed in the ARDS and COVID-negative groups. These results, aligned with the known neurotropism of SARS-CoV-2 and earlier studies, accentuate the need for vigilant psychiatric assessment and support in the era of Long-COVID, especially among younger populations.

6,7-Diphenyl-5-thia-7-aza-spiro-[2.6]nonan-8-one 5,5-dioxide.

The racemic mixture of the title compound, C19H19NO3S, crystallizes in space group P with two homochiral mol-ecules in each asymmetric unit. The seven-membered ring in both mol-ecules is in a pucker-chair conformation. The extended structure exhibits C-H⋯O hydrogen bonds, of which two connect crystallographically independent mol-ecules to generate a chain propagating along the b-axis direction. One C-H grouping of the cyclo-propyl ring is in close contact with the phenyl ring of the neighboring independent mol-ecule in C-H⋯π type inter-actions with carbon atom-ring-centroid distances of 3.544 (5) and 3.596 (4) Å. Other inter-actions are of the parallel-reciprocal type, with the chiral carbon atom of one mol-ecule donating a proton to an oxygen atom of the sulfone group of a symmetry-related mol-ecule and vice-versa. Symmetry-related mol-ecular pairs also exhibit T-type inter-actions between aromatic rings with inter-planar angles of 74.2 (2) and 69.2 (2)° and inter-centroid distances of 4.965 (4) and 5.114 (4) Å.

Methanol on the rocks: green rust transformation promotes the oxidation of methane.

Shared coordination geometries between metal ions within reactive minerals and enzymatic metal cofactors hints at mechanistic and possibly evolutionary homology between particular abiotic chemical mineralogies and biological metabolism. The octahedral coordination of reactive Fe2+/3+ minerals such as green rusts, endemic to anoxic sediments and the early Earth's oceans, mirrors the di-iron reaction centre of soluble methane monooxygenase (sMMO), responsible for methane oxidation in methanotrophy. We show that methane oxidation occurs in tandem with the oxidation of green rust to lepidocrocite and magnetite, mimicking radical-mediated methane oxidation found in sMMO to yield not only methanol but also halogenated hydrocarbons in the presence of seawater. This naturally occurring geochemical pathway for CH4 oxidation elucidates a previously unidentified carbon cycling mechanism in modern and ancient environments and reveals clues into mineral-mediated reactions in the synthesis of organic compounds necessary for the emergence of life.

The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer.

Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative tumors that display neuroendocrine features [neuroendocrine prostate cancer (NEPC)]. On the basis of RNA sequencing (RNA-seq) data from a clinical cohort of tissue from benign prostate, locally advanced prostate cancer, metastatic castration-resistant prostate cancer and NEPC, we developed a multi-step bioinformatics pipeline to identify NEPC-specific, overexpressed gene transcripts that encode cell surface proteins. This included the identification of known NEPC surface protein CEACAM5 as well as other potentially targetable proteins (e.g., HMMR and CESLR3). We further showed that cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) knockdown results in reduced NEPC tumor cell proliferation and migration in vitro. We provide in vivo data including laser capture microdissection followed by RNA-seq data supporting a causal role of CELSR3 in the development and/or maintenance of the phenotype associated with NEPC. Finally, we provide initial data that suggests CELSR3 is a target for T-cell redirection therapeutics. Further work is now needed to fully evaluate the utility of targeting CELSR3 with T-cell redirection or other similar therapeutics as a potential new strategy for patients with NEPC. Significance: The development of effective treatment for patients with NEPC remains an unmet clinical need. We have identified specific surface proteins, including CELSR3, that may serve as novel biomarkers or therapeutic targets for NEPC.

Does it really matter that I do not remember my night? Consequences related to blacking out among college student drinkers.

BACKGROUND: Alcohol-induced blackouts (AIBs) are experienced frequently by college student drinkers and are more likely to occur on days with high-intensity drinking (HID; 8+ for females/10+ for males) than non-HID days. Research suggests that AIBs are associated with experiencing other alcohol-related consequences (ARCs), including more serious ARCs (SARCs; e.g., legal and sexual consequences), but we do not know whether individuals experience more ARCs and more SARCs on occasions when they black out than when they do not black out. This study examines the associations between AIBs and the total number of both ARCs and SARCs. METHODS: Students (N = 462, 51.7% female, 87.7% White, Mage = 20.1) were assessed across 6 weekends via e-surveys (80%-97% response rate). Multilevel models were used to test for main effects, controlling for drinking (HID or estimated blood alcohol concentration; eBAC) and sex. RESULTS: Drinking days when an AIB was experienced were associated with more total ARCs (b = 3.54, 95% CI: 3.10, 3.99) and more SARCs (b = 0.77, 95% CI: 0.60, 0.95) per day than non-AIB days. The more frequently a person experienced an AIB, the more total ARCs (b = 5.33, 95% CI: 4.40, 6.25) and SARCs (1.05, 95% CI: 0.80, 1.30) they reported on average. CONCLUSION: Alcohol-induced blackout days were associated with higher levels of harm than non-AIB days, even at the same levels of drinking. Interventions that focus on reducing the occurrence of AIBs and factors that contribute to them, in addition to reducing alcohol consumption, may help reduce total harm associated with drinking among college students.

Appendiceal neuroendocrine neoplasms and resection of the mesoappendix: a retrospective comparative study.

PURPOSE: Incidental appendiceal neoplasms are identified in approximately 1% of the specimens of suspected appendicitis. The current institutional policy is to perform en bloc mesoappendix resection during routine laparoscopic appendicectomy allowing for staging, reducing the need for oncological right hemicolectomy (ORH). Herein, we review en bloc mesoappendicectomy in clinical practice and its effects on the rate of ORH. METHODS: We reviewed all cases of appendicectomy performed at the Auckland City Hospital between 1 May 2014 and 31 May 2019. Clinical notes and histopathological reports were reviewed. All neoplasms, surgical techniques and the need for further surgery were analysed. RESULTS: A total of 2455 appendicectomies were performed with an approximately similar number of procedures between the sexes and an overall median age of 31 years. Overall, 86% (n = 2098) of the specimens included resection of the mesoappendix, and 58 (2.4%) appendiceal neoplasms were identified. Of them, 33 (1.3%) specimens included neuroendocrine appendiceal neoplasms. Eleven (33%) patients with appendiceal neuroendocrine neoplasms were recommended ORH. One of these patients may have avoided additional surgery, whereas 3 (9.1%) patients with tumours of 10-20 mm avoided ORH because their mesoappendix was resected. CONCLUSION: At our centre, there has been a significant change in the practice of mesoappendix resection, and we support resection of the mesoappendix during appendicectomy. The procedure is technically straightforward and safe, incurs no increases in costs or time, allows for accurate tumour staging and guides decisions regarding further surgical interventions.

Intensity-dependent gamma electrical stimulation regulates microglial activation, reduces beta-amyloid load, and facilitates memory in a mouse model of Alzheimer's disease.

BACKGROUND: Gamma sensory stimulation may reduce AD-specific pathology. Yet, the efficacy of alternating electrical current stimulation in animal models of AD is unknown, and prior research has not addressed intensity-dependent effects. METHODS: The intensity-dependent effect of gamma electrical stimulation (GES) with a sinusoidal alternating current at 40 Hz on Aß clearance and microglia modulation were assessed in 5xFAD mouse hippocampus and cortex, as well as the behavioral performance of the animals with the Morris Water Maze. RESULTS: One hour of epidural GES delivered over a month significantly (1) reduced Aß load in the AD brain, (2) increased microglia cell counts, decreased cell body size, increased length of cellular processes of the Iba1 + cells, and (3) improved behavioral performance (learning & memory). All these effects were most pronounced when a higher stimulation current was applied. CONCLUSION: The efficacy of GES on the reduction of AD pathology and the intensity-dependent feature provide guidance for the development of this promising therapeutic approach.

Testing Mechanisms of Change for Text Message-Delivered Cognitive Behavioral Therapy: Randomized Clinical Trial for Young Adult Depression.

BACKGROUND: Current psychiatric epidemiological evidence estimates that 17% of young adults (aged 18-25 years) experienced a major depressive episode in 2020, relative to 8.4% of all adults aged ≥26 years. Young adults with a major depressive episode in the past year are the least likely to receive treatment for depression compared with other age groups. OBJECTIVE: We conducted a randomized clinical trial following our initial 4-week SMS text message-delivered cognitive behavioral therapy (CBT-txt) for depression in young adults. We sought to test mechanisms of change for CBT-txt. METHODS: Based on participant feedback, outcome data, and the empirical literature, we increased the treatment dosage from 4-8 weeks and tested 3 mechanisms of change with 103 young adults in the United States. Participants were from 34 states, recruited from Facebook and Instagram and presenting with at least moderate depressive symptomatology. Web-based assessments occurred at baseline prior to randomization and at 1, 2, and 3 months after enrollment. The primary outcome, the severity of depressive symptoms, was assessed using the Beck Depression Inventory II. Behavioral activation, perseverative thinking, and cognitive distortions were measured as mechanisms of change. Participants were randomized to CBT-txt or a waitlist control condition. Those assigned to the CBT-txt intervention condition received 474 fully automated SMS text messages, delivered every other day over a 64-day period and averaging 14.8 (SD 2.4) SMS text messages per treatment day. Intervention texts are delivered via TextIt, a web-based automated SMS text messaging platform. RESULTS: Across all 3 months of the study, participants in the CBT-txt group showed significantly larger decreases in depressive symptoms than those in the control group (P<.001 at each follow-up), producing a medium-to-large effect size (Cohen d=0.76). Over half (25/47, 53%) of the treatment group moved into the "high-end functioning" category, representing no or minimal clinically significant depressive symptoms, compared with 15% (8/53) of the control condition. Mediation analysis showed that CBT-txt appeared to lead to greater increases in behavioral activation and greater decreases in cognitive distortions and perseverative thinking across the 3-month follow-up period, which were then associated with larger baseline to 3-month decreases in depression. The size of the indirect effects was substantial: 57%, 41%, and 50% of the CBT-txt effect on changes in depression were mediated by changes in behavioral activation, cognitive distortions, and perseverative thinking, respectively. Models including all 3 mediators simultaneously showed that 63% of the CBT-txt effect was mediated by the combined indirect effects. CONCLUSIONS: Results provide evidence for the efficacy of CBT-txt to reduce young adult depressive symptoms through hypothesized mechanisms. To the best of our knowledge, CBT-txt is unique in its SMS text message-delivered modality, the strong clinical evidence supporting efficacy and mechanisms of change. TRIAL REGISTRATION: ClinicalTrials.gov NCT05551702; https://clinicaltrials.gov/study/NCT05551702.

A self-sustaining serpentinization mega-engine feeds the fougerite nanoengines implicated in the emergence of guided metabolism.

The demonstration by Ivan Barnes et al. that the serpentinization of fresh Alpine-type ultramafic rocks results in the exhalation of hot alkaline fluids is foundational to the submarine alkaline vent theory (AVT) for life's emergence to its 'improbable' thermodynamic state. In AVT, such alkaline fluids ≤ 150°C, bearing H2 > CH4 > HS--generated and driven convectively by a serpentinizing exothermic mega-engine operating in the ultramafic crust-exhale into the iron-rich, CO2> > > NO3--bearing Hadean ocean to result in hydrothermal precipitate mounds comprising macromolecular ferroferric-carbonate oxyhydroxide and minor sulfide. As the nanocrystalline minerals fougerite/green rust and mackinawite (FeS), they compose the spontaneously precipitated inorganic membranes that keep the highly contrasting solutions apart, thereby maintaining redox and pH disequilibria. They do so in the form of fine chimneys and chemical gardens. The same disequilibria drive the reduction of CO2 to HCOO- or CO, and the oxidation of CH4 to a methyl group-the two products reacting to form acetate in a sequence antedating the 'energy-producing' acetyl coenzyme-A pathway. Fougerite is a 2D-layered mineral in which the hydrous interlayers themselves harbor 2D solutions, in effect constricted to ~ 1D by preferentially directed electron hopping/tunneling, and proton Gröthuss 'bucket-brigading' when subject to charge. As a redox-driven nanoengine or peristaltic pump, fougerite forces the ordered reduction of nitrate to ammonium, the amination of pyruvate and oxalate to alanine and glycine, and their condensation to short peptides. In turn, these peptides have the flexibility to sequester the founding inorganic iron oxyhydroxide, sulfide, and pyrophosphate clusters, to produce metal- and phosphate-dosed organic films and cells. As the feed to the hydrothermal mound fails, the only equivalent sustenance on offer to the first autotrophs is the still mildly serpentinizing upper crust beneath. While the conditions here are very much less bountiful, they do offer the similar feed and disequilibria the survivors are accustomed to. Sometime during this transition, a replicating non-ribosomal guidance system is discovered to provide the rules to take on the incrementally changing surroundings. The details of how these replicating apparatuses emerged are the hard problem, but by doing so the progenote archaea and bacteria could begin to colonize what would become the deep biosphere. Indeed, that the anaerobic nitrate-respiring methanotrophic archaea and the deep-branching Acetothermia presently comprise a portion of that microbiome occupying serpentinizing rocks offers circumstantial support for this notion. However, the inescapable, if jarring conclusion is drawn that, absent fougerite/green rust, there would be no structured channelway to life.