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BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Genome-wide association studies (GWAS) in long-lived human populations have led to identification of variants associated with Alzheimer's disease and cardiovascular disease, the latter being the most common cause of mortality in people worldwide. In contrast, naturally occurring cancer represents the leading cause of death in pet dogs, and specific breeds like the Golden Retriever (GR) carry up to a 65% cancer-related death rate. We hypothesized that GWAS of long-lived GRs might lead to the identification of genetic variants capable of modifying longevity within this cancer-predisposed breed. A GWAS was performed comparing GR dogs ≥ 14 years to dogs dying prior to age 12 which revealed a significant association to ERBB4, the only member of the epidermal growth factor receptor family capable of serving as both a tumor suppressor gene and an oncogene. No coding variants were identified, however, distinct haplotypes in the 5'UTR were associated with reduced lifespan in two separate populations of GR dogs. When all GR dogs were analyzed together (n = 304), the presence of haplotype 3 was associated with shorter survival (11.8 years vs. 12.8 years, p = 0.024). GRs homozygous for haplotype 3 had the shortest survival, and GRs homozygous for haplotype 1 had the longest survival (11.6 years vs. 13.5 years, p = 0.0008). Sub-analyses revealed that the difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was specific to female dogs (p = 0.009), whereas survival remained significantly different in both male and female GRs homozygous for haplotype 1 or haplotype 3 (p = 0.026 and p = 0.009, respectively). Taken together, these findings implicate a potential role for ERBB4 in GR longevity and provide evidence that within-breed canine lifespan studies could serve as a mechanism to identify favorable or disease-modifying variants important to the axis of aging and cancer.

Localized cutaneous neurofibromas (cNFs) are benign tumors that arise in the dermis of patients affected by neurofibromatosis type 1 syndrome. cNFs are benign lesions: they do not undergo malignant transformation or metastasize. Nevertheless, they can cover a significant proportion of the body, with some individuals developing hundreds to thousands of lesions. cNFs can cause pain, itching, and disfigurement resulting in substantial socio-emotional repercussions. Currently, surgery and laser desiccation are the sole treatment options but may result in scarring and potential regrowth from incomplete removal. To identify effective systemic therapies, we introduce an approach to establish and screen cNF organoids. We optimized conditions to support the ex vivo growth of genomically diverse cNFs. Patient-derived cNF organoids closely recapitulate cellular and molecular features of parental tumors as measured by immunohistopathology, methylation, RNA sequencing, and flow cytometry. Our cNF organoid platform enables rapid screening of hundreds of compounds in a patient- and tumor-specific manner.

Introduction: Severe trauma-induced blood loss can lead to metabolic acidosis, shock, and death. Identification of abnormalities in the bicarbonate and serum markers may be seen before frank changes in vital signs in the hemorrhaging trauma patient, allowing for earlier lifesaving interventions. In this study the author aimed to evaluate the usefulness of serum bicarbonate and other lab markers as predictors of mortality in trauma patients within 30 days after injury.Methods: This retrospective, propensity-matched cohort study used the TriNetX database, covering approximately 92 million patients from 55 healthcare organizations in the United States, including 3.8 million trauma patients in the last two decades. Trauma patients were included if they had lab measurements available the day of the event. The analysis focused on mortality within 30 days post-trauma in comparison to measured lab markers. Cohorts were formed based on ranges of bicarbonate, lactate, and base excess levels.Results: Before propensity score matching, a total of 1,275,363 trauma patients with same-day bicarbonate, lactate, or base excess labs were identified. A significant difference in mortality was found across various serum bicarbonate lab ranges compared to the standard range of 21–27 milliequivalents per liter (mEq/L), post-propensity score matching. The relative risk of death was 6.806 for bicarbonate ≤5 mEq/L; 8.651 for 6–10; 6.746 for 11–15; 2.822 for 16–20; and 1.015 for bicarbonate ≥28. Serum lactate also displayed significant mortality outcomes when compared to a normal level of ≤2 millimoles per liter. Base excess showed similar significant correlation at different values compared to a normal base excessof −2 to 2 mEq/L.Conclusion: This study, approximately 100 times larger than prior studies, associated lower bicarbonate levels with increased mortality in the trauma patient. While lactate and base excess offer prognostic value, lower bicarbonate values have a higher relative risk of death. The greater predictive value of bicarbonate and accessibility during resuscitations suggests that it may be the superior prognostic marker in trauma.

Background: Thirdhand smoke (THS) contains toxic residues, including carcinogens, which persist on surfaces and clothes even after cigarette smoke dissipates. The public awareness of THS and its health effects remain low. Objective: This study examined beliefs about THS among Chinese-speaking former smokers and their non-smoking family members, before and after participating in a family-based THS education program. Methods: We implemented a 2-week THS education intervention delivered by lay health workers with 30 Chinese American dyads (N=60) residing in Northern California, consisting of former smokers who quit within the past 2 years and their family members. THS beliefs were assessed using the Beliefs About Thirdhand Smoke (BATHS) questionnaire administered at pre- and postintervention. Focus groups with 8 former smokers and 7 family participants were conducted. We used multivariable regression with Generalized Estimating Equations to account for time points and household correlations to assess changes in BATHS scores (Overall, Persistence and Health subscales). Focus group transcripts underwent independent coding by two researchers and thematic analysis. Results: The study sample included 30 male former smokers (37% with slight to mild craving for smoking), and 30 family members (97% female) who never smoked. A majority (82%) spoke English less than well, 83% were married, 58% lived with children and 27% with current smokers. All multivariable models showed a significant time x role (former smokers vs family) interaction (p < 0.05). Former smokers had lower BATHS scores than their family at preintervention (p < 0.01), but their scores became similar at post-intervention. Former smokers’ BATHS scores increased from pre- to post-intervention (Overall: p=0.02; Persistence: p=0.03; Health: p=0.04) while family had no significant change. Prominent themes from focus groups supported gaining new knowledge for both persistence and health effects of THS. Both former smokers and family members appreciated learning about cleaning methods and both shared increased family discussions and collaboration in household cleaning post intervention. Conclusion: THS education impacts former smokers and their non-smoking family members differently. Family-based interventions are promising to align beliefs and promote collaboration within households in addressing THS. Future randomized controlled trials should investigate broader impacts of the program on enhancing support for motivating quitting for current smokers, maintaining smoking abstinence, and in reducing THS exposure.

Significance: Thirdhand smoke (THS), which includes secondhand smoke contami- nants, can be re-emitted and re-suspended into the air and are embedded into carpets, floors, and clothing. The awareness of THS and the health impacts from exposure to its harmful residues is low in the general population of the United States, especially in immigrant communities where smoking remains prevalent. Our study implemented a THS family-based intervention to promote THS awareness among Chinese American immigrants. Methods: The THS intervention included an education and home cleaning component delivered by lay health workers to 30 Chinese American dyads (N=60). Dyads consisted of former smokers who quit within the last two years and their non-smoking family member living in the same household. Participants completed pre- and post-in- tervention survey interviews and a sub-sample (N=15; 8 former smokers and 7 family members) participated in a post-intervention focus group. Multivariable regression adjusted for dyadic data was conducted to compare pre- and post-intervention changes in the Beliefs About Thirdhand Smoke (BATHS) overall and subscale (Persistence and Health) scores. Transcriptions from focus group interviews, conducted in Cantonese, were transcribed and translated, coded by two independent researchers and themati- cally analyzed using Dedoose. Results: All participants were born outside the US and 59% immigrated at age 30 or older (range: 7 to 63 years old). A majority (82%) spoke English less than “well” and 87% were married. BATHS scores analyses suggested that former smokers increased their THS awareness from pre- to post-intervention: BATHS Overall (M=3.95 [SD=0.50], p=0.021); Persistence (M=3.95 [SD=0.48], p=0.031) and Health (M=3.94 [SD=0.58], p=0.038), and their post-intervention THS scores became similar to the BATH scores of non-smoking family members which did not change at post-intervention. Thematic analyses of focus group interviews revealed emerging themes highlighting impacts on former smokers in increasing THS knowledge and strengthening desires to create dialogue about tobacco use with friends; for example, a former smoker shared “I will share my [THS] knowledge with others. I think it will help [my friends] as well.” Conclusion: A family-based THS education intervention has promising impacts to advance tobacco control in Chinese American immigrant communities by providing new THS knowledge and encouraging former smokers to become agents of change. Future research on empowering former smokers to become effective agents of change to promote tobacco-free communities is warranted.

BACKGROUND: The Paediatric Difficult Intubation Collaborative identified multiple attempts and persistence with direct laryngoscopy as risk factors for complications in children with difficult tracheal intubations and subsequently engaged in initiatives to reduce repeated attempts and persistence with direct laryngoscopy in children. We hypothesised these efforts would lead to fewer attempts, fewer direct laryngoscopy attempts and decrease complications. METHODS: Paediatric patients less than 18 years of age with difficult direct laryngoscopy were enrolled in the Paediatric Difficult Intubation Registry. We define patients with difficult direct laryngoscopy as those in whom (1) an attending or consultant obtained a Cormack Lehane Grade 3 or 4 view on direct laryngoscopy, (2) limited mouth opening makes direct laryngoscopy impossible, (3) direct laryngoscopy failed in the preceding 6 months, and (4) direct laryngoscopy was deferred due to perceived risk of harm or poor chance of success. We used a 5:1 propensity score match to compare an early cohort from the initial Paediatric Difficult Intubation Registry analysis (August 6, 2012-January 31, 2015, 785 patients, 13 centres) and a current cohort from the Registry (March 4, 2017-March 31, 2023, 3925 patients, 43 centres). The primary outcome was first attempt success rate between cohorts. Success was defined as confirmed endotracheal intubation and assessed by the treating clinician. Secondary outcomes were eventual success rate, number of attempts at intubation, number of attempts with direct laryngoscopy, the incidence of persistence with direct laryngoscopy, use of supplemental oxygen, all complications, and severe complications. FINDINGS: First-attempt success rate was higher in the current cohort (42% vs 32%, OR 1.5 95% CI 1.3-1.8, p

Electronic nicotine delivery systems (ENDS) continue to rapidly evolve. Current products pose unique challenges and opportunities for researchers and regulators. This commentary aims to highlight research gaps, particularly in toxicity research, and provide guidance on priority research questions for the tobacco regulatory community. Disposable flavoured ENDS have become the most popular device class among youth and may contain higher nicotine levels than JUUL devices. They also exhibit enhanced harmful and potentially harmful constituents production, contain elevated levels of synthetic coolants and pose environmental concerns. Synthetic nicotine and flavour capsules are innovations that have recently enabled the circumvention of Food and Drug Administration oversight. Coil-less ENDS offer the promise of delivering fewer toxicants due to the absence of heating coils, but initial studies show that these products exhibit similar toxicological profiles compared with JUULs. Each of these topic areas requires further research to understand and mitigate their impact on human health, especially their risks to young users.

Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1-4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5-9) and MPP8 (refs. 10-12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC-Sin3-NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.

We evaluated spatial-temporal risk for Lyme disease in northwestern North Carolina, USA, by using individual-level canine Borrelia burgdorferi seroprevalence data collected during 2017–2021 at routine veterinary screenings for tickborne diseases. Seroprevalence in dogs increased from 2.2% (47/2,130) in 2017 to 11.2% (339/3,033) in 2021. The percentage of incident seropositivity increased from 2.1% (45/2,130) in 2017 to 7.6% (231/3,033) in 2021. Exploratory geographic analyses found canine seroprevalence shifted from clustered (2017, Moran’s I = 0.30) to dispersed (2021, Moran’s I = −0.20). Elevation, slope, aspect, and forest land cover density were associated with canine seroprevalence within various household buffer regions in 2017. Slope was associated with seroprevalence at the household level in 2021. Results support the use of individual-level canine seroprevalence data for monitoring human risk for Lyme disease. Establishing sentinel veterinary clinics within Lyme disease–emergent communities might promote prevention and control efforts and provide opportunities for educational and behavioral interventions.

Abstract Large-scale implementation of interprofessional education across the United States Veterans Health Administration has supported advancement of a new model of collaborative practice, the Whole Health System, centering on the patient and what matters most to them. Other health care systems can consider similar educational efforts for health care transformation.

Image-guided superficial radiation therapy (IGSRT) combines superficial radiation therapy (SRT) with full dermal visualization (FDV) via high-resolution dermal ultrasound (HRDUS) for the treatment of non-melanoma skin cancer (NMSC). The gold standard for IGSRT delivery includes a comprehensive cancer care model with support for dermatologists from a multidisciplinary team. When delivered in this model, IGSRT can achieve cure rates of 99% for treatment of NMSC. This paper focuses on the benefits of HRDUS used in conjunction with SRT for NMSC. Medical records from 7 dermatology clinics of 883 patients with 1507 cases of NMSC treated with IGSRT between 2017 and 2018 were retrospectively reviewed. In total, 92% of the NMSC lesions showed daily depth fluctuations, 60.32% of lesions did not require changes during therapy, and nearly 40% of lesions required at least one compensatory change during therapy. In total, 83% of NMSC lesions were labeled as high risk based on the 2024 NCCN guidelines. Increasing and decreasing tumor depth measurements during IGSRT inform dermatologists when adaptive changes in energy (kV), TDF, and dose will result in more efficacy and less toxicity, respectively.

We examine whether one of the most popular observation systems in teacher evaluation--the Framework for Teaching (FFT)--captures the range of instructional skills teachers need to be effective. We focus on the case of special educators, who are likely to use instructional approaches that, although supported by research, are de-emphasized in common observation systems. Drawing on 206 lessons from 51 teachers, we compare FFT scores to an observation system from special education. We find that FFT's psychometric properties are consistent with previous studies, but the system is limited in assessing the quality of instructional practices used in special education. We discuss implications of these findings for two practical uses of observations--supporting teacher development and informing human capital decisions.

The lack of connectedness experienced by college students during the COVID-19 pandemic was problematic. An innovative approach undertaken in a (virtual) graduate classroom at Clemson University was the concept of team teaching. Team teaching allows a group of instructors to work together to enhance student learning. Upon course completion, students (N =57) completed a brief survey regarding their perceptions of team teaching. The scale ranged from extremely positive (1) to extremely negative (5). The sample as a whole found team teaching to be a positive experience (M =1.87, SD =0.94), felt that team teaching assisted in their learning (M =1.51, SD =0.72), and found value to having two instructors (M =1.6, SD =0.76). Overall, based on the results, team teaching is a strategy that should be considered in virtual classroom environments as it can provide students with increased support and varying perspectives.

This study explored the feasibility of using fish skin bandages as a therapeutic option for third-degree skin burns. Following the California wildfires, clinical observations of animals with third-degree skin burns demonstrated increased comfort levels and reduced pain when treated with tilapia fish skin. Despite the promises of this therapy, there are few studies explaining the healing mechanisms behind the application of tilapia fish skin. In this study, mice with third-degree burns were treated with either a hydrocolloid adhesive bandage (control) (n = 16) or fish skin (n = 16) 7 days post-burn. Mice were subjected to histologic, hematologic, molecular, and gross evaluation at days 7, 16, and 28 post-burn. The fish skin offered no benefit to overall wound closure compared to hydrocolloids. Additionally, we detected no difference between fish skin and control treatments in regard to hypermetabolism or hematologic values. However, the fish skin groups exhibited 2 times more vascularization and 2 times higher expression of antimicrobial defensin peptide in comparison to controls. Proteomic analysis of the fish skin revealed the presence of antimicrobial peptides. Collectively, these data suggest that fish skin can serve as an innovative and cost-effective therapeutic alternative for burn victims to facilitate vascularization and reduce bacterial infection.

Introduction: Tension hydrothorax is an uncommon emergent condition in which hemodynamic instability and respiratory compromise may occur. Emergency physicians may diagnose tension hydrothorax by point-of-care ultrasound. Case Series: We discuss the key sonographic features assisting in identification. Four patients with history of malignancy who were found to have tension hydrothorax exhibited the following common ultrasound findings: massive, left-sided pleural effusion; complete, compressive atelectasis; and shift of cardiac structures into the right hemithorax, resulting in right-sided probe placement to obtain cardiac views. Conclusion: This is the first instance to our knowledge of point-of-care ultrasound findings in tension hydrothorax to be described in the literature.

Historically, the burden of Lyme disease has been concentrated in the Northeast and upper Midwestern regions of the United States (1). Recent data suggest a southward expansion into areas of [...]