Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage.

Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a calcium-dependent nuclear softening driven by loss of H3K9me3-marked heterochromatin. The resulting changes in chromatin rheology and architecture are required to insulate genetic material from mechanical force. Failure to mount this nuclear mechanoresponse results in DNA damage. Persistent, high-amplitude stretch induces supracellular alignment of tissue to redistribute mechanical energy before it reaches the nucleus. This tissue-scale mechanoadaptation functions through a separate pathway mediated by cell-cell contacts and allows cells/tissues to switch off nuclear mechanotransduction to restore initial chromatin state. Our work identifies an unconventional role of chromatin in altering its own mechanical state to maintain genome integrity in response to deformation.

Proton radiation boosts the efficacy of mesothelin-targeting chimeric antigen receptor T cell therapy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents a challenge in oncology, with limited treatment options for advanced-stage patients. Chimeric antigen receptor T cell (CAR T) therapy targeting mesothelin (MSLN) shows promise, but challenges such as the hostile immunosuppressive tumor microenvironment (TME) hinder its efficacy. This study explores the synergistic potential of combining proton radiation therapy (RT) with MSLN-targeting CAR T therapy in a syngeneic PDAC model. Proton RT significantly increased MSLN expression in tumor cells and caused a significant increase in CAR T cell infiltration into tumors. The combination therapy reshaped the immunosuppressive TME, promoting antitumorigenic M1 polarized macrophages and reducing myeloid-derived suppressor cells (MDSC). In a flank PDAC model, the combination therapy demonstrated superior attenuation of tumor growth and improved survival compared to individual treatments alone. In an orthotopic PDAC model treated with image-guided proton RT, tumor growth was significantly reduced in the combination group compared to the RT treatment alone. Further, the combination therapy induced an abscopal effect in a dual-flank tumor model, with increased serum interferon-γ levels and enhanced proliferation of extratumoral CAR T cells. In conclusion, combining proton RT with MSLN-targeting CAR T therapy proves effective in modulating the TME, enhancing CAR T cell trafficking, and exerting systemic antitumor effects. Thus, this combinatorial approach could present a promising strategy for improving outcomes in unresectable PDAC.

ATP allosterically stabilizes integrin-linked kinase for efficient force generation.

SignificanceThe pseudokinase integrin-linked kinase (ILK) is a central component of focal adhesions, cytoplasmic multiprotein complexes that integrate and transduce biochemical and mechanical signals from the extracellular environment into the cell and vice versa. However, the precise molecular functions, particularly the mechanosensory properties of ILK and the significance of retained adenosine triphosphate (ATP) binding, are still unclear. Combining molecular-dynamics simulations with cell biology, we establish a role for ATP binding to pseudokinases. We find that ATP promotes the structural stability of ILK, allosterically influences the interaction between ILK and its binding partner parvin at adhesions, and enhances the mechanoresistance of this complex. On the cellular level, ATP binding facilitates efficient traction force buildup, focal adhesion stabilization, and efficient cell migration.

Bacteriophage therapy reduces Staphylococcus aureus in a porcine and human ex vivo burn wound infection model.

Burn wounds are a major burden, with high mortality rates due to infections. Staphylococcus aureus is a major causative agent of burn wound infections, which can be difficult to treat because of antibiotic resistance and biofilm formation. An alternative to antibiotics is the use of bacteriophages, viruses that infect and kill bacteria. We investigated the efficacy of bacteriophage therapy for burn wound infections, in both a porcine and a newly developed human ex vivo skin model. In both models, the efficacy of a reference antibiotic treatment (fusidic acid) and bacteriophage treatment was determined for a single treatment, successive treatment, and prophylaxis. Both models showed a reduction in bacterial load after a single bacteriophage treatment. Increasing the frequency of bacteriophage treatments increased bacteriophage efficacy in the human ex vivo skin model, but not in the porcine model. In both models, prophylaxis with bacteriophages increased treatment efficacy. In all cases, bacteriophage treatment outperformed fusidic acid treatment. Both models allowed investigation of bacteriophage-bacteria dynamics in burn wounds. Overall, bacteriophage treatment outperformed antibiotic control underlining the potential of bacteriophage therapy for the treatment of burn wound infections, especially when used prophylactically.

Differential gene expression between central and peripheral retinal regions in dogs and comparison with humans.

The dog retina contains a central macula-like region, and there are reports of central retinal disorders in dogs with shared genetic etiologies with humans. Defining central/peripheral gene expression profiles may provide insight into the suitability of dogs as models for human disorders. We determined central/peripheral posterior eye gene expression profiles in dogs and interrogated inherited retinal and macular disease-associated genes for differential expression between central and peripheral regions. Bulk tissue RNA sequencing was performed on 8 mm samples of the dog central and superior peripheral regions, sampling retina and retinal pigmented epithelium/choroid separately. Reads were mapped to CanFam3.1, read counts were analyzed to determine significantly differentially expressed genes (DEGs). A similar analytic pipeline was used with a published bulk-tissue RNA sequencing human dataset. Pathways and processes involved in significantly DEGs were identified (Database for Annotation, Visualization and Integrated Discovery). Dogs and humans shared the extent and direction of central retinal differential gene expression, with multiple shared biological pathways implicated in differential expression. Many genes implicated in heritable retinal disorders in dogs and humans were differentially expressed between central and periphery. Approximately half of genes associated with human age-related macular degeneration were differentially expressed in human and dog tissues. We have identified similarities and differences in central/peripheral gene expression profiles between dogs and humans which can be applied to further define the relevance of dogs as models for human retinal disorders.

Community engagement and power dynamics in conservation philanthropy grant making.

Funding decisions influence where, how, and by whom conservation is pursued globally. In the context of growing calls for more participatory, Indigenous-led, and socially just conservation, we undertook the first empirical investigation of how philanthropic foundations working in marine conservation globally engage communities in grant-making decisions. We paid particular attention to whether and how community engagement practices reinforce or disrupt existing power dynamics. We conducted semistructured remote interviews with 46 individuals from 32 marine conservation foundations to identify how conservation foundations engage communities in setting their priorities and deciding which organizations and projects to fund. We found that community engagement in foundation decision-making was limited in practice. Eleven of the 32 foundations reported some form of community engagement in funding decisions. Two of these foundations empowered communities to shape funding priorities and projects through strong forms of engagement. Many engagement practices were one way, one time, or indirect and confined to certain points in decision-making processes. These weaker practices limited community input and reinforced unequal power relations, which may undermine the legitimacy, equity, and effectiveness of conservation efforts. We suggest that foundations aim for stronger forms of community engagement and reflect on how their grant-making practices affect power relations between foundations and communities.

Participación comunitaria y dinámicas de poder en la concesión de subsidios para la filantropía de la conservación Resumen Realizamos la primera investigación empírica sobre la forma en que las fundaciones filantrópicas que trabajan con la conservación marina a nivel mundial involucran a las comunidades en las decisiones para la concesión de subsidios. Prestamos especial atención a cómo y si las prácticas de participación ciudadana refuerzan o interrumpen las dinámicas de poder existentes. Entrevistamos de forma remota a 46 individuos de 32 fundaciones de conservación marina para identificar cómo las fundaciones de conservación involucran a las comunidades para establecer sus prioridades y decidir cuáles organizaciones y proyectos financiar. Encontramos que la participación comunitaria en las decisiones de financiamiento estaba limitada en la práctica. Once de las 32 fundaciones reportaron algún tipo de participación ciudadana en sus decisiones de financiamiento. Dos de estas fundaciones empoderaron a las comunidades para que formaran las prioridades de financiamiento y a los proyectos por medio de una participación sólida. Muchas de las prácticas de participación eran de una manera, de una vez o indirectas y confinadas a ciertos puntos en el proceso de decisión. Estas prácticas más débiles limitaron la aportación comunitaria y reforzaron las relaciones desiguales de poder, lo que puede debilitar la legitimidad, equidad y eficiencia de los esfuerzos de conservación. Sugerimos que las fundaciones busquen maneras más sólidas de involucrar a la comunidad y reflexionen sobre el efecto de sus prácticas de concesión de subsidios sobre las relaciones de poder entre las fundaciones y las comunidades.

Effect of Early Administration of Vasopressin on New-Onset Arrhythmia Development in Patients With Septic Shock: A Retrospective, Observational Cohort Study.

Background: Adjunctive vasopressin use in septic shock reduces catecholamine requirements and is associated with a lower incidence of new-onset arrhythmias (NOAs). The association of vasopressin timing on NOA development is ill-described. Objective: To determine whether early administration of vasopressin was associated with a lower incidence of NOA in septic shock patients. Methods: A retrospective analysis of intensive care unit (ICU) patients at a large, academic medical center. Septic shock patients who required vasopressin and norepinephrine were eligible for inclusion. Patients were excluded for receipt of other vasoactive agents, history of cardiac arrhythmias, or outside hospital admission. Early vasopressin was defined as receipt within 6 hours of septic shock onset. The primary outcome was incidence of NOA. Results: In total, 436 patients, 220 (50.4%) in the early and 216 (49.6%) in the late vasopressin group, were included. Early vasopressin was not associated with a lower incidence of NOA compared with late vasopressin (9% vs 7%, median absolute difference [95% confidence interval, CI]: -2.1 [-7.2, 3.0], P = 0.41). Early vasopressin patients were observed to have shorter shock duration (2 vs 4 days, median absolute difference [95% CI]: 2 [1, 2], P < 0.001), and ICU length of stay (6 vs 7 days, median absolute difference [95% CI]: 1 [0, 2], P = 0.02). Conclusions and Relevance: Early vasopressin use was not associated with a lower incidence of NOA. Additional studies are needed to elucidate the effect of vasopressin timing on NOA and other clinical outcomes.

New measures of number line estimation performance reveal children's ordinal understanding of numbers.

Children's performance on the number line estimation task, often measured by the percentage of absolute error, predicts their later mathematics achievement. This task may also reveal (a) children's ordinal understanding of the target numbers in relation to each other and the benchmarks (e.g., endpoints, midpoint) and (b) the ordinal skills that are a necessary precursor to children's ability to understand the interval nature of a number line as measured by percentage of absolute error. Using data from 104 U.S. kindergartners, we measured whether children's estimates were correctly sequenced across trials and correctly positioned relative to given benchmarks within trials at two time points. For both time points, we found that each ordinal error measure revealed a distinct pattern of data distribution, providing opportunities to tap into different aspects of children's ordinal understanding. Furthermore, children who made fewer ordinal errors scored higher on the Test of Early Mathematics Ability and showed greater improvement on their interval understanding of numbers as reflected by a larger reduction of percentage of absolute error from Time 1 to Time 2. The findings suggest that our number line measures reveal individual differences in children's ordinal understanding of numbers, and that such understanding may be a precursor to their interval understanding and later mathematics performance.

Gap in knowledge of health benefits and risks of combined oral contraceptives among Lebanese women.

BACKGROUND: Oral Contraceptive Pills (OCPs) are among the most commonly used forms of contraception, but they are associated with several health benefits and risks. This study aims to determine the gap in knowledge of the underlying health benefits and risks of OCPs among Lebanese women and to identify the factors that might influence their beliefs. METHODS: A questionnaire was completed by 817 Lebanese women aged 18-64 years old and assessed sociodemographic details, medical information, contraceptive practices, knowledge of underlying health benefits and risks, and information needs related to OCPs. RESULTS: Among the total participants, 41.5% of women reported using OCPs at some point in their lives yet 46.6% denied receiving information about their benefits and 48% denied receiving information about their risks. The mean total OCP knowledge score was 5.70 out of 25, the mean OCP risk knowledge score was 4.09 out of 15, and the mean OCP benefit knowledge score was 0.77 out of 6. Sociodemographic factors associated with greater total knowledge, risk knowledge and benefit knowledge included OCP usage, being a student, confidence in one's knowledge and satisfaction with one's information. Both the total and risk knowledge scores were found to be higher in women who found that receiving information related to OCPs was important. Finally, participants who lived in central governates had greater total knowledge scores, whereas those with higher levels of education and a family history of endometrial cancer demonstrated better benefit knowledge. CONCLUSIONS: This study highlighted the poor knowledge of health benefits and risks associated with OCP use among Lebanese women and the associated sociodemographic factors that might influence their beliefs.

Technical article: Overview of hospital-based data capture systems that acquire continuous ECG and physiologic data.

Data capture systems that acquire continuous hospital-based electrocardiographic (ECG) and physiologic (vital signs) data can foster robust research (i.e., large sample sizes from consecutive patients). However, the application of these systems and the data generated are complex and requires careful human oversight to ensure that accurate and high quality data are procured. This technical article will describe two different data capture systems created by our research group designed to examine false alarms associated with alarm fatigue in nurses. The following aspects regarding these data capture systems will be discussed: (1) history of development; (2) summary of advantages, challenges, and important considerations; (3) their use in research; (4) their use in clinical care; and (5) future developments.

Adverse events related to suction electrocautery devices in adenotonsillectomy: Analysis of the MAUDE database.

OBJECTIVE: To identify adverse events (AEs) related to suction electrocautery use during adenotonsillectomy. METHODS: The US Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database was searched using the terms "suction cautery," "suction electrocautery," "suction Bovie," and "suction coagulator" from January 2014 to December 2023. RESULTS: 165 AE reports were gathered from the MAUDE database medical device reports (MDRs). 36 met inclusion criteria. Patient injuries were found in 22 (61.1 %) reports and device malfunction events were found in 14 (38.9 %) reports. All patient injuries were thermal burns (N = 22, 100 %). Location of burn injuries included the lip (N = 6, 27.3 %), oral commissure (N = 5, 22.7 %), and tongue (N = 4, 18.2 %). The most common cause of an AE was inadequate device insulation (N = 7, 19.4 %). CONCLUSION: The suction electrocautery apparatus may malfunction and cause patient burn injuries. Device failures mainly result from inadequate device insulation, coagulation problems, and detachment of device components. Surgeons must be aware of these potential complications and counsel parents and patients regarding AEs.

Does resident involvement in tonsillectomy affect outcomes?

OBJECTIVE: Tonsillectomy is essentially a solo surgery with a well-described complication profile. It may serve as a good benchmark to evaluate the resident-as-surgeon. This study examined complications such as post-tonsillectomy bleeding in children undergoing tonsillectomy by attending surgeons (AS) or pediatric otolaryngologist-supervised residents. METHODS: Charts were reviewed of all children aged 12 and under who had tonsillectomy +/- adenoidectomy at a children's hospital between Jan 2019 and Dec 2020. Patient age, gender, BMI, indication for surgery, surgical technique, presence of a resident surgeon, primary bleeding, secondary bleeding, treatment of bleeding, other Emergency Room (ER) visits, and clinic phone calls were recorded. Binary logistic regression was performed. RESULTS: 2051 total children (1092 (53.2 %) males and 956 (46.6 %) females) with a mean age of 6.1 years (95 % CI 6.0-6.2) were included. 1910 (93.0 %) underwent surgery for tonsillar obstruction. 1557 (75.9 %) underwent monopolar cautery tonsillectomy. 661 (32.2 %) had a resident surgeon. 274 (13.4 %) had a related ER visit within 15 days. 18 (0.9 %) had a primary bleed and 155 (7.6 %) had a secondary bleed. Binary logistic regression showed that significant predictors of postoperative ER visits were patient age (OR = 1.101, 95 % CI = 1.050-1.154, p < .001) and resident involvement (OR = 0.585, 95 % CI = 0.429-,797, p < .001). Only age was associated with overall postoperative bleeding incidence (OR = 1.131, 95 % CI = 1.068-1.197, p < .001), as well as secondary bleeding (OR = 1.128, 95 % CI = 1.063-1.197, p < .001). There were no significant predictors of primary bleeding. CONCLUSION: Resident involvement in pediatric tonsillectomy is associated with decreased postoperative ER utilization and does not appear to increase common postoperative complications including bleeding and dehydration.

Second opinions: Do otolaryngologist demographics matter?

OBJECTIVE: Pediatric patients and their caregivers may receive information from their primary care physician (PCP) that does not match current American Academy of Otolaryngology (AAO) guidelines. The purpose of this study is to evaluate the frequency of parents deciding to seek a second opinion based on the demographics of pediatric otolaryngologists who deliver guideline supported advice, contrary to advice from their child's PCP. METHODS: A survey was distributed to parents in a pediatric otolaryngology clinic between June 2021 and July 2023. Demographics included parent age category, gender, race, and age of youngest child. The survey included a scenario depicting recurrent otitis media with clear ears and a suggestion to defer tympanostomy tube insertion per AAO guidelines after their child's PCP recommended tubes. Thirteen variations of otolaryngologist photos were used in the case, including a control case with no picture. RESULTS: Of the 658 participants, 460 (69.9 %) were female. 551 (83.7 %) were aged 30-49 years, 70 (10.7 %) were younger, and 37 (5.6 %) were older. 545 (82.8 %) were White, 30 (4.6 %) were Black, 20 (3.0 %) were Asian, and 31 (4.7 %) were Hispanic. 39.9 % of parents would seek a second opinion if an otolaryngologist recommended watchful waiting following evaluation of their child's otitis media. Participants given the control case were 2.23 times more likely to listen to the otolaryngologist's advice (p = .025). If a picture was provided, respondents were more likely to follow advice given if the pictured otolaryngologist was female (p = .025, OR = 1.47) or Asian (p = .042, OR = 1.53). CONCLUSION: In this group, there is evidence that physician race and gender may influence decision making when considering action versus monitoring in the context of recurrent otitis media.

Americans with disabilities act cases initiated by individuals with cochlear implants in the United States.

OBJECTIVE: The Americans with Disabilities Act (ADA) is a federal law that forbids discrimination against individuals with certain disabilities, including hearing impairment. This study aimed to determine the nature of ADA discrimination complaints in individuals with cochlear implants. METHODS: A search for court decisions containing the terms "cochlear implant" and ("Americans with Disabilities Act" or "ADA") from 1985 to 2021 was performed with the Westlaw Campus Research legal database. Cases were included and analyzed if at least one of the plaintiffs had a cochlear implant and was claiming discrimination related to their hearing impairment based on the ADA. RESULTS: 24 cases initiated between 2003 and 2021 in 19 US states were identified based on inclusion criteria. The highest number of cases occurred in California (N = 4, 16.7 %). The alleged discrimination most frequently took place at a K-12 school (N = 9, 37.5 %), workplace (N = 7, 29.2 %), or during an encounter with police/correctional officers (N = 4, 16.7 %). Fourteen (58.3 %) cases involved complaints under Title II (Public Services) of the ADA. Seven (29.2 %) involved Title I (Employment) and 4 (16.7 %) involved Title III (Public Accommodations). Summary judgment was given in favor of the defendant or the case was dismissed entirely in 16 (66.7 %) of the cases. CONCLUSION: Patients with cochlear implants are still at risk of discrimination because of their disability. Cochlear implantees, school employees, workplace supervisors, and law enforcement personnel can benefit from ADA education.

Improving New Graduate Nurse Retention With a Transition to Emergency Nursing Practice Program.

INTRODUCTION: Emergency department turnover rates increased at Sentara Northern Virginia Medical Center. Most applicants were new graduate registered nurses. A strength, weakness, opportunity, threat analysis revealed 3 weaknesses regarding new graduate registered nurses in emergency departments. Transition to practice program was necessary, new graduate registered nurse competency needed to progress rapidly, and retention rates needed improvement. METHODS: The emergency department registered nurse transition to practice pathway was created to address these challenges. Retention statistics were garnered through new graduate registered nurses length of employment. Improving retention rates at Sentara Northern Virginia Medical Center led to expansion of the program to the other 11 hospitals in the system. Self-report surveys were created later to evaluate the new graduate registered nursess' satisfaction with the program and perception of clinical confidence. RESULTS: Using the emergency department registered nurse transition to practice pathway, turnover rates at Sentara Northern Virginia Medical Center dropped from 46% to 5.1%. Post expansion, the overall program retention rates were 96% at 6 months, and 86% at 1 year. The 2-year retention rate prior to COVID-19 was 82%, afterward, it dropped to 65%. Most surveyed new graduate registered nurses had a confidence level of 25% or less on the first day. After their 17-week orientation, 54% reported confidence levels had risen to 75%. Within 6 months, 81% reported 75% confidence, at 1 year, 87% reported levels between 75% and 100%, and at 2 years, 100% reported a confidence level between 75% and 100%. DISCUSSION: This development of the emergency department registered nurse transition to practice pathway resulted in improved emergency department registered nurse retention and confidence. Savings from reduced turnover and reduced temporary labor staffing were achieved with this program. Implementation takes careful resource management, ongoing analysis, and research to validate return on investment.

NF-κB/c-Rel DNA-binding is reduced in substantia nigra and peripheral blood mononuclear cells of Parkinson's disease patients.

Although Parkinson's disease (PD) key neuropathological hallmarks are well known, the underlying pathogenic mechanisms of the disease still need to be elucidated to identify innovative disease-modifying drugs and specific biomarkers. NF-κB transcription factors are involved in regulating several processes associated with neurodegeneration, such as neuroinflammation and cell death, that could be related to PD pathology. NF-κB/c-Rel deficient (c-rel-/-) mice develop a progressive PD-like phenotype. The c-rel-/- mice present both prodromal and motor symptoms as well as key neuropathological features, including nigrostriatal dopaminergic neurons degeneration, accumulation of pro-apoptotic NF-κB/RelA acetylated at the lysine 310 residue (Ac-RelA(lys310)) and progressive caudo-rostral brain deposition of alpha-synuclein. c-Rel inhibition can exacerbate MPTP-induced neurotoxicity in mice. These findings support the claim that misregulation of c-Rel protein may be implicated in PD pathophysiology. In this study, we aimed at evaluating c-Rel levels and DNA-binding activity in human brains and peripheral blood mononuclear cells (PBMCs) of sporadic PD patients. We analyzed c-Rel protein content and activity in frozen substantia nigra (SN) samples from post-mortem brains of 10 PD patients and 9 age-matched controls as well as in PBMCs from 72 PD patients and 40 age-matched controls. c-Rel DNA-binding was significantly lower and inversely correlated with Ac-RelA(lys310) content in post-mortem SN of sporadic PD cases, when compared to healthy controls. c-Rel DNA-binding activity was also reduced in PBMCs of followed-up PD subjects. The decrease of c-Rel activity in PBMCs from PD patients appeared to be independent from dopaminergic medication or disease progression, as it was evident even in early stage, drug-naïve patients. Remarkably, the levels of c-Rel protein were comparable in PD and control subjects, pointing out a putative role for post-translational modifications of the protein in c-Rel dysfunctions. These findings support that PD is characterized by the loss of NF-κB/c-Rel activity that potentially has a role in PD pathophysiology. Future studies will be aimed at addressing whether the reduction of c-Rel DNA-binding could constitute a novel biomarker for PD.

Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression.

Cancer cells are embedded within the tissue and interact dynamically with its components during cancer progression. Understanding the contribution of cellular components within the tumor microenvironment is crucial for the success of therapeutic applications. Here, we reveal the presence of perivascular GFAP+/Plp1+ cells within the tumor microenvironment. Using in vivo inducible Cre/loxP mediated systems, we demonstrated that these cells derive from tissue-resident Schwann cells. Genetic ablation of endogenous Schwann cells slowed down tumor growth and angiogenesis. Schwann cell-specific depletion also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of tumor biopsies revealed that increased expression of Schwann cell-related genes within melanoma was associated with improved survival. Collectively, our study suggests that Schwann cells regulate tumor progression, indicating that manipulation of Schwann cells may provide a valuable tool to improve cancer patients' outcomes.

Radiation exposure and leukaemia risk among cohorts of persons exposed to low and moderate doses of external ionising radiation in childhood.

BACKGROUND: Many high-dose groups demonstrate increased leukaemia risks, with risk greatest following childhood exposure; risks at low/moderate doses are less clear. METHODS: We conducted a pooled analysis of the major radiation-associated leukaemias (acute myeloid leukaemia (AML) with/without the inclusion of myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL)) in ten childhood-exposed groups, including Japanese atomic bomb survivors, four therapeutically irradiated and five diagnostically exposed cohorts, a mixture of incidence and mortality data. Relative/absolute risk Poisson regression models were fitted. RESULTS: Of 365 cases/deaths of leukaemias excluding chronic lymphocytic leukaemia, there were 272 AML/CML/ALL among 310,905 persons (7,641,362 person-years), with mean active bone marrow (ABM) dose of 0.11 Gy (range 0-5.95). We estimated significant (P < 0.005) linear excess relative risks/Gy (ERR/Gy) for: AML (n = 140) = 1.48 (95% CI 0.59-2.85), CML (n = 61) = 1.77 (95% CI 0.38-4.50), and ALL (n = 71) = 6.65 (95% CI 2.79-14.83). There is upward curvature in the dose response for ALL and AML over the full dose range, although at lower doses (<0.5 Gy) curvature for ALL is downwards. DISCUSSION: We found increased ERR/Gy for all major types of radiation-associated leukaemia after childhood exposure to ABM doses that were predominantly (for 99%) <1 Gy, and consistent with our prior analysis focusing on <100 mGy.

Robotic Versus Laparoscopic Ventral Hernia Repair: Two-Year Results From a Prospective, Multicenter, Blinded Randomized Clinical Trial.

OBJECTIVE: Report the 2-year outcomes of a multicenter randomized controlled trial comparing robotic versus laparoscopic intraperitoneal onlay mesh ventral hernia repair. BACKGROUND: Ventral hernia repair is one of the most common operations performed by general surgeons. To our knowledge, no studies have been published to date comparing long-term outcomes of laparoscopic versus robotic ventral hernia repair. METHODS: The trial was registered at clinicaltrials.gov (NCT03490266). Clinical outcomes included surgical site infection, surgical site occurrence, hernia occurrence, readmission, reoperation, and mortality. RESULTS: A total of 175 consecutive patients were approached that were deemed eligible for elective minimally invasive ventral hernia repair. In all, 124 were randomized and 101 completed follow-up at 2 years. Two-year follow-up was completed in 54 patients (83%) in the robotic arm and 47 patients (80%) in the laparoscopic arm. No differences were seen in surgical site infection or surgical site occurrence. Hernia recurrence occurred in 2 patients (4%) receiving robotic repair versus in 6 patients (13%) receiving laparoscopic repair (relative risk: 0.3, 95% CI: 0.06-1.39; P =0.12). No patients (0%) required reoperation in the robotic arm whereas 5 patients (11%) underwent reoperation in the laparoscopic arm ( P =0.019, relative risk not calculatable due to null outcome). CONCLUSIONS: Robotic ventral hernia repair demonstrated at least similar if not improved outcomes at 2 years compared with laparoscopy. There is potential benefit with robotic repair; however, additional multi-center trials and longer follow-up are needed to validate the hypothesis-generating findings of this study.

Hydrostatic pressure prevents chondrocyte differentiation through heterochromatin remodeling.

Articular cartilage protects and lubricates joints for smooth motion and transmission of loads. Owing to its high water content, chondrocytes within the cartilage are exposed to high levels of hydrostatic pressure, which has been shown to promote chondrocyte identity through unknown mechanisms. Here, we investigate the effects of hydrostatic pressure on chondrocyte state and behavior, and discover that application of hydrostatic pressure promotes chondrocyte quiescence and prevents maturation towards the hypertrophic state. Mechanistically, hydrostatic pressure reduces the amount of trimethylated H3K9 (K3K9me3)-marked constitutive heterochromatin and concomitantly increases H3K27me3-marked facultative heterochromatin. Reduced levels of H3K9me3 attenuates expression of pre-hypertrophic genes, replication and transcription, thereby reducing replicative stress. Conversely, promoting replicative stress by inhibition of topoisomerase II decreases Sox9 expression, suggesting that it enhances chondrocyte maturation. Our results reveal how hydrostatic pressure triggers chromatin remodeling to impact cell fate and function.This article has an associated First Person interview with the first author of the paper.