Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy.

BACKGROUND: Combining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models. METHODS: Two bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit. RESULTS: Compared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations. CONCLUSION: The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.

The American Society for Microbiology collaboration with the CDC Laboratory Medicine Best Practices initiative for evidence-based laboratory medicine.

SUMMARYClinical medicine has embraced the use of evidence for patient treatment decisions; however, the evaluation strategy for evidence in laboratory medicine practices has lagged. It was not until the end of the 20th century that the Institute of Medicine (IOM), now the National Academy of Medicine, and the Centers for Disease Control and Prevention, Division of Laboratory Systems (CDC DLS), focused on laboratory tests and how testing processes can be designed to benefit patient care. In collaboration with CDC DLS, the American Society for Microbiology (ASM) used an evidence review method developed by the CDC DLS to develop a program for creating laboratory testing guidelines and practices. The CDC DLS method is called the Laboratory Medicine Best Practices (LMBP) initiative and uses the A-6 cycle method. Adaptations made by ASM are called Evidence-based Laboratory Medicine Practice Guidelines (EBLMPG). This review details how the ASM Systematic Review (SR) Processes were developed and executed collaboratively with CDC's DLS. The review also describes the ASM transition from LMBP to the organization's current EBLMPG, maintaining a commitment to working with agencies in the U.S. Department of Health and Human Services and other partners to ensure that EBLMPG evidence is readily understood and consistently used.

Real-word outcomes for high-risk non-muscle-invasive bladder cancer: screened patients for the BRAVO trial.

OBJECTIVE: To report real-world outcomes for high-risk non-muscle-invasive bladder cancer (HRNMIBC), including bacillus Calmette-Guérin (BCG) and radical cystectomy (RC), as randomised comparisons of these have not been possible. METHODS: We detail consecutive participants screened for the BRAVO randomised controlled trial comparing RC with BCG (International Standard Randomised Controlled Trial Number [ISRCTN]12509361). Patients were prospectively registered and case-note review used for outcomes. The primary outcome was overall survival. Secondary outcomes included recurrence, progression, metastasis, and bladder cancer-specific survival. RESULTS AND LIMITATIONS: A total of 193 patients were screened, including 106 (54.9%) who received BCG, 43 (22.3%) primary RC, 37 (19.2%) 'other' treatment and seven (3.6%) hyperthermic intravesical mitomycin C. All-cause death occurred in 55 (28.5%) patients at median (interquartile range [IQR]) of 29.0 (19.5-42.0) months. In multivariable analysis, overall mortality was more common in older patients (hazard ratio [HR] 2.63, 95% confidence interval [CI] 1.35-5.13; Cox P = 0.004 for age >70 years), those recruited from district hospitals (HR 0.53, 95% CI 0.3-0.95; P = 0.032) and those who did not undergo RC as their first treatment (HR 2.16, 95% CI 1.17-3.99; P = 0.014). In all, 17 (8.8%) patients died from bladder cancer (BC) at median (IQR) of 22.5 (19-36.25) months. In multivariable analysis, BC-specific mortality was more common in older patients (HR 4.87, 95% CI 1.1-21.6; P = 0.037) and those with Tis/T1 disease (HR 2.26, 95% CI 1.23-4.16; P = 0.008) but did not vary with initial treatment. CONCLUSIONS: Patients with HRNMIBC are at high-risk of mortality. Those choosing RC as their initial treatment have lower risks of mortality than others, although this may reflect fitness and selection.

There is no limitation for CO2 excretion across the lung in exercising American alligators (Alligator mississippiensis).

Vertebrates utilize various respiratory organs such as gills, lungs and skin in combination with diverse cardiovascular structures, including single-, three- and four-chambered hearts, to enable oxygen delivery and carbon dioxide removal. They also exhibit differences in aerobic and anaerobic metabolism during exertion, but the cardiorespiratory gas transport of all vertebrates is a four-step process governed by Fick's Principle and Fick's Law of Diffusion over the entire range of metabolic rates. Hillman et al. (2013) suggested that previous exercise studies have focused too narrowly on mammals and proposed that the cardiorespiratory system's excess capacity serves an evolutionary role in enhancing CO2 excretion in non-mammalian vertebrates. In contrast, an analysis by Hicks and Wang (2021) concluded that vertebrates maintain effective gas exchange even at peak activity, finding no evidence of arterial hypercapnia at maximal oxygen consumption and thus challenging the proposal of significant limitations to pulmonary or branchial CO2 efflux. In the present study, we investigated the limits for CO2 exchange in exercising American alligators (Alligator mississippiensis) and provide evidence that the cardiorespiratory system is adequately built to sustain CO2 excretion during strenuous exercise and maintain arterial PCO2, with no evidence of diffusion limitation for pulmonary CO2 excretion.

Remote Patient Monitoring and Machine Learning in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Dual Systematic Literature Review and Narrative Synthesis.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with high mortality, morbidity, and poor quality of life and constitute a substantial burden to patients and health care systems. New approaches to prevent or reduce the severity of AECOPD are urgently needed. Internationally, this has prompted increased interest in the potential of remote patient monitoring (RPM) and digital medicine. RPM refers to the direct transmission of patient-reported outcomes, physiological, and functional data, including heart rate, weight, blood pressure, oxygen saturation, physical activity, and lung function (spirometry), directly to health care professionals through automation, web-based data entry, or phone-based data entry. Machine learning has the potential to enhance RPM in chronic obstructive pulmonary disease by increasing the accuracy and precision of AECOPD prediction systems. OBJECTIVE: This study aimed to conduct a dual systematic review. The first review focuses on randomized controlled trials where RPM was used as an intervention to treat or improve AECOPD. The second review examines studies that combined machine learning with RPM to predict AECOPD. We review the evidence and concepts behind RPM and machine learning and discuss the strengths, limitations, and clinical use of available systems. We have generated a list of recommendations needed to deliver patient and health care system benefits. METHODS: A comprehensive search strategy, encompassing the Scopus and Web of Science databases, was used to identify relevant studies. A total of 2 independent reviewers (HMGG and CM) conducted study selection, data extraction, and quality assessment, with discrepancies resolved through consensus. Data synthesis involved evidence assessment using a Critical Appraisal Skills Programme checklist and a narrative synthesis. Reporting followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: These narrative syntheses suggest that 57% (16/28) of the randomized controlled trials for RPM interventions fail to achieve the required level of evidence for better outcomes in AECOPD. However, the integration of machine learning into RPM demonstrates promise for increasing the predictive accuracy of AECOPD and, therefore, early intervention. CONCLUSIONS: This review suggests a transition toward the integration of machine learning into RPM for predicting AECOPD. We discuss particular RPM indices that have the potential to improve AECOPD prediction and highlight research gaps concerning patient factors and the maintained adoption of RPM. Furthermore, we emphasize the importance of a more comprehensive examination of patient and health care burdens associated with RPM, along with the development of practical solutions.

Three-dimensional chromatin mapping of sensory neurons reveals that promoter-enhancer looping is required for axonal regeneration.

The in vivo three-dimensional genomic architecture of adult mature neurons at homeostasis and after medically relevant perturbations such as axonal injury remains elusive. Here, we address this knowledge gap by mapping the three-dimensional chromatin architecture and gene expression program at homeostasis and after sciatic nerve injury in wild-type and cohesin-deficient mouse sensory dorsal root ganglia neurons via combinatorial Hi-C, promoter-capture Hi-C, CUT&Tag for H3K27ac and RNA-seq. We find that genes involved in axonal regeneration form long-range, complex chromatin loops, and that cohesin is required for the full induction of the regenerative transcriptional program. Importantly, loss of cohesin results in disruption of chromatin architecture and severely impaired nerve regeneration. Complex enhancer-promoter loops are also enriched in the human fetal cortical plate, where the axonal growth potential is highest, and are lost in mature adult neurons. Together, these data provide an original three-dimensional chromatin map of adult sensory neurons in vivo and demonstrate a role for cohesin-dependent long-range promoter interactions in nerve regeneration.

Microfluidic technologies for lipid vesicle generation.

Encapsulating biological and non-biological materials in lipid vesicles presents significant potential in both industrial and academic settings. When smaller than 100 nm, lipid vesicles and lipid nanoparticles are ideal vehicles for drug delivery, facilitating the delivery of payloads, improving pharmacokinetics, and reducing the off-target effects of therapeutics. When larger than 1 µm, vesicles are useful as model membranes for biophysical studies, as synthetic cell chassis, as bio-inspired supramolecular devices, and as the basis of protocells to explore the origin of life. As applications of lipid vesicles gain prominence in the fields of nanomedicine, biotechnology, and synthetic biology, there is a demand for advanced technologies for their controlled construction, with microfluidic methods at the forefront of these developments. Compared to conventional bulk methods, emerging microfluidic methods offer advantages such as precise size control, increased production throughput, high encapsulation efficiency, user-defined membrane properties (i.e., lipid composition, vesicular architecture, compartmentalisation, membrane asymmetry, etc.), and potential integration with lab-on-chip manipulation and analysis modules. We provide a review of microfluidic lipid vesicle generation technologies, focusing on recent advances and state-of-the-art techniques. Principal technologies are described, and key research milestones are highlighted. The advantages and limitations of each approach are evaluated, and challenges and opportunities for microfluidic engineering of lipid vesicles to underpin a new generation of therapeutics, vaccines, sensors, and bio-inspired technologies are presented.

Study protocol for writing to heal: A culturally based brief expressive writing intervention for Chinese immigrant breast cancer survivors.

BACKGROUND: This study uses a randomized controlled trial (RCT) to test the health benefits of expressive writing that is culturally adapted for Chinese immigrant breast cancer survivors (BCSs) and to characterize how acculturation moderates the effects of expressive writing interventions. METHODS: We will recruit Chinese immigrant BCSs (N = 240) diagnosed with stage 0-III breast cancer and within 5 years of completion of primary treatment. Recruitment will occur primarily through community-based organizations and cancer registries. Participants will be randomly assigned either to a control condition to write about neutral topics or to one of two intervention conditions, self-regulation or self-cultivation, both of which aim to promote adaptive cognitive processes but differ in how they achieve this goal. The self-regulation intervention culturally adapts a Western expressive writing paradigm and incorporates emotional disclosure, whereas the self-cultivation intervention originates from Asian cultural values without disclosing emotions. Participants in all three conditions will be asked to write in their preferred language for three 30-minute sessions. The primary outcome will be quality of life (QOL) at the 6- and 12-month follow-ups, and the secondary outcomes will be perceived stress, stress biomarkers, and medical appointments for cancer-related morbidities. DISCUSSION: This project will be the first large RCT to test culturally based brief interventions to improve QOL and reduce stress among Chinese immigrant BCSs. This project is expected to address two important needs of Chinese immigrant BCSs: their unmet psychological needs and the lack of culturally competent mental health care for Chinese immigrant BCSs. The immediate product of this line of research will be empirically evaluated, culturally responsive interventions ready for dissemination to Chinese immigrant BCSs across the United States. CLINICALTRIALS.GOV IDENTIFIER: NCT04754412.

New insights into the ovulatory process in the human ovary.

BACKGROUND: Successful ovulation is essential for natural conception and fertility. Defects in the ovulatory process are associated with various conditions of infertility or subfertility in women. However, our understanding of the intra-ovarian biochemical mechanisms underlying this process in women has lagged compared to our understanding of animal models. This has been largely due to the limited availability of human ovarian samples that can be used to examine changes across the ovulatory period and delineate the underlying cellular/molecular mechanisms in women. Despite this challenge, steady progress has been made to improve our knowledge of the ovulatory process in women by: (i) collecting granulosa cells across the IVF interval, (ii) creating a novel approach to collecting follicular cells and tissues across the periovulatory period from normally cycling women, and (iii) developing unique in vitro models to examine the LH surge or hCG administration-induced ovulatory changes in gene expression, the regulatory mechanisms underlying the ovulatory changes, and the specific functions of the ovulatory factors. OBJECTIVE AND RATIONALE: The objective of this review is to summarize findings generated using in vivo and in vitro models of human ovulation, with the goal of providing new insights into the mechanisms underlying the ovulatory process in women. SEARCH METHODS: This review is based on the authors' own studies and a search of the relevant literature on human ovulation to date using PubMed search terms such as 'human ovulation EGF-signaling', 'human ovulation steroidogenesis', 'human ovulation transcription factor', 'human ovulation prostaglandin', 'human ovulation proteinase', 'human ovulation angiogenesis' 'human ovulation chemokine', 'human ovulatory disorder', 'human granulosa cell culture'. Our approach includes comparing the data from the authors' studies with the existing microarray or RNA-seq datasets generated using ovarian cells obtained throughout the ovulatory period from humans, monkeys, and mice. OUTCOMES: Current findings from studies using in vivo and in vitro models demonstrate that the LH surge or hCG administration increases the expression of ovulatory mediators, including EGF-like factors, steroids, transcription factors, prostaglandins, proteolytic systems, and other autocrine and paracrine factors, similar to those observed in other animal models such as rodents, ruminants, and monkeys. However, the specific ovulatory factors induced, their expression pattern, and their regulatory mechanisms vary among different species. These species-specific differences stress the necessity of utilizing human samples to delineate the mechanisms underlying the ovulatory process in women. WIDER IMPLICATIONS: The data from human ovulation in vivo and in vitro models have begun to fill the gaps in our understanding of the ovulatory process in women. Further efforts are needed to discover novel ovulatory factors. One approach to address these gaps is to improve existing in vitro models to more closely mimic in vivo ovulatory conditions in humans. This is critically important as the knowledge obtained from these human studies can be translated directly to aid in the diagnosis of ovulation-associated pathological conditions, for the development of more effective treatment to help women with anovulatory infertility or, conversely, to better manage ovulation for contraceptive purposes. REGISTRATION NUMBER: N/A.

Examining the Equivalence Between Imagery and Execution-Does Imagery Comprise the Intended Spatial Trajectory?

The functional equivalence model suggests a common internal representation initiates both imagery and execution. This suggestion is supported by the mental chronometry effect, where there is a positive relation between task difficulty (as defined by the Index of Difficulty; ID) and imagined movement time. The present study extends this logic by examining whether imagery captures the spatial trajectory. Participants were initially tasked with the imagery and execution of a rapid aiming movement under different IDs. These initial attempts were adapted to configure auditory tones at early (25%) and late (75%) intervals for a separate set of imagery trials. If a tone had sounded, participants had to estimate post-trial where their imagined limb would have been located. The findings revealed increases in ID that coincided with increases in imagined and executed movement times. However, participant mean and standard deviation of estimated locations revealed limited differences between the early and late tones. Further inspection revealed some evidence for these estimated locations shifting further along in space following more rapid imagined movements. While equivalence is clearly evident within the temporal domain, there is comparatively little to suggest that this logic extends to the resolution required for simulating the spatial characteristics of movement.

Dose de-intensified 3-day photon, proton, or brachytherapy: a nonrandomized controlled partial breast irradiation trial.

BACKGROUND: The optimal approach for partial breast irradiation (PBI) is unknown. We investigated a novel de-intensified 3-fraction PBI regimen for photons, protons, and brachytherapy. METHODS: A multicenter nonrandomized controlled trial with primary outcome of adverse cosmesis at 3 years versus pre-PBI. Eligibility criteria were ≥ age 50 years treated with breast-conserving surgery for node-negative estrogen receptor positive (ER+) invasive breast cancer or any ductal carcinoma in-situ (DCIS) measuring ≤ 2.5 cm. Photon and proton PBI were prescribed 21.9 Gy (RBE) and brachytherapy 21 Gy in 3 fractions. Radiotherapy technique and use of adjuvant endocrine therapy was selected at physician and patient discretion. RESULTS: Between June 17, 2015 and July 13, 2017, 161 eligible patients were treated with photons (56), protons (49), or brachytherapy (56). Median patient age was 66.8 years. 126 (78.3%) had invasive breast cancer (all ER+) and 35 (21.7%) had DCIS (88.6% ER+). 54.0% of patients with invasive breast cancer and 25.8% of patients with ER+ DCIS initiated and adhered to prescribed endocrine therapy. The proportion of patients with adverse cosmesis (by trained nurse assessment) was 14.5% at baseline, 2.3% at 3 years (difference -12.2%, 95% CI (-100%, -6.4%)). Adverse cosmesis at last-follow-up, with median follow-up 5 years, was 5.7% by nurse assessment, 5.6% by panel assessment of digital photographs, and 5.2% by patient self-report. There were no observed clinically meaningful changes in other patient reported outcomes, and just two grade 2 or higher adverse events, both grade 2, in the brachytherapy cohort. 5-year local recurrence-free and progression-free survival were 98.0% and 95.5%, respectively. There were no local recurrences amongst 60 patients with invasive breast cancer and Ki67 ≤ 13.25%. CONCLUSIONS: De-intensified 3-day PBI provided favorable disease control, tolerability, and cosmetic outcomes, meeting the pre-specified criteria for acceptability. This approach is an attractive option for small node-negative ER+ BC and DCIS patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02453737.

A Phase 1 single ascending dose study of pure oral harmine in healthy volunteers.

BACKGROUND: Harmine is a component of the hallucinogenic brew, Ayahuasca, which also contains the psychoactive compound, N, N-dimethyltryptamine. Whether pharmaceutical-grade harmine hydrochloride (HCl) has psychoactive effects, the doses at which these might occur, and the dose-response relationship to side effects and safety in humans are unknown. METHODS: We conducted a Phase 1, open-label single ascending dose trial in healthy adults with normal body mass index and no prior psychiatric illness. The primary goal was to determine the maximum tolerated dose (MTD) of oral pharmaceutical-grade harmine HCl and to characterize safety and tolerability. A secondary goal was to ascertain whether any oral dose has psychoactive effects. RESULTS: Thirty-four adult participants, aged 18-55 years, were screened for study eligibility. Twenty-five participants met eligibility criteria and were randomized to a single dose of 100, 200, 300, or 500 mg of harmine HCl, respectively, using a continuous reassessment method. The most common adverse events (AEs) observed were gastrointestinal and/or neurological, dose-related, and of mild to moderate severity. The MTD was determined to be between 100 and 200 mg and is weight-based, with 90% of those participants receiving >2.7 mg/kg experiencing a dose-limiting toxicity. No serious AEs of harmine HCl were identified. CONCLUSIONS: Harmine HCl can be orally administered to healthy participants in doses <2.7 mg/kg with minimal or no AEs. Doses >2.7 mg/kg are associated with vomiting, drowsiness, and limited psychoactivity. This study is the first to systematically characterize the psychoactive effects of pharmaceutical quality harmine in healthy participants.

The Surgery of Celsus' De Medicina.

Celsus' De Medicina (first century ce) is the first comprehensive treatise on medicine and surgery to survive from antiquity. Bridging the gap between the Hippocratic Corpus and the works of Galen, it documents the important advances in anatomy and surgery of the Alexandrian school during the Hellenistic era. De Medicina contains an anatomically based system of surgery and strikingly modern concepts of wound management, as well as the first accounts of hemostasis by ligature, per primam healing of wounds, amputation, and complex, elective operations, including lithotomy and inguinal herniotomy. The possibility (and desirability) of per primam healing, thereby permitting elective surgical procedures, was ignored until rediscovered in the 19th century; its recognition by Celsus prompts a re-evaluation of the excellence of ancient surgery.

Ab Initio Calculation of Coupling-Constant Averaged Exchange-Correlation Holes for Spherically Symmetric Atoms.

Accurate approximation of the exchange-correlation (XC) energy in density functional theory (DFT) calculations is essential for reliably modeling electronic systems. Many such approximations are developed from models of the XC hole; accurate reference XC holes for real electronic systems are crucial for evaluating the accuracy of these models however the availability of reliable reference data is limited to a few systems. In this study, we employ the Lieb optimization with a coupled cluster singles and doubles (CCSD) reference to construct accurate coupling-constant averaged XC holes, resolved into individual exchange and correlation components, for five spherically symmetric atoms: He, Li, Be, N, and Ne. Alongside providing a new set of reference data for the construction and evaluation of model XC holes, we compare our data against the exchange and correlation hole models of the established local density approximation (LDA) and Perdew-Burke-Ernzerhof (PBE) density functional approximations. Our analysis confirms the established rationalization for the limitations of LDA and the improvement observed with PBE in terms of the hole depth and its long-range decay, which is demonstrated in real-space for this series of spherically symmetric atoms.

Hangman's Fractures: A Review of Current Concepts in Evaluation and Management.

STUDY DESIGN: Review article. OBJECTIVE: To provide a comprehensive review and update on the evaluation and management of Hangman's fractures. SUMMARY OF BACKGROUND DATA: Hangman's fractures are the second most common fracture of the C2 vertebrae, and the prevalence is increasing with our aging population. Although these injuries are associated with good clinical outcomes and low rates of neurologic injury, they must be promptly recognized and treated according to patient and fracture factors. METHODS: A review of the literature. RESULTS: Neurologic injuries are uncommon in typical Hangman's fractures but are more of a concern in atypical Hangman's fractures due to lack of dissociation of the posterior ring of C2. The nonoperative treatment of stable type I, II, and atypical fractures with external immobilization leads to excellent long-term outcomes as does the operative treatment of unstable type IIa, III, and atypical fractures. CONCLUSIONS: Stable injury patterns can be treated with immobilization alone, whereas unstable injury patterns necessitate surgical treatment. Prompt diagnosis and treatment Hangman's fractures is paramount, and when managed properly, patients can have excellent clinical and neurologic outcomes.

Characterization of additive gene-environment interactions for colorectal cancer risk.

BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.

Drastic hourly changes in hand hygiene workload and performance rates: A multicenter time series analysis.

BACKGROUND: High hand hygiene (HH) workload is a commonly cited barrier to optimal HH performance. The objective of this study was to assess trends of HH workload as defined by HH opportunities (HHO) and performance rates over different timescales using automated HH monitoring system data. METHODS: This multiyear retrospective observational study was conducted in 58 inpatient units located in 10 North American hospitals. HHO and HH rates were analyzed by time series mixed effects general additive model. RESULTS: Median HH rates peaked at 50.0 between 6 and 7 AM with a trough of 38.2 at 5 PM. HHO over hours in a day were the highest at 184 per hospital unit per hour at 10 AM with a trough of 49.0 between 2 and 3 AM. Median rates for day and night shifts were 40.8 and 45.5, respectively (P = .078). Weekend day shift had the lowest median rate (39.4) compared with any other 12-hour shift (P < .1018). The median rates and HHO varied little across days in a week and months. CONCLUSIONS: HH workload and performance rates were negatively correlated and changed drastically over hours in a day. Hospitals should consider HH workload in the development and timely delivery of improvement interventions.

Preventing OsteoPorosis in Spinal Cord Injury (POPSCI) Study-Early Zoledronic Acid Infusion in Patients with Acute Spinal Cord Injury.

Accelerated sub-lesional bone loss is common in the first 2-3 years after traumatic spinal cord injury (TSCI), particularly in the distal femur and proximal tibia. Few studies have explored efficacy of antiresorptives for acute bone loss prevention post-TSCI, with limited data for knee bone mineral density (BMD) or beyond two years follow-up. An open-label non-randomized study was performed at Royal North Shore Hospital and Royal Rehab Centre, Sydney between 2018 and 2023. An 'acute interventional cohort' (n = 11) with TSCI (duration ≤ 12-weeks) received a single infusion of 4 mg zoledronic acid (ZOL) at baseline. A 'chronic non-interventional cohort' (n = 9) with TSCI (duration 1-5-years) did not receive ZOL. All participants underwent baseline and 6-monthly blood tests (including CTx and P1NP) and 12-monthly DXA BMD scans (including distal femur and proximal tibia). Participants were predominantly Caucasian and male (mean age 38.4 years). At baseline, the 'acute' cohort had higher serum CTx, P1NP and sclerostin concentrations, while the 'chronic' cohort had lower left hip and knee BMD. Majority with acute TSCI experienced an acute phase reaction after ZOL (9/11; 82%). In the acute cohort, left hip BMD fell by mean ~ 15% by 48 months. Left distal femoral and proximal tibial BMD declined by mean ~ 6-13% at 12 months and ~ 20-23% at 48 months, with a tendency towards greater BMD loss in motor-complete TSCI. A single early ZOL infusion in acute TSCI could not attenuate rapidly declining hip and knee BMD. Prospective controlled studies are required to establish the optimal strategy for preventing early bone loss after acute TSCI.

Novel Pannexin 1 isoform is increased in cancer.

Pannexin 1 (PANX1) is upregulated in many cancers, where its activity and signalling promote tumorigenic properties. Here, we report a novel ∼25 kDa isoform of human PANX1 (hPANX1-25K) which lacks the N-terminus and was detected in several human cancer cell lines including melanoma, osteosarcoma, breast cancer and glioblastoma multiforme. This isoform was increased upon hPANX1 CRISPR/Cas9 deletion targeting the first exon near M1, suggesting a potential alternative translation initiation (ATI) site. hPANX1-25K was confirmed to be a hPANX1 isoform via mass spectrometry, can be N-linked glycosylated at N254, and can interact with both ß-catenin and full length hPANX1. A double deletion of hPANX1 and hPANX1-25K reduces cell growth and viability in cancer cells. hPANX1-25K is prevalent throughout melanoma progression, and its levels are increased in squamous cell carcinoma cells and patient-derived tumours, compared to keratinocytes and normal skin, indicating that it may be differentially regulated in normal and cancer cells.

Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche.

Hematopoietic stem and progenitor cells (HSPC) are regulated by interactions with stromal cells in the bone marrow (BM) cavity, which can be segregated into two spatially defined central marrow (CM) and endosteal (Endo) compartments. However, the importance of this spatial compartmentalization for BM responses to inflammation and neoplasia remains largely unknown. Here, we extensively validate a combination of scRNA-seq profiling and matching flow cytometry isolation that reproducibly identifies 7 key CM and Endo populations across mouse strains and accurately surveys both niche locations. We demonstrate that different perturbations exert specific effects on different compartments, with type I interferon responses causing CM mesenchymal stromal cells to adopt an inflammatory phenotype associated with overproduction of chemokines modulating local monocyte dynamics in the surrounding microenvironment. Our results provide a comprehensive method for molecular and functional stromal characterization and highlight the importance of altered stomal cell activity in regulating hematopoietic responses to inflammatory challenges.