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While injuries sustained from body armour backface deformation (BFD) have not been well-documented in military injury trauma registries, data from US law enforcement officers, animal tests and currently available data pertaining to military combatants has shown that BFD can not only cause minor injuries, but also result in serious trauma. However, the nature and severity of injuries sustained depends on a multitude of factors including the projectile type, the impact location and velocity, and the specific type of body armour worn. The difficulties involved in current measurement techniques for ballistic testing has led researchers to seek alternative techniques to evaluate the level of protection from body armour, such as the finite element (FE) method. In the current study, a systematic review of the open literature was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. The aim was to summarise the literature pertaining to the development and application of FE models to investigate body armour BFD and behind armour blunt trauma (BABT), and included FE models representing the projectile, clay-based mediums, ballistic gelatine and the human torso. Using the keywords 'behind armour*', 'ballistic blunt trauma', 'BABT', 'backface signature', 'backface deformation', 'BFS', 'BFD', 'wound ballistic', 'ballistic impact testing', 'body armour', 'bullet proof vest', 'ballistic vest', 'Finite Element*' and 'FE', an electronic database search of EBSCOhost, Google Scholar, ProQuest, Scopus, Standards, Web of Science and PubMed was conducted, and included peer-reviewed journal articles, review papers, research reports, conference papers, and MSc or PhD theses. While this research demonstrates the potential of FE analysis for recreating realistic blunt impact scenarios and enhancing the current understanding of BABT mechanisms, a common limitation in most studies is the lack of validation. Thus, in order to address this issue, it is proposed that injury predictions from FE models be correlated with trauma data from soldiers who have sustained BABT. Consequently, pressure and energy distributions within the organs can be used to interpret the effects of non-penetrating ballistic impacts on the human torso. Bridging the gap between simulation and real-world data is essential in order to validate FE models and enhance their utility in optimising body armour design and employing injury mitigation strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the role of plasma extracellular vesicles (EVs) in understanding colorectal cancer (CRC) progression and recurrence to potentially improve disease prognosis. Using advanced SWATH-MS proteomics, EV proteins from CRC patients across four stages and healthy controls were analysed. This study identified 11 key proteins differentiating early-stage CRC from healthy individuals and 14 proteins associated with tumour recurrence risk. These proteins reflect changes in cancer-related processes, including metabolism, cytoskeletal remodelling, and immune response. The findings provide valuable insights into the role of EVs in CRC and emphasise the need to standardise methods for EV isolation and analysis to enhance biomarker discovery and allow seamless clinical applications Background: Recent advancements in understanding plasma extracellular vesicles (EVs) and their role in disease biology have provided additional unique insights into the study of Colorectal Cancer (CRC). Methods: This study aimed to gain biological insights into disease progression from plasma-derived extracellular vesicle proteomic profiles of 80 patients (20 from each CRC stage I–IV) against 20 healthy age- and sex-matched controls using a high-resolution SWATH-MS proteomics with a reproducible centrifugation method to isolate plasma EVs. Results: We applied the High-Stringency Human Proteome Project (HPP) guidelines for SWATH-MS analysis, which refined our initial EV protein identification from 1362 proteins (10,993 peptides) to a more reliable and confident subset of 853 proteins (6231 peptides). In early-stage CRC, we identified 11 plasma EV proteins with differential expression between patients and healthy controls (three up-regulated and eight down-regulated), many of which are involved in key cancer hallmarks. Additionally, within the same cohort, we analysed EV proteins associated with tumour recurrence to identify potential prognostic indicators for CRC. A subset of up-regulated proteins associated with extracellular vesicle formation (GDI1, NSF, and TMED9) and the down-regulation of TSG101 suggest that micro-metastasis may have occurred earlier than previously anticipated. Discussion: By employing stringent proteomic analysis and a robust SWATH-MS approach, we identified dysregulated EV proteins that potentially indicate early-stage CRC and predict recurrence risk, including proteins involved in metabolism, cytoskeletal remodelling, and immune response. While our findings underline discrepancies with other studies due to differing isolation and stringency parameters, they provide valuable insights into the complexity of the EV proteome, emphasising the need for standardised protocols and larger, well-controlled studies to validate potential biomarkers. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review synthesizes recent advancements in understanding subchondral bone (SCB) biomechanics using computed tomography (CT) and micro-computed tomography (micro-CT) imaging in large animal models, particularly horses. Recent Findings: Recent studies highlight the complexity of SCB biomechanics, revealing variability in density, microstructure, and biomechanical properties across the depth of SCB from the joint surface, as well as at different joint locations. Early SCB abnormalities have been identified as predictive markers for both osteoarthritis (OA) and stress fractures. The development of standing CT systems has improved the practicality and accuracy of live animal imaging, aiding early diagnosis of SCB pathologies. Summary: While imaging advancements have enhanced our understanding of SCB, further research is required to elucidate the underlying mechanisms of joint disease and articular surface failure. Combining imaging with mechanical testing, computational modelling, and artificial intelligence (AI) promises earlier detection and better management of joint disease. Future research should refine these modalities and integrate them into clinical practice to enhance joint health outcomes in veterinary and human medicine. [ABSTRACT FROM AUTHOR]

Droplet flows, termed misting, are significant lubrication flow mechanisms to, in and around the piston assembly. Therefore, these are important in piston assembly tribology and engine performance. Crankcase lubricant degradation rate has been hypothesised to be influenced by lubricant droplet flows through the piston assembly and crankcase, but not previously confirmed. Lubricant was sampled from the sump, top ring zone (TRZ), and mist and aerosol from the crankcase during an extended run. The physical and chemical degradation of these samples was characterised. Droplet flows were intermediate in degradation and fuel dilution between TRZ and sump. Flows with smaller droplet sizes were more degraded that those with larger droplets. The degradation of polymers was dependent on their molecular architecture. [ABSTRACT FROM AUTHOR]

A research protocol is a document that outlines the proposed research idea and is submitted to funding agencies, institutions, or journals for approval. Writing a research protocol represents a challenge, particularly for early-career researchers. In this guide, we aim to provide detailed guidance with the key components and offer practical tips for crafting a research protocol in line with the various study designs. Specifically, the structure of a research protocol should contain the following items: (1) a title that is specific, catchy, and impressive within the word limitation; (2) an abstract that briefs the critical points of the study; (3) an introduction highlighting the study context from broad to narrow and defining the knowledge gap; (4) a justification underlining the significance of the proposed study; (5) Specific, Measurable, Attainable, Relevant, and Time-bound (SMART) objective(s) and aim(s); (6) a methodology covering seven sub-items, including [i] study design and settings, [ii] study subjects, [iii] sample size calculation and sampling, [iv] participants recruitment and follow-up, [v] questionnaire development, [vi] potential variables and outcomes, and [vii] data analysis plan; (7) dissemination of the results; (8) ethics and conflict of interests; (9) budgets analysis/ funding disclosure; and (10) references. This guide will give an overview of these steps and provide clear and concise tips on how to successfully draft a scientific protocol. With careful planning and appropriate guidance, it is possible to develop a well-structured and compelling protocol to obtain approval for the conduction of the study or funding from agencies, institutions, or organizations. [ABSTRACT FROM AUTHOR]

Police officers and staff who investigate child sexual abuse material (CSAM) may be at elevated risk for mental health problems, which may be mitigated or exacerbated by institutional and interpersonal factors. The current work examined mental health in a large sample of UK CSAM investigators (N = 661). Results suggest substantially elevated rates of depression and anxiety but not posttraumatic stress disorder (PTSD). Feeling successful and supported powerfully buffered against negative outcomes, whereas moral injury—particularly feelings of institutional betrayal—predicted worse outcomes. Although exposure to CSAM and contact with victims predicted worse outcomes, these effects were much smaller. Regarding coping styles, self‐blame, rumination, catastrophizing, withdrawal, ignoring, and negative religious coping predicted worse outcomes, whereas positive refocusing, seeking distraction, and social support were effective. These results held controlling for demographics. These results suggest that UK CSAM police officers and staff experience elevated depression and anxiety, but institutional and interpersonal support can buffer outcomes. [ABSTRACT FROM AUTHOR]

Bone-anchored percutaneous implants, commonly referred to as osseointegrated implants, are gaining popularity as an alternative to sockets for attaching a prosthetic limb to an amputated femur. While these implants have several advantages, femoral fractures are relatively common in these patients, occurring in 6.3% of femurs within 4 years. This study aimed to develop a novel method to quantify femoral strength under all possible external loads acting on the distal implant. Finite element analysis was used to explore combinations of forces and moments that, when applied on the bone-anchored implant, were just sufficient to fracture the femur. The 6-dimensional envelope generated in the current study provided a quantitative description of the strength of the femur-implant construct. All the femoral fractures were predicted in the trochanteric region, corresponding to where most in vivo fractures have been reported. The 6-dimensional envelopes developed in the current study may be useful in the design of fail-safe devices that could reduce femoral fractures in patients with bone-anchored percutaneous femoral implants. The framework presented may also be used for determining patient suitability for bone-anchored percutaneous implants, and for evaluating the functional performance of implant designs. [ABSTRACT FROM AUTHOR]

Background Following endoscopic retrograde cholangiopancreatography (ERCP), post-ERCP pancreatitis (PEP) is the most common complication. The host's innate immune response to periprocedural pancreatic injury is the hallmark of its pathogenesis. Investigating cytokine signatures associated with PEP and its risk factors can guide understanding of PEP immunopathogenesis. Methods We conducted a single-center, prospective, observational pilot study in adults at high-risk for PEP. Seven serum cytokines relevant to early acute pancreatitis pathogenesis, angiopoietin-2, hepatocyte growth factor (HGF), interleukin-6 (IL-6), IL-8, monocyte chemotactic protein-1, resistin, and soluble tumor necrosis factor-a receptor 1, were measured in sera collected 2 h pre- and post-ERCP. Levels were compared among healthy controls and ERCP participants who either did or did not develop PEP. Heat maps were constructed to perform a multidimensional exploratory analysis that aimed to determine the cytokine signatures associated with PEP and its participant-related risk factors (female sex, young age, and obesity). Results A total of 65 participants were enrolled (36 undergoing ERCP and 29 healthy controls). Eight of the 36 (22.2%) ERCP participants developed PEP. Baseline IL-8 levels measured before ERCP were elevated in participants who developed PEP (7.5 vs. 14.8 pg/mL, P=0.02), and most strongly upregulated in women under 40 years of age. HGF levels post-ERCP were higher in participants with PEP (738.0 vs. 556.6 pg/mL, P=0.04), and most strongly upregulated in obese participants. Conclusions Pre-ERCP IL-8 and post-ERCP HGF are associated with the development of PEP. Findings from this pilot study can inform the design of translational work in the immunopathogenesis of PEP. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to theoretically hypothesize and empirically examine the impact of economic policy uncertainty (EPU) on firms' innovation performance as well as the contingency conditions of this relationship. Design/methodology/approach: This study collects and combines secondary longitudinal data from multiple sources to test for a direct impact of EPU on firms' innovation performance. It further examines the moderating effects of firms' operational and marketing capabilities. A series of robustness checks are performed to ensure the consistency of the findings. Findings: In contrast to the common belief that EPU reduces the innovativeness of firms, the authors find an inverted-U relationship between EPU and innovation performance, indicating that a moderate level of EPU actually promotes innovation. Further analysis suggests that firms' operational and marketing capabilities make the inverted-U relationship steeper, further enhancing firms' innovation performance at a moderate level of EPU. Originality/value: This study adds to the emerging literature that investigates the operational implications of EPU, which enhances our understanding of the potential bright side of EPU and broadens the scope of operational risk management. [ABSTRACT FROM AUTHOR]

Metastasis and recurrence are the main challenges in cancer treatment. Among various therapeutic approaches, immunotherapy holds promise for preventing metastasis and recurrence. In this study, we evaluated the efficacy of treating primary cancer and blocking metastasis and recurrence with photo-immunotherapeutic nanoparticles, which were synthesized using two types of charged polysaccharides. Codium fragile polysaccharide (CFP), which exhibits immune-stimulating properties and carries a negative charge, was combined with positively charged chitosan to synthesize nanoparticles. Additionally, indocyanine green (ICG), a photosensitizer, was loaded inside these particles and was referred to as chitosan-CFP-ICG (CC-ICG). Murine colon cancer cells (CT-26) internalized CC-ICG, and subsequent 808-nanometer laser irradiation promoted apoptotic/necrotic cell death. Moreover, intratumoral injection of CC-ICG, with 808-nanometer laser irradiation eliminated CT-26 tumors in mice. Rechallenged lung metastases of CT-26 cancer were inhibited by dendritic cell activation-mediated cytotoxic T lymphocyte stimulation in mice cured by CC-ICG. These results demonstrated that CC-ICG is a natural tumor therapeutic with the potential to treat primary tumors and suppress metastasis and recurrence. [ABSTRACT FROM AUTHOR]

Cytokines operate in concert to maintain immune homeostasis and coordinate immune responses. In cases of ER+ breast cancer, peripheral immune cells exhibit altered responses to several cytokines, and these alterations are correlated strongly with patient outcomes. To develop a systems-level understanding of this dysregulation, we measured a panel of cytokine responses and receptor abundances in the peripheral blood of healthy controls and ER+ breast cancer patients across immune cell types. Using tensor factorization to model this multidimensional data, we found that breast cancer patients exhibited widespread alterations in response, including drastically reduced response to IL-10 and heightened basal levels of pSmad2/3 and pSTAT4. ER+ patients also featured upregulation of PD-L1, IL6Rα, and IL2Rα, among other receptors. Despite this, alterations in response to cytokines were not explained by changes in receptor abundances. Thus, tensor factorization helped to reveal a coordinated reprogramming of the immune system that was consistent across our cohort. [ABSTRACT FROM AUTHOR]

Electric vehicles (EVs) continue to evolve, and sales continue to increase as the world pushes toward improved sustainability. This drives the need for research to understand the unique environments in which fluids operate within the Electric Drive Units (EDUs) of EVs in order to improve durability and reduce frictional losses. However, for this to happen, test rigs are required to operate with an electric current passing across the test parts and through the lubricant. Very few electrified test rigs currently exist, with most being adaptations of rigs undertaken by academia and independent and national research labs. In this work, the PCS Mini Traction Machine (MTM) was modified to supply a voltage across a tribological contact. New parts for the MTM were designed in collaboration with the instrument manufacturer. Work was undertaken in both the author's labs and the manufacturer's labs with the aim of bringing a commercially available unit to market as quickly as possible. A test matrix was completed on the MTM utilizing a range of temperatures, loads, and voltage inputs for three different lubricants commonly used in EDUs. The test matrix consisted of 36 test conditions, with some runs performed in triplicate, resulting in 81 tests for each oil and a total matrix of 243 tests. The test matrix was run to obtain the results and to test the robustness of the rig design. After testing was completed, the MTM disc wear scars were measured. The results from these measurements indicate that the application of alternating current (AC) and direct current (DC) causes a significant increase in the wear scar compared to non-electrified test conditions. This, in turn, results in increased traction values under non-electrified conditions. It was also noted that the repeatability of the traction curves and end-of-test wear was reduced under both AC and DC electrified conditions. [ABSTRACT FROM AUTHOR]

Revision total hip arthroplasty (rTHA) involving acetabular defects is a complex procedure associated with lower rates of success than primary THA. Computational modeling has played a key role in surgical planning and prediction of postoperative outcomes following primary THA, but modeling applications in rTHA for acetabular defects remain poorly understood. This study aimed to systematically review the use of computational modeling in acetabular defect classification, implant selection and placement, implant design, and postoperative joint functional performance evaluation following rTHA involving acetabular defects. The databases of Web of Science, Scopus, Medline, Embase, Global Health and Central were searched. Fifty‐three relevant articles met the inclusion criteria, and their quality were evaluated using a modified Downs and Black evaluation criteria framework. Manual image segmentation from computed tomography scans, which is time consuming, remains the primary method used to generate 3D models of hip bone; however, statistical shape models, once developed, can be used to estimate pre‐defect anatomy rapidly. Finite element modeling, which has been used to estimate bone stresses and strains, and implant micromotion postoperatively, has played a key role in custom and off‐the‐shelf implant design, mitigation of stress shielding, and prediction of bone remodeling and implant stability. However, model validation is challenging and requires rigorous evaluation and comparison with respect to mid‐ to long‐term clinical outcomes. Development of fast, accurate methods to model acetabular defects, including statistical shape models and artificial neural networks, may ultimately improve uptake of and expand applications in modeling and simulation of rTHA for the research setting and clinic. [ABSTRACT FROM AUTHOR]

With current plans for manned missions to Mars and beyond, the need to better understand, prevent, and counteract the harmful effects of long-duration spaceflight on the body is becoming increasingly important. In this study, an automated heart-on-a-chip platform was flown to the International Space Station on a 1-mo mission during which contractile cardiac function was monitored in real-time. Upon return to Earth, engineered human heart tissues (EHTs) were further analyzed with ultrastructural imaging and RNA sequencing to investigate the impact of prolonged microgravity on cardiomyocyte function and health. Spaceflight EHTs exhibited significantly reduced twitch forces, increased incidences of arrhythmias, and increased signs of sarcomere disruption and mitochondrial damage. Transcriptomic analyses showed an up-regulation of genes and pathways associated with metabolic disorders, heart failure, oxidative stress, and inflammation, while genes related to contractility and calcium signaling showed significant down-regulation. Finally, in silico modeling revealed a potential link between oxidative stress and mitochondrial dysfunction that corresponded with RNA sequencing results. This represents an in vitro model to faithfully reproduce the adverse effects of spaceflight on three-dimensional (3D)-engineered heart tissue. [ABSTRACT FROM AUTHOR]

Frequent recurrence and metastasis caused by cancer stem cells (CSCs) are major challenges in lung cancer treatment. Therefore, identifying and characterizing specific CSC targets are crucial for the success of prospective targeted therapies. In this study, it is found that upregulated TOR Signaling Pathway Regulator‐Like (TIPRL) in lung CSCs causes sustained activation of the calcium/calmodulin‐dependent protein kinase kinase 2 (CaMKK2) signaling pathway by binding to CaMKK2, thereby maintaining stemness and survival. CaMKK2‐mediated activation of CaM kinase 4 (CaMK4) leads to phosphorylation of cAMP response element‐binding protein (CREB) at Ser129 and Ser133, which is necessary for its maximum activation and the downstream constitutive expression of its target genes (Bcl2 and HMG20A). TIPRL depletion sensitizes lung CSCs to afatinib‐induced cell death and reduces distal metastasis of lung cancer in vivo. It is determined that CREB activates the transcription of TIPRL in lung CSCs. The positive feedback loop consisting of CREB and TIPRL induces the sustained activation of the CaMKK2‐CaMK4‐CREB axis as a driving force and upregulates the expression of stemness‐ and survival‐related genes, promoting tumorigenesis in patients with lung cancer. Thus, TIPRL and the CaMKK2 signaling axis may be promising targets for overcoming drug resistance and reducing metastasis in lung cancer. [ABSTRACT FROM AUTHOR]

Seaweed extracts, especially fucoidan, are well known for their immune-modulating abilities. In this current study, we extracted fucoidan from Costaria costata, a seaweed commonly found in coastal Asia, and examined its anti-inflammatory effect. Fucoidan was extracted from dried C. costata (FCC) using an alcohol extraction method at an extraction rate of 4.5 ± 0.21%. The extracted FCC comprised the highest proportion of carbohydrates, along with sulfate and uronic acid. The immune regulatory effect of FCC was examined using bone marrow-derived dendritic cells (BMDCs). Pretreatment with FCC dose-dependently decreased the lipopolysaccharide (LPS)-induced upregulation of co-stimulatory molecules and major histocompatibility complex. In addition, FCC prevented morphological changes in LPS-induced BMDCs. Moreover, treatment of LPS-induced BMDCs with FCC suppressed the secretion of pro-inflammatory cytokines. In C57BL/6 mice, oral administration of FCC suppressed LPS-induced lung inflammation, reducing the secretion of pro-inflammatory cytokines in the bronchoalveolar lavage fluid. Finally, the administration of FCC suppressed LPS-induced sepsis. Therefore, FCC could be developed as a health supplement based on the observed anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

The Volkswagen emissions scandal began in 2015, when the U.S. Environmental Protection Agency announced that diesel cars produced by Volkswagen from 2009 through 2015 were in violation of emissions standards. The authors analyze the impact of this announcement on transaction prices for Volkswagen cars on the U.S. eBay Motors. The main focus is on Volkswagen cars other than the 2009–2015 diesel models—namely, vehicles that did not violate agency standards, enabling an assessment of whether the negative shock received by the emissions standards violators spilled over to other Volkswagen models that were in compliance. The difference-in-differences results show that final bid prices declined after the announcement by 14% for nonviolating diesel cars and 9% for nonviolating gasoline cars. The analysis also provides little evidence of considerable changes in the numbers of participating bidders, bidding strategies, numbers of listings, and reserve-price strategies, suggesting that the drops in prices likely resulted from lowered willingness to pay from buyers. [ABSTRACT FROM AUTHOR]

Background/Objectives: Germline genetic testing is recommended for younger patients with idiopathic pancreatitis but there has been a lack of consensus in recommendations for those over age 35. We aimed to analyze the results of genetic testing among subjects of varying ages. Methods: Individuals who underwent germline multigene testing for pancreatitis susceptibility genes (CASR, CFTR, CPA1, CTRC, PRSS1, SPINK1) through a large commercial laboratory between 2017 and 2022 were included. Test results and information collected from test requisition forms were evaluated. Multivariable logistic regression models were performed to identify factors associated with a positive pancreatitis panel (pathogenic, likely pathogenic, and/or increased risk variants) in pancreatitis-related genes. Results: Overall, 2,468 subjects with primary indication of acute pancreatitis (AP) (n = 401), chronic pancreatitis (CP) (n = 631), pancreatic cancer (n = 128), or other indications (n = 1,308) completed germline testing. Among patients with AP or CP, the prevalence of any positive result for those <35 versus ≥35 years of age was 32.1% and 24.5% (p = 0.007), and the prevalence of a clinically meaningful result was 10.8% and 5.4%, respectively (p = 0.001). Positive family history of pancreatitis was associated with increased odds ratio (OR) of 8.59 (95% confidence interval (CI) 2.92–25.25) for a clinically significant panel result while each 5-year increase in age at test completion had lower odds (OR 0.89, 95% CI 0.83–0.95). Conclusions: The highest prevalence of pathogenic variants is seen in younger individuals with a positive family history of pancreatitis. However, clinically meaningful results are identified in older subjects, suggesting that genetic counseling and testing should be considered for all age groups. [ABSTRACT FROM AUTHOR]

The columnar grains in additively manufactured alloys increase the tendency to form solidification cracks and cause anisotropy. Studying the effect of process parameters on microstructure development helps to guide the manufacturing of the equiaxed grain microstructure. First, the effect of process conditions on the melt pool dimensions using in situ synchrotron X‐ray imaging and thermal profile and solidification condition using finite element simulation and calculation of thermodynamics phase diagrams of CrMnFeCoNi high‐entropy alloy fabricated by directed energy deposition is studied. Increasing the laser power reduces the thermal gradient to solidification rate ratio, pushing the solidification closer to the columnar‐equiaxed transition. Nevertheless, the simulations still indicate the columnar microstructure for all scan conditions in contrast to the experimental observation that shows single‐wall samples built at 200 W consisted of dominantly equiaxed grains, whereas columnar grains are dominant in samples built at 100 W. It is believed that in addition to the effect of thermal gradient and solidification rate, the chemical segregation (Mn and Ni) during solidification may promote dendrite detachment, hence assisting the transition to equiaxed grains. The multitrack deposition results in more solid beneath a new melt pool, increasing the thermal gradient that promotes more columnar grains in comparison to single tracks. [ABSTRACT FROM AUTHOR]

Clinical decision-making for individuals with 46,XY disorders/differences of sex development (DSD) remains unsettled and controversial. The North American DSD Clinician Survey examines the recommendations of a large group of clinical specialists over the last two decades. Active members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology were invited to respond to a web-based survey at three different timepoints: 2003–2004 (T1), 2010–2011 (T2), and 2019–2020 (T3). Data from 429 participants in T1, 435 in T2, and 264 in T3 were included in this study. The participants were presented with three XY newborn clinical case scenarios—micropenis, partial androgen insensitivity syndrome, and iatrogenic penile ablation—and asked for clinical management recommendations. The main outcomes assessed included the recommended gender of rearing, surgical decision-maker (parent or patient), timing of genital surgery, and age at which to disclose medical details and surgical history to the patient. For all scenarios, the overwhelming majority recommended rearing as male, including a significant increase across timepoints in those recommending a male gender of rearing for the infant with penile ablation. The proportions recommending female gender of rearing declined significantly across timepoints. In general, most recommended parents (in consultation with the physician) serve as surgical decision-makers, but these proportions declined significantly across timepoints. Recommendations on the timing of surgery varied based on the patient's gender and type of surgery. There has been a shift in recommendations away from the "optimal gender policy" regarding gender of rearing and surgical interventions for patients with XY DSD. [ABSTRACT FROM AUTHOR]

Background: Cancer cells in severely hypoxic regions have been reported to invade towards tumour blood vessels after surviving radiotherapy in a postirradiation reoxygenation- and hypoxia-inducible factor (HIF)-dependent manner and cause recurrence. However, how HIF induces invasiveness of irradiated and reoxygenated cancer cells remains unclear. Methods: Here, we identified human minor histocompatibility antigen 1 (HMHA1), which has been suggested to function in cytoskeleton dynamics and cellular motility, as a responsible factor and elucidated its mechanism of action using molecular and cellular biology techniques. Results: HMHA1 expression was found to be induced at the transcription initiation level in a HIF-dependent manner under hypoxia. Boyden chamber invasion assay revealed that the induction of HMHA1 expression is required for the increase in invasion of hypoxic cancer cells. Reoxygenation treatment after ionising radiation in vitro that mimics dynamic changes of a microenvironment in hypoxic regions of tumour tissues after radiation therapy further enhanced HMHA1 expression and invasive potential of HMHA1 wildtype cancer cells in ROS- and HIF-dependent manners, but not of HMHA1 knockout cells. Conclusion: These results together provide insights into a potential molecular mechanism of the acquisition of invasiveness by hypoxic cancer cells after radiotherapy via the activation of the ROS/HIF/HMHA1 axis. [ABSTRACT FROM AUTHOR]

The glucagon-like peptide-1 receptor (GLP-1R) agonists reduce glycated hemoglobin in patients with type 2 diabetes. Mounting evidence indicates that the potential of GLP-1R agonists, mimicking a 30 amino acid ligand, GLP-1, extends to the treatment of neurodegenerative conditions, with a particular focus on Alzheimer's disease (AD). However, the mechanism that underlies regulation of GLP-1R availability in the brain with AD remains poorly understood. Here, using whole transcriptome RNA-Seq of the human postmortem caudate nucleus with AD and chronic hydrocephalus (CH) in the elderly, we found that GLP-1R and select mRNAs expressed in glucose dysmetabolism and dyslipidemia were significantly altered. Furthermore, we detected human RNA indicating a deficiency in doublecortin (DCX) levels and the presence of ferroptosis in the caudate nucleus impacted by AD. Using the genome data viewer, we assessed mutability of GLP-1R and 39 other genes by two factors associated with high mutation rates in chromosomes of four species. Surprisingly, we identified that nucleotide sizes of GLP-1R transcript exceptionally differed in all four species of humans, chimpanzees, rats, and mice by up to 6-fold. Taken together, the protein network database analysis suggests that reduced GLP-1R in the aged human brain is associated with glucose dysmetabolism, ferroptosis, and reduced DCX+ neurons, that may contribute to AD. [ABSTRACT FROM AUTHOR]

Background: The Royal Prince Alfred Hospital (RPAH) and Chris O'Brien Lifehouse (COBLH) established a formal Sarcoma of the Pelvic and Abdominal Retroperitoneum Collaboration (SPARC) in November 2020. An established multidisciplinary team (MDT) with the aims to centralise patient referrals and treatment, establish database and research, coordinate surgical resections is critical in improving patient outcomes and quality of life. Methods: A prospective database was established in October 2021. Clinical, pathological and radiological data points were recorded for all patients since the inception of SPARC. Quality of Life questionnaires were included and follow‐up planned regularly for 5 years. Results: From November 2020 to Feb 2024, 294 new referrals were discussed at the MDT meeting. Majority were from the metropolitan area (182) followed by regional NSW (87), interstate (20) and five internationals. 141 operations were performed during this period compared to 119 operations from 2010 to November 2020 in RPAH. The inception of the SPARC program has resulted in exponential growth in operations, improving from the previous rate of 15 cases annually to 35. Liposarcomas followed by leiomyosarcomas are the most common types of sarcomas resected. The majority were extended resections (81.6%) and 22% were pelvic exenterations. Overall R0 rate is 54.6%, R1 38.3% and R2 1.4% (131 (92.9%) had R0/R1 resections. Overall complication rate is 35.5% with one in‐hospital mortality. Conclusion: Success and expansion of a robust retroperitoneal sarcoma program requires a collaborative surgical approach, an MDT meeting, centralized referral process, and a research team in specialized tertiary institutions. [ABSTRACT FROM AUTHOR]

Background: Internet-based parental programmes may improve parental wellbeing and mitigate the burden of mental health issues during the perinatal period. However, few studies have explored the cost and clinical impacts of such interventions. In the present study, we sought to evaluate the cost-effectiveness associated with an online cognitive behaviour therapy intervention (Baby Steps Wellbeing) to an information-only programme (Baby Care). Methods: An alongside-trial cost-effectiveness analysis was undertaken using data from a randomised clinical trial comparing the Baby Steps Wellbeing intervention to Baby Care. Direct healthcare costs, as well as indirect costs attributed to income loss, were considered. The Assessment of Quality of Life-8 Dimensions multi-attribute utility instrument was used to estimate participant utilities, and subsequently calculate quality-adjusted life years (QALYs). Incremental cost-effectiveness ratios were calculated to assess the cost-effectiveness of the intervention. The economic evaluation adopted a societal perspective. Results: In total, 496 parents were randomised to either the Baby Steps Wellbeing intervention or the Baby Care control arm. No significant differences in costs (−$27, 95% confidence interval (CI): −$1189–$1134) or QALYs (0.051, 95% CI: −0.097–0.200) were identified. Bootstrapped results showed that the Baby Steps Wellbeing programme was cost-saving and health improving in 38% of simulations and cost-effective in another 37% of simulations. Conclusions: The Baby Steps Wellbeing programme was slightly cost-saving with slightly improved health outcomes compared with Baby Care. Bootstrapped results indicate the Baby Steps Wellbeing was cost-effective in 75% of simulations. Overall, the Baby Steps Wellbeing programme is an online programme that is cost-effective. Trial registration: Australian & New Zealand Clinical Trials Registry: ANZCTR12614001256662. [ABSTRACT FROM AUTHOR]

The glucagon-like peptide-1 receptor (GLP-1R) agonists reduce glycated hemoglobin in patients with type 2 diabetes. Mounting evidence indicates that the potential of GLP-1R agonists, mimicking a 30 amino acid ligand, GLP-1, extends to the treatment of neurodegenerative conditions, with a particular focus on Alzheimer's disease (AD). However, the mechanism that underlies regulation of GLP-1R availability in the brain with AD remains poorly understood. Here, using whole transcriptome RNA-Seq of the human postmortem caudate nucleus with AD and chronic hydrocephalus (CH) in the elderly, we found that GLP-1R and select mRNAs expressed in glucose dysmetabolism and dyslipidemia were significantly altered. Furthermore, we detected human RNA indicating a deficiency in doublecortin (DCX) levels and the presence of ferroptosis in the caudate nucleus impacted by AD. Using the genome data viewer, we assessed mutability of GLP-1R and 39 other genes by two factors associated with high mutation rates in chromosomes of four species. Surprisingly, we identified that nucleotide sizes of GLP-1R transcript exceptionally differed in all four species of humans, chimpanzees, rats, and mice by up to 6-fold. Taken together, the protein network database analysis suggests that reduced GLP-1R in the aged human brain is associated with glucose dysmetabolism, ferroptosis, and reduced DCX+ neurons, that may contribute to AD. [ABSTRACT FROM AUTHOR]

Purpose: Despite lung cancer is one of the leading causes of cancer-related deaths, it remains hard to discover effective diagnostic and therapeutic approaches. Moreover, the five-year survival rate is relatively lower than other tumors. So urgent needs for finding a new theranostic target to treat lung cancer effectively. This study aims to present SOCS3 and NOD2 proteins as novel targets for diagnosis and therapy. Methods: We first confirmed SOCS3 expression level in patients' tissues. Then, we applied knockdown and overexpression of SOCS3 on lung cancer cell lines and performed proliferation, migration, and invasion assay. After that, we found NOD2 is a target of SOCS3 and introduced overexpression of NOD2 to A549 for verifying reduced tumorigenicity of lung cancer cells. Results: We identified protein expression level of SOCS3 was frequently higher in tumor tissues than adjacent normal tissues. Truly, overexpression of SOCS3 promoted proliferation, migration, and invasion capacity of lung cancer cells. We found that SOCS3 interacts with NOD2 and SOCS3 ubiquitinates NOD2 directly. Furthermore, lung cancer tissues with higher SOCS3 expression showed lower NOD2 expression. We confirmed overexpression of NOD2 leads to suppressed tumorigenicity of lung cancer cells, and these effects occurred through MAPK pathway. Conclusion: Collectively, our work reveals novel roles of SOCS3 in lung tumorigenesis and proposes SOCS3 as a promising biomarker candidate for therapeutic and diagnostic target for lung cancer. [ABSTRACT FROM AUTHOR]

Extracorporeal shock wave lithotripsy (ESWL) is used for the treatment of pancreatic duct stones (PDS) in patients with chronic pancreatitis (CP). We aimed to develop a CT based index to predict the required number of ESWL sessions for technical success. We retrospectively evaluated patients with PDS secondary to CP who underwent ESWL. Technical success was defined as the complete fragmentation of stones to <3 mm. CT features including PDS size, number, location, and density in Hounsfield units (HU) were noted. We analyzed the relationship between PDS characteristics and the number of ESWL sessions required for technical success. A multiple linear regression model was used to combine size and density into the pancreatic duct stone (PDS) index that was translated into a web-based calculator. There were 206 subjects (mean age 38.6 ± 13.7 years, 59.2% male) who underwent ESWL. PDS size showed a moderate correlation with the number of ESWL sessions (r = 0.42, p < 0.01). PDS in the head required a fewer number of sessions in comparison to those in the body (1.4 ± 0.6 vs. 1.6 ± 0.7, p = 0.01). There was a strong correlation between PDS density and the number of ESWL sessions (r = 0.617, p-value <0.01). The PDS index {0.3793 + [0.0009755 x PDS density (HU)] + [0.02549 x PDS size (mm)]} could accurately predict the required number of ESWL sessions with an AUC of 0.872 (p < 0.01). The PDS index is a useful predictor of the number of ESWL sessions needed for technical success that can help in planning and patient counseling. [ABSTRACT FROM AUTHOR]

Exocrine pancreatic dysfunction (EPD) is a malabsorptive complication of pancreatic disorders that can lead to a host of symptoms ranging from flatulence to diarrhea and contribute to weight loss and metabolic bone disease. It is increasingly recognized to occur after acute pancreatitis (AP), including episodes with mild severity. The risk of developing EPD after AP is influenced by a range of factors, including the degree of acinar cell destruction and inflammation during AP, and persistent structural derangements following AP. In this article, we discuss the epidemiology, pathophysiology, and clinical management of EPD after AP while highlighting key knowledge gaps. [ABSTRACT FROM AUTHOR]

A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment. [ABSTRACT FROM AUTHOR]

46,XX individuals born with severely masculinized genitals due to congenital adrenal hyperplasia (CAH) who have been assigned male at birth and reared male can successfully establish a male gender identity/role, find employment, marry, function sexually with a female partner, and develop positive mental health status. While there were a few individuals who reportedly did not fare well or who changed gender to female, the majority of those identifying as males appear to have an overall good quality of life. Parental/family support, along with the support of others, appears essential to a positive outcome as a male, or as a female. This paper suggests that serious consideration should be given to male gender assignment and rearing and, in certain situations, is justified. Disorders of sex differentiation teams should inform parents about the option for male assignment and rearing in 46,XX CAH infants with severe genital masculinization, which is a rare condition. To provide this option is concordant with the principles of ethics, transparency and with the Endocrine Society Guidelines and the American Academy of Pediatrics’ policy of fully informed consent. [ABSTRACT FROM AUTHOR]

Total temporomandibular joint replacement (TMJR) surgery is the established treatment for severe temporomandibular joint disorders. While TMJR surgery is known to increase mouth-opening capacity, reduce pain and improve quality of life, little is known about post-surgical jaw function during activities of daily living such as biting and chewing. The aim of this study was to use subject-specific 3D bite force measurements to evaluate the magnitude and direction of joint loading in unilateral total TMJR patients and compare these data to those in healthy control subjects. An optoelectronic tracking system was used to measure jaw kinematics while biting a rubber sample for 5 unilateral total TMJR patients and 8 controls. Finite element simulations driven by the measured kinematics were employed to calculate the resultant bite force generated when compressing the rubber between teeth during biting tasks. Subject-specific musculoskeletal models were subsequently used to calculate muscle and TMJ loading. Unilateral total TMJR patients generated a bite force of 249.6 ± 24.4 N and 164.2 ± 62.3 N when biting on the contralateral and ipsilateral molars, respectively. In contrast, controls generated a bite force of 317.1 ± 206.6 N. Unilateral total TMJR patients biting on the contralateral molars had a significantly higher lateral TMJ force direction (median difference: 63.6°, p = 0.028) and a significantly lower ratio of working TMJ force to bite force (median difference: 0.17, p = 0.049) than controls. Results of this study may guide TMJ prosthesis design and evaluation of dental implants. [ABSTRACT FROM AUTHOR]

To understand possible predictors of the onset of menses after gonadotropin-releasing hormone agonist treatment cessation in girls with central precocious puberty (CPP). This exploratory post hoc analysis of a phase 3 and 4 trial of girls with CPP treated with once-monthly intramuscular leuprolide acetate examined onset of menses after treatment completion using a time-to-event analysis. Pretreatment and end-of-treatment chronologic age (CA), bone age (BA)/CA ratio, and Tanner breast stage; pretreatment menses status; and end-of-treatment BA and body mass index (BMI) were studied as potential factors influencing the onset of menses. Median time to first menses after stopping treatment was 18.3 months among 35 girls (mean age at onset of treatment, 6.8 years) examined. Of 26 girls experiencing menses, 11 (42 %) menstruated at 16–21 months after stopping treatment. Most girls with pretreatment BA/CA≥1.4 started menstruating very close to 18 months after stopping treatment; those with less advanced BA/CA experienced menses at 9–18 months. End-of-treatment BA/CA≥1.2 was associated with a quicker onset of menses (14.5 vs. 18.5 months for BA/CA<1.2, p=0.006). End-of-treatment BA≥12 years predicted longer time to menses. No relationship with time to menses was observed for pretreatment menarche status, pretreatment or end-of-treatment Tanner breast stage (<3/≥3) or CA (<6/≥6 or ≤11/>11), or end-of-treatment BMI percentiles (<85.6/≥85.6 and <92.6/≥92.6). Pretreatment menarche status or CA do not appear to predict onset of menses, but pre- and end-of-treatment BA/CA may be helpful in anticipating time to first menses after stopping treatment. [ABSTRACT FROM AUTHOR]

Several aspects of clinical management of 46,XX congenital adrenal hyperplasia (CAH) remain unsettled and controversial. The North American Disorders/Differences of Sex Development (DSD) Clinician Survey investigated changes, over the last two decades, in clinical recommendations by specialists involved in the management of newborns with DSD. Members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology participated in a web-based survey at three timepoints: 2003–2004 (T1, n = 432), 2010–2011 (T2, n = 441), and 2020 (T3, n = 272). Participants were presented with two clinical case scenarios—newborns with 46,XX CAH and either mild-to-moderate or severe genital masculinization—and asked for clinical recommendations. Across timepoints, most participants recommended rearing the newborn as a girl, that parents (in consultation with physicians) should make surgical decisions, performing early genitoplasty, and disclosing surgical history at younger ages. Several trends were identified: a small, but significant shift toward recommending a gender other than girl; recommending that adolescent patients serve as the genital surgery decision maker; performing genital surgery at later ages; and disclosing surgical details at younger ages. This is the first study assessing physician recommendations across two decades. Despite variability in the recommendations, most experts followed CAH clinical practice guidelines. The observation that some of the emerging trends do not align with expert opinion or empirical evidence should serve as both a cautionary note and a call for prospective studies examining patient outcomes associated with these changes. [ABSTRACT FROM AUTHOR]

Improving the scalability of tissue imaging throughput with bright, coherent X-rays requires identifying and mitigating artifacts resulting from the interactions between X-rays and matter. At synchrotron sources, long-term imaging of soft tissues in solution can result in gas bubble formation or cavitation, which dramatically compromises image quality and integrity of the samples. By combining in-line phase-contrast imaging with gas chromatography in real time, we were able to track the onset and evolution of high-energy X-ray-induced gas bubbles in ethanol-embedded soft tissue samples for tens of minutes (two to three times the typical scan times). We demonstrate quantitatively that vacuum degassing of the sample during preparation can significantly delay bubble formation, offering up to a twofold improvement in dose tolerance, depending on the tissue type. However, once nucleated, bubble growth is faster in degassed than undegassed samples, indicating their distinct metastable states at bubble onset. Gas chromatography analysis shows increased solvent vaporization concurrent with bubble formation, yet the quantities of dissolved gasses remain unchanged. By coupling features extracted from the radiographs with computational analysis of bubble characteristics, we uncover dose-controlled kinetics and nucleation site-specific growth. These hallmark signatures provide quantitative constraints on the driving mechanisms of bubble formation and growth. Overall, the observations highlight bubble formation as a critical yet often overlooked hurdle in upscaling X-ray imaging for biological tissues and soft materials and we offer an empirical foundation for their understanding and imaging protocol optimization. More importantly, our approaches establish a top-down scheme to decipher the complex, multiscale radiation-matter interactions in these applications. [ABSTRACT FROM AUTHOR]

Simple Summary: In solid tumors, oxygen concentration varies between different regions. Generally, while oxygen supply is sufficient in the vicinity of blood vessels, the concentration of oxygen gradually drops as the distance from the blood vessel increases. In the regions with low oxygen content (hypoxic regions), cancer cells acquire various malignant properties, like invasiveness, altered metabolism, and therapy resistance, leading to recurrence and poor clinical outcomes of patients. Hypoxia-inducible factor (HIF) is a major regulator of hypoxia responses. Herein, we summarized how tumor hypoxia activates different mechanisms, in both HIF-dependent and HIF-independent manners, and contributes to the acquisition of chemotherapy resistance. We also discussed the involvement of epigenetic regulation in hypoxia-induced chemoresistance, with a specific example of ATAD2 protein degradation inducing drug resistance under hypoxia. Finally, we briefly reviewed some current clinical trials that target HIF and tumor hypoxia for cancer treatment or therapy sensitization. In hypoxic regions of malignant solid tumors, cancer cells acquire resistance to conventional therapies, such as chemotherapy and radiotherapy, causing poor prognosis in patients with cancer. It is widely recognized that some of the key genes behind this are hypoxia-inducible transcription factors, e.g., hypoxia-inducible factor 1 (HIF-1). Since HIF-1 activity is suppressed by two representative 2-oxoglutarate-dependent dioxygenases (2-OGDDs), PHDs (prolyl-4-hydroxylases), and FIH-1 (factor inhibiting hypoxia-inducible factor 1), the inactivation of 2-OGDD has been associated with cancer therapy resistance by the activation of HIF-1. Recent studies have also revealed the importance of hypoxia-responsive mechanisms independent of HIF-1 and its isoforms (collectively, HIFs). In this article, we collate the accumulated knowledge of HIF-1-dependent and independent mechanisms responsible for resistance of hypoxic cancer cells to anticancer drugs and briefly discuss the interplay between hypoxia responses, like EMT and UPR, and chemoresistance. In addition, we introduce a novel HIF-independent mechanism, which is epigenetically mediated by an acetylated histone reader protein, ATAD2, which we recently clarified. [ABSTRACT FROM AUTHOR]

Objective: To compare perioperative morbidity, functional and quality‐of‐life (QoL) outcomes in patients with partial cystectomy vs radical cystectomy as part of pelvic exenteration. Patients and Methods: Retrospective analysis of a prospectively maintained database of pelvic exenteration patients (1998–2021) was conducted in a single centre. Study outcomes included postoperative complications, quality‐of‐life, functional and stoma‐related outcomes. The 36‐item Short‐Form Health Survey Physical and Mental Health Components, Functional Assessment of Cancer Therapy‐Colorectal questionnaires and Distress Thermometer were available pre‐ and postoperatively. QoL outcomes were compared at the various time points. Stoma embarrassment and care scores were compared between patients with a colostomy, urostomy, and both. Results: Urological complications were similar between both groups, but patients with partial cystectomy experienced less wound‐related complications. Overall, 34/81 (42%) partial cystectomy patients reported one or more long‐term voiding complication (i.e., incontinence [17 patients], frequency [six], retention [three], high post‐voiding residuals [10], permanent suprapubic catheter/indwelling catheter [14], recurrent urinary tract infection [nine], percutaneous nephrostomy [three], progression to urostomy [three]). The QoL improved following surgery in both the partial and radical cystectomy groups, differences between cohorts were not significant. Patients with two stomas reported higher embarrassment scores than patients with one stoma, although this did not result in more difficulties in stoma care. Conclusions: Partial cystectomy patients have fewer postoperative wound‐related complications than radical cystectomy patients, but often experience long‐term voiding issues. The QoL outcomes are similar for both cohorts, with significant improvement following surgery. [ABSTRACT FROM AUTHOR]

While modern science and technology have produced astounding advances, their contributions to social welfare often fall short of expectations. This Article provides a holistic framework for promoting "socially responsive" innovation that increases the social benefits, decreases the social harms, and improves the distributional effects of massive investments in science and technology. Traditionally, policymakers have relied significantly on centralized governance regimes such as mission-based science funding and technological regulation to guide the development and use of new innovations. While valuable, centralized approaches feature several shortcomings, and this Article proposes a distributed model of innovation governance to supplement them. In so doing, it draws on the CHIPS and Science Act of 2022, which bolstered the National Science Foundation's longstanding practice of considering the broader social impacts of proposed research projects when awarding research grants. Building on these reforms, this Article proposes a model of distributed innovation governance that extends beyond central policymakers to confer greater authority to promote socially responsive innovation on a wide range of public and private stakeholders, peer reviewers, scientists, and engineers. This Article argues for orienting various innovation gatekeepers--including federal funding agencies, scientific journals and conferences, and the Patent and Trademark Office--toward considering the broader social impacts (not just technical merit) of innovative projects when awarding key resources. By tying research funds, publication and presentation opportunities, and patents to assessments of social impact, this proposal creates a powerful incentive for scientists and inventors to consider and improve the contributions of their work to social welfare. This Article shows how government action can shift norms in the innovative community--including among private actors--to embrace socially responsive science and technology. This distributed governance model offers several benefits, including preserving scientific autonomy, guarding against the overpoliticization of innovation policy, and exploiting significant amounts of private information distributed among scientists and engineers. [ABSTRACT FROM AUTHOR]

Background: Day‐only emergency surgery for abscess drainage is poorly implemented in Australia. This study assessed the feasibility, outcomes, cost, and impact of an acute day‐only surgery (ADOS) program. Method: A retrospective pre‐post implementation study of patients requiring abscess drainage in theatre was performed. Following implementation of an ADOS program for abscess management, eligible patients were discharged from the emergency department and prioritized first on the following day's emergency list. Outcomes from the first 12 months of the ADOS era were compared with those of the preceding 6 months (pre‐ADOS). Primary outcome was length of hospital stay (LOS). Secondary outcomes included 30‐day complications, admission costs, and impact on overall emergency theatre workflow (measured by emergency appendicectomy metrics). Results: Overall, 266 patients during the ADOS era (including 95 eligible for the ADOS pathway) were compared with 115 patients during the pre‐ADOS era. Baseline characteristics were comparable. Median LOS was shorter during the ADOS era (21.9 h (IQR 11.8–43.3) vs. 30.1 h (IQR 24.7–48.8), P < 0.001). Median LOS was 10.2 h (IQR 8.9–13.1) for patients on the ADOS pathway. There were no significant differences in 30‐day complications (9.3% vs. 9.5%), emergency department re‐presentations (7.4% vs. 5.1%), or abscess recurrence (5.6% vs. 5.7%). Average cost per patient was lower during the ADOS era ($4155 vs. $4916, p = 0.005). ADOS did not appear to materially impact other emergency procedures. Conclusion: ADOS for abscess drainage is feasible, safe, and produces cost savings, while being implemented without significant additional resources. [ABSTRACT FROM AUTHOR]

The article discusses the Peri-interventional Outcome Study in the Elderly (POSE), a research project conducted across Europe to assess the mortality rates and outcomes of elderly patients undergoing anesthesia. The study involved 9497 patients aged 80 years and older who underwent surgery or nonsurgical interventions. A survey was conducted among participating centers to evaluate the study organization and design. The results showed that most participants learned about the study from colleagues and were motivated to participate due to the study's relevance and their clinical interest in geriatric anesthesia. The survey also provided insights into the duration of assessments, changes in clinical practice, and interest in future studies. The POSE study was considered important for improving the treatment of the elderly population, and the data collected will contribute to future research in the field. [Extracted from the article]

The biology of metastatic breast cancer (MBC) is understudied, primarily due to the difficulty of procuring multiple samples from patients with oligometastatic breast cancer. We developed a rapid postmortem tissue procurement program that allows the collection and analysis of numerous metastatic lesions, subclinical locations, and potential pre-metastatic niches that fall within this scope. We conducted a rapid postmortem tissue collection study on 9 patients with MBC. Patients and their families consented to donate tissues immediately after death in an IRB-approved study. Various disease subtypes, progression histories, organ involvement, and final causes of death are reported. In patients with hormone receptor-positive (HR+) disease, estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 expression were heterogeneous across metastatic lesions within individual patients. Disease phenotype at the end of life trended toward complete loss of HR expression. Nearly all (n = 7) patients exhibited extensive tumor involvement of additional organs that had not been previously diagnosed clinically and were not retrospectively visible on recent imaging. Of these seven individuals, three included organs uncommonly associated with MBC: kidney, spleen, pancreas, and ovary. Finally, we identified clinically undetectable micrometastases in several organs uncommonly involved in MBC. Our findings raise several clinically relevant questions regarding the mechanisms of metastatic progression. Insights from this study argue for better surveillance strategies for monitoring MBC. We highlight the need to capture more accurate biomarker information in the context of heterogeneous disease and urge the consideration of treatment strategies that combine multiple targeted therapies. [ABSTRACT FROM AUTHOR]

A novel large surface area microparticle paclitaxel (LSAM-PTX) has unique properties of long retention in cystic spaces while maintaining high drug concentration. We prospectively evaluated the safety and response of EUS-guided fine needle injection (EUS-FNI) of LSAM-PTX to chemoablate branch duct (BD)-IPMNs. Subjects diagnosed with BD-IPMNs exhibiting at least one worrisome criteria and considered non-surgical were enrolled in a multicenter clinical trial (NCT03188991) and subsequently included in an Expanded Access Protocol (EAP) where they received EUS-FNI of LSAM-PTX (15 mg/mL). Six BD-IPMNs measuring (mean ± SD) 3.18 ± 0.76 cm in diameter among 5 subjects (mean age: 66 years) were treated by EUS-FNI of LSAM-PTX. A mean of 4 doses of LSAM-PTX (mean dose/cyst: 73 ± 31 mg) were administered, and subjects were followed for up to 32 months. The mean volume reduction/cyst ranged from 42 to 89% (9.58 ± 5.1 ml to 2.2 ± 1.1 ml (p = 0.016)). The mean surface area reduction ranged from 31 to 83% (21.9 ± 8.7 cm2 to 5.7 ± 2.5 cm2 (p = 0.009)). Higher dosing-frequency of EUS-FNI of LSAM-PTX significantly correlated with a reduction in cyst volume (R2 = 0.87, p = 0.03) and surface area (R2 = 0.83, p = 0.04). Comparing pre- and post-ablation samples, molecular analysis of the cyst fluid revealed a loss of IPMN-associated mutations in 5 cases (83.3%), while reemergence was observed in 1 case and persistence in 1 case. Intracystic changes (fibrosis/calcification) were observed in 83.3% (n = 5). One subject developed mild acute pancreatitis (1 of 22 EUS-FNIs of LSAM-PTX). In this EAP, EUS-FNI of LSAM-PTX into BD-IPMNs was safe and resulted in volume and surface area reduction, morphological changes, and loss of pathogenic mutations. [ABSTRACT FROM AUTHOR]

Ubiquitin-like modifier-activating enzyme 6 (UBA6) is a member of the E1 enzyme family, which initiates the ubiquitin–proteasome system (UPS). The UPS plays critical roles not only in protein degradation but also in various cellular functions, including neuronal signaling, myocardial remodeling, immune cell differentiation, and cancer development. However, the specific role of UBA6 in cellular functions is not fully elucidated in comparison with the roles of the UPS. It has been known that the E1 enzyme is associated with the motility of cancer cells. In this study, we verified the physiological roles of UBA6 in lung cancer cells through gene-silencing siRNA targeting UBA6 (siUBA6). The siUBA6 treatment attenuated the migration of H1975 cells, along with a decrease in lysosomal Ca2+ release. While autophagosomal proteins remained unchanged, lysosomal proteins, including TRPML1 and TPC2, were decreased in siUBA6-transfected cells. Moreover, siUBA6 induced the production of multivesicular bodies (MVBs), accompanied by an increase in MVB markers in siUBA6-transfected H1975 cells. Additionally, the expression of the exosomal marker CD63 and extracellular vesicles was increased by siUBA6 treatment. Our findings suggest that knock-down of UBA6 induces lysosomal TRPML1 depletion and inhibits endosomal trafficking to lysosome, and subsequently, leads to the accumulation of MVBs and enhanced exosomal secretion in lung cancer cells. [ABSTRACT FROM AUTHOR]