Search

This article reviews the use of subcutaneous insulin for hospitalized patients. Topics include the rationale for using insulin; scheduled insulin therapy to cover basal and nutritional needs; correction therapy; dose determination; establishment of timing of insulin action appropriate to the pattern of carbohydrate exposure; education of caregivers; and the design of hospital systems that will promote quality and help staff to manage complexity. [ABSTRACT FROM AUTHOR]

The portability of non-invasive ultrasound has resulted in an expansion of its utilization into a variety of clinical settings. Since ultrasound is recommended for initial vein cannulation during catheter placement, it is conceivable that ultrasound may also be used to verify catheter position. The purpose of this study was to evaluate the feasibility of tunneled hemodialysis catheter placement without the use of fluoroscopy. Determination of appropriate catheter length using physical exam measurements and verification of correct placement using portable ultrasound were examiner. A total of 61 subjects, 31 with and 30 without a tunneled hemodialysis catheter underwent echocardiographic examination using the SONOSITE 180PLUS (HCU; Bothell, WA) portable ultrasound. The investigator, using dynamic ultrasound imaging, was able to identify correct position in 30 of the 31 subjects with catheters. Still echocardiographic images were reviewed by two cardiologists and determined to be inconclusive. Physical examination measurements correlated well with the interventional radiologist guide-wire measurements (p <.01; r = 0.65) and concluded to be a useful method for determining appropriate cuffed catheter length. [ABSTRACT FROM AUTHOR]

A sample consisting of 689 junior high school rural adolescents was surveyed about their perceptions of being a teen parent and their current sexual behavior. A risk factor analysis also was conducted to determine factors that significantly predict whether adolescents had engaged in sexual intercourse. Results indicate that one in nine adolescents had engaged in sexual intercourse (11%). The risk factor analyses showed that smoking and efficacy expectations of not engaging in sexual intercourse were significant predictors for both genders. For the most part, adolescents responded positively on four constructs: 1) attitudes toward being a teen parent; 2) efficacy expectations of not engaging in sexual intercourse; 3) benefits of being a teen parent; and 4) and barriers to being a teen parent. However, when analyses were conducted for males and females separately, females scored higher on each factor. Overall, results indicate these teens recognized problems that may occur from being a teen parent. [ABSTRACT FROM AUTHOR]

Background: A number of noninvasive alternatives to hysterectomy have become available as treatments for uterine fibroids. These alternative therapies, however, may not relieve all symptoms. Consequently, the need for patient-reported outcomes to assess symptom reduction of uterine fibroids has become increasingly important to evaluate the clinical success of patients who choose these alternative therapies. The purpose of the study was to examine the responsiveness of the Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) with treatment of uterine fibroids.Methods: The responsiveness of the UFS-QOL was assessed as a post-hoc analysis of patients treated with MRI-guided focused ultrasound thermal ablation (MRgFUS) for uterine fibroids. The UFS-QOL and SF-36 were completed at baseline and months 1, 3, and 6. Patient perceived overall treatment effect (OTE) was assessed at month 3, while satisfaction with treatment was collected at month 6. The responsiveness of the UFS-QOL was examined using effect sizes and change scores by patient-reported overall treatment effect and satisfaction.Results: A total of 102 women with complete UFS-QOL data were included in the analysis; the mean age was 45 years and 79% were Caucasian. From baseline to 6 months, significant improvements were observed in UFS-QOL Symptom Severity and all Health-Related Quality of Life (HRQL) subscale scores (p < 0.0001). When examining change in general health status over the 6-month follow-up period, significant improvements were noted in all 8 SF-36 subscales. The UFS-QOL was highly responsive with subscale effect sizes ranging from 0.74 for Sexual Function to -1.9 for Symptom Severity. Improvements in UFS-QOL subscales were associated with patient perceptions of perceived benefit and treatment satisfaction.Conclusion: The UFS-QOL is responsive to treatment for uterine fibroids and is a useful outcome measure for uterine-sparing uterine fibroid treatments. [ABSTRACT FROM AUTHOR]

Late-stage breast cancer metastasis is driven by dysregulated TGF-β signaling, but the underlying molecular mechanisms have not been fully elucidated. We attempted to recapitulate tumor and metastatic microenvironments via the use of biomechanically compliant or rigid 3D organotypic cultures and combined them with global microRNA (miR) profiling analyses to identify miRs that were upregulated in metastatic breast cancer cells by TGF-β. Here we establish miR-181a as a TGF-β-regulated "metastamir" that enhanced the metastatic potential of breast cancers by promoting epithelial-mesenchymal transition, migratory, and invasive phenotypes. Mechanistically, inactivation of miR-181a elevated the expression of the proapoptotic molecule Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a expression was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in human breast cancer patients. Collectively, our findings strongly implicate miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, and consequently, as a potential therapeutic target in metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival., Materials and Methods: InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of melanoma recurrence or relapse. Methylation classes, distinguished by consensus clustering of 850K methylation data, were evaluated for their clinicopathologic characteristics, 5-year survival status, and differentially methylated gene sets., Results: Among 422 InterMEL melanomas, consensus clustering revealed three primary melanoma methylation classes (MethylClasses): a CpG island methylator phenotype (CIMP) class, an intermediate methylation (IM) class, and a low methylation (LM) class. CIMP and IM were associated with higher AJCC stage (both P = .002), Breslow thickness (CIMP P = .002; IM P = .006), and mitotic index (both P < .001) compared with LM, while IM had higher N stage than CIMP ( P = .01) and LM ( P = .007). CIMP and IM had a 2-fold higher likelihood of 5-year death from melanoma than LM (CIMP odds ratio [OR], 2.16 [95% CI, 1.18 to 3.96]; IM OR, 2.00 [95% CI, 1.12 to 3.58]) in a multivariable model adjusted for age, sex, log Breslow thickness, ulceration, mitotic index, and N stage. Despite more extensive CpG island hypermethylation in CIMP, CIMP and IM shared similar patterns of differential methylation and gene set enrichment compared with LM., Conclusion: Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.

Post-traumatic osteoarthritis develops following an inciting injury to a joint and results in cartilage degeneration. Mechanical loading, including articulation, drives anabolic responses in cartilage clinically, in vivo, and in vitro. Tribological articulation, or sliding of cartilage on a glass counterface, has long been used as an in vitro tool to study cartilage tissue behavior. However, it is unclear if tribological articulation affects chondrocyte fate following injury, and if the timing of articulation impacts the resultant effect. The goal of this study was to investigate the effect of tribological articulation on injured cartilage tissue at two time points: (i) performed immediately after injury and (ii) 24 h after injury. Neonatal bovine femoral cartilage explants were injured using a rapid spring-loaded impactor and subsequently subjected to tribological articulation. Cell death due to impact injury was highest near the articular surface, suggesting a strain-dependent mechanism. Immediate articulation following injury mitigated cell death compared to injury alone or delayed articulation; markers for both general cell death and early-stage apoptosis were markedly decreased in the explants that were immediately slid. Interestingly, mitigation of cell death due to sliding was most predominant at the cartilage surface. Tribological articulation is known to create fluid flow within the tissue, predominantly at the articular surface, which could drive the protective response seen here. Altogether, this work shows that perturbations to the cellular environment immediately following cartilage injury significantly impact chondrocyte fate., (© 2024 Orthopaedic Research Society.)

Background: Breast cancer (BrCa) is the most common cancer for women globally. BrCa incidence varies by age and differs between racial groups, with Black women having an earlier age of onset and higher mortality compared to White women. The underlying biological mechanisms of this disparity remain uncertain. Here, we address this knowledge gap by examining the association between overall epigenetic age acceleration and BrCa initiation as well as the mediating role of race., Results: We measured whole-genome methylation (866,238 CpGs) using the Illumina EPIC array in blood DNA extracted from 209 women recruited from University Hospitals Cleveland Medical Center. Overall and intrinsic epigenetic age acceleration was calculated-accounting for the estimated white blood cell distribution-using the second-generation biological clock GrimAge. After quality control, 149 BrCa patients and 42 disease-free controls remained. The overall chronological mean age at BrCa diagnosis was 57.4 ± 11.4 years and nearly one-third of BrCa cases were self-reported Black women (29.5%). When comparing BrCa cases to disease-free controls, GrimAge acceleration was 2.48 years greater (p-value = 0.0056), while intrinsic epigenetic age acceleration was 1.72 years higher (p-value = 0.026) for cases compared to controls. After adjusting for known BrCa risk factors, we observed BrCa risk increased by 14% [odds ratio (OR) = 1.14; 95% CI: 1.05, 1.25] for a one-year increase in GrimAge acceleration. The stratified analysis by self-reported race revealed differing ORs for GrimAge acceleration: White women (OR = 1.17; 95% CI: 1.03, 1.36), and Black women (OR = 1.08; 95% CI: 0.96, 1.23). However, our limited sample size failed to detect a statistically significant interaction for self-reported race (p-value >0.05) when examining GrimAge acceleration with BrCa risk., Conclusions: Our study demonstrated that epigenetic age acceleration is associated with BrCa risk, and the association suggests variation by self-reported race. Although our sample size is limited, these results highlight a potential biological mechanism for BrCa risk and identifies a novel research area of BrCa health disparities requiring further inquiry., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Symptomatic HIV-associated neurocognitive disorder (HAND) is a complication of HIV (cognitive impairment, difficulties with everyday functioning). If detected early, interventions assist with optimizing care, avoiding rapid decline and enhancing coping. There remains inconsistency surrounding screening/diagnosis information within Australian healthcare professionals and community settings. A scoping review of academic literature, government policies and non-government organisations (NGOs) was conducted to map existing screening/diagnosis information using the guidelines of Joanna Briggs Institute. A literature search of EBSCOhost and Medline (dates: 2015-2021), the Australian government NGO web domains, Google and unpublished academic works was conducted (July 2021) and updated (December 2022) to identify Australian items (past 5 years). Seventeen items met the inclusion criteria. No government guidelines were identified. Various HIV-related organisations proposed different diagnostic guidelines. Most HAND research originated in Sydney. The most accessible information was from Dementia Australia, with some inaccuracies noted. There is scant Australian research/information on HAND screening/diagnosis. HAND translational research and screening/diagnosis standards are urgently needed to inform best practices. The Australian context is used to discuss international implications regarding higher-income countries with similar patterns/healthcare.

Purpose: Studies have reported inverse associations of pre-diagnosis recreational physical activity (RPA) level with all-cause and breast cancer (BCa)-specific mortality among BCa patients. However, the association between pre-diagnosis RPA level and BCa recurrence is unclear. We investigated the association between pre-diagnosis RPA level and risk of BCa recurrence in the California Teachers Study (CTS)., Methods: Stage I-IIIb BCa survivors (n = 6,479) were followed with median of 7.4 years, and 474 BCa recurrence cases were identified. Long-term (from high school to age at baseline questionnaire, or, age 55 years, whichever was younger) and baseline (past 3 years reported at baseline questionnaire) pre-diagnosis RPA levels were converted to metabolic equivalent of task-hours per week (MET-hrs/wk). Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of BCa recurrence overall and by estrogen receptor (ER)/progesterone receptor (PR) status., Results: Long-term RPA was not associated with BCa recurrence risk (p trend  = 0.99). The inverse association between baseline pre-diagnosis RPA level and BCa recurrence risk was marginally significant (≥26.0 vs. <3.4 MET-hrs/wk: HR = 0.79, 95% CI = 0.60-1.03; p trend  = 0.07). However, the association became non-significant after adjusting for post-diagnosis RPA (p trend  = 0.65). An inverse association between baseline pre-diagnosis RPA level and BCa recurrence risk was observed in ER-PR- cases (≥26.0 vs. <3.4 MET-hrs/wk: HR = 0.31, 95% CI = 0.13-0.72; p trend  = 0.04), but not in ER+ or PR+ cases (p trend  = 0.97)., Conclusions: Our data indicates that the benefit of baseline RPA on BCa recurrence may differ by tumor characteristics. This information may be particularly important for populations at higher risk of ER-PR- BCa., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Primates face severe challenges from climate change, with warming expected to increase animals' thermoregulatory demands. Primates have limited long-term options to cope with climate change, but possess a remarkable capacity for behavioral plasticity. This creates an urgency to better understand the behavioral mechanisms primates use to thermoregulate. While considerable information exists on primate behavioral thermoregulation, it is often scattered in the literature in a manner that is difficult to integrate. This review evaluates the status of the available literature on primate behavioral thermoregulation to facilitate future research. We surveyed peer-reviewed publications on primate thermoregulation for N = 17 behaviors across four thermoregulatory categories: activity budgeting, microhabitat use, body positioning, and evaporative cooling. We recorded data on the primate taxa evaluated, support for a thermoregulatory function, thermal variable assessed, and naturalistic/manipulative study conditions. Behavioral thermoregulation was pervasive across primates, with N = 721 cases of thermoregulatory behaviors identified across N = 284 published studies. Most genera were known to utilize multiple behaviors ( x ¯  = 4.5 ± 3.1 behaviors/genera). Activity budgeting behaviors were the most commonly encountered category in the literature (54.5% of cases), while evaporative cooling behaviors were the least represented (6.9% of cases). Behavioral thermoregulation studies were underrepresented for certain taxonomic groups, including lemurs, lorises, galagos, and Central/South American primates, and there were large within-taxa disparities in representation of genera. Support for a thermoregulatory function was consistently high across all behaviors, spanning both hot- and cold-avoidance strategies. This review reveals asymmetries in the current literature and avenues for future research. Increased knowledge of the impact thermoregulatory behaviors have on biologically relevant outcomes is needed to better assess primate responses to warming environments and develop early indicators of thermal stress., (© 2024 Wiley Periodicals LLC.)

Purpose: Higher pre-diagnosis physical activity (PA) is associated with lower all-cause mortality in breast cancer (BCa) patients. However, the association with pathological complete response (pCR) is unclear. We investigated the association between pre-diagnosis PA level and chemotherapy completion, dose delay, and pCR in BCa patients receiving neoadjuvant chemotherapy (NACT)., Methods: 180 stage I-III BCa patients receiving NACT (mean [SD] age of diagnosis: 60.8 [8.8] years) in the Sister Study were included. Self-reported recreational and total PA levels were converted to metabolic equivalent of task-hours per week (MET-hrs/wk). The pCR was defined as no invasive or in situ residual in breast or lymph node (ypT0 ypN0). Multivariable logistic regression analyses estimated odds ratios (ORs) and 95% confidence intervals (CIs) for treatment outcomes., Results: In this sample, 45 (25.0%) BCa patients achieved pCR. Higher pre-diagnosis recreational PA was not associated with lower likelihood of chemotherapy completion (highest vs. lowest tertile: OR = 0.87, 95% CI = 0.30-2.56; P trend  = 0.84), greater dose delay (OR = 1.45, 95% CI = 0.54-3.92; P trend  = 0.46), or greater odds of pCR (OR = 1.28, 95% CI = 0.49-3.34; P trend  = 0.44). Associations were similar for pre-diagnosis total PA. Meeting the recommended level of recreational PA was not associated with pCR overall (≥ 7.5 vs. < 7.5 MET-hrs/wk: OR = 1.33, 95% CI = 0.59-3.01)., Conclusions: Although small sample size and limited information on exercise closer to time of diagnosis limit interpretation, pre-diagnosis PA was not convincingly associated with treatment tolerance or treatment efficacy in BCa patients receiving NACT. Future investigations are needed to better understand the impact of pre-diagnosis PA on BCa treatment., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Since improvements in cancer screening, diagnosis, and therapeutics, cancer disparities have existed. Marginalized populations (e.g., racial and ethnic minorities, sexual and gender minorities, lower-income individuals, those living in rural areas, and persons living with disabilities) have worse cancer-related outcomes. Early detection of cancer substantially improves outcomes, yet uptake of recommended cancer screenings varies widely. Multi-cancer early detection (MCED) tests use biomarkers in the blood to detect two or more cancers in a single assay. These assays show potential for population screening for some cancers-including those disproportionally affecting marginalized communities. MCEDs may also reduce access barriers to early detection, a primary factor in cancer-related outcome disparities. However, for the promise of MCEDs to be realized, during their development and testing, we are obligated to be cautious to design them in a way that reduces the myriad of structural, systematic, and personal barriers contributing to disparities. Further, they must not create new barriers. Population studies and clinical trials should include diverse populations, and tests must work equally well in all populations. The tests must be affordable. It is critical that we establish trust within marginalized communities, the healthcare system, and the MCED tests themselves. Tests should be expected to have high specificity, as a positive MCED finding will trigger additional, oftentimes invasive and expensive, imaging or other diagnosis tests and/or biopsies. Finally, there should be a way to help all individuals with a positive test to navigate the system for follow-up diagnostics and treatment, if warranted, that is accessible to all., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Thompson and Baskin.)

Background: There is limited published data regarding the distribution of esophageal cancer patients by sub-regions, districts and ethnicity in Uganda., Objectives: To study the distribution by sub-regions, districts, ethnicity and sub-regions post-care outcomes of esophageal cancer patients in care over ten years at the Uganda Cancer Institute., Methods: Patients' charts with confirmed diagnoses of esophageal cancer for 2009-2019 were identified. Case information, which included demographics, clinical presentation, distribution by sub-regions, districts, ethnicity and sub-regions post-care outcomes, were retrospectively abstracted., Results: Central 671(34.15%), Southwestern 308(15.67%), Elgon 176(8.95%) and East central 163(8.29%) sub-regions had most patients. Mostly from administrative districts of Wakiso 167(8.50%), Mbarara 51(2.59%), Tororo 53(2.70%), Busia 33(1.68). Baganda, Banyakole, Bagisu and Basoga ethnic groups predominate. Patients from neighbouring countries were mainly from Rwanda 56(2.85%), South Sudan 24(1.22%), then Kenya 21(1.07%), and Rwandese, Dinka and Luo by ethnicity, respectively. Central and Southwestern sub-regions had the most post-care outcomes of the patients regarding living, death, and loss to follow-up., Conclusion: Patients are commonly from the administrative districts of Central, Southwestern, Elgon and East Central sub-regions and neighbouring countries of Rwanda, South Sudan and Kenya. Baganda, Banyakole, Bagisu and Basoga are the main ethnic groups. Central and Southwestern sub-regions are with most post-care outcomes., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 Obayo S et al.)

Effective implementation of cancer screening programs can reduce disease-specific incidence and mortality. Screening is currently recommended for breast, cervical, colorectal and lung cancer. However, initial and repeat adherence to screening tests in accordance with current guidelines is sub-optimal, with the lowest rates observed in historically underserved groups. If used in concert with recommended cancer screening tests, new biospecimen-based multi-cancer early detection (MCED) tests could help to identify more cancers that may be amendable to effective treatment. Clinical trials designed to assess the safety and efficacy of MCED tests to assess their potential for reducing cancer mortality are needed and many are underway. In the conduct of MCED test trials, it is crucial that participant recruitment efforts successfully engage participants from diverse populations experiencing cancer disparities. Strategic partnerships involving health systems, clinical practices, and communities can increase the reach of MCED trial recruitment efforts among populations experiencing disparities. This goal can be achieved by developing health system-based learning communities that build understanding of and trust in biomedical research; and by applying innovative methods for identifying eligible trial patients, educating potential participants about research trials, and engaging eligible individuals in shared decision making (SDM) about trial participation. This article describes how a developing consortium of health systems has used this approach to encourage the uptake of cancer screening in a wide range of populations and how such a strategy can facilitate the enrollment of persons from diverse patient and community populations in MCED trials., Competing Interests: AB holds equity stake in MeTree and You, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Thompson, Buchanan, Myers and Weinberg.)

BACKGROUND Cases involving penetrating abdominal trauma may be complex and often involve damage to multiple organ systems. Synthetic, biologic, and reinforced biologic matrices/reinforced tissue matrices (RBMs/RTMs) are frequently used in hernia repair and other surgical procedures requiring reinforcement, including trauma cases that require abdominal repair. CASE REPORT The first case was a 35-year-old male patient with a stab wound (SW) to the right side of the chest and the abdomen resulting in damage to the diaphragm, epicardium, liver, and duodenum. The second case was a 22-year-old male patient who suffered multiple traumas after an automated trencher accident, including a skull fracture with exposed brain and major lacerations to the shoulder and abdomen causing a large right-flank hernia. In both cases, OviTex® (TELA Bio, Inc., Malvern, PA), a reinforced tissue matrix (RTM), was used to help obtain and maintain abdominal wall closure. We also present an institutional economic analysis using data from the author's institution with average case cost and future projections for procedure volume and product usage volume through 2021. CONCLUSIONS We report favorable outcomes in a series of patients with contaminated (CDC Wound Class III) surgical fields who underwent abdominal wall closure and reinforcement with OviTex RTM. Our work adds to the growing body of literature suggesting that reinforced biologics offer a potential alternative to biological meshes in the setting of a contaminated surgical field. Additionally, in comparison to other commonly available biologic matrices, use of OviTex RTM may be a cost-effective option to achieve abdominal wall closure even in complex cases.

The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties 1-3 . Here we report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions-in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain., (© 2023. The Author(s).)

Background: Chronic levels of inflammation are associated with higher risk of many chronic diseases. Physical activity (PA) lowers the risk of cancer, cardiovascular disease (CVD), diabetes and others. One mechanism for PA-induced protection may be through the immune system. We investigated the association between leisure-time PA and peripheral immune cell populations in a large nationally representative sample of the US general population., Methods: A total of 17,093 participants [mean (SE) age of 41.6 (0.3) years] of the National Health and Nutrition Examination Survey 1999-2018 were included. Self-reported leisure-time PA was converted to metabolic equivalent of task hours per week (MET-hrs/wk). White blood cell (WBC) count, WBC ratios, and platelet count were derived. Multivariable linear regression analyses were used to estimate associations between leisure-time PA level and peripheral immune cell populations. Multivariable logistic regression analyses were used to estimate associations between leisure-time PA and metrics of WBC count and neutrophil-to-lymphocyte ratio (NLR) which may predict mortality., Results: A higher leisure-time PA level was associated with a lower WBC count (> 14.0 vs. < 1.2 MET-hrs/wk adjusted mean (95% confidence interval [CI]): 7.12 (6.86, 7.38) vs. 7.38 (7.12, 7.64) 1000 cells/μL, P trend  < 0.001) and a lower NLR (> 14.0 vs. < 1.2 MET-hrs/wk adjusted mean (95% CI) 2.04 (1.90, 2.18) vs. 2.13 (1.99, 2.28), P trend  = 0.007). Leisure-time PA level was not associated with lymphocyte-to-monocyte ratio (LMR; P trend  = 0.25) or platelet-to-lymphocyte ratio (PLR; P trend  = 0.69). Compared to the lowest leisure-time PA level (< 1.2 MET-hrs/wk), the highest leisure-time PA level (≥ 14.0 MET-hrs/wk) was associated with a lower probability of a high WBC count (> 8.1 × 10 9  cells/L; odds ratio [OR] = 0.76, 95% CI = 0.66-0.88) and high NLR (> 2.68; OR = 0.84, 95% CI = 0.72-0.99), which may predict CVD and all-cause mortality. The highest leisure-time PA level also linked to a lower probability of a high WBC count (≥ 8.3 × 10 9  cells/L; OR = 0.76, 95% CI = 0.66-0.88), which may predict cancer mortality., Conclusions: We observed an inverse association between leisure-time PA level, WBC count, and NLR, particularly for neutrophil levels. These results suggest that participants at higher levels of leisure-time PA may have lower levels of inflammation, which may be important for future chronic disease outcomes., (© 2023. The Author(s).)

Healthy synovium is critical for joint homeostasis. Synovial inflammation (synovitis) is implicated in the onset, progression and symptomatic presentation of arthritic joint diseases such as rheumatoid arthritis and osteoarthritis. Thus, the synovium is a promising target for the development of novel, disease-modifying therapeutics. However, target exploration is hampered by a lack of good pre-clinical models that accurately replicate human physiology and that are developed in a way that allows for widespread uptake. The current study presents a multi-channel, microfluidic, organ-on-a-chip (OOAC) model, comprising a 3D configuration of the human synovium and its associated vasculature, with biomechanical and inflammatory stimulation, built upon a commercially available OOAC platform. Healthy human fibroblast-like synoviocytes (hFLS) were co-cultured with human umbilical vein endothelial cells (HUVECs) with appropriate matrix proteins, separated by a flexible, porous membrane. The model was developed within the Emulate organ-chip platform enabling the application of physiological biomechanical stimulation in the form of fluid shear and cyclic tensile strain. The hFLS exhibited characteristic morphology, cytoskeletal architecture and matrix protein deposition. Synovial inflammation was initiated through the addition of interleukin-1 β (IL-1 β ) into the synovium channel resulting in the increased secretion of inflammatory and catabolic mediators, interleukin-6 (IL-6), prostaglandin E2 (PGE 2 ), matrix metalloproteinase 1 (MMP-1), as well as the synovial fluid constituent protein, hyaluronan. Enhanced expression of the inflammatory marker, intercellular adhesion molecule-1 (ICAM-1), was observed in HUVECs in the vascular channel, accompanied by increased attachment of circulating monocytes. This vascularised human synovium-on-a-chip model recapitulates a number of the functional characteristics of both healthy and inflamed human synovium. Thus, this model offers the first human synovium organ-chip suitable for widespread adoption to understand synovial joint disease mechanisms, permit the identification of novel therapeutic targets and support pre-clinical testing of therapies., (Creative Commons Attribution license.)

Introduction: Stroke is a major cause of death and disability worldwide, and it often results in depression, anxiety, stress, and cognitive impairment in survivors. There is a lack of community-based cognitive interventions for stroke survivors. This pilot single trial aimed to assess the feasibility, acceptability, and perceived effectiveness of a community-based cognitive intervention program called Train-Your-Brain (TYB) for stroke survivors and caregivers. The study focused on improvements in emotional and psychological well-being, as well as cognitive functioning., Methods: A quasi-experimental design was used in this study. A total of 48 participants were recruited and assessed using Depression, Anxiety, Stress Scale - 21 items (DASS-21), Montreal Cognitive Assessment (MoCA) and Symbol Digits Modality Test (SDMT) before and after the intervention. The TYB program consisted of nine sessions and was conducted via the Zoom software application. Participants provided feedback on the program, highlighting areas for improvement., Results: Twenty-seven stroke survivors and 21 caregivers completed the program. Participants expressed high satisfaction with the TYB program but recommended avoiding assessments in December and customizing the program for stroke survivors and caregivers. Stroke survivors showed significant improvements in depression and stress scores, while caregivers experienced no significant improvements after the program. While there was a slight improvement in stroke survivors' cognitive scores after the program, it was not statistically significant. Caregivers, however, experienced a significant decline in cognitive scores., Discussion: The TYB program provided group support and validation, resulting in improved mood and reduced stress among stroke survivors. Cultural collectivism played a significant role in fostering group cohesion. However, the program's limited focus on caregivers and timing of assessments during the December holidays may have affected the outcomes. The TYB program demonstrated feasibility and potential effectiveness in alleviating psychological distress and enhancing cognitive function among stroke survivors. Future research should explore long-term effects, larger sample sizes, and non-English-speaking populations to enhance generalizability. Tailored interventions for caregivers are necessary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher., (Copyright © 2023 Tham, Phua, Ho, Yan, Chen, Zuo, Thompson and Dong.)

Background: Oesophageal cancer is the seventh most common cancer and the sixth leading cause of cancer death worldwide, and its incidence varies globally. In Uganda, the incidence and trend are on the increase. However, there is a paucity of published data regarding this population's oesophageal cancer clinicopathologic characterisation and treatment outcomes., Objectives: To study the patients' clinicopathologic characteristics and treatment outcomes of oesophageal cancer over 10 years at the Uganda Cancer Institute., Methods: Patients' charts with histologically confirmed diagnoses of oesophageal cancer for 2009-2019 were identified. Case information, which included patient demographics, history of alcohol use or smoking, tumour location, histological type, tumour grade, clinical TNM (Tumour, Node, Metastasis) staging treatment exposure and treatment outcomes, was evaluated retrospectively. The median survival time was estimated with the Kaplan-Meier method and the median follow-up period was estimated using the reverse Kaplan-Meier., Results: 1,965 oesophageal cancer patients were identified; 1,380(70.23%) were males and 585(29.77 %) females, their mean age was 60.20 years (±12.66). Most males had a history of both alcohol consumption and smoking 640(46.38%). The lower third of the oesophagus was the most common anatomical location 771(39.24%). The majority had squamous cell carcinoma histological type 1,783(90.74%) followed by adenocarcinomas 182(9.26%) in the distal oesophagus. Poorly differentiated tumour grade 743(37.81%) was predominant. The majority of the patients were in stage IVB, 733(37.30%), and most patients were planned for the best supportive care, 731(37.20%). Radiation alone was offered to 621(31.60%) and feeding gastrostomy to 249(12.70%). Treatment outcomes: at the time of the current analysis, 58.68% had died, 1.48% were alive and 39.84% were lost to follow-up. The median follow-up period was 65 months (IQR:35.83-83.30) with a median survival time of 4.47 months (95% CI: 4.17-4.80)., Conclusion: Treatment outcomes of Ugandan oesophageal cancer patients seeking care are poor as most patients present with advanced disease. There is a significant loss of follow-up after treatment initiation. Therefore, reduction in exposure to known modifiable risk factors, early detection and timely referral for treatment strategies are needed to improve outcomes of these patients in our population. Designing interventions to improve treatment adherence is necessary., Competing Interests: The authors declare that there is no conflict of interest., (© the authors; licensee ecancermedicalscience.)

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AR is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and, until 31 July 2020, was a scientific advisory board member of Thermo Fisher Scientific, Syros Pharmaceuticals, Asimov, and Neogene Therapeutics. From 1 August 2020, AR is an employee of Genentech and has equity in Roche. AR is a named inventor on multiple patents related to single cell and spatial genomics filed by or issued to the Broad Institute., (Copyright: © 2023 Hawrylycz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: This study aimed to test whether prospective memory (PM) was an early cognitive marker of future cognitive decline and incident dementia using longitudinal data spanning 8 years from the Sydney Memory and Ageing Study., Methods: At baseline, 121 participants aged 72-91 years were tested in PM using a validated PM task, Virtual Week, which included time- and event-based tasks presented with varying regularity. Responses were scored "Correct" if completed accurately and "Missed" if the target was not remembered at any time. Measures of cognition were taken at baseline and 2-year intervals over 8 years. Dementia diagnoses were made by expert consensus panels using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Linear mixed models and Cox proportional hazards regression models were used to analyze the data, controlling for potential confounds., Results: Both decreased PM accuracy and missed PM responses were associated with rate of cognitive decline measured by Mini-Mental State Examination over 8 years and global cognitive decline over 4 years. Risk of incident dementia increased with poorer baseline PM ability and missed responses. These effects remained significant after controlling for baseline cognition and were strongest for event-based and regular PM tasks., Discussion: PM is a sensitive early marker of future cognitive decline and risk of incident dementia. PM tasks supported by spontaneous retrieval (event-based) and those with lower retrospective memory demands (regular tasks) function as particularly sensitive predictors. In other words, deficits in performing less effortful PM tasks best predicted cognitive decline. These findings may encourage clinicians to incorporate PM tasks in clinical assessments., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Breast cancer subtypes and their phenotypes parallel different stages of the mammary epithelial cell developmental hierarchy. Discovering mechanisms that control lineage identity could provide novel avenues for mitigating disease progression. Here we report that the transcriptional corepressor TLE3 is a guardian of luminal cell fate in breast cancer and operates independently of the estrogen receptor. In luminal breast cancer, TLE3 actively repressed the gene-expression signature associated with highly aggressive basal-like breast cancers (BLBC). Moreover, maintenance of the luminal lineage depended on the appropriate localization of TLE3 to its transcriptional targets, a process mediated by interactions with FOXA1. By repressing genes that drive BLBC phenotypes, including SOX9 and TGFβ2, TLE3 prevented the acquisition of a hybrid epithelial-mesenchymal state and reduced metastatic capacity and aggressive cellular behaviors. These results establish TLE3 as an essential transcriptional repressor that sustains the more differentiated and less metastatic nature of luminal breast cancers. Approaches to induce TLE3 expression could promote the acquisition of less aggressive, more treatable disease states to extend patient survival., Significance: Transcriptional corepressor TLE3 actively suppresses SOX9 and TGFβ transcriptional programs to sustain the luminal lineage identity of breast cancer cells and to inhibit metastatic progression., (©2023 American Association for Cancer Research.)

Primary cilia regulate and coordinate a variety of cell signaling pathways important in chondrocyte physiology and cartilage development, health, and disease. Despite this, the chondrocyte primary cilium and its associated role in cartilage biology remains poorly understood. Key to elucidating primary cilia structure and function in chondrocytes is the ability to visualize this unique structure. Here we describe materials and methods for immunofluorescence labeling, microscopy, and measurement of chondrocyte primary cilia., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors., (© 2022 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Women with ductal carcinoma in situ (DCIS) have an increased risk of progression to invasive breast cancer. Although not all women with DCIS will progress to invasion, all are treated as such, emphasising the need to identify prognostic biomarkers. We have previously shown that altered myoepithelial cells in DCIS predict disease progression and recurrence. By analysing DCIS duct size in sections of human breast tumour samples, we identified an associated upregulation of integrin β6 and an increase in periductal fibronectin deposition with increased DCIS duct size that associated with the progression of DCIS to invasion. Our modelling of the mechanical stretching myoepithelial cells undergo during DCIS progression confirmed the upregulation of integrin β6 and fibronectin expression in isolated primary and cell line models of normal myoepithelial cells. Our studies reveal that this mechanostimulated DCIS myoepithelial cell phenotype enhances invasion in a TGFβ-mediated upregulation of MMP13. Immunohistochemical analysis identified that MMP13 was specifically upregulated in DCIS, and it was associated with progression to invasion. These findings implicate tissue mechanics in altering the myoepithelial cell phenotype in DCIS, and that these alterations may be used to stratify DCIS patients into low and high risk for invasive progression., (© 2022. Crown.)

Objective: Obesity has emerged as a prominent risk factor for multiple serious disease states, including a variety of cancers, and is increasingly recognized as a primary contributor to preventable cancer risk. However, few studies of leukemia have been conducted in animal models of obesity. This study sought to characterize the impact of obesity, diet, and sex in a murine model of acute promyelocytic leukemia (APL)., Methods: Male and female C57BL/6J.mCG +/PR mice, genetically predisposed to sporadic APL development, and C57BL/6J (wild type) mice were placed on either a high-fat diet (HFD) or a low-fat diet (LFD) for up to 500 days., Results: Relative to LFD-fed mice, HFD-fed animals displayed increased disease penetrance and shortened disease latency as indicated by accelerated disease onset. In addition, a diet-responsive sex difference in APL penetrance and incidence was identified, with LFD-fed male animals displaying increased penetrance and shortened latency relative to female counterparts. In contrast, both HFD-fed male and female mice displayed 100% disease penetrance and insignificant differences in disease latency, indicating that the sexual dimorphism was reduced through HFD feeding., Conclusions: Obesity and obesogenic diet promote the development of APL in vivo, reducing sexual dimorphisms in disease latency and penetrance., (© 2022 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)

The "Train Your Brain" (TYB) cognitive intervention group program was developed based on previous research with the goal of remediating cognitive impairments for elderly Singaporean people with mild cognitive impairment (MCI). This study reports a pilot evaluation of feasibility (defined as participant attendance, retention rate, satisfaction and usefulness) and preliminary efficacy of the TYB program. Nineteen participants with MCI aged ≥ 50 years were recruited from a memory clinic in Singapore, with 14 receiving the TYB intervention. Participants were allocated in order of recruitment into consecutive identical groups for a 9-session program on brain health and cognitive training. Participants received pre- and post-intervention measures of cognition and completed feedback forms reporting on satisfaction with, and utility of, the TYB program. TYB was well attended (85% attendance for the first 6 sessions; 83% for the full 9-session TYB program). Participant satisfaction was high, with positive participant feedback reporting that TYB offered useful cognitive strategies which participants could implement in their daily life. Despite the small sample size and absence of control group, repeated-measures t -tests revealed significant pre- to post-intervention intra-individual improvement in global cognition measured by the Montreal Cognitive Assessment, and in executive function on the Brixton Spatial Anticipation Test. This pilot study provides supportive preliminary evidence for feasibility of TYB, with suggestions of efficacy of this program as a culturally and linguistically appropriate intervention for English-speaking older adults with MCI in Singapore.

Background: An important part of biomedical research is the translation of discoveries into clinical or community applications that impact patient health. For a vast majority of clinical applications and sustainable community interventions, a time-tested way to get innovations to patients is through licensing of the technology and commercial development, often through startups. While biomedical scientists and trainees are schooled in discovery research, the processes of commercialization are foreign or intimidating. Further, many trainees will not aspire to a faculty position, and other avenues of advancement are desirable., Methods: At Case Western Reserve University, we developed and launched a Translational Fellows Program to provide such training for the community, focusing specifically on graduate students and postdoctoral fellows. The goals of this program include familiarizing our trainees with the principles of entrepreneurship, product development, and startups. This is accomplished through study of their laboratory's technology to identify points of translational focus and to increase awareness to potentially move ideas and products toward societal impact. This program leverages much of our existing infrastructure and provides a mechanism for the prioritization of the translation of the technology as well as "release-time" to promote effort., Results: Launched in summer 2020, our first cohort had 3 of the 12 fellows launching startups based on their technology and submitting an National Institutes of Health Small Business Innovation Research (SBIR) proposal. At least 80% reported increased knowledge and confidence in five of six key translational competencies., Conclusion: We are now continuing and improving the program and searching for sustainable support to stabilize the program for a long-term productive future., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2022.)