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Background: Functional dependence and the risks of disability increase with age. The loss of independence is thought to be partially due to a decrease in physical activity. However, in populations, accurate measurement of physical activity is challenging and may not provide information on functional impairment.Methods: This study therefore assessed physical functionality and physical activity level in a group of nonagenarians (11 men/11 women; 93+/-1 years, 66.6+/-2.4 kg, body mass index [BMI]=24+/-1 kg/m2) and a group of participants aged 60-74 years (17 men/15 women; 70+/-1 years, 83.3+/-3.0 kg, BMI=29+/-1 kg/m2) from the Louisiana Healthy Aging Study. Physical activity level was calculated from total energy expenditure (TEE) and resting metabolic rate (RMR). Physical functionality was assessed using the Reduced Continuous Scale Physical Functional Performance Test (CS-PFP10).Results: Nonagenarians had lower absolute (p<.001) and adjusted (p<.007) TEE compared to participants aged 60-74 years which was attributed to a reduction in both RMR and physical activity level. Nonagenarians also had reduced functional performance (p<.001) which was correlated with activity level (r=0.68, p<.001).Conclusions: When compared to individuals aged 60-74 years, 73% of the reduction in TEE in nonagenarians can be attributed to a reduction in physical activity level, the remaining being accounted for by a reduction in RMR. The reduced physical activity in nonagenarians is associated with less physical functionality. This study provides the first objective comparison of physical functionality and actual levels of physical activity in older individuals. [ABSTRACT FROM AUTHOR]

This study examines the hypothesis that highly favorable outcome expectations promote weight loss and hinder weight maintenance. To investigate the effects of outcome expectations and satisfaction with treatment outcomes on weight loss, 349 adults were randomly assigned to 1 of 2 weight loss programs that emphasize either (a) an 'optimistic' message, focusing exclusively on the positive aspects of weight loss, or (b) a 'balanced' message, giving equal time to positive and negative aspects of weight loss. Participants changed their weight loss cognitions in response to the intervention, but there was no significant difference between the intervention treatment groups in short-term or long-term (18-month) weight loss. Independent of treatment message, positive outcome expectations and satisfaction were both associated with weight loss. ((c) 2005 APA, all rights reserved). [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most therapeutically recalcitrant form of breast cancer, which is due in part to the paucity of targeted therapies. A systematic analysis of regulatory elements that extend beyond protein-coding genes could uncover avenues for therapeutic intervention. To this end, we analyzed the regulatory mechanisms of TNBC-specific transcriptional enhancers together with their noncoding enhancer RNA (eRNA) transcripts. The functions of the top 30 eRNA-producing super-enhancers were systematically probed using high-throughput CRISPR-interference assays coupled to RNA sequencing that enabled unbiased detection of target genes genome-wide. Generation of high-resolution Hi-C chromatin interaction maps enabled annotation of the direct target genes for each super-enhancer, which highlighted their proclivity for genes that portend worse clinical outcomes in patients with TNBC. Illustrating the utility of this dataset, deletion of an identified super-enhancer controlling the nearby PODXL gene or specific degradation of its eRNAs led to profound inhibitory effects on target gene expression, cell proliferation, and migration. Furthermore, loss of this super-enhancer suppressed tumor growth and metastasis in TNBC mouse xenograft models. Single-cell RNA sequencing and assay for transposase-accessible chromatin with high-throughput sequencing analyses demonstrated the enhanced activity of this super-enhancer within the malignant cells of TNBC tumor specimens compared with nonmalignant cell types. Collectively, this work examines several fundamental questions about how regulatory information encoded into eRNA-producing super-enhancers drives gene expression networks that underlie the biology of TNBC. Significance: Integrative analysis of eRNA-producing super-enhancers defines molecular mechanisms controlling global patterns of gene expression that regulate clinical outcomes in breast cancer, highlighting the potential of enhancers as biomarkers and therapeutic targets., (©2024 American Association for Cancer Research.)

While the Lapidus bunionectomy is a common procedure utilized to address hallux valgus, the incidence of secondary surgery is not well established. Our primary goal was to determine the incidence of revision surgery and hardware removal following the Lapidus bunionectomy in addition to the risk factors associated with each. A retrospective nested case-control study of adult patients who underwent a Lapidus bunionectomy for symptomatic hallux valgus over a 9-year period was performed. The incidence rates and 95% confidence intervals (CI) of secondary surgery in the 3 years following the procedure along with the estimated independent associations and odds ratios between baseline demographic, clinical, and radiographic characteristics were calculated. Of the original cohort of 2540 patients, 127 were identified (5.0%; CI: 4.1%, 5.8%) who underwent revision surgery and 165 (6.5%; CI: 5.5%, 7.5%) who underwent hardware removal following Lapidus bunionectomy. Initially, the hallux valgus angle, intermetatarsal angle, and tibial sesamoid position were risk factors for revision surgery. However, in adjusted analyses for revision surgery, using a screw for third point of fixation emerged as the only independent risk factor (odds ratio [OR] = 3.01; CI: 1.59, 5.69). In adjusted analyses for hardware removal, female sex (OR = 2.33; CI: 1.08, 5.00) and third point of fixation (OR = 2.92; CI: 1.82, 4.69) emerged as independent risk factors. While the overall risks associated with Lapidus bunionectomy are low and the need for revision surgery are low, this study helps to identify specific risk factors for secondary surgery and hardware removal to help in evaluation and discussion with patients., (Copyright © 2024 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Dysregulated Wnt/β-catenin signaling is a common feature of colorectal cancer (CRC). The T-cell factor/lymphoid enhancer factor (TCF/LEF; hereafter, TCF) family of transcription factors are critical regulators of Wnt/β-catenin target gene expression. Of the four TCF family members, TCF7L1 predominantly functions as a transcriptional repressor. Although TCF7L1 has been ascribed an oncogenic role in CRC, only a few target genes whose expression it regulates have been characterized in this cancer. Through transcriptome analyses of TCF7L1 regulated genes, we noted enrichment for those associated with cellular migration. By silencing and overexpressing TCF7L1 in CRC cell lines, we demonstrated that TCF7L1 promoted migration, invasion, and adhesion. We localized TCF7L1 binding across the CRC genome and overlapped enriched regions with transcriptome data to identify candidate target genes. The growth arrest-specific 1 (GAS1) gene was among these and we demonstrated that GAS1 is a critical mediator of TCF7L1-dependent CRC cell migratory phenotypes. Together, these findings uncover a novel role for TCF7L1 in repressing GAS1 expression to enhance migration and invasion of CRC cells., (© 2024. The Author(s).)

Bacterial defense against phage predation involves diverse defense systems acting individually and concurrently, yet their interactions remain poorly understood. We investigated >100 defense systems in 42,925 bacterial genomes and identified numerous instances of their non-random co-occurrence and negative association. For several pairs of defense systems significantly co-occurring in Escherichia coli strains, we demonstrate synergistic anti-phage activity. Notably, Zorya II synergizes with Druantia III and ietAS defense systems, while tmn exhibits synergy with co-occurring systems Gabija, Septu I, and PrrC. For Gabija, tmn co-opts the sensory switch ATPase domain, enhancing anti-phage activity. Some defense system pairs that are negatively associated in E. coli show synergy and significantly co-occur in other taxa, demonstrating that bacterial immune repertoires are largely shaped by selection for resistance against host-specific phages rather than negative epistasis. Collectively, these findings demonstrate compatibility and synergy between defense systems, allowing bacteria to adopt flexible strategies for phage defense., Competing Interests: Declaration of interests Y.E.G. is a full-time employee of SNIPR Biome., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hallux valgus is a common foot deformity in which many surgical techniques have been introduced. Originally, Paul Lapidus detailed a midfoot arthrodesis technique to address the deformity and medial column instability that served as the foundation for the modified Lapidus bunionectomy. The appreciation of the multiplanar nature of hallux valgus deformity continues to evolve and helps to guide the investigation of the ideal surgical correction to yield more predictable results and reduced complications. Various fixation constructs have been used over the years for the Lapidus bunionectomy without a clear superior fixation technique, and literature supports early weight-bearing with each., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Lower-limb amputation rates in patients with chronic limb-threatening ischemia vary across the United States, with marked disparities in amputation rates by gender, race, and income status. We evaluated the association of patient, hospital, and geographic characteristics with the intensity of vascular care received the year before a major lower-limb amputation and how intensity of care associates with outcomes after amputation., Methods: Using Medicare claims data (2016-2019), beneficiaries diagnosed with chronic limb-threatening ischemia who underwent a major lower-limb amputation were identified. We examined patient, hospital, and geographic characteristics associated with the intensity of vascular care received the year before amputation. Secondary objectives evaluated all-cause mortality and adverse events following amputation., Results: Of 33 036 total Medicare beneficiaries undergoing major amputation, 7885 (23.9%) were due to chronic limb-threatening ischemia; of these, 4988 (63.3%) received low-intensity and 2897 (36.7%) received high-intensity vascular care. Mean age, 76.6 years; women, 38.9%; Black adults, 24.5%; and of low income, 35.2%. After multivariable adjustment, those of low income (odds ratio, 0.65 [95% CI, 0.58-0.72]; P <0.001), and to a lesser extent, men (odds ratio, 0.89 [95% CI, 0.81-0.98]; P =0.019), and those who received care at a safety-net hospital (odds ratio, 0.87 [95% CI, 0.78-0.97]; P =0.012) were most likely to receive low intensity of care before amputation. High-intensity care was associated with a lower risk of all-cause mortality 2 years following amputation (hazard ratio, 0.79 [95% CI, 0.74-0.85]; P <0.001)., Conclusions: Patients who were of low-income status, and to a lesser extent, men, or those cared for at safety-net hospitals were most likely to receive low-intensity vascular care. Low-intensity care was associated with worse long-term event-free survival. These data emphasize the continued disparities that exist in contemporary vascular practice., Competing Interests: Disclosures Dr Quiroga receives personal fees from Boston Scientific and W.L. Gore. Dr Wadhera receives research support from the National Heart, Lung, Blood Institute (NHLBI)/National Institutes of Health (NIH) K23HL148525 and also receives personal fees from CVS Health and Abbott. Dr Secemsky receives research support from NIH/NHLBI K23HL150290, Food and Drug Administration, Harvard Medical School Shore Faculty Development Award, Becton, Dickinson and Company, Boston Scientific, Cook, Cardiovascular Systems, Inc, Laminate Medical, Medtronic, and Philips and receives personal fees from Abbott, Bayer, Becton, Dickinson and Company, Boston Scientific, Cook, Cordis-X, Cardiovascular Systems, Inc, Janssen, Medtronic, Philips, and VentureMed. Dr West, C.M. King, and J.T. Hasegawa are employees of Abbott Vascular. Dr Martinson is a consultant to Abbott Vascular. The other author reports no conflicts.

The Achilles tendon has a high incidence of ruptures often occurring in weekend warriors and the aging population. Based on anatomic studies of the Achilles tendon, ruptures are commonly found in the watershed area proximal to the insertion site. Traditionally, treatment options included conservative therapy with immobilization and a prolonged non-weight-bearing phase versus surgical treatment. Surgical treatment can vary between open, minimally invasive, or percutaneous approaches. In more recent years, early functional rehabilitation with or without surgery has shown to have successful results., Competing Interests: Disclosures The authors have nothing to disclose regarding conflict of interest or commercial relationship related to the content of this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Podiatric residency is only three years to gather as many experiences to understand the various aspects of foot and ankle care including, surgery, clinics, academics, and research to prepare them for the rest of their career. It is also important to find a supportive environment to maximize both education and wellness during these naturally challenging times. The three separate Kaiser Northern California Podiatric Residency Programs have worked diligently to provide a comprehensive opportunities and experiences in all aspects of podiatric resident education., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Our group previously reported that melanoma of the foot is associated with advanced disease on diagnosis and decreased survival. Lesions localized to the toe appeared to have the worst outcomes. In this study, we both expanded our study to include a 10-year population of patient with invasive melanoma of the foot and ankle and investigated additional factors associated with prognosis. Between January 2007 and December 2016, 211 patients underwent biopsy diagnosis and surgery for invasive melanoma in the BLANK health care system. Demographic, pathologic, staging, and localization characteristics were studied for overall survival. Lesions were localized to dorsal foot, plantar foot, toe (nonsubungual), and toe (subungual) locations. Multivariable analysis found Breslow depth, ulceration, lymph node involvement, and subungual toe location to be associated with poorer survival. Overall survival rate for foot melanoma was 70.6%. Overall survival for nonsubungual toe melanoma was 60.7%, compared to 53.1% for subungual toe melanoma. Of the subungual melanomas, 37.5% of presented as deep lesions with a Breslow depth >4.0 mm. Subungual melanoma was statistically significant for and found to be an independent prognostic factor associated with poorer survival and advanced disease. Based on the results of this study, there should be a low threshold to biopsy suspicious lesions of the toe and foot with particular attention to be dedicated to subungual lesions., (Copyright © 2023 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC), in part, by deregulating expression of genes controlled by the T-cell factor (TCF) family of transcription factors. TCFs contain a conserved DNA binding domain that mediates association with TCF binding elements (TBEs) within Wnt-responsive DNA elements (WREs). Intestinal stem cell marker, leucine-rich-repeat containing G-protein-coupled receptor 5 (LGR5), is a Wnt target gene that has been implicated in CRC stem cell plasticity. However, the WREs at the LGR5 gene locus and how TCF factors directly regulate LGR5 gene expression in CRC have not been fully defined. Here, we report that TCF family member, TCF7L1, plays a significant role in regulating LGR5 expression in CRC cells. We demonstrate that TCF7L1 binds to a novel promoter-proximal WRE through association with a consensus TBE at the LGR5 locus to repress LGR5 expression. Using CRISPR activation and interference (CRISPRa/i) technologies to direct epigenetic modulation, we demonstrate that this WRE is a critical regulator of LGR5 expression and spheroid formation capacity of CRC cells. Furthermore, we found that restoring LGR5 expression rescues the TCF7L1-mediated reduction in spheroid formation efficiency. These results demonstrate a role for TCF7L1 in repressing LGR5 gene expression to govern the spheroid formation potential of CRC cells.

There are many factors to consider when treating an Achilles tendon rupture in the acute and chronic/neglected settings. For acute rupture, operative and nonoperative management contribute to a good prognosis with low associated risks. Patient or injury characteristics can assist in the shared decision-making about treatment. In chronic rupture, MRI may help to determine rupture location, gap distance, and tissue material available for repair. Various surgical approaches are used for chronic rupture repair. Treatment of the Achilles tendon rupture generates many interesting and complex discussions on the optimal management., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Opioid drugs are the most effective tools for treating moderate to severe pain. Despite their analgesic efficacy, long-term opioid use can lead to drug tolerance, addiction, and sleep/wake disturbances. While the link between opioids and sleep/wake problems is well-documented, the mechanism underlying opioid-related sleep/wake problems remains largely unresolved. Importantly, intrinsically photosensitive retinal ganglion cells (ipRGCs), the cells that transmit environmental light/dark information to the brain's sleep/circadian centers to regulate sleep/wake behavior, express μ-opioid receptors (MORs). In this study, we explored the potential contribution of ipRGCs to opioid-related sleep/circadian disruptions. Using implanted telemetry transmitters, we measured changes in horizontal locomotor activity and body temperature in mice over the course of a chronic morphine paradigm. Mice lacking MORs expressed by ipRGCs (McKO) exhibited reduced morphine-induced behavioral activation/sensitization compared with control littermates with normal patterns of MOR expression. Contrastingly, mice lacking MORs globally (MKO) did not acquire morphine-induced locomotor activation/sensitization. Control mice also showed morphine-induced hypothermia in both the light and dark phases, while McKO littermates only exhibited morphine-induced hypothermia in the dark. Interestingly, only control animals appeared to acquire tolerance to morphine's hypothermic effect. Morphine, however, did not acutely decrease the body temperature of MKO mice. These findings support the idea that MORs expressed by ipRGCs could contribute to opioid-related sleep/wake problems and thermoregulatory changes.

The Lapidus arthrodesis is a powerful procedure for the correction of hallux valgus with metatarsus primus varus. Yet, first ray instability may persist despite correction of the primary deformity with 2 crossed screw fixation. A third screw is often utilized as the additional point of fixation for noteworthy residual transverse plane motion, but it is not without potential complications. The suture and button fixation device may be an appropriate alternative to the third screw construct. This retrospective cohort study identified clinical / radiographic outcomes and complication rates following a third point of fixation with either a screw or suture and button fixation device in patients undergoing a modified Lapidus arthrodesis. One surgeon performed all of the Lapidus procedure with a third screw while the other surgeon performed all with a suture and button fixation device. Of 136 consecutive patients who underwent a modified Lapidus arthrodesis, 83 (61%) patients required a third point of fixation for satisfactory stabilization of the first ray. Surgical technique was similar between the 2 surgeons; however, one utilized the suture and button fixation device method (n = 36), while the other used a third screw for fixation (n = 47). Many of the clinical outcomes, radiographic results, and the union rate were similar between the 2 methods. Nineteen (40%) complications occurred in the third screw group compared to 6 (17%) in the suture and button fixation device group. However, the third screw group demonstrated 100% maintenance of deformity correction at 1 year versus 95% in the suture and button fixation device group. Although fixation with a suture and button fixation device was associated with fewer complications, a larger study is necessary to determine if these variations are statistically significant., (Copyright © 2021 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Borderline Personality Disorder (BPD) is an often misunderstood and stigmatized mental health difficulty. Increasingly, social media has been used as a forum to share dialogue on such difficulties. This research analysed YouTube comments in response to personal vlogs about living with BPD. The key term 'Living with Borderline Personality Disorder Vlog' was inputted into a YouTube Ireland search, results were displayed by relevance and the top four vlogs that met the criteria were chosen for analysis. A total of 1197 comments (approximately 55,574 words) were analysed using inductive thematic analysis (Braun and Clarke, 2006). Five distinct themes were identified: 1) Sharing advice, support and encouragement, 2) Vlogs destigmatizing, informing and educating, 3) Solidarity, relatability and personal connection, 4) Intense, unstable intrapersonal and interpersonal functioning, 5) Prompting disclosures about mental health struggles. The vlogs gave people insight and understanding, increasing empathy towards those suffering with BPD or with their mental health. The overall picture drawn from the data was one of solidarity, support, de-stigmatization, normalization, sharing, comfort and encouragement. Further research into people's attitudes towards BPD, their opinions and knowledge of the disorder, may help make important changes, inform policies and practice, and ultimately improve the lives of those living with the disorder., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Enhancers are critical regulatory elements in the genome that help orchestrate spatiotemporal patterns of gene expression during development and normal physiology. In cancer, enhancers are often rewired by various genetic and epigenetic mechanisms for the activation of oncogenes that lead to initiation and progression. A key feature of active enhancers is the production of non-coding RNA molecules called enhancer RNAs, whose functions remain unknown but can be used to specify active enhancers de novo. Using a combination of eRNA transcription and chromatin modifications, we have identified a novel enhancer located 30 kb upstream of Colony Stimulating Factor 1 (CSF1). Notably, CSF1 is implicated in the progression of breast cancer, is overexpressed in triple-negative breast cancer (TNBC) cell lines, and its enhancer is primarily active in TNBC patient tumors. Genomic deletion of the enhancer (via CRISPR/Cas9) enabled us to validate this regulatory element as a bona fide enhancer of CSF1 and subsequent cell-based assays revealed profound effects on cancer cell proliferation, colony formation, and migration. Epigenetic silencing of the enhancer via CRISPR-interference assays (dCas9-KRAB) coupled to RNA-sequencing, enabled unbiased identification of additional target genes, such as RSAD2, that are predictive of clinical outcome. Additionally, we repurposed the RNA-guided RNA-targeting CRISPR-Cas13 machinery to specifically degrade the eRNAs transcripts produced at this enhancer to determine the consequences on CSF1 mRNA expression, suggesting a post-transcriptional role for these non-coding transcripts. Finally, we test our eRNA-dependent model of CSF1 enhancer function and demonstrate that our results are extensible to other forms of cancer. Collectively, this work describes a novel enhancer that is active in the TNBC subtype, which is associated with cellular growth, and requires eRNA transcripts for proper enhancer function. These results demonstrate the significant impact of enhancers in cancer biology and highlight their potential as tractable targets for therapeutic intervention.

The special issue editors selected us to form an "adversarial collaboration" because our publications and teaching encompass both supportive and critical attitudes toward the Rorschach and its recently developed system for use, the Rorschach Performance Assessment System (R-PAS). We reviewed the research literature and case law to determine if the Rorschach and specifically R-PAS meet legal standards for admissibility in court. We included evidence on norms, reliability, validity, utility, general acceptance, forensic evaluator use, and response style assessment, as well as United States and selected European case law addressing challenges to mental examination motions, admissibility, and weight. Compared to other psychological tests, the Rorschach is not challenged at unusually high rates. Although the recently introduced R-PAS is not widely referenced in case law, evidence suggests that information from it is likely to be ruled admissible when used by a competent evaluator and selected variables yield scores that are sufficiently reliable and valid to evaluate psychological processes that inform functional psycholegal capacities. We identify effective and ethical but also inappropriate uses (e.g., psychological profiling) of R-PAS in criminal, civil, juvenile, and family court. We recommend specific research to clarify important aspects of R-PAS and advance its utility in forensic mental health assessment.

Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) are a diverse group of neurons that project widely to different brain regions. It is unknown how this small population of neurons organizes its efferent projections. In this study, we hypothesized that individual ARH POMC neurons exclusively innervate select target regions. To investigate this hypothesis, we first verified that only a fraction of ARH POMC neurons innervate the lateral hypothalamus (LH), the paraventricular nucleus of the hypothalamus (PVN), the periaqueductal gray (PAG), or the ventral tegmental area (VTA) using the retrograde tracer cholera toxin B (CTB). Next, two versions of CTB conjugated to distinct fluorophores were injected bilaterally into two of the regions such that PVN and VTA, PAG and VTA, or LH and PVN received tracers simultaneously. These pairs of target sites were chosen based on function and location. Few individual ARH POMC neurons projected to two brain regions at once, suggesting that there are ARH POMC neuron subpopulations organized by their efferent projections. We also investigated whether increasing the activity of POMC neurons could increase the number of ARH POMC neurons labeled with CTB, implying an increase in new synaptic connections to downstream regions. However, chemogenetic enhancement of POMC neuron activity did not increase retrograde tracing of CTB back to ARH POMC neurons from either the LH, PVN, or VTA. Overall, subpopulations of ARH POMC neurons with distinct efferent projections may serve as a way for the POMC population to organize its many functions.