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Objective: Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy., Design: Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry., Results: Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1 + dendritic cell activation and CD8 + T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8 + T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8 + T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs., Conclusion: CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC., Competing Interests: Competing interests: DM is a director of Fibrofind. JL and DM are shareholders in Fibrofind limited. SB owns shares in AstraZeneca. OJS receives funding from AstraZeneca and Novartis. TGB receives research funding support from AstraZeneca. JML receives research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha and AstraZeneca., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.) more...

The International Classification of Functioning, Disability and Health framework recognizes that an individual's functioning post-stroke reflects an interaction between their health condition and contextual factors encompassing personal and environmental factors. Personal factors significantly impact rehabilitation outcomes as they determine how an individual evaluates their situation and copes with their condition in daily life. A key personal factor is self-efficacy-an individual's belief in their capacity to achieve certain outcomes. Self-efficacy influences an individual's motivational state to execute behaviors necessary for achieving desired rehabilitation outcomes. Stroke rehabilitation practice and research now acknowledge self-efficacy and motivation as critical elements in post-stroke recovery, and increasing evidence highlights their contributions to motor (re)learning. Given the informative value of neuroimaging-based biomarkers in stroke, elucidating the neurological underpinnings of self-efficacy and motivation may optimize post-stroke recovery. In this review, we examine the role of self-efficacy and motivation in stroke rehabilitation and recovery, identify potential neural substrates underlying these factors from current neuroimaging literature, and discuss how leveraging these factors and their associated neural substrates has the potential to advance the field of stroke rehabilitation., 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 © 2022 Gangwani, Cain, Collins and Cassidy.) more...

Objective: To explore perspectives of pediatric neurologists regarding sexual and reproductive health care for adolescent women with epilepsy (WWE) and intellectual disability., Methods: We interviewed pediatric neurologists regarding sexual and reproductive health for WWE with intellectual disability. We audio-recorded and transcribed interviews and conducted qualitative analysis., Results: 16 pediatric neurologists participated. Themes included the following: (1) Pediatric neurologists have differing perspectives about how intellectual disability affects WWE's sexual and reproductive health needs, (2) pediatric neurologists provide sexual and reproductive health counseling variable in content and frequency to this population, (3) pediatric neurologists tend to recommend longer-term methods of contraception for this population, and (4) pediatric neurologists are asked to be involved in decision-making around sterilization, yet express ethico-legal reservations., Conclusion: Our findings suggest pediatric neurologists provide variable, often suboptimal, sexual and reproductive health care for WWE and intellectual disability. Themes reveal ethical concerns among neurologists about sexual and reproductive health practices including sterilization. More tailored clinical guidelines and provider training on sexual and reproductive health for this population may be beneficial. more...

Background and Aims: NAFLD is the most common hepatic pathology in western countries and no treatment is currently available. NAFLD is characterized by the aberrant hepatocellular accumulation of fatty acids in the form of lipid droplets (LDs). Recently, it was shown that liver LD degradation occurs through a process termed lipophagy, a form of autophagy. However, the molecular mechanisms governing liver lipophagy are elusive. Here, we aimed to ascertain the key molecular players that regulate hepatic lipophagy and their importance in NAFLD., Approach and Results: We analyzed the formation and degradation of LD in vitro (fibroblasts and primary mouse hepatocytes), in vivo and ex vivo (mouse and human liver slices) and focused on the role of the autophagy master regulator mammalian target of rapamycin complex (mTORC) 1 and the LD coating protein perilipin (Plin) 3 in these processes. We show that the autophagy machinery is recruited to the LD on hepatic overload of oleic acid in all experimental settings. This led to activation of lipophagy, a process that was abolished by Plin3 knockdown using RNA interference. Furthermore, Plin3 directly interacted with the autophagy proteins focal adhesion interaction protein 200 KDa and autophagy-related 16L, suggesting that Plin3 functions as a docking protein or is involved in autophagosome formation to activate lipophagy. Finally, we show that mTORC1 phosphorylated Plin3 to promote LD degradation., Conclusions: These results reveal that mTORC1 regulates liver lipophagy through a mechanism dependent on Plin3 phosphorylation. We propose that stimulating this pathway can enhance lipophagy in hepatocytes to help protect the liver from lipid-mediated toxicity, thus offering a therapeutic strategy in NAFLD., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.) more...

Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-β1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in Rel ΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease. more...

Climate change and environmental pollution from health care present urgent, complex challenges. The US health care sector produces 10% of total US greenhouse gas emissions, which have negative influences on human and environmental health. The emergency department (ED) is an important place in the hospital to become more environmentally responsible and "climate smart," a term referring to the combination of low-carbon and resilient health care strategies. Our intent is to educate and motivate emergency providers to action by providing a guide to sustainable health care and an approach to creating a climate-smart ED., (Copyright © 2019 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.) more...

Background: Studies conducted in orthopedic surgery have suggested that patients with anxiety have less symptomatic improvement following surgery than those without. We hypothesized for this study that patients with anxiety traits experience less symptomatic improvement following pelvic organ prolapse surgery than patients without., Methods: All patients presenting for prolapse repair surgery were offered enrollment in this prospective cohort study. Prior to surgery, subjects were asked to complete the Spielberger State-Trait Anxiety Inventory and the Pelvic Floor Distress Inventory 20. Subjects were also asked to list up to five goals related to the outcome of surgery for goal-attainment scaling. At the 6-8-week postoperative visit, subjects were asked to repeat the STAI and PFDI questionnaires and respond to the single question tool assessing Patient Global Impression of Improvement. Subjects were also asked to rate on a Visual Assessment Scale how well preoperative goals were met. All three questionnaires were repeated at >12 weeks following surgery., Results: A total of 32 patients with anxiety trait and 58 without were recruited. Preoperatively, the mean STAI-T was 45.0 (± 7.2.) and 27.7 (± 4.9) for subjects with and without anxiety; PFDI 20 scores were 96.1 (± 48.8) and 94.7 (± 57.5), respectively. At 12+ weeks postoperatively, the mean PFDI-20 for subjects with anxiety was 31.3 (± 20.9) and 30.3 (± 27.9) (p = 0.22) for those without., Conclusions: We did not find the anxiety trait to be a predictor of subjective outcomes following pelvic organ prolapse surgery. more...

Introduction and Hypothesis: The pelvic organ prolapse quantification system (POP-Q) is the most commonly used method to quantify the extent of pelvic organ prolapse. However, it does not include assessment of anterior vaginal wall length (AVL). The objectives of this study were to characterize AVL and distance to the sacrospinous ligament (SSL), and to examine associations between total vaginal length (TVL), AVL, body mass index (BMI) and age., Methods: This was a retrospective chart review of 139 patients with cervix in situ presenting during an 8-month period for initial evaluation to the University of Rochester Medical Center Urogynecology practice. AVL, TVL and distance to the SSL were measured in addition to POP-Q measurements. Age, height, BMI, presenting complaint and prolapse stage were obtained from medical records. Simple linear regression was used to assess the relationship between TVL and AVL. Multivariate regression was used to test independent variables., Results: The mean ± SD TVL, AVL and distance to the SSL were 9.4 ± 1.2 cm, 7.4 ± 0.9 cm and 7.2 ± 0.9 cm, respectively. All three measurements approached a normal distribution. TVL decreased slightly with age. No association was found between vaginal length and BMI or parity., Conclusions: AVL is a useful measurement that may aid in surgical decision-making. Providers should consider using AVL when planning sacrospinous hysteropexy. more...

Susan Schnall speaks about the lingering effects of Agent Orange-and what remains to be done about them.

The outcomes of species recovery programs have been mixed; high-profile population recoveries contrast with species-level extinctions. Each conservation intervention has its own challenges, but to inform more effective management it is imperative to assess whether correlates of wider recovery program success or failure can be identified. To contribute to evidence-based improvement of future conservation strategies, we conducted a global quantitative analysis of 48 mammalian recovery programs. We reviewed available scientific literature and conducted semistructured interviews with conservation professionals involved in different recovery programs to investigate ecological, management, and political factors associated with population recoveries or declines. Identifying and removing threats was significantly associated with increasing population trend and decreasing conservation dependence, emphasizing that populations are likely to continue to be compromised in the absence of effective threat mitigation and supporting the need for threat monitoring and adaptive management in response to new and potential threats. Lack of habitat and small population size were cited as limiting factors in 56% and 42% of recovery programs, respectively, and both were statistically associated with increased longer term dependence on conservation intervention, demonstrating the importance of increasing population numbers quickly and restoring and protecting habitat. Poor stakeholder coordination and management were also regularly cited by respondents as key weaknesses in recovery programs, indicating the importance of effective leadership and shared goals and management plans. Project outcomes were not influenced by biological or ecological variables such as body mass or habitat, which suggests that these insights into correlates of conservation success and failure are likely to be generalizable across mammals., (© 2016 Society for Conservation Biology.) more...

Biodegradable collagen scaffolds are used clinically for oral soft tissue augmentation to support wound healing. This study sought to provide a novel ex vivo model for analyzing healing kinetics and gene expression of primary human gingival fibroblasts (hGF) within collagen scaffolds. Sponge type and gel type scaffolds with and without platelet-derived growth factor-BB (PDGF) were assessed in an hGF containing matrix. Morphology was evaluated with scanning electron microscopy, and hGF metabolic activity using MTT. We quantitated the population kinetics within the scaffolds based on cell density and distance from the scaffold border of DiI-labled hGFs over a two-week observation period. Gene expression was evaluated with gene array and qPCR. The sponge type scaffolds showed a porous morphology. Absolute cell number and distance was higher in sponge type scaffolds when compared to gel type scaffolds, in particular during the first week of observation. PDGF incorporated scaffolds increased cell numbers, distance, and formazan formation in the MTT assay. Gene expression dynamics revealed the induction of key genes associated with the generation of oral tissue. DKK1, CYR61, CTGF, TGFBR1 levels were increased and integrin ITGA2 levels were decreased in the sponge type scaffolds compared to the gel type scaffold. The results suggest that this novel model of oral wound healing provides insights into population kinetics and gene expression dynamics of biodegradable scaffolds. more...

Background: Pancreatic cancer cells exist in a hypoxic microenvironment containing numerous factors that impact tumor survival, proliferation, and metastasis. MicroRNAs (miRs) are differentially expressed in cancer but also altered by hypoxia. We hypothesized that hypoxia could induce expression of miR-21, an oncomir in pancreatic cancer cells., Materials and Methods: We examined how hypoxia regulates miR-21 expression in pancreatic cancer cell lines (BxPC-3, AsPC-1) by stem-loop RT-PCR. Chromatin immunoprecipitation assays were used to study how hypoxia alters hypoxia-inducible factor (HIF)-1α binding to the hypoxia response element of miR-21. BxPC-3 and AsPC-1 cells were transfected with a constitutively stable HIF-1α subunit or vector control (pcDNA3.1) to determine the influence of miR-21 in normoxia. The effect of mature miR-21 sense and antisense oligonucleotides on proliferation and apoptosis in hypoxic and normoxic conditions was assessed via WST-1 assay and flow cytometry., Results: MiR-21 levels increased in all cell lines grown in hypoxic conditions versus normoxia, whereas siRNA targeting HIF-1α reduced miR-21 expression. Hypoxic conditions resulted in direct binding of HIF-1α to the predicted binding site in miR-21. Transfection with a constitutively stable HIF-1α expression plasmid in normoxia resulted in upregulated miR-21, similar to that seen in hypoxia. Cells transfected with antisense constructs targeting miR-21 had reduced proliferation and increased apoptosis in normoxia, whereas miR-21 overexpression abrogated hypoxia-associated reductions in proliferation., Conclusions: MiR-21 is induced by hypoxia in pancreatic cancer cells via HIF-1α upregulation. MiR-21 overexpression allows cells to avoid apoptosis in a hypoxic microenvironment. Inhibition of miR-21 expression may increase cellular susceptibility to hypoxia in pancreatic cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.) more...

Background: MicroRNAs (miRNAs) are small non-coding genes which become dysregulated in cancer and may predict survival. The role of miRNAs in outcomes in cholangiocarcinoma (CC) has not been reported., Methods: RNA was extracted from 32 resected CCs along with adjacent uninvolved bile duct epithelium. A total of 43 miRNAs were quantified using NanoString™. Clinicopathologic characteristics and outcomes were captured and compared. Overall survival curves were created using the Kaplan-Meier method; factors, including miRNA expression, were compared by log-rank, chi-squared or Cox regression analyses., Results: Absolute expression of each miRNA was compared with overall survival after excluding perioperative deaths (n= 3). One upregulated (miR-151-3p; P= 0.003) and one downregulated (miR-126; P= 0.023) miRNA in resected CC relative to adjacent normal bile duct epithelium correlated with survival on univariate analysis. Clinical factors and these miRNAs were compared. Dysregulated miR-151-3p and miR-126, respectively, were the only factors that correlated with improved overall survival [41.5 months vs. 12.3 months (P= 0.002) and 21.9 months vs. 15.1 months (P= 0.02), respectively]. In eight patients, both miRNAs were dysregulated. In the remainder, only one or neither showed dysregulation. Concomitant dysregulation correlated with the best overall survival (58.7 months vs. 15.1 months; P < 0.000; n= 8); clinicopathologic factors in these groups were otherwise similar., Conclusions: In resected CC, the concomitant dysregulation of both miR-151-3p and miR-126 was the factor related to the greatest improvement in overall survival. Further analysis of the targets of these miRNAs may yield potential therapeutic targets or prognostic biomarkers., (© 2012 International Hepato-Pancreato-Biliary Association.) more...

Background: Osteopontin (OPN) is a secreted protein of the extracellular matrix. It has been used as a marker for tumor aggressiveness and correlated with clinical outcomes in several solid tumors, such as liver, lung, and breast. We determined the OPN expression and its influence on survival in patients with resected pancreatic adenocarcinoma., Methods: Tissue microarrays were constructed from 245 resected pancreatic adenocarcinomas. Immunohistochemical staining for OPN was undertaken and compared to normal pancreas (n = 12). OPN expression was then correlated with patient demographics, tumor size, grade, node, and margin status. Survival curves were created by the Kaplan-Meier method and compared by log rank analysis., Results: In total, 181 (74 %) of pancreatic adenocarcinoma tissues expressed OPN compared to 7 (58 %) of normal controls (p = 0.004). Expression was observed predominantly in the cytoplasm of the tumor cells. The median and 2 year overall survival was longer when OPN was expressed (17.1 vs. 11.6 months, and 38 vs. 24 %, respectively, p = 0.04). Multivariate analysis showed OPN expression and T stage to be independent predictors of overall survival, while other histopathologic factors such as tumor grade, tumor size, and nodal status were not., Conclusions: These results suggest that the presence of OPN expression in pancreatic adenocarcinoma may have a protective effect independent of tumor stage. This emphasizes the importance of the interaction between pancreatic cancer cells and their stromal elements. more...

Objective: In this pilot study, we determined the effectiveness of a weighted vest on attention to task for second-grade general education students with difficulty attending., Method: We used an intervention and a control group and an ABA design to compare participants' percentage of time on task with and without a vest. Ten participants from nine elementary schools in a suburban Texas school district were randomly assigned to an intervention or a control group. Control group participants wore a nonweighted vest. Participants, classroom teachers, and research assistants who coded the data were blind as to the group to which the participants were assigned., Results: A repeated measures analysis of variance indicated no significant differences between groups or between baseline, intervention, and withdrawal conditions., Conclusion: Our results indicated that the weighted vests were not effective in increasing time on task. These results should be generalized cautiously owing to the small sample size and participant selection process. more...

The objective of this study was to investigate whether life satisfaction and depressive symptoms are independent predictors of mortality in a non-Western sample of adults. The sample included 5,131 adults (ages 50-95 at baseline) in Taiwan who participated in the Survey of Health and Living Status of the Near Elderly and Elderly. There were 1,815 deaths recorded over a 10-year period. Higher life satisfaction significantly predicted lower risk of mortality after controlling for age, sex, education, marital status, and health status. Depressive symptoms significantly predicted higher risk of mortality. A significant interaction with age revealed that the protective effect of life satisfaction weakened with age. The results suggest that life satisfaction and depressive symptoms independently predict mortality risk in adults., ((c) 2009 APA, all rights reserved.) more...

This report consolidates previous recommendations and adds new ones for infection control in dental settings. Recommendations are provided regarding 1) educating and protecting dental health-care personnel; 2) preventing transmission of bloodborne pathogens; 3) hand hygiene; 4) personal protective equipment; 5) contact dermatitis and latex hypersensitivity; 6) sterilization and disinfection of patient-care items; 7) environmental infection control; 8) dental unit waterlines, biofilm, and water quality; and 9) special considerations (e.g., dental handpieces and other devices, radiology, parenteral medications, oral surgical procedures, and dental laboratories). These recommendations were developed in collaboration with and after review by authorities on infection control from CDC and other public agencies, academia, and private and professional organizations. more...