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Purpose: Oncological treatments, such as radiotherapy, which requires consistent electricity, the presence of specialized clinical teams, and daily patient access to treatment facilities, are frequently disrupted by extreme weather events, posing several health hazards to patients. This study explores the association between declared wildfire disasters during radiotherapy and overall survival among patients with non-small cell lung cancer (NSCLC)., Methods: The study population consisted of 202,935 adults with inoperable Stage III NSCLC, who initiated radiotherapy from 2004 through 2019. Exposure was defined as a wildfire disaster declaration in the county of the treatment facility within 12 weeks of initiating radiotherapy. Overall survival was defined as the interval (months) between age at diagnosis and age at death, date of last contact, or study end. Cox proportional hazards was used to estimate crude and adjusted hazard ratios and 95% confidence intervals with inverse probability weighting., Results: Patients exposed to a wildfire disaster declaration during radiation treatment had worse overall survival (HR, 1.03; 95% CI 1.00-1.06; p = 0.02), compared to unexposed patients in adjusted models., Conclusion: Exposure to a wildfire disaster during radiotherapy is associated with worse overall survival among patients with stage III non-operable NSCLC. This finding underscores the critical need for developing adaptation strategies within the healthcare sector, especially in oncology., Competing Interests: Declarations. Competing interest: The authors declare no competing interests. Ethical approval: The institutional review board of the Morehouse School of Medicine granted an exemption for this study in accordance with 45 CFR §46.102(f). Consent to participate: The study used de-identified data and therefore was deemed exempt from informed consent., (© 2025. The Author(s).)

Strontium isotope ( 87 Sr/ 86 Sr) analysis with reference to strontium isotope landscapes (Sr isoscapes) allows reconstructing mobility and migration in archaeology, ecology, and forensics. However, despite the vast potential of research involving 87 Sr/ 86 Sr analysis particularly in Africa, Sr isoscapes remain unavailable for the largest parts of the continent. Here, we measure the 87 Sr/ 86 Sr ratios in 778 environmental samples from 24 African countries and combine this data with published data to model a bioavailable Sr isoscape for sub-Saharan Africa using random forest regression. We demonstrate the efficacy of this Sr isoscape, in combination with other lines of evidence, to trace the African roots of individuals from historic slavery contexts, particularly those with highly radiogenic 87 Sr/ 86 Sr ratios uncommon in the African Diaspora. Our study provides an extensive African 87 Sr/ 86 Sr dataset which includes scientifically marginalized regions of Africa, with significant implications for the archaeology of the transatlantic slave trade, wildlife ecology, conservation, and forensics., Competing Interests: Competing interests: The authors declare no competing interest., (© 2024. The Author(s).)

Purpose: Finite element (FE) models for determining the orthodontic forces delivered by clear aligners often lack validation. The aim of this study was to develop and validate accurate FE models for clear aligners, considering the small but important geometrical variations from the thermoforming process and the creep behavior of the aligner material., Methods and Materials: The tooth misalignment considered was a 2.4° torque aberration (rotation about the mesial-distal axis at the level of the center of resistance) of the maxillary left central incisor. FE models were created from Micro-CT scans of a model dental arch and five nominally identical aligners with the aforementioned misfit. Fitting of the aligners onto the dental arch was simulated using Abaqus's Interference Fit function, followed by surface-to-surface frictional interaction. Stress relaxation of the aligner material was measured using double-cantilever beam bending and modeled with a Prony series. The assembled FE models were validated by comparing the predicted forces and moments delivered to the maxillary left central incisor with experimental data, obtained with a custom-built but fully calibrated apparatus., Results: Good agreement between prediction and measurement was obtained for both the short- and long-term forces and moments. In the short-term, i.e., after 30 s, the dominant force in the labial-lingual direction had a maximum difference of 2.9% between experiment and simulation, and the dominant moment about the mesial-distal axis had a maximum difference of 8.3%. In the long-term, i.e., after 4 h, the experimental and numerical forces had a maximum difference of 8.4%. There were statistically significant differences in the forces delivered among the nominally identical aligners, which were predicted by the geometrically accurate FE models and attributed to the variations in the points of contact between the aligners and the dental arch. The decay in force applied was affected by both the viscoelastic material behavior and friction between the aligner and arch., Conclusion: For accurate prediction of the forces and moments delivered by thermoplastic aligners, FE models that can accurately capture the point contacts between the aligners and the underlying teeth are essential. Stress relaxation of the aligners could be adequately modeled using the Prony series to represent the temporal changes of their elastic modulus., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Osteoarthritis (OA) is a major source of pain and disability worldwide. Understanding of disease progression is evolving, but OA is increasingly thought to be a multifactorial disease in which the innate immune system plays a role in regulating and perpetuating low-grade inflammation. The aim of this study was to enhance our understanding of OA immunopathogenesis through characterization of the transcriptomic responses in OA joints, with the goal to facilitate the development of targeted therapies., Methods: Single-cell RNA sequencing (scRNA-seq) was completed on cells isolated from the synovial fluid of three normal and three OA equine joints. In addition to synovial fluid, scRNA-seq was also performed on synovium from one normal joint and one OA joint., Results: Characterization of 28,639 cells isolated from normal and OA-affected equine synovial fluid revealed the composition to be entirely immune cells (CD45 + ) with 8 major populations and 26 subpopulations identified. In synovial fluid, we found myeloid cells (macrophage and dendritic cells) to be overrepresented and T cells (CD4 and CD8) to be underrepresented in OA relative to normal joints. Through subcluster and differential abundance analysis of T cells we further identified a relative overrepresentation of IL23R + gamma-delta (γδ) T cells in OA-affected joints (a cell type we report to be enriched in gene signatures associated with T helper 17 mediated immunity). Analysis of an additional 17,690 cells (11 distinct cell type clusters) obtained from synovium of one horse led to the identification of an OA-associated reduction in the relative abundance of synovial macrophages, which contrasts with the increased relative abundance of macrophages in synovial fluid. Completion of cell-cell interaction analysis implicated myeloid cells in disease progression, suggesting that the myeloid-myeloid interactions were increased in OA-affected joints., Conclusions: Overall, this work provides key insights into the composition of equine synovial fluid and synovium in health and OA. The data generated in this study provides equine-specific cell type gene signatures which can be applied to future investigations. Furthermore, our analysis highlights the potential role of macrophages and IL23R + γδ T cells in OA immunopathogenesis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-24-40/coif). Z.J.W. reports that stipend funding was provided by NIH/NCATS Colorado CTSA T32TR004366. L.M.P. reports that this study was funded by the Foundation for the Horse, Grayson Jockey Club Research Foundation, Colorado State University College Research Council Interdisciplinary Pilot Award, NIH/NCATS CTSA 5TL1TR002533-02 (L.M.P.), NIH 5T32OD010437-19 (L.M.P.), and Carolyn Quan and Porter Bennett. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background: Non-human primate (NHPs) conservation sites could be sites of exchange of pathogens involved in infectious diseases. It is important to assess the potential risks associated with this type of structure. The objective of this study was to carry out a risk assessment of the Primatology Centre housed in the Interdisciplinary Centre for Medical Research of Franceville (CIRMF)., Methods: A questionnaire was administered to the centre's staff to assess the risk associated with each workstation, followed by a review of the various pathogens identified in NHPs. The data were analysed using two diagrams: the Kiviat diagram and the Pareto diagram., Results: Based on our results, a variety of pathogens such as viruses, bacteria and parasites, potentially transmissible to humans, were described in the NHPs at the Primatology Centre of CIRMF. The position most exposed to zoonotic risks was that of animal handlers., Conclusion: The Primatology Centre of CIRMF is a potential transfer site for the transfer of zoonotic agents. To avoid the risk of parasite exchange between staff and animals, the implementation of biosecurity measures is essential., (© 2024 The Author(s). Journal of Medical Primatology published by John Wiley & Sons Ltd.)

This article discusses a novel approach to immediate nipple reconstruction during skin-sparing mastectomy with Wise-pattern design, a common procedure in direct-to-implant breast reconstruction. Traditionally, nipple reconstruction is performed as a second procedure, incurring additional costs and potential complications. This novel technique involves a simple modification to the Wise-pattern flap during the initial mastectomy, allowing for one-step reconstruction. The procedure includes preoperative markings of the Wise-pattern design, with a U-shaped flap added at the top angle to create the nipple position. This U-shaped flap, containing both skin and subcutaneous tissue, is then folded over itself and sutured, resulting in an inverted T-shaped incision with the reconstructed nipple at the apex. This article emphasizes the avoidance of a secondary operation for nipple reconstruction, avoiding additional costs and potential complications associated with flap loss, especially in postradiation patients. The technique was applied to five consecutive cases, with patient satisfaction reported as very high. Follow-up at 6 months showed no venous congestion or flap loss, and in patients without adjuvant radiation, the reconstructed nipple maintained almost all its initial postoperative height. Minor loss of nipple protrusion over time was comparable to traditional nipple reconstruction (eg, skate flap), and the construction of the new nipple required only an average of 10 extra minutes. Although larger-scale studies are needed for a comprehensive evaluation, the preliminary results suggest promising outcomes and encourage larger-scale safety and outcomes studies of this technique in Wise-pattern skin-sparing reconstructions., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Neurofilament Light Chain (NfL) is an emerging blood biomarker of neuro-axonal injury and neurodegeneration with the potential to be used in the clinical management of various neurological conditions. Various NfL immunoassays are in development on high-throughput automated systems, but little information is available related to the comparability between assays. In this study, we performed a head-to-head comparison of four NfL immunoassays using plasma samples from individuals with various neurological conditions., Methods: EDTA plasma samples in which NfL was ordered clinically were stratified according to diagnosis. NfL concentrations (pg/mL) in plasma were obtained using the Quanterix Simoa®, the Roche Elecsys, the Siemens Healthineers Atellica®IM, and the Fujirebio Lumipulse® NfL assays. Passing-Bablok regression analyses were performed to assess the correlation and bias between methods. Additionally, the distribution of NfL concentrations for each assay was assessed in three disease groups: amyotrophic lateral sclerosis (ALS) upon initial diagnosis, ALS treated, and multiple sclerosis (MS)., Results: The R 2 between assays were all ≥ 0.95, however, significant proportional bias was observed between some assays. In particular, the Roche Elecsys assay NfL concentrations were significantly lower (∼85 %) when compared against the other three assays. The four assays were comparable with regards to the percentage of patients that were identified as having an elevated NfL result in the various clinical groups: ALS initial diagnoses (83-94 %), ALS untreated (93-100 %), and MS (8-18 %)., Conclusions: This is the first study describing a head-to-head comparison of four automated NfL immunoassays. We demonstrate that there is a strong correlation between assays but a lack of standardization which is evident by the bias observed between some of the evaluated methods. These analytical differences will be important to consider when using NfL as a biomarker of neurodegeneration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SL Ashrafzadeh-Kian reports no disclosures. DJ Figdore reports no disclosures. B Larson reports no disclosures. R Deters reports no disclosures. C Abou-Diwan is a salaried employee of Siemens Healthineers. JA Bornhorst has participated on an advisory board for Sunbird Bio and received an honorarium from Roche Diagnostics. A Algeciras-Schimnich has participated in advisory boards for Roche Diagnostics, Fujirebio Diagnostics, and Siemens Healthineers., (Copyright © 2024 Elsevier B.V. All rights reserved.)

How populations adapt to their environment is a fundamental question in biology. Yet we know surprisingly little about this process, especially for endangered species such as non-human great apes. Chimpanzees, our closest living relatives, are particularly interesting because they inhabit diverse habitats, from rainforest to woodland-savannah. Whether genetic adaptation facilitates such habitat diversity remains unknown, despite having wide implications for evolutionary biology and conservation. Using 828 newly generated exomes from wild chimpanzees, we find evidence of fine-scale genetic adaptation to habitat. Notably, adaptation to malaria in forest chimpanzees is mediated by the same genes underlying adaptation to malaria in humans. This work demonstrates the power of non-invasive samples to reveal genetic adaptations in endangered populations and highlights the importance of adaptive genetic diversity for chimpanzees., Competing Interests: Competing interests: The authors declare no competing interests.

Background: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival., Methods: Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs., Results: K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations., Conclusions: Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer., (© 2024. The Author(s).)

Oxygenic photosynthetic organisms use Photosystem II (PSII) to oxidize water and reduce plastoquinone. Here, we review the mechanisms by which PSII is assembled and turned over in the model green alga Chlamydomonas reinhardtii . This species has been used to make key discoveries in PSII research due to its metabolic flexibility and amenability to genetic approaches. PSII subunits originate from both nuclear and chloroplastic gene products in Chlamydomonas . Nuclear-encoded PSII subunits are transported into the chloroplast and chloroplast-encoded PSII subunits are translated by a coordinated mechanism. Active PSII dimers are built from discrete reaction center complexes in a process facilitated by assembly factors. The phosphorylation of core subunits affects supercomplex formation and localization within the thylakoid network. Proteolysis primarily targets the D1 subunit, which when replaced, allows PSII to be reactivated and completes a repair cycle. While PSII has been extensively studied using Chlamydomonas as a model species, important questions remain about its assembly and repair which are presented here.

In previous studies, a significant increase in the incidence of pancreatic cancer among younger women compared to men in the United States was noted. However, the specific histopathologic characteristics were not delineated. This population-based study aimed to assess whether this disproportionate rise in pancreatic cancer in younger women was contributed by pancreatic ductal adenocarcinoma (PDAC) or pancreatic neuroendocrine tumors (PanNET). The United States Cancer Statistics (USCS) database was used to identify patients with pancreatic cancer between 2001 and 2018. The results showed that, in younger adults, the incidence of PDAC has increased in women [average annual percentage change (AAPC) = 0.62%], while it has remained stable in men (AAPC = -0.09%). The PDAC incidence rate among women increased at a greater rate compared to men with a statistically significant difference in AAPC ( p < 0.001), with neither identical nor parallel trends. In contrast, cases of PanNET did not demonstrate a statistically significant sex-specific AAPC difference. In conclusion, this study demonstrated that the dramatic increase in the incidence rate of PDAC explains the disproportionate rise in pancreatic cancer incidence in younger women. This prompts further prospective studies to investigate the underlying reasons for these sex-specific disparities in PDAC.

Background: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival., Methods: Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs., Results: K17 expression had profound effects on the exclusion of intratumoral CD8 + T cells and was also associated with decreased numbers of peritumoral CD8 + T cells, CD16 + macrophages, and CD163 + macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8 + T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations., Conclusions: Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer., Competing Interests: Competing interests KRS and LEH are consultants to KDx Diagnostics Inc. EB is an employee of Perthera and owns stock in the company. EFP has received compensation as an officer of Perthera, Inc. and owns stock in the company. He has also consulted for Theralink Technologies, Inc. and received compensation as Chair of their Science Advisory Board and owns stock in the company. Other authors report no competing interests with the current study.

The utilization of tumor spheroids and organoids has greatly facilitated mechanistic understanding of tumor growth and invasion and lead to more effective high-throughput analysis of potential chemotherapeutic agents. In spheroid and organoid systems, tumor invasion occurs in three dimensions and monitoring this behavior can be data intensive. Quantitative correlation of tumor invasion with protease activity can further exacerbate data storage issues. The present method utilizes the "Hit Pick" approach to provide quantitative analysis and correlation of tumor invasion and membrane type 1 matrix metalloproteinase (MT1-MMP) activity in a rapid fashion with greatly reduced data storage requirements compared with standard image analysis approaches. Inhibition of MT1-MMP activity in spheroids can also be monitored by the present approach., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Liposomal local anaesthetic solutions may provide extended-duration analgesia postoperatively but have not been assessed following intra-peritoneal local infiltration in any species., Objectives: To evaluate two doses of 1.33% liposomal bupivacaine (LB) versus 0.75% bupivacaine HCL (BHCl) for analgesia following laparoscopic ovariectomy in mares., Study Design: Prospective cohort study., Methods: Fifteen healthy Quarter Horse mares (age 2-20 years) with normal bilateral ovarian palpation and appearance were enrolled. Horses were restrained in standing stocks and administered an α-2 agonist, butorphanol, and flunixin meglumine, followed by a variable rate infusion of sedation with α-2 agonists. Bilateral paralumbar fossa ovariectomies were performed. Treatment with either 30 ml 0.75% BHCl followed by 20 or 40 ml LB 13.3% (LB20 and LB40) volume expanded with saline to 80 ml total (n = 6/group) or 80 ml BHCl alone (n = 3, BCHL) was infused around incision sites and each mesovarium (LB or BHCl) prior to ovariectomy. Horses were monitored for 72 h by physical examination, algometry, and pain scoring (composite pain scale by Bussieres et al., Horse Grimace Scale). Abdominocentesis with peritoneal fluid analysis was performed at 72 h., Results: Analgesia achieved with all treatment protocols allowed completion of ovariectomy procedures. Pressure algometry scores were lower in BHCl-treated horses versus both LB groups overall. Pain scores were improved with LB-treated horses in a dose-dependent fashion (Horse Grimace Scale scores LB40 < LB20 < BHCL; composite pain scale scores LB40 < BHCL, LB20 < BHCL, BHCL, and LB20 did not differ). Peritoneal fluid total protein was lower in LB40 versus LB20 and BHCL horses. No complications from LB administration were appreciated., Main Limitations: Small patient sample size, lack of follow-up past 72 h or histopathology., Conclusions: Analgesia duration was extended and pain scores improved postoperatively with LB versus BHCl in a dose-dependent fashion. Further clinical evaluation of extended-duration local anaesthetics in horses for improved postoperative pain management is warranted., (© 2022 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Gun homicide rates have risen 35% across the USA since the start of the COVID-19 pandemic. One promising intervention to prevent violent crime is summer youth employment programs (SYEPs), which provide youth with meaningful workplace experiences, prosocial engagements, and developmental opportunities during the summer months, when many otherwise lack structure. This paper presents a cost analysis of violence prevention-focused SYEPs to help implementers understand the costs generally and in their own community contexts-to advocate for adoption and secure funding of, effectively budget for, and successfully implement SYEPs. Researchers use an ingredient-based costing approach and provide a template for implementers to use and adapt for their context. SYEPs with the goal of reaching youth who are justice-involved or at risk of being victims or perpetrators of violence can cost $3331 per youth assisted, with 54% of this cost directly paid to youth through stipends. Cost per youth is driven by the intensity of the mentoring and support that community organizations provide to the program participants. Knowing the cost per youth assisted can inform further analysis, implementation, and expansion of SYEPs., (© 2023. The New York Academy of Medicine.)

Introduction: Artificial intelligence remote monitoring of clear aligner therapy has recently gained popularity. It uses deep learning algorithms on a patient's mobile smartphone to determine readiness to progress to the next aligner (ie, GO vs NO-GO) and identify areas in which the teeth are not tracking with the clear aligners. This study aimed to assess the repeatability of the Go or No-Go instructions provided by the application and to determine the 3-dimensional discrepancies that constitute an unseat., Methods: Thirty patients in treatment with clear aligners at an academic clinic were scanned twice using a remote monitoring application on a smartphone, and the results were compared. Gauge repeatability and reproducibility analysis were performed. Intraoral and remote monitoring scans were obtained on the same day from 24 additional clear aligner patients that completed treatment using their final aligners. The intraoral scan after using the final aligner and the stereolithography file of the planned position at the final aligner was compared with measure the maximum discrepancies between the actual and planned position of the teeth., Results: Gauge compatibility of 44.7% was noted. In total 83.3% of patient instructions agreed between Scan 1 and 2, but 0% agreed completely on which and/or how many teeth had tracking issues. Patients who received GO instruction had mean greatest discrepancies of 1.997 mm, 1.901 mm, 0.530 mm, 8.911°, 7.827°, and 7.049° in mesiodistal, buccolingual, occlusogingival, tip, torque, and rotational dimensions, respectively. These discrepancies were not significantly different from patients receiving NO-GO instruction (1.771 mm, 1.808 mm, 0.606 mm, 8.673°, 8.134°, and 6.719° for the corresponding categories)., Conclusions: Despite the study's limitations, these findings suggest concerns with the consistency of remote monitoring instructions because of gauge compatibility over the industry standard. Similarly, large discrepancies in tooth position for patients receiving GO and NO-GO instruction suggest that artificial intelligence decisions were inconsistent with quantitative findings., (Copyright © 2023 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Objectives: The aims of the study were to describe the well-being and lifestyle behaviors of health-system pharmacists during the COVID-19 pandemic and to determine the relationships among well-being, perceptions of workplace wellness support, and self-reported concern of having made a medication error., Methods: Pharmacist ( N = 10,445) were randomly sampled for a health and well-being survey. Multiple logistic regression assessed associations with wellness support and concerns of medication error., Results: The response rate was 6.4% ( N = 665). Pharmacists whose workplaces very much supported wellness were 3× more likely to have no depression, anxiety, and stress; 10× more likely to have no burnout; and 15× more likely to have a higher professional quality of life. Those with burnout had double the concern of having made a medication error in the last 3 months., Conclusions: Healthcare leadership must fix system issues that cause burnout and actualize wellness cultures to improve pharmacist well-being., Competing Interests: Conflict of interest: M.M., B.L., and A.L.D. are associated with the American Society of Health-System Pharmacists. A.L.D. has Merck individual stock. The other authors declare no conflict of interest., (Copyright © 2023 American College of Occupational and Environmental Medicine.)

Transmission electron microscopy (TEM) enables users to study materials at their fundamental, atomic scale. Complex experiments routinely generate thousands of images with numerous parameters that require time-consuming and complicated analysis. AXON synchronicity is a machine-vision synchronization (MVS) software solution designed to address the pain points inherent to TEM studies. Once installed on the microscope, it enables the continuous synchronization of images and metadata generated by the microscope, detector, and in situ systems during an experiment. This connectivity enables the application of machine-vision algorithms that apply a combination of spatial, beam, and digital corrections to center and track a region of interest within the field of view and provide immediate image stabilization. In addition to the substantial improvement in resolution afforded by such stabilization, metadata synchronization enables the application of computational and image analysis algorithms that calculate variables between images. This calculated metadata can be used to analyze trends or identify key areas of interest within a dataset, leading to new insights and the development of more sophisticated machine-vision capabilities in the future. One such module that builds on this calculated metadata is dose calibration and management. The dose module provides state-of-the-art calibration, tracking, and management of both the electron fluence (e - /Å 2 ·s -1 ) and cumulative dose (e - /Å 2 ) that is delivered to specific areas of the sample on a pixel-by-pixel basis. This enables a comprehensive overview of the interaction between the electron beam and the sample. Experiment analysis is streamlined through a dedicated analysis software in which datasets consisting of images and corresponding metadata are easily visualized, sorted, filtered, and exported. Combined, these tools facilitate efficient collaborations and experimental analysis, encourage data mining and enhance the microscopy experience.

One factor that can contribute to the development of hypertrophic scar contracture is mechanical stress. Mechanical cyclic stretch stimuli enhance the secretion of endothelin-1 (ET-1) from keratinocyte. Cyclical stretching of fibroblasts also increases the expression level of the transient receptor potential ion channel (TRPC3), which is known to couple with the endothelin receptor and induce intracellular Ca2+ signaling via the calcineurin/nuclear factor of activated T cells (NFAT) pathway. The aim of this study was to investigate the relationship between keratinocytes and fibroblasts when they are stretched., Methods: The conditioned medium from stretched keratinocyte was added to the fibroblast populated collagen lattice. Then, we analyzed the levels of endothelin receptor in the human hypertrophic scar tissue and stretched fibroblasts. To address the function of TRPC3, we have used an overexpression system with the collagen lattice. Finally, the TRPC3 overexpressing fibroblasts were transplanted to mouse dorsal skin, and the rate of skin wound contraction was assessed., Results: Conditioned medium from stretched keratinocytes increased the rate of contraction of fibroblast populated collagen lattice. In human hypertrophic scar and stretched fibroblasts, endothelin receptor type B was increased. Cyclic stretching of TRPC3 overexpressing fibroblasts activated NFATc4, and stretched human fibroblasts showed more activation of NFATc4 in response to ET-1. The wound treated with TRPC3 overexpressing fibroblasts showed more contraction than control wound., Conclusion: These findings suggest that cyclical stretching of wounds have an effect on both keratinocytes and fibroblasts, where keratinocytes secret more ET-1, and fibroblasts develop more sensitivity to ET-1 by expressing more endothelin receptors and TRPC3., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. Financial support for this study was provided by JSPS KAKENHI (grant nos.: 16K15755, 20K09856) and Grant-in-Aid for Researchers, Hyogo Medical University, 2017–2018. Disclosure statements are at the end of this article, following the correspondence information., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25 years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Objective: Evaluation of circulating fibroblast growth factor 23 (FGF23) concentrations plays a key role in the differential diagnosis of patients presenting with hypophosphatemia. FGF23 concentrations obtained by different immunoassays are not comparable and subsequently, differences in the clinical performance of the assays might arise. In this study, we evaluated the clinical performance of the Medfrontier FGF23 Intact immunoassay (MedFrontier, Minaris Medical Co, Ltd, Tokyo, Japan) in clinically relevant hypophosphatemic conditions., Methods: Intact FGF23 (iFGF23) was measured in serum samples from 61 patients with FGF23-dependent hypophosphatemia (42-tumor induced osteomalacia [TIO] and 19-X-linked hypophosphatemia [XLH]); 8 patients with FGF23-independent hypophosphatemia (6-Fanconi Syndrome and 2-Vitamin D dependent rickets); 10 normophosphatemic patients; 15 chronic kidney disease (CKD) stage-2/3 and 20 CKD stage-4/5 patients; and a healthy control population. Disease-specific differences in measured iFGF23 concentrations and FGF23 concentration association with phosphate concentrations were reported., Results: iFGF23 concentrations were significantly elevated in 90% and 84% of TIO and XLH hypophosphatemia patients as compared to healthy controls (both TIO and XLH, P = .0001). There was no significant correlation between iFGF23 and phosphate concentrations (P = .74 and P = .86) for TIO and XLH, respectively. Patients with CKD showed a significant increase in serum iFGF23 as the estimated glomerular filtration rate decreased (ρ = -0.79, P ≤ 0.0001)., Conclusions: This study evaluated the clinical performance of the MedFrontier iFGF23 assay in a large cohort of XLH and TIO Caucasian and Asian patients. The clinical sensitivity of this iFGF23 assay is appropriate for clinical use., Competing Interests: Disclosure N.I. receives research support from Kyowa Kirin Co. Ltd. All other authors have no multiplicity of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Membrane type 1 matrix metalloproteinase (MT1-MMP) has been shown to be crucial for tumor angiogenesis, invasion, and metastasis, and thus MT1-MMP is a high priority target for potential cancer therapies. To properly evaluate MT1-MMP inhibitors, a screening protocol is desired by which enzyme activity can be quantified in a tumor microenvironment-like model system. In the present study, we applied a fluorogenic, collagen model triple-helical substrate to quantify MT1-MMP activity for tumor spheroids embedded in a collagen hydrogel. The substrate was designed to be MT1-MMP selective and to possess fluorescent properties compatible with cell-based assays. The proteolysis of the substrate correlated to glioma spheroid invasion. In turn, the application of either small molecule or protein-based MMP inhibitors reduced proteolytic activity and glioma spheroid invasion. The presence of MT1-MMP in glioma spheroids was confirmed by western blotting. Thus, spheroid invasion was dependent on MT1-MMP activity, and inhibitors of MT1-MMP and invasion could be conveniently screened in a high-throughput format. The combination of the fluorogenic, triple-helical substrate, the three-dimensional tumor spheroids embedded in collagen, and Hit-Pick software resulted in an easily adaptable in vivo-like tumor microenvironment for rapidly processing inhibitor potential for anti-cancer use.

Groin infections in vascular surgery are common and compromise the goal of limb preservation. Strategies to prevent deep space infection (DSI) include incision orientation and muscle flaps. Literature evaluating prophylactic flaps preventing DSI is scarce. We aimed to compare prophylactic sartorius flaps to layered closure in preventing readmission for DSI, along with the effect of incision orientation. This was a retrospective study of vascular surgery patients at a single institution with femoral artery exposure from 2017-2021. Patients with active groin infections were excluded. Prophylactic sartorius flaps were compared to those with layered closure regarding 30-day hospital readmission for DSI. Oblique versus vertical incisions was compared regarding the primary outcome. Fifty-three patients received sartorius flaps, and 122 received layered closure. Seventy patients had oblique incisions, and 105 patients had vertical incisions. Sartorius flaps had a higher rate of previous groin surgery compared to layered closure (45.3% vs. 24.7%, p<0.01). Vertical incisions had a higher rate of previous groin surgery (38.1% vs. 20.0%, p<0.02), while oblique incisions had a higher rate of obesity (24.3% vs. 8.6%, p<0.01). There was a lower rate of DSI in sartorius flaps compared to layered closure (1.9% vs. 6.6%, p=2.80), although not statistically significant due to lack of power. There was no difference in DSI in the oblique versus vertical incisions (4.3% and 5.7%, p=0.760). Patients with prophylactic sartorius flaps experienced fewer DSI, although further evaluation with increased sample size is required for adequate study power. We believe sartorius flaps are a simple solution to prevent groin complications., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Larson et al.)

We present a case of a giant phyllodes tumor (PT) requiring simple mastectomy with en bloc pectoralis major resection and immediate deep inferior epigastric perforator (DIEP) flap reconstruction. This patient presented with a four-year history of an enlarging breast mass with ultrasound-guided biopsy results consistent with atypical fibroepithelial proliferation that was highly concerning for a borderline phyllodes tumor. In this large, rare breast tumor that required en bloc pectoralis major resection, we describe the novel use of an immediate single pedicled DIEP flap for the resulting chest wall defect. The patient's postoperative course was uncomplicated, and she reported satisfactory cosmetic and functional outcomes at her initial postoperative follow-up visits. Our findings support the use of simple mastectomy with en bloc resection and immediate single-pedicled DIEP flap for the definitive treatment of giant phyllodes tumors. Our experience shows this is a safe and effective technique for achieving adequate oncologic resection while maintaining postoperative function and cosmesis, which are essential for patient quality of life., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Larson et al.)

Purpose: The aim of this study was to assess the effect of eight different facemasks on speech perception and listening effort in listeners with normal hearing (NH) and hearing loss by manipulating both mask type and background noise levels., Method: Forty adults listened to Quick Speech-in-Noise Test sentences recorded by a female talker through eight different facemasks including a baseline condition with no mask. Listeners were tested in the sound field positioned 6 ft from the loudspeaker. Signal-to-noise ratio (SNR) loss and listening effort were measured., Results: Listeners with NH exhibited a mild SNR loss, whereas those with hearing loss experienced a moderate SNR loss. Scores for the mild hearing loss group were significantly poorer (higher) than those with slight hearing loss. Speech perception performance was best in the no mask, KN95, and surgical mask conditions and poorest in the cloth mask and cloth mask plus face shield conditions for all groups. As listening effort decreased, speech perception increased for all groups., Conclusions: The impact of different types of facemasks on speech perception in noise was demonstrated in this study indicating that as the SNR was reduced, listening effort increased and speech perception performance decreased for listeners with NH and slight/mild hearing loss. No mask, KN95, and surgical masks had the least impact on performance, whereas cloth masks posed a significant detriment to communication. If communication is to occur in a background of noise while wearing masks, a KN95 mask and an SNR of at least +15 dB is recommended regardless of hearing status.

Purpose: Clear thermoplastic aligners have become popular in orthodontics, but the biomechanics of these devices is not well understood. Neither is the tooth movement induced by such devices. The aim of this study was to develop and validate finite element (FE) models for clear thermoplastic teeth aligners for orthodontic force prediction., Methods and Materials: FE models were created from Micro-CT scans of an aligner and a model arch of teeth with one of the incisors tipped buccal-lingually by 2.4°. The models were uniformly meshed with 0.3-mm long elements. Linear-elastic mechanical properties provided by the material manufacturers were used. Fitting of the two components was simulated using Abaqus's interference fit, followed by frictional surface-to-surface interaction. The assembled FE model was validated by comparing its prediction for the teeth-aligner gaps and aligner surface strains with experimental data. The experimental teeth-aligner gaps were obtained from the Micro-CT scans whereas the aligner surface strains were measured using a 2-camera digital image correlation (DIC) system., Results: Good agreement between prediction and measurement was obtained for both the teeth-aligner gaps and aligner surface strains. The linear regression between prediction and measurement for teeth-aligner gaps sampled at different positions had a R 2 value of 0.99. The mean difference between prediction and measurement for the aligner surface strains (von Mises) over 1544 nodes on the labial side and 1929 nodes on the lingual side was 0.07% and 0.01%, respectively, both being lower than the mean background noise., Conclusion: A FE model for clear thermoplastic teeth aligners has been successfully developed and validated. The model can therefore be used with confidence to predict the forces and moments applied to teeth by the aligners, thus improving our understanding of the biomechanics of such devices and the tooth movement they induce., Competing Interests: Declaration of competing interest 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Access to and the cost of induction treatment for cryptococcal meningitis (CM) is rapidly changing. The newly-announced price for flucytosine ($0.75 per 500 mg pill) and possibly lower prices for liposomal amphotericin B (AmB-L) create opportunities to reduce CM treatment costs compared to the current standard treatment in low- and middle-income countries. Methods: We developed an Excel-based cost model to estimate health system treatment costs for CM over a two-week induction phase for multiple treatment combinations, newly feasible with improved access to flucytosine and AmB-L. CM treatment costs include medications, laboratory tests and other hospital-based costs (bed-day costs and healthcare worker time). We report results from applying the model using country-specific information for South Africa, Uganda, Nigeria, and Botswana. Results: A 14-day induction-phase of seven days of inpatient AmB-D with flucytosine, followed by seven days of high-dose fluconazole as an outpatient, will cost health systems less than a 14-day hospital stay with AmB-D and fluconazole. If daily AmB-L replaces AmB-D for those with baseline renal dysfunction, with a cost of $50 or less per 50 mg vial, incremental costs would still be less than the AmB-D with fluconazole regimen. Simple oral combinations (e.g., seven days of flucytosine with fluconazole as an inpatient) are practical when AmB-D is not available, and treatment costs would remain less than the current standard treatment. Conclusions : Improved access to and lower prices for flucytosine and AmB-L create opportunities for improving CM treatment regimens. An induction regimen of flucytosine and AmB-D for seven days is less costly than standard care in the settings studied here. As this regimen has also been shown to be more effective than current standard care, countries should prioritize scaling up flucytosine access. The cost of AmB-L based regimens is highly dependent on the price of AmB-L, which currently remains unclear., Competing Interests: Competing interests: AS receives fees from the CDC foundation (Project 950) and the Drugs for Neglected Diseases Initiative (DNDi). All other authors declared no competing interests., (Copyright: © 2022 Larson B et al.)

Knowledge on the population history of endangered species is critical for conservation, but whole-genome data on chimpanzees ( Pan troglodytes ) is geographically sparse. Here, we produced the first non-invasive geolocalized catalog of genomic diversity by capturing chromosome 21 from 828 non-invasive samples collected at 48 sampling sites across Africa. The four recognized subspecies show clear genetic differentiation correlating with known barriers, while previously undescribed genetic exchange suggests that these have been permeable on a local scale. We obtained a detailed reconstruction of population stratification and fine-scale patterns of isolation, migration, and connectivity, including a comprehensive picture of admixture with bonobos ( Pan paniscus ). Unlike humans, chimpanzees did not experience extended episodes of long-distance migrations, which might have limited cultural transmission. Finally, based on local rare variation, we implement a fine-grained geolocalization approach demonstrating improved precision in determining the origin of confiscated chimpanzees., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Background: Given the ongoing battle with opioid abuse and overuse in the United States, new strategies are consistently being implemented to reduce opioid utilization and overprescribing., Objectives: The purpose of this study was to determine if a more regulated explicit pain management instruction plan could reduce the number of opioids taken., Methods: Blinded randomized prospective study comparing a total of 110 (Group A = 55, Group B = 55) women who underwent elective outpatient bilateral breast reduction surgery by 2 different plastic surgeons. Patients were randomly divided into either Group A (control) that received general pain management instructions or Group B (experimental) that received explicit pain management instructions from the surgeons and nurses. Participants were asked to record the number of times they treated their pain with each separate modality. They were also asked to record their average daily pain scale for the days that they were treating their pain., Results: Patients in Group B took on average 1.5 oxycodone (5 mg) and patients in Group A took on average 5.7 oxycodone (5 mg) (P < 0.01). Thirty-four patients in Group B took no oxycodone. Patients in Group B also had statistically significant lower subjective pain scores., Conclusions: Based on these results, it appears that standardizing how patients are instructed to treat their pain postoperatively may reduce the number of narcotics needed, thus reducing the number of narcotics prescribed without compromising pain control., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We present a case of a chronic perineal sinus following abdominoperineal resection with management via endoscopic electrocauterization. This patient presented with 1 year of bloody, mucus drainage from a perineal wound following abdominoperineal resection for anastomotic leak and stricture from a remote low anterior resection for T2N1 rectal cancer. We describe a novel use of endoscopic electrocautery to debride, de-epithelialize and ultimately eliminate the sinus cavity. The patient's postoperative course was uncomplicated and reported decreased drainage at 2- and 4-week postoperative follow-up. Long-term plans include sequential drain downsizing to facilitate cavity closure. Our findings suggest that endoscopic electrocauterization can safely and effectively reduce chronic perineal sinus drainage to facilitate cavity elimination, while avoiding morbidity associated with more invasive operative interventions., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2022.)

Introduction: Access to and the cost of induction treatment for cryptococcal meningitis (CM) is rapidly changing. The newly-announced price for flucytosine ($0.75 per 500 mg pill) and possibly lower prices for liposomal amphotericin B (AmB-L) create opportunities to reduce CM treatment costs compared to the current standard treatment in low- and middle-income countries. Methods: We developed an Excel-based cost model to estimate health system treatment costs for CM over a two-week induction phase for multiple treatment combinations, newly feasible with improved access to flucytosine and AmB-L. CM treatment costs include medications, laboratory tests and other hospital-based costs (bed-day costs and healthcare worker time). We report results from applying the model using country-specific information for South Africa, Uganda, Nigeria, and Botswana. Results: A 14-day induction-phase of seven days of inpatient AmB-D with flucytosine, followed by seven days of high-dose fluconazole as an outpatient, will cost health systems less than a 14-day hospital stay with AmB-D and fluconazole. If daily AmB-L replaces AmB-D for those with baseline renal dysfunction, with a cost of $50 or less per 50 mg vial, incremental costs would still be less than the AmB-D with fluconazole regimen. Simple oral combinations (e.g., seven days of flucytosine with fluconazole as an inpatient) are practical when AmB-D is not available, and treatment costs would remain less than the current standard treatment. Conclusions : Improved access to, and lower prices for flucytosine and AmB-L create opportunities for improving CM treatment regimens. An induction regimen of flucytosine and AmB-D for seven days is less costly than standard care in the settings studied here. As this regimen has also been shown to be more effective than current standard care, countries should prioritize scaling up flucytosine access. The cost of AmB-L based regimens is highly dependent on the price of AmB-L, which currently remains unclear., Competing Interests: Competing interests: AS receives fees from the CDC foundation (Project 950) and the Drugs for Neglected Diseases Initiative (DNDi). All other authors declared no competing interests., (Copyright: © 2022 Larson B et al.)

Background and Aim: The emergence of antibiotic resistance is a major problem worldwide. Antibiotics are often used to prevent or treat infections in livestock. This study aimed to investigate antibiotic resistance in enterococci in Gabonese livestock., Materials and Methods: We collected 174 animal samples (46 laying hens, 24 swine, 62 cattle, and 42 sheep) from farms in four provinces of Gabon. Bacterial strains belonging to the genus Enterococcus were obtained using selective media and polymerase chain reaction targeting the tuf gene. Antibiotic susceptibility was determined by the disk diffusion method on Mueller-Hinton agar., Results: Enterococci were present in 160 of the samples (97%), distributed as follows: laying hens (100%, 41/41), swine (100%, 22/22), small ruminants (88%, 37/42), and cattle (100%, 60/60). Resistance to cephalothin/cephalexin, streptomycin, and rifampicin (RIF) was high, and resistance to vancomycin (VAN), erythromycin, and tetracycline was moderate. A high diversity of resistance was found in Haut-Ogooué and Estuaire provinces. Laying hens and swine showed moderate levels of resistance to ciprofloxacin and penicillin, while sheep and cattle had high levels of resistance to RIF. All species showed a high level of resistance to VAN. We found various patterns of multiple resistances in the isolates, and the multiple resistance indexes ranged from 0.2 to 0.8., Conclusion: This study shows that livestock in Gabon can be considered potential reservoirs of resistance., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Desire, et al.)

More than 2.5 million people in the United States develop pressure injuries annually, which are one of the most common complications occurring in hospitals. Despite being common, hospital-acquired pressure injuries (HAPIs) are largely considered preventable by regular patient turning. Although current methodologies to prompt on-time repositioning have limited efficacy, a wearable patient sensor has been shown to optimize turning practices and improve clinical outcomes. The purpose of this study was to assess the cost-effectiveness of patient-wearable sensor in the prevention of HAPIs in acutely ill patients when compared to standard practice alone. A decision analytic model was developed to simulate the expected costs and outcomes from the payer's perspective using data from published literature, including a recently published randomized controlled trial. Both univariate and probabilistic sensitivity analysis were conducted. The patient-wearable sensor was found to be cost saving (dominant). It resulted in better clinical outcomes (77% reduction in HAPIs) compared to standard care and an expected cost savings of $6,621 per patient over a one-year period. Applying the model to a cohort of 1,000 patients, an estimated 203 HAPIs would be avoided with annualized cost reduction of $6,222,884 through all patient treatment settings. The probabilistic analysis returned similar results. In conclusion, the patient-wearable sensor was found to be cost-effective in the prevention of HAPIs and cost-saving to payers and hospitals. These results suggest that patient-wearable sensors should be considered as a cost-effective alternative to standard care in the prevention of HAPIs., (© 2021. The Author(s).)

Methods to enhance the ergogenic effects of music are of interest to athletes of all abilities. The aim of this pilot study was to investigate the ergogenic effects of two commercially available methods of music augmentation: auditory beats and vibrotactile stimulation. Six male and five female cyclists/triathletes cycled for 7 minutes at three different intensities: a rate of perceived exertion (RPE) of 11 ("light"), RPE of 15 ("hard"), and a 7-minute time-trial. Before each 7-minute bout of cycling, participants listened to 10 minutes of self-selected music (MUS), or the same music with the addition of either isochronic auditory beats (ABS) or vibrotactile stimulation via SUBPAC TM (VIB). MUS, ABS and VIB trials were performed in a randomized order. Power output was measured during cycling and felt arousal and feeling scores were recorded at timepoints throughout the protocol. The results found the augmented MUS interventions did not influence power output with no significant main effect of trial ( p = 0.44, η 2 = 0.09) or trial × cycling intensity interaction ( p = 0.11, η 2 = 0.20). Similarly, both felt arousal and feeling scores were unchanged between the MUS, ABS, and VIB trials ( p > 0.05). In conclusion, this pilot study indicated an ineffectiveness of the ABS and VIB to affect subsequent 7-min cycling performance compared to self-selected MUS alone., Competing Interests: BL was employed by Red Bull North America. The authors declare that this study received funding from Red Bull North America. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2021 Fry, Braren, Pitaro, Larson and Putrino.)

Introduction: Carcinosarcoma, also known as malignant mixed Mullerian tumor (MMMT) is a malignant biphasic neoplasm consisting of carcinomatous and malignant non-epithelial components of mesenchymal origin. MMMTs typically arise from the female genital tract in patients over 40 years old. Primary extragenital MMMTs are extremely rare with published literature totaling 40 reported cases. The primary peritoneal carcinosarcoma is an aggressive tumor as patients with this tumor have an average survival of 7.6 months. Surgical debulking is the mainstay of treatment for these tumors and systemic chemotherapy is advised in all cases. Case: A 48-year-old Amish female presented with 5 day history of bloating and abdominal pain superimposed on a 1 year history of worsening fatigue and intermittent bloody bowel movements. She was found to have a pelvic mass on physical exam. Computed tomography scan of the abdomen and pelvis that demonstrated stricturing of the sigmoid colon, and a large multi-cystic mass in the midline pelvis measuring 12.5 × 9.9 × 11.7 cm. Colonoscopy showed stenosis due to external compression without intraluminal lesion. CEA and CA 125 levels were elevated and CA 19-9 was normal. Exploratory laparotomy was performed with en-bloc resection of a 15 cm mass originating from the sigmoid colon mesentery with several other small tumor deposits throughout the mesentery. Pathology diagnosed primary peritoneal carcinosarcoma Mullerian-type with three positive lymph nodes. Conclusion: Malignant mixed Mullerian tumor (carcinosarcoma) caries a universally grim prognosis. Herein, we report a unique case of primary peritoneal carcinosarcoma and discuss the work-up and surgical management of this rare tumor., 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 © 2021 Erz, Smith, Larson and Ma.)

Background: During public health emergencies, people with opioid use disorder (PWOUD) may be particularly impacted. Emergent disasters such as the COVID-19 pandemic disrupt already-strained harm reduction efforts and treatment availability. This study aims to answer three research questions. How do public health emergencies impact PWOUD? How can health systems respond to novel public health emergencies to serve PWOUD? How can the results of this scoping review be contextualized to the province of Alberta to inform local stakeholder responses to the pandemic?, Methods: We conducted a scoping review using the 6-stage Arksey and O'Malley framework to analyse early-pandemic and pre-pandemic disaster literature. The results of the scoping review were contextualized to the local pandemic response, through a Nominal Group Technique (NGT) process with frontline providers and stakeholders in Alberta, Canada., Results: Sixty one scientific journal articles and 72 grey literature resources were included after full-text screening. Forty sources pertained to early COVID-19 responses, and 21 focused on OUD treatment during other disasters. PWOUD may be more impacted than the general population by common COVID-19 stressors including loss of income, isolation, lack of rewarding activities, housing instability, as well as fear and anxiety. They may also face unique challenges including threats to drug supplies, stigma, difficulty accessing clean substance use supplies, and closure of substance use treatment centres. All of these impacts put PWOUD at risk of negative outcomes including fatal overdose. Two NGT groups were held. One group (n = 7) represented voices from urban services, and the other (n = 4) Indigenous contexts. Stakeholders suggested that simultaneous attention to multiple crises, with adequate resources to allow attention to both social and health systems issues, can prepare a system to serve PWOUD during disasters., Conclusion: This scoping review and NGT study uncovers how disasters impact PWOUD and offers suggestions for better serving PWOUD., (© 2021. The Author(s).)

We present a rare case of recurrent primary midgut volvulus in an elderly female with an interesting intraoperative finding of an abnormally elongated small bowel mesentery. This patient presented with symptoms of obstruction, including nausea, vomiting and obstipation, similar to previous episodes of volvulus for which she underwent exploratory laparotomies and reduction of the volvulus. We describe a novel use for enteropexy in which we effectively shortened the small bowel mesentery in an effort to eliminate the source of recurrent volvulus. The patient's post-operative course was complicated by prolonged ileus requiring total parenteral nutrition. However, she had not developed signs or symptoms of bowel ischemia or recurrent volvulus at the time of this writing. Our findings suggest that enteropexy is an effective technique for preventing recurrent midgut volvulus primarily caused by abnormally elongated mesentery., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2021.)

Understanding variation in host-associated microbial communities is important given the relevance of microbiomes to host physiology and health. Using 560 fecal samples collected from wild chimpanzees (Pan troglodytes) across their range, we assessed how geography, genetics, climate, vegetation, and diet relate to gut microbial community structure (prokaryotes, eukaryotic parasites) at multiple spatial scales. We observed a high degree of regional specificity in the microbiome composition, which was associated with host genetics, available plant foods, and potentially with cultural differences in tool use, which affect diet. Genetic differences drove community composition at large scales, while vegetation and potentially tool use drove within-region differences, likely due to their influence on diet. Unlike industrialized human populations in the United States, where regional differences in the gut microbiome are undetectable, chimpanzee gut microbiomes are far more variable across space, suggesting that technological developments have decoupled humans from their local environments, obscuring regional differences that could have been important during human evolution. IMPORTANCE Gut microbial communities are drivers of primate physiology and health, but the factors that influence the gut microbiome in wild primate populations remain largely undetermined. We report data from a continent-wide survey of wild chimpanzee gut microbiota and highlight the effects of genetics, vegetation, and potentially even tool use at different spatial scales on the chimpanzee gut microbiome, including bacteria, archaea, and eukaryotic parasites. Microbial community dissimilarity was strongly correlated with chimpanzee population genetic dissimilarity, and vegetation composition and consumption of algae, honey, nuts, and termites were potentially associated with additional divergence in microbial communities between sampling sites. Our results suggest that host genetics, geography, and climate play a far stronger role in structuring the gut microbiome in chimpanzees than in humans.

Introduction: Access to and the cost of induction treatment for cryptococcal meningitis (CM) is rapidly changing. The newly-announced price for flucytosine ($0.75 per 500 mg pill) and possibly lower prices for liposomal amphotericin B (AmB-L) create opportunities to reduce CM treatment costs compared to the current standard treatment in low- and middle-income countries. Methods: We developed an Excel-based cost model to estimate health system treatment costs for CM over a two-week induction phase for multiple treatment combinations, newly feasible with improved access to flucytosine and AmB-L. CM treatment costs include medications, laboratory tests and other hospital-based costs (bed-day costs and healthcare worker time). We report results from applying the model using country-specific information for South Africa, Uganda, Nigeria, and Botswana. Results: A 14-day induction-phase of seven days of inpatient AmB-D with flucytosine, followed by seven days of high-dose fluconazole as an outpatient, will cost health systems less than a 14-day hospital stay with AmB-D and fluconazole. If daily AmB-L replaces AmB-D for those with baseline renal dysfunction, with a cost of $50 or less per 50 mg vial, incremental costs would still be less than the AmB-D with fluconazole regimen. Simple oral combinations (e.g., seven days of flucytosine with fluconazole as an inpatient) are practical when AmB-D is not available, and treatment costs would remain less than the current standard treatment. Conclusions : Improved access to, and lower prices for flucytosine and AmB-L create opportunities for improving CM treatment regimens. An induction regimen of flucytosine and AmB-D for seven days is less costly than standard care in the settings studied here. As this regimen has also been shown to be more effective than current standard care, countries should prioritize scaling up flucytosine access. The cost of AmB-L based regimens is highly dependent on the price of AmB-L, which currently remains unclear., Competing Interests: Competing interests: AS receives fees from the CDC foundation (Project 950) and the Drugs for Neglected Diseases Initiative (DNDi). All other authors declared no competing interests., (Copyright: © 2021 Larson B et al.)

Objectives : A significant gap in our knowledge concerns sexual health among the older lesbian, gay, and bisexual (LGB) population. Methods : We compared a community-based sample of self-identified LGB older adults (n = 128) with population-based samples of behaviorally-defined LGB older adults (i.e., reporting same-sex experiences) (n = 112) and behaviorally-defined older heterosexuals (i.e., reporting no same-sex experiences) (n = 2,893) from the National Social Life, Health and Aging Project (NSHAP). Differences in sexual activity and sexual problems were examined. Results : Older LGB adults were as likely to remain sexually active as older heterosexuals. Gay and bisexual men were more likely than heterosexual men to report some sexual problems. Regardless of sexual orientation, older adults rarely had their sexual health needs addressed in healthcare settings. Conclusions : Results highlight the need for more research on LGB older adult sexual health. Clinical Implications : The lack of attention to LGB older adults' sexual health in healthcare settings may be exacerbated by ageism and heterosexism, leading these individuals to avoid disclosing their sexual orientations and avoid conversations about sexuality. Mental health practitioners require education on associations between sexual health and mental health, and how sexual health problems may contribute to mental health concerns in vulnerable populations like older LGB adults.

Depressurization and sample processing delays may impact the outcome of shipboard microbial incubations of samples collected from the deep sea. To address this knowledge gap, we developed a remotely operated vehicle (ROV)-powered incubator instrument to carry out and compare results from in situ and shipboard RNA stable isotope probing (RNA-SIP) experiments to identify the key chemolithoautotrophic microbes and metabolisms in diffuse, low-temperature venting fluids from Axial Seamount. All the incubations showed microbial uptake of labeled bicarbonate primarily by thermophilic autotrophic Epsilonbacteraeota that oxidized hydrogen coupled with nitrate reduction. However, the in situ seafloor incubations showed higher abundances of transcripts annotated for aerobic processes, suggesting that oxygen was lost from the hydrothermal fluid samples prior to shipboard analysis. Furthermore, transcripts for thermal stress proteins such as heat shock chaperones and proteases were significantly more abundant in the shipboard incubations, suggesting that depressurization induced thermal stress in the metabolically active microbes in these incubations. Together, the results indicate that while the autotrophic microbial communities in the shipboard and seafloor experiments behaved similarly, there were distinct differences that provide new insight into the activities of natural microbial assemblages under nearly native conditions in the ocean. IMPORTANCE Diverse microbial communities drive biogeochemical cycles in Earth's ocean, yet studying these organisms and processes is often limited by technological capabilities, especially in the deep ocean. In this study, we used a novel marine microbial incubator instrument capable of in situ experimentation to investigate microbial primary producers at deep-sea hydrothermal vents. We carried out identical stable isotope probing experiments coupled to RNA sequencing both on the seafloor and on the ship to examine thermophilic, microbial autotrophs in venting fluids from an active submarine volcano. Our results indicate that microbial communities were significantly impacted by the effects of depressurization and sample processing delays, with shipboard microbial communities being more stressed than seafloor incubations. Differences in metabolism were also apparent and are likely linked to the chemistry of the fluid at the beginning of the experiment. Microbial experimentation in the natural habitat provides new insights into understanding microbial activities in the ocean., (Copyright © 2021 Fortunato et al.)

Pressure injuries are one of the most common and costly complications occurring in US hospitals. With up to 3 million patients affected each year, hospital-acquired pressure injuries (HAPIs) place a substantial burden on the US healthcare system. In the current study, US hospital discharge records from 9.6 million patients during the period from October 2009 through September 2014 were analysed to determine the incremental cost of hospital-acquired pressure injuries by stage. Of the 46 108 patients experiencing HAPI, 16.3% had Stage 1, 41.0% had Stage 2, 7.0% had Stage 3, 2.8% had Stage 4, 7.3% had unstageable, 14.6% had unspecified, and 10.9% had missing staging information. In propensity score-adjusted models, increasing HAPI severity was significantly associated with higher total costs and increased overall length of stay when compared with patients not experiencing a HAPI at the index hospitalisation. The average incremental cost for a HAPI was $21 767. Increasing HAPI severity was significantly associated with greater risk of in-hospital mortality at the index hospitalisation compared with patients with no HAPI, as well as 1.5 to 2 times greater risk of 30-, 60-, and 90-day readmissions. Additionally, increasing HAPI severity was significantly associated with increasing risk of other hospital-acquired conditions, such as pneumonia, urinary tract infections, and venous thromboembolism during the index hospitalisation. By preventing pressure injuries, hospitals have the potential to reduce unreimbursed treatment expenditures, reduce length of stay, minimise readmissions, prevent associated complications, and improve overall outcomes for their patients., (© 2020 Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Large brains and behavioural innovation are positively correlated, species-specific traits, associated with the behavioural flexibility animals need for adapting to seasonal and unpredictable habitats. Similar ecological challenges would have been important drivers throughout human evolution. However, studies examining the influence of environmental variability on within-species behavioural diversity are lacking despite the critical assumption that population diversification precedes genetic divergence and speciation. Here, using a dataset of 144 wild chimpanzee (Pan troglodytes) communities, we show that chimpanzees exhibit greater behavioural diversity in environments with more variability - in both recent and historical timescales. Notably, distance from Pleistocene forest refugia is associated with the presence of a larger number of behavioural traits, including both tool and non-tool use behaviours. Since more than half of the behaviours investigated are also likely to be cultural, we suggest that environmental variability was a critical evolutionary force promoting the behavioural, as well as cultural diversification of great apes.

Background: The Woza Asibonisane Community Responses (CR) Programme was developed to prevent HIV infections and gender-based violence (GBV) within four provinces in South Africa. The Centre for Communication Impact (CCI) in collaboration with six partner non-governmental organizations (NGOs) implemented the programme, which was comprised of multiple types of group discussion and education activities organized and facilitated by each NGO. To date, little information exists on the cost of implementing such multi-objective, multi-activity, community-based programmes. To address this information gap, we estimated the annual cost of implementing the CR Programme for each NGO., Methods: We used standard methods to estimate the costs for each NGO, which involved a package of multiple activities targeted to distinct subpopulations in specific locations. The primary sources of information came from the implementing organizations. Costs (US dollars, 2017) are reported for each partner for one implementation year (the U.S. Government fiscal year (10/2016-09/2017). In addition to total costs disaggregated by main input categories, a common metric--cost per participant intervention hour--is used to summarize costs across partners., Results: Each activity included in the CR program involve organizing and bringing together a group of people from the target population to a location and then completing the curriculum for that activity. Activities were held in community settings (meeting hall, community center, sports grounds, schools, etc.). The annual cost per NGO varied substantially, from $260,302 to $740,413, as did scale based on estimated total participant hours, from 101,703 to 187,792 participant hours. The cost per participant hour varied from $2.8-$4.6, with NGO labor disaggregated into salaries for management and salaries for service delivery (providing the activity curriculum) contributing to the largest share of costs per participant hour., Conclusions: The cost of implementing any community-based program depends on: (1) what the program implements; (2) the resources used; and (3) unit costs for such resources. Reporting on costs alone, however, does not provide enough information to evaluate if the costs are 'too high' or 'too low' without a clearer understanding of the benefits produced by the program, and if the benefits would change if resources (and therefore costs) were changed.

Targeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack of understanding of how these therapies affect the unsuspecting bystanders of the stromal microenvironment. Cetuximab, a monoclonal antibody therapy targeting the epidermal growth factor receptor (EGFR), is given in combination with chemotherapy as the standard of care for a subset of metastatic colorectal cancer patients. The overall response to this treatment is underwhelming and, while genetic mutations that confer resistance have been identified, it is still not known why this drug is ineffective for some patients. We discovered that cancer-associated fibroblasts (CAFs), a major cellular subset of the tumor stroma, can provide a source of cancer cell resistance. Specifically, we observed that upon treatment with cetuximab, CAFs increased their secretion of EGF, which was sufficient to render neighboring cancer cells resistant to cetuximab treatment through sustained mitogen-activated protein kinases (MAPK) signaling. Furthermore, we show the cetuximab-induced EGF secretion to be specific to CAFs and not to cancer cells or normal fibroblasts. Altogether, this work emphasizes the importance of the tumor microenvironment and considering the potential unintended consequences of therapeutically targeting cancer-driving proteins on non-tumorigenic cell types.

Background: Individuals who are homeless or vulnerably housed are at an increased risk for mental illness, other morbidities and premature death. Standard case management interventions as well as more intensive models with practitioner support, such as assertive community treatment, critical time interventions, and intensive case management, may improve healthcare navigation and outcomes. However, the definitions of these models as well as the fidelity and adaptations in real world interventions are highly variable. We conducted a systematic review to examine the effectiveness and cost-effectiveness of case management interventions on health and social outcomes for homeless populations., Methods and Findings: We searched Medline, Embase and 7 other electronic databases for trials on case management or care coordination, from the inception of these databases to July 2019. We sought outcomes on housing stability, mental health, quality of life, substance use, hospitalization, income and employment, and cost-effectiveness. We calculated pooled random effects estimates and assessed the certainty of the evidence using the GRADE approach. Our search identified 13,811 citations; and 56 primary studies met our full inclusion criteria. Standard case management had both limited and short-term effects on substance use and housing outcomes and showed potential to increase hostility and depression. Intensive case management substantially reduced the number of days spent homeless (SMD -0.22 95% CI -0.40 to -0.03), as well as substance and alcohol use. Critical time interventions and assertive community treatment were found to have a protective effect in terms of rehospitalizations and a promising effect on housing stability. Assertive community treatment was found to be cost-effective compared to standard case management., Conclusions: Case management approaches were found to improve some if not all of the health and social outcomes that were examined in this study. The important factors were likely delivery intensity, the number and type of caseloads, hospital versus community programs and varying levels of participant needs. More research is needed to fully understand how to continue to obtain the increased benefits inherent in intensive case management, even in community settings where feasibility considerations lead to larger caseloads and less-intensive follow-up., Competing Interests: David Ponka, Claire Kendall, Vicky Stergiopoulos, Anne Andermann, Peter Tugwell and Kevin Pottie are principal investigators in an ongoing project to develop Canadian evidence-based guidelines for providing social programs and healthcare services to people who are homeless and vulnerably housed. Terry Hannigan was paid an honorarium by the Bruyère Research Institute to provide consultations on this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors declare no other conflicts of interest.

Micronuclei are small, extranuclear bodies that are distinct from the primary cell nucleus. Micronucleus formation is an aberrant event that suggests a history of genotoxic stress or chromosome mis-segregation events. Accordingly, assays evaluating micronucleus formation serve as useful tools within the fields of toxicology and oncology. Here, we describe a novel micronucleus formation assay that utilizes a high-throughput imaging platform and automated image analysis software for accurate detection and rapid quantification of micronuclei at the single cell level. We show that our image analysis parameters are capable of identifying dose-dependent increases in micronucleus formation within three distinct cell lines following treatment with two established genotoxic agents, etoposide or bleomycin. We further show that this assay detects micronuclei induced through silencing of the established chromosome instability gene, SMC1A . Thus, the micronucleus formation assay described here is a versatile and efficient alternative to more laborious cytological approaches, and greatly increases throughput, which will be particularly beneficial for large-scale chemical or genetic screens.