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Alcohol use disorder (AUD) poses a significant public health concern, with limited, high-efficacy, treatment options. Our lab has demonstrated that minocycline, an antibiotic with neuroprotective and immunomodulatory properties, is effective in reducing alcohol consumption in rodent models. We then synthesized antimicrobial-free minocycline derivatives to utilize their neuroprotective and immunomodulatory activities while mitigating antibiotic-related side effects. 10-Butyl Ether Minocycline (BEM) was chosen as a lead molecule based on efficacy and physicochemical properties from the library of compounds synthesized. Here, we report that BEM significantly reduced alcohol consumption in the Chronic Intermittent Ethanol (CIE) mouse model of alcohol dependence. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy and aggression affect up to 90% of Alzheimer's disease (AD) patients. These symptoms significantly increase caregiver stress and institutionalization rates, and more importantly they are correlated with faster cognitive decline. However, the neuronal basis of NPS in AD remains largely unknown. Here, we review current understanding of NPS and related pathology in studies of AD patients and AD mouse models. Clinical studies indicate that NPS prevalence and severity vary across different AD stages and types. Neuroimaging and postmortem studies have suggested that pathological changes in the anterior cingulate cortex, hippocampus, prefrontal cortex, and amygdala are linked to NPS, although the precise mechanisms remain unclear. Studies of AD mouse models have indicated that amyloid-beta and tau-related neurodegeneration in the hippocampus, prefrontal cortex, and anterior cingulate cortex are correlated with NPS-like behavioral deficits. A better understanding of the NPS phenotypes and related pathological changes will pave the way for developing a better management strategy for NPS in AD patients. [ABSTRACT FROM AUTHOR]

Introduced by the Hatch‐Waxman Amendments of 1984, 505(b)(2) applications permit the US Food and Drug Administration to rely, for approval of a new drug application, on information from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. This pathway is designed to circumvent the unnecessary duplication of studies already conducted on a previously approved drug. It can lead to a considerably more efficient and expedited route to approval compared to a traditional development path. Model‐informed drug development refers to the utilization of a diverse array of quantitative models in drug development to streamline the decision‐making process. In this approach, diverse quantitative models that integrate knowledge of physiology, disease processes, and drug pharmacology are employed to address drug development challenges and guide regulatory decisions. Integration of these model‐informed approaches into 505(b)(2) regulatory submissions and decision‐making can further expedite the approval of new drugs. This article discusses some applications of model‐informed approaches that were used to support 505(b)(2) drug development and regulatory actions. Specifically, various quantitative models such as population pharmacokinetic and exposure‐response models have been employed to provide evidence of effectiveness, guide dosing in subgroups such as subjects with hepatic or renal impairment, and inform policies. These case study examples collectively underscore the significance of model‐informed approaches in drug development and regulatory decisions associated with 505(b)(2) submissions. [ABSTRACT FROM AUTHOR]

Gulf War Illness (GWI) afflicts US military personnel who served in the Persian Gulf War. Suspect causal agents include exposure to pyridostigmine (PB), permethrin (PM) and N,N-diethyl-m-toluamide (DEET). Prominent symptoms include cognitive deficits, such as memory impairment. In aging animal models, we have documented the beneficial effect of the flavanol (-)-epicatechin (Epi) on hippocampus structure and related function. Using a rat model of GWI, we examined the effects of Epi on hippocampus inflammation, oxidative stress, mitochondrial dysfunction, cell death/survival pathways, and memory endpoints. Male Wistar rats underwent 3 weeks of exposure to either vehicles or DEET, PM, PB, and stress. Subgroups of GWI rats were then allocated to receive orally 15 days of either water (vehicle) or 1 mg/kg/day of Epi treatment. Object recognition tasks were performed to assess memory. Hippocampus samples were analyzed. Epi treatment yields significant improvements in short- and long-term memory versus GWI rats. Hippocampus oxidative stress and pro-inflammatory cytokine levels showed significant increases with GWI that were largely normalized with Epi becoming comparable to controls. Significant increases in markers of hippocampus neuroinflammation and cell death were noted with GWI and were also largely reduced with Epi. Neuronal survival signaling pathways were adversely impacted by GWI and were partially or fully restored by Epi. Markers of mitochondrial function were adversely impacted by GWI and were fully restored by Epi. In conclusion, in an animal model of GWI, Epi beneficially impacts recognized markers of hippocampus neuroinflammation, oxidative stress, cell survival, neurotoxicity and mitochondrial function leading to improved memory. [ABSTRACT FROM AUTHOR]

Background: Limited treatment options exist for damaged nerves and despite impressive advances in tissue engineering, scientists and clinicians have yet to fully replicate nerve development and recruitment. Innervation is a critical feature for normal organ function. While most organs are innervated prior to birth, a rare example of postnatal nerve recruitment occurs in the natural development of secondary teeth during adolescence. Many animals undergo postnatal shedding of deciduous teeth with development and eruption of secondary teeth, a process requiring recruitment of nerve and vasculature to each tooth pulp for viability. Here, the investigators created a novel model for the study of postnatal innervation by exploiting the natural phenomenon of tooth-driven nerve recruitment. Methods: The investigators theorized that developing teeth possess a special capacity to induce innervation which could be harnessed in a clinical setting for nerve regeneration, and hyptothesized that a transplant model could be created to capture this phenomenon. In this descriptive study, a rat model of autologous tooth transplantation and de novo nerve recruitment was developed by surgically transferring whole developing molars to the autologous tibia. Results: Downstream histological analysis performed 6 to 14 weeks after surgery demonstrated integration of molar into tibia in 81% of postoperative rats, with progressive pulpal expression of nerve marker ß-tubulin III suggestive of neuronal recruitment. Conclusions: These findings provide a novel model for the study of organ transplantation and support the theory that developing dental tissues may retain nerve-inductive properties postnatally. [ABSTRACT FROM AUTHOR]

Objective: To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years. Background: Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely. Methods: The Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health‐care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period. Results: Twenty‐five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non‐pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods. Conclusions: These research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise. Plain Language Summary: The American Headache Society led a large, international, multistakeholder process to identify headache research topics that should be prioritized during the next 10 years. With input from headache clinicians, scientists, people with headache, representatives from headache organizations, health‐care industry representatives, and the public, 25 research priorities within 8 categories were identified. These research priorities can help guide headache researchers when planning their studies and as benchmarks by which the headache field can measure its progress over time. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic osteoarthritis (PTOA) arises secondarily to joint trauma and is driven by catabolic inflammatory pathways. Alpha-2-macroglobulin (α2M) is a naturally occurring proteinase inhibitor found in human serum and synovial fluid that binds proteases as well as proinflammatory cytokines involved in the pathogenesis of PTOA. Purpose: (1) To investigate the therapeutic potential of intra-articular α2M injections during the acute stages of PTOA by inhibiting inflammatory pathways driven by the cytokines expressed by the synovium in a large preclinical Yucatan minipig model and (2) to determine if 3 intra-articular α2M injections have greater chondroprotective effects compared with 1 intra-articular injection. Study Design: Controlled laboratory study. Methods: A total of 48 Yucatan minipigs were randomized into 4 groups (n = 12 each): (1) modified intra-articular drilling (mIAD) and saline (mIAD + saline), (2) mIAD and 1 intra-articular α2M injection (mIAD +α2M-1), (3) mIAD and 3 α2M injections (mIAD +α2M-3), and (4) sham control. Surgical hindlimbs were harvested at 15 weeks after surgery. Cartilage degeneration, synovial changes, inflammatory gene expression, and matrix metalloproteinase levels were evaluated. Gait asymmetry was measured before and after surgery using a pressure-sensing walkway system. Results: Macroscopic lesion areas and microscopic cartilage degeneration scores were lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P <.05) and similar to those in the sham group (P >.05). Synovial membrane scores of the mIAD +α2M-1 and mIAD +α2M-3 groups were lower than that of the mIAD + saline group (P <.05) and higher than that of the sham group (P <.05). Interleukin-1 beta, nuclear factor kappa B, and tumor necrosis factor alpha mRNA expression in the synovium and matrix metalloproteinase-1 levels in synovial fluid were significantly lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P <.05). No significant differences were observed between the mIAD +α2M-1 and mIAD +α2M-3 groups for all measured outcomes. There were early changes in gait (P <.05) between preoperative and postoperative time points for the mIAD + saline, mIAD +α2M-1, and mIAD +α2M-3 groups that normalized by 15 weeks. Conclusion: Animals receiving early α2M treatment exhibited less cartilage damage, milder synovitis, and lower inflammation compared with animals with no α2M treatment. These results exemplify the early anti-inflammatory effects of α2M and provide evidence that intra-articular α2M injections may slow the progression of PTOA. Clinical Relevance: In patients presenting with an acute joint injury, an early intervention with α2M may have the potential to reduce cartilage degeneration from catabolic pathways and delay the development of PTOA. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockade has shown remarkable efficacy across various cancers but has failed to improve outcomes in patients with relapsed medulloblastoma (MB). While it is thought that the cold, immunosuppressive tumor microenvironment of MB accounts for this poor efficacy, the precise mechanisms contributing to immune suppression in this context remain unclear. In this study, we explore the immune landscape of MB using a previously unexplored syngeneic mouse model. Our study demonstrates that this model faithfully recapitulates the cold, immunosuppressive tumor microenvironment observed in human disease. Importantly, our research uncovers mechanisms employed by myeloid cells and tumor cells to evade immune detection while highlighting the therapeutic potential of targeting V-domain Ig Suppressor of T-cell Activation (VISTA), a novel inhibitory immune checkpoint, to enhance anti-tumor immunity. Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor–cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA–VSIG axis to enhance anti-tumor responses. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the predominant cause of dementia on a global scale, significantly impacting the health of the elderly population. The pathogenesis of AD is closely linked to neuroinflammation. The present study employs a bibliometric analysis to examine research pertaining to neuroinflammation and AD within the last decade, with the objective of providing a comprehensive overview of the current research profile, hotspots and trends. Methods: This research conducted a comprehensive review of publications within the Science Citation Index Expanded of the Web of Science Core Collection Database spanning the years 2014 to 2024. Bibliometric analyses were performed using VOSviewer (version 1.6.19) and CiteSpace (version 6.3.R1) software to visualize data on countries, institutions, authors, journals, keywords, and references. Results: A total of 3,833 publications on neuroinflammation and AD were included from January 2014 to January 2024. Publications were mainly from the United States and China. Zetterberg, Henrik emerged as the author with the highest publication output, while Edison, Paul was identified as the most cited author. The most productive journal was Journal of Alzheimers Disease, and the most co-cited was Journal of Neuroinflammation. Research hotspot focused on microglia, mouse models, oxidative stress, and amyloid-beta through keyword analysis. Additionally, keywords such as blood-brain barrier and tau protein exhibited prolonged citation bursts from 2022 to 2024. Conclusion: This study provides a comprehensive review of the last 10 years of research on neuroinflammation and AD, including the number and impact of research findings, research hotspots, and future trends. The quantity of publications in this field is increasing, mainly in the United States and China, and there is a need to further strengthen close cooperation with different countries and institutions worldwide. Presently, research hotspots are primarily concentrated on microglia, with a focus on inhibiting their pro-inflammatory responses and promoting their anti-inflammatory functions as a potential direction for future investigations. [ABSTRACT FROM AUTHOR]

Introduction: The goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)- associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of neurodegenerative tauopathy and Alzheimer's disease (AD). Methods: We used LC-MS/MS, ELISA and bioinformatic approaches to investigate the effect of treatment with fasudil on the brain proteomic profile in PS19 tau transgenic mice. We also explored the efficacy of fasudil in reducing tau phosphorylation, and the potential beneficial and/or toxic effects of its administration in mice. Results: Proteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood-brain barrier (BBB) gap junction metabolic pathways. We also observed a significant negative correlation between the brain levels of phosphorylated tau (pTau) at residue 396 and both fasudil and its metabolite hydroxyfasudil. Conclusions: Our results provide evidence on the activation of proteins and pathways related to mitochondria and BBB functions by fasudil treatment and support its further development and therapeutic potential for AD. [ABSTRACT FROM AUTHOR]

Baicalin has been acknowledged for its anti-inflammatory properties. However, its potential impact on osteoarthritis (OA) has not yet been explored. Therefore, our study aimed to examine the effects of Baicalin on OA, both in laboratory and animal models. To evaluate its efficacy, human chondrocytes affected by OA were treated with interleukin-1β and/or Baicalin. The effects were then assessed through viability tests using the cell counting kit-8 (CCK-8) method and flow cytometry. In addition, we analyzed the expressions of various factors such as FOXO1, autophagy, apoptosis, and cartilage synthesis and breakdown to corroborate the effects of Baicalin. We also assessed the severity of OA through analysis of tissue samples. Our findings demonstrate that Baicalin effectively suppresses inflammatory cytokines and MMP-13 levels caused by collagenase-induced osteoarthritis, while simultaneously preserving the levels of Aggrecan and Col2. Furthermore, Baicalin has been shown to enhance autophagy. Through the use of FOXO1 inhibitors, lentivirus-mediated knockdown, and chromatin immunoprecipitation, we verified that Baicalin exerts its protective effects by activating FOXO1, which binds to the Beclin-1 promoter, thereby promoting autophagy. In conclusion, our results show that Baicalin has potential as a therapeutic agent for treating OA (Clinical Trial Registration number: 2023-61). [ABSTRACT FROM AUTHOR]

Herbal-induced liver injury (HILI) continues to increase in prevalence each year due to the ongoing popularity of herbal supplements and complementary and alternative medicines. A detailed literature review of case reports and clinical studies published from March 2021 to March 2023 was performed. We discuss the epidemiology and diagnosis of HILI as well as the current and proposed laws and regulations. The 2021 ACG guidelines and 2022 AASLD practice guidelines for the diagnosis and management of drug and herbal-induced liver injury are discussed. We describe updates to previously reported etiologies of HILI such as ayurveda, ashwagandha, turmeric, kratom, green tea extract, and garcinia cambogia. Newly described supplements resulting in HILI, such as tinospora cordifolia, horse chestnut, alkaline water, and more, are described. We discuss newly and previously identified hepatoprotective herbal supplements as they have been reported in the study of animal models and human liver cells. This review suggests the need for ongoing research on the causes and mechanisms of HILI to ensure its proper diagnosis, prevention, and treatment in the future. The goal of this review is to provide novice and expert readers with knowledge regarding the possible etiologies of HILI and a general overview. [ABSTRACT FROM AUTHOR]

Rare cancers and other rare nonmalignant tumors comprise 25% of all cancer diagnoses and account for 25% of all cancer deaths. They are difficult to study due to many factors, including infrequent occurrence, lack of a universal infrastructure for data and/or tissue collection, and a paucity of disease models to test potential treatments. For each individual rare cancer, the limited number of diagnosed cases makes it difficult to recruit sufficient patients for clinical studies, and rare cancer research studies are often siloed. As a result, progress has been slow for many of these cancers. While rare cancer research efforts have increased over time, the breadth of the research landscape is not known. A recent literature search revealed a sharp increase in rare tumor, and rare cancer publications began in the early 2000s. To identify rare cancer research efforts being conducted in the US and globally, we conducted an online search of rare tumor/rare cancer research programs and identified 76 programs. To gain a deeper understanding of these programs, we composed and conducted a survey to ask programs for details about their research efforts. Of the 42 programs contacted to complete the survey, 23 programs responded. Survey results show most programs are collecting clinical data, molecular data, and biospecimens, and many are conducting molecular analyses. This landscape analysis demonstrates that multiple rare cancer research efforts are ongoing, and the rare cancer community may benefit from collaboration among stakeholders to accelerate research and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Small cell lung cancer (SCLC) is the most malignant lung cancer type. Due to the high rates of metastasis and drug resistance, effective therapeutic strategies remain lacking. Tanshinone IIA (Tan IIA) has been reported to exhibit anti-tumor activity. Therefore, this study investigated the ability and underlying mechanism of Tan IIA to inhibit the metastasis and proliferation of SCLC. Methods: H1688 and H446 cells were treated in vitro with Tan IIA (0, 1, 2 and 4 µM) or LY294002 (10 µM) for 24, 48, 72 h. H1688 and H446 cell migration was evaluated in wound healing and transwell migration assays. RNA-sequencing helped assess gene expression. BALB/c nude mice were injected with H1688 cells and treated with the Tan IIA group (10 mg/kg/day) or a control. Expression of E-cadherin, vimentin and PI3K/Akt signaling pathway proteins in tumors and H1688 was investigated by immunohistochemical analysis and western blot. Results: Tan IIA inhibited H1688 and H446 cell proliferation without inducing apoptosis and suppressed H1688 and H446 cell migration. E-cadherin expression was increased, while vimentin expression was reduced after administration of Tan IIA. RNA-sequencing revealed that some genes related with the PI3K/Akt signaling pathway were altered using Tan IIA treatment. Furthermore, western blot helped detect PI3K and p-Akt expression was also reduced by Tan IIA treatment. Tan IIA inhibited tumor growth in vivo. Moreover, Tan IIA increased tumoral expression of E-cadherin accompanied by PI3K and p-Akt downregulation. Conclusion: Tan IIA suppresses SCLC proliferation and metastasis by inhibiting the PI3K/Akt signaling pathway, thereby highlighting the potential of Tan IIA as a new and relatively safe drug candidate to treat SCLC. [ABSTRACT FROM AUTHOR]

Dementia remains one of the leading causes of morbidity and mortality in older adults. Alzheimer's disease (AD) is the most common type of dementia, affecting over 55 million people worldwide. AD is characterized by distinct neurobiological changes, including amyloid-beta protein deposits and tau neurofibrillary tangles, which cause cognitive decline and subsequent behavioral changes, such as distress, insomnia, depression, and anxiety. Recent literature suggests a strong connection between stress systems and AD progression. This presents a promising direction for future AD research. In this review, two systems involved in regulating stress and AD pathogenesis will be highlighted: serotonin (5-HT) and corticotropin releasing factor (CRF). Throughout the review, we summarize critical findings in the field while discussing common limitations with two animal models (3xTg-AD and TgF344-AD), novel pharmacotherapies, and potential early-intervention treatment options. We conclude by highlighting promising future pharmacotherapies and translational animal models of AD and anxiety. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian tumors mobilize a heterogenous population of myeloid cells. While these cells initially contribute to anti-tumor immunity, as cancer progresses, they switch from immunostimulatory to immunosuppressive. Ovarian cancer is most frequently restricted to the peritoneal cavity, negating the need for systemic delivery of therapeutics. With a goal of targeting and activating myeloid cells in the tumor microenvironment, this study sought to determine which nanoparticle characteristics enhance uptake by myeloid cells in vitro and in vivo using an animal model of ovarian cancer. Lipids coating a mesoporous silica core were optimized for surface charge, formulation, and inclusion of immunogenic monophosphoryl lipid A. Benefits of a mesoporous core include opportunities for loading with additional therapeutics, such as antigens to direct immune responses or other therapeutic payloads that facilitate anti-cancer immune responses. Immunogenic lipid-coated mesoporous silica nanoparticles (ILM) present pathogen-associated molecular patterns (PAMPs) on the nanoparticle surface to engage pathogen-associated receptors on immune cells. The mesoporous core is capable of loading additional immunogens, antigens or drugs. In this study, the impact of lipid composition, surface potential and intercalation of lipophilic monophosphoryl lipid A (MPL-A) in the lipid coat on nanoparticle properties and cellular interactions is presented. Loading and retention of the model antigen ovalbumin into the mesoporous silica core were found to be similar for all nanoparticle formulations, with presentation of ova peptide (SIINFEKL) by major histocompatibility complex (MHC) evaluated to facilitate the selection of an anionic nanoparticle composition. ILM were able to induce lysosomal tubulation and streaming of lysosomes towards the cell surface in dendritic cells, leading to an enhanced surface presentation of MHC. Myeloid cells robustly internalized all ILM formulations; however, non-myeloid cells selectively internalized cationic ILM in vitro in the presence of 20% serum. Interestingly, ILM administration to the peritoneal cavity of mice with disseminated ovarian cancer resulted in selective accumulation of ILM in tumor-associated tissues (>80%), regardless of nanoparticle surface charge or the presence of MPL-A. Immunofluorescence analysis of the omental tumor showed that ILMs, regardless of surface charge, were localized within clusters of CD11b+ myeloid cells 24 h post administration. Selective uptake of ILMs by myeloid cells in vivo indicates that these cells outcompete other cell populations in the ovarian tumor microenvironment, making them a strong target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aims: A cost‐effectiveness analysis was conducted to compare insulin glargine 300 U/mL (Gla‐300) versus insulin degludec 100 U/mL (IDeg‐100) in insulin‐naïve adults with type 2 diabetes (T2D) sub‐optimally controlled with oral anti‐diabetic drugs (OADs). Methods: The BRAVO diabetes model was used to assess costs and outcomes for once‐daily Gla‐300 versus once‐daily IDeg‐100 from a US healthcare sector perspective. Baseline clinical data were based on BRIGHT, a 24‐week, non‐inferiority, randomised control trial comparing Gla‐300 and IDeg‐100 in adults with T2D sub‐optimally controlled with OADs (with or without glucagon‐like peptide‐1 receptor agonists). Treatment costs were based on doses observed in BRIGHT as well as net prices. Costs associated with complications were based on published literature. Lifetime costs (US$) and quality‐adjusted life‐years (QALYs) were predicted and used to calculate incremental cost‐effectiveness ratio estimates; extensive scenario and sensitivity analyses were conducted. Results: Overall lifetime medical costs were estimated to be $327,904 and $330,154 for people receiving Gla‐300 and IDeg‐100, respectively; insulin costs were $43,477 and $44,367, respectively. People receiving Gla‐300 gained 8.024 QALYs and 18.55 life‐years, while people receiving IDeg‐100 gained 7.997 QALYs and 18.52 life‐years. Because Gla‐300 was associated with a cost‐saving of $2250 and 0.027 additional QALYs, it was considered to be dominant compared with IDeg‐100. Results of the scenario and sensitivity analyses confirmed the robustness of the base case results. Conclusion: Gla‐300 was the dominant treatment option compared with IDeg‐100 based on the willingness‐to‐pay threshold of $50,000/QALY. Results remained robust against a wide range of alternative assumptions on key parameters. [ABSTRACT FROM AUTHOR]

Golden berries (Physalis peruviana) are esteemed for their healing properties and widespread use in traditional medicine, particularly for their neuroprotective benefits. This work aims to evaluate the neuroprotective effect of golden berry total leaf extract cultivated in Egypt (TLE) against cyclophosphamide (CP)-induced neurotoxicity and to identify the chemical composition of different organs of P. peruviana from both Egypt and USA. Metabolite profiling of TLE was conducted using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS/MS). In the animal model experiment, CP (100 mg/kg, i.p.) was administered once weekly for four weeks to induce neurocognitive dysfunction. Concurrently, TLE (500 mg/kg, orally) was administered twice weekly throughout the four weeks to evaluate its effectiveness in alleviating CP-induced neuronal deficits. Behavioral assessments, Morris water maze and passive avoidance tests, were conducted, followed by, histological evaluations of brain tissue samples. Additionally, biochemical analyses were performed on hippocampal tissue samples, examining the following markers, acetylcholinesterase activity (AChE), malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) activity, nuclear factor kappa B (p-NF-κB p65) (Ser536), Interleukin 1β (IL-1β), Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), B-cell lymphoma 2 (Bcl-2), and Bax (Bcl-2-associated X) levels. TLE significantly preserved hippocampal neurons and improved cognitive performance in behavioral tests. TLE achieved these beneficial effects by suppressing AChE activity, diminishing the oxidative stress and restoring redox balance via inhibiting p-NFκB/IL-1β,/TNFα/IL-6 cascades. Leaf extract revealed the highest total phenolic content (TPC) (2.7 ± 6.41 mg GAE/g extract) and total flavonoid content (TFC) (0.37 ± 1.19 mg QE/g) and the strongest antioxidant effects in Ferric Reducing Antioxidant Power (FRAP) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays with IC 50 values of 21.13 ± 1.48 and 18.19 ± 1.29 μg/mL, respectively. UHPLC–QTOF-MS/MS analysis resulted in the tentative identification of 20 metabolites including phenolic acids, flavonoids, hydroxycinnamic acid amides, and alkyl resorcinols. Findings verify for the first time the neuroprotective potential of golden berry leaf, currently discarded as agricultural waste, and highlight its multifaceted mechanism of neuroprotection in CP-induced neurotoxicity, suggesting its suitability as a promising therapeutic agent for neurotoxicity management. [Display omitted] [ABSTRACT FROM AUTHOR]

In 2017, Jane Goodall, the well-known primatologist, wrote a letter to the United States Food and Drug Administration criticising the use of animals to test brain-based theories of addiction. She reasoned that we already know about addiction by observing humans. Several scientists countered that research with humans cannot answer important questions about understanding, preventing, and treating addiction. This commentary draws on epidemiology, psychology, psychodynamic models, learning theories and existentialism. It highlights effective prevention and treatment approaches that are not based on brain models of addiction. Jane Goodall's letter, has, perhaps unwittingly, provided a focal point for reconsidering what kind of research is required to further our understanding of addiction. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores in vivo models of prostate cancer currently published in the literature, with the focus on the prostate cancer mouse models that have recently been proposed. The information that researchers currently have about such models is critical for the information that they hope to obtain from future studies. Therefore, it is important that the various models currently published in the literature are systematically brought together. With the benefits and drawbacks of various types of prostate cancer models provided in this review, combined with their relationships to different signaling pathways and stages of tumor progression, the researcher may tackle the question of which model or gene of interest associated with the development of prostate cancer bests suits their future studies. In 2022, prostate cancer (PCa) is estimated to be the most commonly diagnosed cancer in men in the United States—almost 270,000 American men are estimated to be diagnosed with PCa in 2022. This review compares and contrasts in vivo models of PCa with regards to the altered genes, signaling pathways, and stages of tumor progression associated with each model. The main type of model included in this review are genetically engineered mouse models, which include conditional and constitutive knockout model. 2D cell lines, 3D organoids and spheroids, xenografts and allografts, and patient derived models are also included. The major applications, advantages and disadvantages, and ease of use and cost are unique to each type of model, but they all make it easier to translate the tumor progression that is seen in the mouse prostate to the human prostate. Although both human and mouse prostates are androgen-dependent, the fact that the native, genetically unaltered prostate in mice cannot give rise to carcinoma is an especially critical component of PCa models. Thanks to the similarities between the mouse and human genome, our knowledge of PCa has been expanded, and will continue to do so, through models of PCa. [ABSTRACT FROM AUTHOR]

Ultraviolet radiation (UVR) exposure is the major risk factor for melanoma. However, epidemiologic studies on UVR and noncutaneous cancers have reported inconsistent results, with some suggesting an inverse relationship potentially mediated by vitamin D. To address this, we examined 3 US prospective cohorts, the Health Professionals Follow-up Study (HPFS) (1986) and Nurses' Health Study (NHS) I and II (1976 and 1989), for associations between cumulative erythemal UVR and incident cancer risk, excluding nonmelanoma skin cancer. We used a validated spatiotemporal model to calculate erythemal UVR. Participants (47,714 men; 212,449 women) were stratified into quintiles by cumulative average erythemal UVR, using the first quintile as referent, for Cox proportional hazards regression analysis. In the multivariable-adjusted meta-analysis of all cohorts, compared with the lowest quintile, risk of any cancer was slightly increased across all other quintiles (highest quintile hazard ratio (HR) = 1.04, 95% confidence interval (CI): 1.01, 1.07; P for heterogeneity = 0.41). All UVR quintiles were associated with similarly increased risk of any cancer excluding melanoma. As expected, erythemal UVR was positively associated with risk of melanoma (highest quintile HR = 1.17, 95% CI: 1.04, 1.31; P for heterogeneity = 0.83). These findings suggest that elevated UVR is associated with increased risk of both melanoma and noncutaneous cancers. [ABSTRACT FROM AUTHOR]

Purpose: COVID‐19 mortality rates are higher in rural versus urban areas in the United States, threatening to exacerbate the existing rural mortality penalty. To save lives and facilitate economic recovery, we must achieve widespread vaccination coverage. This study compared adult COVID‐19 vaccination rates across the US rural‐urban continuum and across different types of rural counties. Methods: We retrieved vaccination rates as of August 11, 2021, for adults aged 18+ for the 2,869 counties for which data were available from the CDC. We merged these with county‐level data on demographic and socioeconomic composition, health care infrastructure, 2020 Trump vote share, and USDA labor market type. We then used regression models to examine predictors of COVID‐19 vaccination rates across the USDA's 9‐category rural‐urban continuum codes and separately within rural counties by labor market type. Findings: As of August 11, 45.8% of adults in rural counties had been fully vaccinated, compared to 59.8% in urban counties. In unadjusted regression models, average rates declined monotonically with increasing rurality. Lower rural rates are explained by a combination of lower educational attainment and higher Trump vote share. Within rural counties, rates are lowest in farming and mining‐dependent counties and highest in recreation‐dependent counties, with differences explained by a combination of educational attainment, health care infrastructure, and Trump vote share. Conclusion: Lower vaccination rates in rural areas is concerning given higher rural COVID‐19 mortality rates and recent surges in cases. At this point, mandates may be the most effective strategy for increasing vaccination rates. [ABSTRACT FROM AUTHOR]

Objective: To explore the association of educational institution religious affiliation with provision of sexual health services and rates of sexual violence. Participants: Analysis of 500 US college/university websites; secondary data obtained from National Center for Education Statistics (NCES). Methods: Content analysis documented institutional religious affiliation and availability of sexual health services. Chi-square tests examined association of services with religious affiliation, while negative binomial models compared rape/fondling rates obtained from NCES between Christian/non-Christian schools. Results: Results demonstrated an overall deficit in services, with Christian campuses significantly less likely to offer 13 service. Christian schools had increased reports of rape (years 2015/2016) and fondling (year 2015). Conclusions: Results highlight insufficiency of sexual health services and the need for future research on specific forms of services available and other factors impacting sexual violence. Findings illuminate the importance of a campus' social environment on sexual assault occurrences/reporting and structuring services to meet student needs. [ABSTRACT FROM AUTHOR]

This paper is based on an empirical study using in-depth qualitative interviews that examines how Roman Catholic undergraduate seminarians in the United States understand gender, sexuality and masculinity. The findings describe how seminarians reject interactionist and social constructionist models of gender, and rely on a strict biological based model where sex/gender are seen as a unified concept. This leads them to adopt an "essential male inclusivity", where they argue that all people assigned male at birth have equal claim to "manhood", which eases pressures on them to act in gender normative ways. The social-psychological and identity-based motivations of these beliefs are examined in connection to their life in the seminary and other anticipated occupational characteristics. In contrast, the seminary's mandates around both celibacy and compulsory heterosexuality, make sexuality more fraught than gender for seminarians. The larger consequences of these perspectives are also explored in regard to gender inequality, homophobia, and the lack of acceptance for the LGBTIQ+ community. [ABSTRACT FROM AUTHOR]

Advances in genetic technology and small molecule drug development have paved the way for clinical trials in Charcot‐Marie‐Tooth disease (CMT); however, the current FDA‐approved clinical trial outcome measures are insensitive to detect a meaningful clinical response. There is, therefore, a need to identify sensitive outcome measures or clinically relevant biomarkers. The aim of this study was to further evaluate plasma neurofilament light chain (NFL) as a disease biomarker in CMT. Plasma NFL was measured using SIMOA technology in both a cross‐sectional study of a US cohort of CMT patients and longitudinally over 6 years in a UK CMT cohort. In addition, plasma NFL was measured longitudinally in two mouse models of CMT2D. Plasma concentrations of NFL were increased in a US cohort of patients with CMT1B, CMT1X and CMT2A but not CMT2E compared with controls. In a separate UK cohort, over a 6‐year interval, there was no significant change in plasma NFL concentration in CMT1A or HSN1, but a small but significant reduction in patients with CMT1X. Plasma NFL was increased in wild type compared to GARSC201R mice. There was no significant difference in plasma NFL in GARSP278KY compared to wild type mice. In patients with CMT1A, the small difference in cross‐sectional NFL concentration vs healthy controls and the lack of change over time suggests that plasma NFL may lack sufficient sensitivity to detect a clinically meaningful treatment response in adulthood. [ABSTRACT FROM AUTHOR]

Background Cruise travel contributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission when there were relatively few cases in the United States. By 14 March 2020, the Centers for Disease Control and Prevention (CDC) issued a No Sail Order suspending US cruise operations; the last US passenger ship docked on 16 April. Methods We analyzed SARS-CoV-2 outbreaks on cruises in US waters or carrying US citizens and used regression models to compare voyage characteristics. We used compartmental models to simulate the potential impact of 4 interventions (screening for coronavirus disease 2019 (COVID-19) symptoms; viral testing on 2 days and isolation of positive persons; reduction of passengers by 40%, crew by 20%, and reducing port visits to 1) for 7-day and 14-day voyages. Results During 19 January to 16 April 2020, 89 voyages on 70 ships had known SARS-CoV-2 outbreaks; 16 ships had recurrent outbreaks. There were 1669 reverse transcription polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infections and 29 confirmed deaths. Longer voyages were associated with more cases (adjusted incidence rate ratio, 1.10, 95% confidence interval [CI]: 1.03–1.17, P  < .003). Mathematical models showed that 7-day voyages had about 70% fewer cases than 14-day voyages. On 7-day voyages, the most effective interventions were reducing the number of individuals onboard (43.3% reduction in total infections) and testing passengers and crew (42% reduction in total infections). All four interventions reduced transmission by 80.1%, but no single intervention or combination eliminated transmission. Results were similar for 14-day voyages. Conclusions SARS-CoV-2 outbreaks on cruises were common during January–April 2020. Despite all interventions modeled, cruise travel still poses a significant SARS-CoV-2 transmission risk. [ABSTRACT FROM AUTHOR]

Background: Pseudomonas aeruginosa (PA) is a common cause of respiratory infection and morbidity. Pseudomonas elastase is an important virulence factor regulated by the lasR gene. Whether PA elastase activity is associated with worse clinical outcomes in ICU patients is unknown.Research Question: Is there an association between PA elastase activity and worse host outcomes in a cohort of ICU patients?Methods: PA respiratory isolates from 238 unique ICU patients from two tertiary-care centers within the University of Pittsburgh Medical Center health system were prospectively collected and screened for total protease and elastase activity, biofilm production, antimicrobial resistance, and polymicrobial status. The association between pathogen characteristics and 30-day and 90-day mortality was calculated using logistic regression. For subgroup analysis, two patterns of early (≤72 h) and late sample (>72 h) collection from the index ICU admission were distinguished using a finite mixture model. Lung inflammation and injury was evaluated in a mouse model using a PA high elastase vs low elastase producer.Results: PA elastase activity was common in ICU respiratory isolates representing 75% of samples and was associated with increased 30-day mortality (adjusted OR [95% CI]: 1.39 [1.05-1.83]). Subgroup analysis demonstrated that elastase activity was a risk factor for 30- and 90-day mortality in the early sample group, whereas antimicrobial resistance was a risk factor for 90-day mortality in the late sample group. Whole genome sequencing of high and low elastase producers showed that predicted loss-of-function lasR genotypes were less common among high elastase producers. Mice infected with a high elastase producer showed increased lung bacterial burden and inflammatory profile compared with mice infected with a low elastase producer.Interpretation: Elastase activity is associated with 30-day ICU mortality. A high elastase producing clinical isolate confers increased lung tissue inflammation compared with a low elastase producer in vivo. [ABSTRACT FROM AUTHOR]

Background: In 2015, the National Institutes of Health (NIH) established a policy on sex as a biological variable (SABV) in an effort to address the overrepresentation of men and male animals in biomedical research and the lack of attention to sex-based responses to medical treatments. However, questions remain regarding how U.S. biomedical researchers perceive the impact of the SABV policy on their own research and on translational science more broadly. Materials and Methods: A national survey of U.S. scientists who use vertebrate animals in their research was conducted. Respondents were asked how they select and use animal species as model organisms as well as how they perceive the impact of the SABV policy on their research practices. Results: Almost all respondents reported that they had previously heard of the NIH SABV policy, and over one-third had altered their study designs to comply with the policy. There were robust differences in perceptions of the SABV policy based on researchers' primary species of model organism. However, there was no significant difference in the likelihood of researchers analyzing their results by sex based on whether they had received recent NIH funding. Conclusions: While many researchers report adhering to the SABV policy requirements, more work needs to be done to ensure that the policy is being evenly applied to researchers using all types of animal models and that researchers adhere to the policy after receiving NIH funding, particularly in terms of reporting on and analyzing SABV in their study findings for publication. [ABSTRACT FROM AUTHOR]

Qualitative research has found that men may reconstruct masculinity to navigate perceived tensions between depression and masculine norms. However, research has not fully attended to the gendered tensions and conflicts men may encounter in navigating multiple explanatory models of depression. To address this gap, we conducted 11 semi-structured interviews with men living in the United States who had been diagnosed with depression within the past month (n = 7) or the past 3 years (n = 4). Using a thematic analysis with elements of discourse analysis, we identified two interpretive repertoires used to make sense out of depression. These repertoires, which we labeled (a) the biomedical model and (b) the responsible agent model, were analyzed for their thematic contents and rhetorical functions. The majority (n = 8) of participants drew upon both repertoires, although participants differed in how they navigated between them. Some participants' uptake of the two repertoires appeared more dualistic and rigid while other participants' intra-individual variation appeared more dialectical and flexible. These findings reveal greater uptake of biomedical discourse in men's accounts of depression than has been previously documented in the qualitative literature, suggest the need for further research on how masculinity relates to flexible or rigid explanatory styles, and affirm the importance of attending to complexity in men's accounts of depression. [ABSTRACT FROM AUTHOR]

Background: Remimazolam is a new benzodiazepine for procedural sedation and general anaesthesia. The aim of this study was to characterise its pharmacokinetic properties and safety in renally and hepatically impaired subjects.Methods: Two separate trials were conducted in patients with hepatic (n=11) or renal impairment (n=11) compared with matched healthy subjects (n=9 and n=12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design' trial, using a single bolus of remimazolam 0.1 mg kg-1 i.v., whereas the renal impairment trial was an open-label trial of a single bolus dose of remimazolam 1.5 mg i.v. Remimazolam plasma concentrations over time were analysed by population pharmacokinetic modelling.Results: Remimazolam pharmacokinetic properties were adequately described by a three-compartment, recirculatory model. Exposure in subjects with severe hepatic impairment was 38.1% higher (i.e. clearance was 38.1% lower) compared with healthy volunteers. This increase caused a slightly delayed recovery (8.0 min for healthy, 12.1 min for moderate, and 16.7 min for severe hepatic impairment). With renal impairment, plasma clearance was comparable with that measured in healthy subjects. Simulations of Cmax after a bolus dose of 10 mg showed no relevant impact of hepatic or renal impairment. The overall incidence of adverse events was low, and all adverse events were mild.Conclusions: As Cmax after a remimazolam bolus i.v. was not affected by hepatic or renal impairment, no dose adjustments are required. No unexpected adverse events related to remimazolam were seen in subjects with renal or hepatic impairment.Clinical Trial Registration: Hepatic impairment trial: ClinicalTrials.gov, NCT01790607 (https://clinicaltrials.gov/ct2/show/NCT01790607). Renal impairment trial: EudraCT Number: 2014-004575-23. [ABSTRACT FROM AUTHOR]

Alcohol is a known teratogen, and developmental exposure to ethanol results in fetal alcohol spectrum disorder (FASD). Children born with FASD can exhibit a range of symptoms including low birth weight, microcephaly, and neurobehavioral problems. Treatment of patients with FASD is estimated to cost 4 billion dollars per year in the United States alone, and 2 million dollars per affected individual's lifetime. We have established Drosophila melanogaster as a model organism for the study of FASD. Here we report that mutations in Dementin (Dmtn), the Drosophila ortholog of the Alzheimer's disease-associated protein TMCC2, convey sensitivity to developmental ethanol exposure, and provide evidence that Dmtn expression is disrupted by ethanol. In addition, we find that flies reared on ethanol exhibit mild climbing defects suggestive of neurodegeneration. Surprisingly, our data also suggest that flies reared on ethanol age more slowly than control animals, and we find that a number of slow-aging mutants are sensitive to developmental ethanol exposure. Finally, we find that flies reared on ethanol showed a persistent upregulation of genes encoding antioxidant enzymes, which may contribute to a reduced rate of central nervous system aging. Thus, in addition to the well-documented negative effects of developmental alcohol exposure on the nervous system, there may be a previously unsuspected neuroprotective effect in adult animals. [ABSTRACT FROM AUTHOR]

A central challenge in applied ecology is understanding the effect of anthropogenic fatalities on wildlife populations and predicting which populations may be particularly vulnerable and in greatest need of management attention. We used three approaches to investigate the potential effects of fatalities from collisions with wind turbines on 14 raptor species for both current (106 GW) and anticipated future (241 GW) levels of installed wind energy capacity in the United States. Our goals were to identify species at relatively high vs low risk of experiencing population declines from turbine collisions and to also compare results generated from these approaches. Two of the approaches used a calculated turbine‐caused mortality rate to decrement population growth, where population trends were derived either from the North American Breeding Bird Survey or from a matrix model parameterized from literature‐derived demographic values. The third approach was potential biological removal, which estimates the number of fatalities that allow a population to reach and maintain its optimal sustainable population set by management objectives. Different results among the methods reveal substantial gaps in knowledge and uncertainty in both demographic parameters and species‐specific estimates of fatalities from wind turbines. Our results suggest that, of the 14 species studied, those with relatively higher potential of population‐level impacts from wind turbine collisions included barn owl, ferruginous hawk, golden eagle, American kestrel, and red‐tailed hawk. Burrowing owl, Cooper's hawk, great horned owl, northern harrier, turkey vulture, and osprey had a relatively lower potential for population impacts, and results were not easily interpretable for merlin, prairie falcon, and Swainson's hawk. Projections of current levels of fatalities to future wind energy scenarios at 241 GW of installed capacity suggest some species could experience population declines because of turbine collisions. Populations of those species may benefit from research to identify tools to prevent or reduce raptor collisions with wind turbines. [ABSTRACT FROM AUTHOR]

Opioid use disorder (OUD) has become a leading cause of death in the United States, yet current therapeutic strategies remain highly inadequate. To identify potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride reduced the physical signs associated with opioid withdrawal. In rat models of neuropathic pain, finasteride did not alter the antinociceptive effect of opioids and reduced withdrawal-induced hyperalgesia. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish in a fashion akin to the effects of finasteride. These results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new treatment option for this disorder. [ABSTRACT FROM AUTHOR]

BACKGROUND: During food animal production, animals are exposed to, colonized by, and sometimes infected with bacteria that may contaminate animal products with susceptible and multidrug-resistant organisms (MDRO). The United States' Organic Foods Production Act resulted in decreased antibiotic use in some animal production operations. Some studies have reported that decreased antibiotic use is associated with reduced MDRO on mea OBJECTIVES: The aim of this study was to investigate associations of meat production and processing methods with MDRO and overall bacterial contamination of retail meats. METHODS: Bacterial contamination data from 2012 to 2017 for chicken breast, ground beef, ground turkey, and pork chops were downloaded from the National Antimicrobial Resistance Monitoring System. Poisson regression models with robust variance were used to estimate associations with MDRO contamination and any contamination (adjusted for year and meat type) overall, and according to bacteria genus (Salmonella, Campylobacter, Enterococcus, Escherichia coli) and meat type. RESULTS: A total of 39,349 retail meat samples were linked to 216 conventional, 123 split (conventional and organic), and three organic processing facilities. MDRO contamination was similar in conventionally produced meats processed at split vs. conventional facilities but was significantly lower in organically produced meats processed at split facilities [adjusted prevalance ratio (aPR)=0.43; 95% CI: 0.30, 0.63]. Meat processed by split vs. conventional processors had higher or similar MDRO contamination for all tested bacterial genera except Campylobacter (aPR=0.29; 95% CI: 0.13, 0.64). The prevalence of any contamination was lower in samples processed at split vs. conventional facilities for aggregated samples (aPR=0.70; 95% CI: 0.68, 0.73) and all meat types and bacterial genera. DISCUSSION: Organically produced and processed retail meat samples had a significantly lower prevalence of MDRO than conventionally produced and processed samples had, whereas meat from split processors had a lower prevalence of any contamination than samples from conventional processors had. Additional studies are needed to confirm findings and clarify specific production and processing practices that might explain them. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal surgery is a highly specialized field in surgery that deals with the surgical intervention of disease processes of the colon, rectum, and anus. Gaining proficiency in this field requires training both inside and outside of the operating room. Simulation plays a key role in training surgeons in colorectal surgery. The goal of this study is to review the currently available simulators for training in the field of colorectal surgery. Methods: A review of the literature was conducted to identify simulators that are both physical such as benchtop, live animal, and cadaver, as wells as virtual reality (VR) simulators. Any reported validity evidence for these simulators were also presented. Results: There are several benchtop physical models made of silicone for training in basic colorectal tasks, such as hand-sewn and stapled anastomosis. To improve realism, explanted animal and cadaveric specimens were also used for training. To improve repeatability, objective assessment, both commercial and VR simulators also exist for training in both open and laparoscopic colorectal surgery and emerging areas such as endoscopic submucosal dissection. Conclusion: Simulation-based training in colorectal surgery is here to stay and is going to play a significant role in training, credentialing, and quality improvements. [ABSTRACT FROM AUTHOR]

Background: Administrative claims do not contain ejection fraction information for heart failure patients. We recently developed and validated a claims-based model to predict ejection fraction subtype.Methods: Heart failure patients aged 65 years or above from US Medicare fee-for-service claims were identified using diagnoses recorded after a 6-month baseline period of continuous enrollment, which was used to identify predictors and to apply the claims-based model to distinguish heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Patients were followed for the composite outcome of time to first worsening heart failure event (heart failure hospitalization or outpatient intravenous diuretic treatment) or all-cause mortality.Results: A total of 3,134,414 heart failure patients with an average age of 79 years were identified, of which 200,950 (6.4%) were classified as HFrEF. Among those classified as HFrEF, men comprised a larger proportion (68% vs 41%) and the average age was lower (76 vs 79 years) compared with HFpEF. History of myocardial infarction was more common in HFrEF (32% vs 13%), while hypertension was more common in HFpEF (71% vs 77%). One-year cumulative incidence of the composite endpoint was 42.6% for HFrEF and 36.9% for HFpEF. One-year all-cause mortality incidence was similar between the groups (27.4% for HFrEF and 26.4% for HFpEF), however, cardiovascular mortality was higher for HFrEF (15.6% vs 11.3%), whereas noncardiovascular mortality was higher for HFpEF (11.8% vs 15.1%).Conclusion: We replicated well-documented differences in key patient characteristics and cause-specific outcomes between HFrEF and HFpEF in populations identified based on the application of a claims-based model. [ABSTRACT FROM AUTHOR]

Rationale: Aberrant lung remodeling in idiopathic pulmonary fibrosis (IPF) is characterized by elevated MMP9 (matrix metalloproteinase 9) expression, but the precise role of this matrix metalloproteinase in this disease has yet to be fully elucidated.Objectives: To evaluate antifibrotic effects of MMP9 inhibition on IPF.Methods: Quantitative genomic, proteomic, and functional analyses both in vitro and in vivo were used to determine MMP9 expression in IPF cells and the effects of MMP9 inhibition on profibrotic mechanisms.Measurements and Main Results: In the present study, we demonstrate that MMP9 expression was increased in airway basal cell (ABC)-like cells from IPF lungs compared with ABC cells from normal lungs. The inhibition of MMP9 activity with an anti-MMP9 antibody, andecaliximab, blocked TGF-β1 (transforming growth factor β1)-induced Smad2 phosphorylation. However, in a subset of cells from patients with IPF, TGF-β1 activation in their ABC-like cells was unaffected or enhanced by MMP9 blockade (i.e., nonresponders). Further analysis of nonresponder ABC-like cells treated with andecaliximab revealed an association with type 1 IFN expression, and the addition of IFNα to these cells modulated both MMP9 expression and TGF-β1 activation. Finally, the inhibition of MMP9 ameliorated pulmonary fibrosis induced by responder lung cells but not a nonresponder in a humanized immunodeficient mouse model of IPF.Conclusions: Together, these data demonstrate that MMP9 regulates the activation of ABC-like cells in IPF and that targeting this MMP might be beneficial to a subset of patients with IPF who show sufficient expression of type 1 IFNs. [ABSTRACT FROM AUTHOR]

Since 2016, results from physiologically based pharmacokinetic (PBPK) analyses have been routinely found in the clinical pharmacology section of regulatory applications submitted to the US Food and Drug Administration (FDA). In 2018, the Food and Drug Administration's Office of Clinical Pharmacology published a commentary summarizing the application of PBPK modeling in the submissions it received between 2008 and 2017 and its impact on prescribing information. In this commentary, we provide an update on the application of PBPK modeling in submissions received between 2018 and 2019 and highlight a few notable examples. [ABSTRACT FROM AUTHOR]

Background: Persistent and relapsing babesiosis caused by Babesia microti often occurs in immunocompromised patients, and has been associated with resistance to antimicrobial agents such as atovaquone. Given the rising incidence of babesiosis in the United States, novel drugs are urgently needed. In the current study, we tested whether clofazimine (CFZ), an antibiotic used to treat leprosy and drug-resistant tuberculosis, is effective against B. microti.Methods: Mice with severe combined immunodeficiency were infected with 107B. microti-infected erythrocytes. Parasites were detected by means of microscopic examination of Giemsa-stained blood smears or nested polymerase chain reaction. CFZ was administered orally.Results: Uninterrupted monotherapy with CFZ curtailed the rise of parasitemia and achieved radical cure. B. microti parasites and B. microti DNA were cleared by days 10 and 50 of therapy, respectively. A 7-day administration of CFZ delayed the rise of parasitemia by 22 days. This rise was caused by B. microti isolates that did not carry mutations in the cytochrome b gene. Accordingly, a 14-day administration of CFZ was sufficient to resolve high-grade parasitemia caused by atovaquone-resistant B. microti parasites.Conclusions: Clofazimine is effective against B. microti infection in the immunocompromised host. Additional preclinical studies are required to identify the minimal dose and dosage of CFZ for babesiosis. [ABSTRACT FROM AUTHOR]

While disparities in healthcare outcomes and services for vulnerable populations have been documented, the extent to which vulnerable burn populations demonstrate disparities in long-term care is relatively underexplored. This study's goal was to assess for differences in long-term occupational or physical therapy (OT/PT) and psychological service use after burn injury in vulnerable populations. Data from the Burn Model System National Database (2006-2015) were analyzed. The vulnerable group included participants in one or more of these categories: 65 years of age or older, nonwhite, no insurance or Medicaid insurance, preinjury receipt of psychological therapy or counseling, preinjury alcohol and/or drug misuse, or with a preexisting disability. Primary outcomes investigated were receipt of OT/PT and psychological services. Secondary outcomes included nine OT/PT subcategories. Outcomes were examined at 6, 12, and 24 months postinjury. One thousand one hundred thirty-six burn survivors (692 vulnerable; 444 nonvulnerable) were included. The vulnerable group was mostly female, unemployed at time of injury, and with smaller burns. Both groups received similar OT/PT and psychological services at all time points. Adjusted regression analyses found that while the groups received similar amounts services, some vulnerable subgroups received significantly more services. Participants 65 years of age or older, who received psychological therapy or counseling prior to injury, and with a preexisting disability received more OT/PT and psychological or peer support services at follow-up. Overall, vulnerable and nonvulnerable groups received comparable OT/PT and psychological services. The importance of long-term care among vulnerable subgroups of the burn population is highlighted by this study. Future work is needed to determine adequate levels of follow-up services. [ABSTRACT FROM AUTHOR]

Reprogramming diseased cells with mutated genes into induced pluripotent stem cells (iPSCs) can allow studies of disease mechanism and correct the mutation. Oculofaciocardiodental (OFCD) syndrome is a developmental disorder caused by heterozygous mutations in the X-linked BCL-6 corepressor (BCOR) gene. In this present study, we aimed to reprogram stem cells from a tooth apical papilla (SCAP) of a patient with OFCD, termed SCAP-O, into iPSCs. The SCAP-O carry a copy of the BCOR gene having 1 nucleotide deletion in 1 of the alleles, therefore harboring a mixture of cells expressing either normal (SCAP-OBCOR-WT) or mutated (SCAP-OBCOR-mut) BCOR transcripts. We subcloned SCAP-O and separated SCAP-OBCOR-WT and SCAP-OBCOR-mut as verified by sequencing. The selected subclone SCAP-OBCOR-mut expressed only the mutated BCOR transcripts and remained in such condition after multiple passages. We reprogrammed SCAP-O and subclone SCAP-OBCOR-mut into transgene-free iPSCs using an excisable lentiviral vector system (hSTEMCCA-loxP) carrying 4 reprogramming factors in a single cassette, followed by removal of transgenes via Cre-mediated excision. We found that after reprogramming SCAP-O or subclone SCAP-OBCOR-mut into iPSCs, some of the iPSC clones expressed either solely the normal BCOR-WT or BCOR-mut transcripts, while other clones expressed both BCOR-WT and BCOR-mut transcripts. This is our first step toward establishing OFCD study models by generating isogenic control BCOR-WT iPSCs versus BCOR-mut iPSCs. [ABSTRACT FROM AUTHOR]

Background/case Studies: Despite decreased blood use, there are supply limitations. Therefore, it is important to determine the number of people potentially eligible to donate blood. This study updates an analysis from 2007 to estimate the pool of eligible blood donors in the United States.Study Design/methods: We developed a revised epidemiologic model to account for changes in donor exclusion factors based on AABB standards. Donor exclusionary factors were identified and epidemiologic databases selected to enumerate the population prevalence of the donor exclusion factors. Prevalence data were adjusted for age, duration of exclusion, and comorbidities. The number of excluded individuals is calculated to estimate the current size of the eligible blood donor pool. The current study incorporates changes in demographic characteristics that have altered the pool of eligible blood donors.Results/findings: The pool of eligible blood donors increased by approximately 93.9 million from 111 million persons in 2007 to 204.9 million persons in 2018, while the population of the United States increased by 34 million persons (from 293 million to 327 million). The number of donor exclusion factors increased from 31 to 38. Overall, the pool of eligible blood donors increased from 37.9% to 62.6% of the total population. The single largest change impacting the pool of eligible blood donors is the inclusion of individuals 65 years and older, increasing the eligible blood donor pool by 51 million of the new 93.9 million persons However, this increase in number of potential donors 65 years and older is offset by a corresponding increase in the prevalence of donor exclusion factor impact in individuals aged 65 years and above.Conclusion: A very large number of people are potentially eligible to donate blood. Therefore, blood supply limitations appear to be due to other factors. We suggest that these factors are differences in social commitments by changing demographic populations and the elimination of high-cost blood collection operations by blood suppliers. [ABSTRACT FROM AUTHOR]

Objectives: To assess and compare the face (FV) and content validity (CV) of three ex vivo animal models for simulation training in pediatric laryngotracheal reconstruction (LTR). Methods: Feasibility of performing LTR was assessed on the head and neck of three different animals (lamb/suckling-pig/rabbit) and laryngeal dimensions and qualitative observations were recorded. A 19-item five-point Likert scale questionnaire was completed for each model to assess FV and CV. Data was prospectively collected and analyzed using descriptive and nonparametric statistics. Results: All three models were suitable for LTR simulation with laryngeal dimensions corresponding to 0-2 years (rabbit), 5-10 (pig) and >10 years (lamb model). Five trainees and five expert pediatric otolaryngologists performed LTR on each model. The overall median FV score was 5 for the lamb model (IQR 4-5), 3 for the rabbit (IQR 2-3), and 4 for the pig (IQR 4-4). The overall median CV score was 5 for the lamb (IQR 5-5), 2 for the rabbit (IQR 2-3), and 4 for the pig model (IQR 4-4). Comparison of the models demonstrated the lamb to be favored as the most realistic and practical model for simulation training in pediatric LTR, with both the lamb and the porcine model attaining validation thresholds. Conclusion: Our study is the first comparative validation assessment of animal models for use in pediatric LTR simulation and it supports the use of ex vivo lamb and porcine models for use in LTR surgical skills training. The lamb model was the favored simulation model while the rabbit was considered inferior for simulation training in pediatric LTR. Level of Evidence: 3b [ABSTRACT FROM AUTHOR]

Owing to changing weather patterns, catastrophic natural disasters are expected to happen more frequently and cause dramatic life and economic losses worldwide. The United States experienced a historically high record of weather disasters in 2017, with the economic losses exceeding 300 billion dollars. A major contributor to economic loss and threat to public safety is damage, destruction, and failure of civil structures in the strong-wind dominated disasters. There is a pressing need for reconstruction and redesign of critical civil structures to better cope with high winds to mitigate the loss of lives and properties. This paper takes a biomimetic perspective to link problem areas with potential solutions for future bio-inspired technology development, by identifying the most vulnerable aspects of civil structures in strong winds on one side and wind-resilient examples of biological systems on the other side. Of particular interest are plants that thrive in high winds, as they have likely adapted to manage the harsh environment under pressure of natural selection. Specific biological examples include the Saguaro cactus (Carnegiea gigantean Britton & Rose), reed grass, and shape reconfiguration of leaves. A review of problem areas, abstracted principles, and exemplary biological role models shall inform and guide towards new designs of wind-resilient civil structures. [ABSTRACT FROM AUTHOR]

In patients with renal insufficiency, dose adjustments based on creatinine clearance and body weight have been a component of imipenem dosage instructions. The objective of the current analysis was to provide revised dosing recommendations by evaluating the impact of creatinine clearance and body weight on the pharmacokinetics of imipenem. A population pharmacokinetics model was developed with data from 465 patients and 3300 pharmacokinetic samples. Simulations provided data to support revision of the dosing recommendations to remove body weight–adjusted dosing, and the analysis formed the basis for updates that are reflected on the current imipenem label for both the United States and Europe. The optimized regimen provided an advantage in terms of improved target attainment at breakpoint minimum inhibitory concentration values of 1 and 2 μg/mL, as low‐body‐weight patients maintained >90% probability of target attainment compared to <90% probability of target attainment achieved with the previously approved regimen. It was concluded that additional dose adjustments for body weight were not necessary and the new scheme would simplify dosing while maintaining patient safety and efficacy. [ABSTRACT FROM AUTHOR]

Background: Infected wounds are painful and cannot heal, with antibiotics showing reduced efficacy. Appropriate wound electrotherapy may limit incident planktonic and polymicrobial colonization, inhibit biofilm formation and accelerate healing.Methods: The Modular Adaptive Electrotherapy Delivery System (MAEDS) is a lightweight, flexible, battery-powered disposable bandage which delivers controlled reliable electrotherapy to the wound for up to 7 days. Large full-thickness excisional wounds (6 cm diameter) were created in a porcine model and freshly cultured 0.5 McFarland green fluorescent protein-labeled Pseudomonas aeruginosa evenly applied to the wound bed. Control wounds received standard wound care, Tegaderm HP Transparent Dressing (3 M Health Care, St. Paul, MN, USA) applied in a sterile fashion. Treatment wounds received MAEDS electrotherapy for up to 28 days or until healed. Onboard Bluetooth facilitated remote real-time monitoring of MAEDS function. Dressing changes occurred on postoperative day (POD) 1, 3, 5, 7, 10, 14, 21, and 28. Punch biopsies were taken at the wound margin and center. Bacterial samples were processed to determine infection status.Results: Acute infected wounds treated with MAEDS electrotherapy were 92% smaller than baseline by POD21. Healing rate was significantly faster (p < 0.01) and infection significantly decreased (p < 0.0001) at POD10, relative to control wounds.Conclusion: The MAEDS electrotherapy can significantly inhibit infection and enhance healing rate in acute infected wounds. [ABSTRACT FROM AUTHOR]

Objectives: Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of influenza virus infection. We evaluated the efficacy of delayed oral treatment with baloxavir marboxil in combination with a neuraminidase inhibitor in a mouse model of lethal influenza virus infection.Methods: The inhibitory potency of baloxavir acid (the active form of baloxavir marboxil) in combination with neuraminidase inhibitors was tested in vitro. The therapeutic effects of baloxavir marboxil and oseltamivir phosphate, or combinations thereof, were evaluated in mice lethally infected with influenza virus A/PR/8/34; treatments started 96 h post-infection.Results: Combinations of baloxavir acid and neuraminidase inhibitor exhibited synergistic potency against viral replication by means of inhibition of cytopathic effects in vitro. In mice, baloxavir marboxil monotherapy (15 or 50 mg/kg twice daily) significantly and dose-dependently reduced virus titre 24 h after administration and completely prevented mortality, whereas oseltamivir phosphate treatments were not as effective. In this model, a suboptimal dose of baloxavir marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional efficacy compared with monotherapy in terms of virus-induced mortality, elevation of cytokine/chemokine levels and pathological changes in the lung.Conclusions: Baloxavir marboxil monotherapy with 96 h-delayed oral dosing achieved drastic reductions in virus titre, inflammatory response and mortality in a mouse model. Combination treatment with baloxavir acid and oseltamivir acid in vitro and baloxavir marboxil and oseltamivir phosphate in mice produced synergistic responses against influenza virus infections, suggesting that treating humans with the combination may be beneficial. [ABSTRACT FROM AUTHOR]

Background: Aortic Occlusion Balloons (AOB) are used for hemorrhage control in hemodynamically unstable patients. Stability of an AOB is essential for reliable aortic occlusion. The primary aim of this study is to determine whether different types of AOB migrate after total, intermittent or partial occlusion in a porcine aorta positioned in an in vitro model.Materials and Methods: A porcine thoracic aortic section was positioned in a model of the human circulation. Primary and secondary migration was tested in Cook Coda™ 2-9.0-35-120-32 and 2-10-35-140-46, Cook Medical, USA; Rescue balloon™ Tokai RB-167080-E, Tokai Medical Products, Japan; Reliant™ AB46, Medtronic, USA; Russian prototype AOB; ER-REBOA™, Prytime Medical Devices, USA; LeMaitre™ 28 and 45 Aortic Occlusion Catheter, LeMaitre Vascular, USA. These AOB were tested in hypotensive, normotensive and hypertensive scenarios. Migration in total occlusion, intermittent occlusion and partial occlusion was recorded for all AOB.Results: Limited primary migration occurred in all AOB after total occlusion. The Cook Coda™ 2-9.0-35-120-32 balloon showed maximal migration in 1 test cycle. No migration occurred during intermittent occlusion. Kinking occurs in various degrees but does not seem to prevent a successful occlusion of the aorta. No migration occurred during partial occlusion except in the Russian prototype AOB. In a partial occlusion scenario, distal perfusion occurred only with 5 ml remaining in all balloon types.Conclusions: All AOB were successful in full aortic occlusion. Limited primary migration occurred in all AOB after total occlusion only the Cook Coda™ 2-9.0-35-120-32 balloon showed maximal migration once. No migration occurred during intermittent occlusion, during partial occlusion only the Russian prototype AOB migrated. Stiffness and size of the catheter are important factors in preventing migration and kinking. [ABSTRACT FROM AUTHOR]

Objective: Analyses of crash data have shown that older, obese, and/or female occupants have a higher risk of injury in frontal crashes compared to the rest of the population. The objective of this study was to use parametric finite element (FE) human models to assess the increased injury risks and identify safety concerns for these vulnerable populations. Methods: We sampled 100 occupants based on age, sex, stature, and body mass index (BMI) to span a wide range of the U.S. adult population. The target anatomical geometry for each of the 100 models was predicted by the statistical geometry models for the rib cage, pelvis, femur, tibia, and external body surface developed previously. A regional landmark-based mesh morphing method was used to morph the Global Human Body Models Consortium (GHBMC) M50-OS model into the target geometries. The morphed human models were then positioned in a validated generic vehicle driver compartment model using a statistical driving posture model. Frontal crash simulations based on U.S. New Car Assessment Program (U.S. NCAP) were conducted. Body region injury risks were calculated based on the risk curves used in the US NCAP, except that scaling was used for the neck, chest, and knee-thigh-hip injury risk curves based on the sizes of the bony structures in the corresponding body regions. Age effects were also considered for predicting chest injury risk. Results: The simulations demonstrated that driver stature and body shape affect occupant interactions with the restraints and consequently affect occupant kinematics and injury risks in severe frontal crashes. U-shaped relations between occupant stature/weight and head injury risk were observed. Chest injury risk was strongly affected by age and sex, with older female occupants having the highest risk. A strong correlation was also observed between BMI and knee-thigh-hip injury risk, whereas none of the occupant parameters meaningfully affected neck injury risks. Conclusions: This study is the first to use a large set of diverse FE human models to investigate the combined effects of age, sex, stature, and BMI on injury risks in frontal crashes. The study demonstrated that parametric human models can effectively predict the injury trends for the population and may now be used to optimize restraint systems for people who are not similar in size and shape to the available anthropomorphic test devices (ATDs). New restraints that adapt to occupant age, sex, stature, and body shape may improve crash safety for all occupants. [ABSTRACT FROM AUTHOR]

The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden of chronic pain faced by >100 million Americans. Motivated by this challenge, a natural product extracts library was screened and identified a plant extract that targets activity of voltage-gated calcium channels. This profile is of interest as a potential treatment for neuropathic pain. The active extract derived from the desert lavender plant native to southwestern United States, when subjected to bioassay-guided fractionation, afforded 3 compounds identified as pentacyclic triterpenoids, betulinic acid (BA), oleanolic acid, and ursolic acid. Betulinic acid inhibited depolarization-evoked calcium influx in dorsal root ganglion (DRG) neurons predominantly through targeting low-voltage-gated (Cav3 or T-type) and CaV2.2 (N-type) calcium channels. Voltage-clamp electrophysiology experiments revealed a reduction of Ca, but not Na, currents in sensory neurons after BA exposure. Betulinic acid inhibited spontaneous excitatory postsynaptic currents and depolarization-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices. Notably, BA did not engage human mu, delta, or kappa opioid receptors. Intrathecal administration of BA reversed mechanical allodynia in rat models of chemotherapy-induced peripheral neuropathy and HIV-associated peripheral sensory neuropathy as well as a mouse model of partial sciatic nerve ligation without effects on locomotion. The broad-spectrum biological and medicinal properties reported, including anti-HIV and anticancer activities of BA and its derivatives, position this plant-derived small molecule natural product as a potential nonopioid therapy for management of chronic pain. [ABSTRACT FROM AUTHOR]