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Background: Borrelia persica causes tick-borne relapsing fever in Israel, the eastern Mediterranean basin, and Asia. Relapsing fever is associated with severe illness and potentially death in humans and animals. Since B. persica infection has rarely been described in wild animals, the aim of this study was to evaluate the prevalence of infection with B. persica in wild carnivores in Israel., Methods: Spleen and blood clot samples from wild carnivores, which underwent necropsy, were tested for the presence of Borrelia DNA by real-time polymerase chain reaction (PCR). PCR products were sequenced, and the spirochete loads were quantified using a specific quantitative PCR (qPCR)., Results: A total of 140 samples from 74 wild carnivores were analyzed for the presence of Borrelia DNA. Six out of the 74 (8.1%) animals were found positive for B. persica by PCR and sequencing of the flagellin B gene, of which 4/74 (5.4%) were also positive by PCR for the glycerophosphodiester phosphodiesterase (glpQ) gene. Positive samples were obtained from three European badgers, and one striped hyena, golden jackal, and red fox each. All B. persica-positive animals were young males (P < 0.0001). Quantifiable results were obtained from 3/5 spleen and 4/5 blood samples. The spirochete loads in the blood were significantly higher than those found in the spleen (P = 0.034)., Conclusions: The prevalence of B. persica infection found in wild carnivores brought for necropsy was unexpectedly high, suggesting that this infection is widespread in some wild animal species in Israel. This is the first report of B. persica infection in the European badger and striped hyena. These carnivores have a wide geographical range of activity, and the results of this survey raise the possibility that they may serve as reservoir hosts for B. persica., (© 2023. The Author(s).)

Background: Following the shooting at Sandy Hook Elementary School, the Hartford Consensus produced the Stop the Bleed program to train bystanders in hemorrhage control. In our region, the police bureau delivers critical incident training to public schools, offering instruction in responding to violent or dangerous situations. Until now, widespread training in hemorrhage control has been lacking. Our group developed, implemented and evaluated a novel program integrating hemorrhage control into critical incident training for school staff in order to blunt the impact of mass casualty events on children., Methods: The staff of 25 elementary and middle schools attended a 90-minute course incorporating Stop the Bleed into the critical incident training curriculum, delivered on-site by police officers, nurses and doctors over a three-day period. The joint program was named Protect Our Kids. At the conclusion of the course, hemorrhage control kits and educational materials were provided and a four-question survey to assess the quality of training using a ten-point Likert scale was completed by participants and trainers., Results: One thousand eighteen educators underwent training. A majority were teachers (78.2%), followed by para-educators (5.8%), counselors (4.4%) and principals (2%). Widely covered by local and state media, the Protect Our Kids program was rated as excellent and effective by a majority of trainees and all trainers rated the program as excellent., Conclusions: Through collaboration between trauma centers, police and school systems, a large-scale training program for hemorrhage control and critical incident response can be effectively delivered to schools., (© 2021. The Author(s).)

Background: Fractalkine (CX3CL1; FKN) is a chemokine expressed by neurons that mediates communication between neurons and microglia. By regulating microglial activity, CX3CL1 can mitigate the damaging effects of chronic microglial inflammation within the brain, a state that plays a major role in aging and neurodegeneration. CX3CL1 is present in two forms, a full-length membrane-bound form and a soluble cleaved form (sFKN), generated by a disintegrin and metalloproteinase (ADAM) 10 or 17. Levels of sFKN decrease with aging, which could lead to enhanced inflammation, deficits in synaptic remodeling, and subsequent declines in cognition. Recently, the idea that these two forms of CX3CL1 may display differential activities within the CNS has garnered increased attention, but remains unresolved., Methods: Here, we assessed the consequences of CX3CL1 knockout (CX3CL1 -/- ) on cognitive behavior as well as the functional rescue with the two different forms of CX3CL1 in mice. CX3CL1 -/- mice were treated with adeno-associated virus (AAV) expressing either green fluorescent protein (GFP), sFKN, or an obligate membrane-bound form of CX3CL1 (mFKN) and then subjected to behavioral testing to assess cognition and motor function. Following behavioral analysis, brains were collected and analyzed for markers of neurogenesis, or prepared for electrophysiology to measure long-term potentiation (LTP) in hippocampal slices., Results: CX3CL1 -/- mice showed significant deficits in cognitive tasks for long-term memory and spatial learning and memory in addition to demonstrating enhanced basal motor performance. These alterations correlated with deficits in both hippocampal neurogenesis and LTP. Treatment of CX3CL1 -/- mice with AAV-sFKN partially corrected changes in both cognitive and motor function and restored neurogenesis and LTP to levels similar to wild-type animals. Treatment with AAV-mFKN partially restored spatial learning and memory in CX3CL1 -/- mice, but did not rescue long-term memory, or neurogenesis., Conclusions: These results are the first to demonstrate that CX3CL1 knockout causes significant cognitive deficits that can be rescued by treatment with sFKN and only partially rescued with mFKN. This suggests that treatments that restore signaling of soluble forms of CX3CL1 may be a viable therapeutic option for aging and disease.

Background: Thyroid cancer is the most common endocrine malignancy. Some advanced disease is, or becomes, resistant to radioactive iodine therapy (refractory disease); this holds poor prognosis of 10% 10-year overall survival. Whilst Sorafenib and Lenvatinib are now licenced for the treatment of progressive iodine refractory thyroid cancer, these treatments require continuing treatment and can be associated with significant toxicity. Evidence from a pilot study has demonstrated feasibility of Selumetinib to allow the reintroduction of I-131 therapy; this larger, multicentre study is required to demonstrate the broader clinical impact of this approach before progression to a confirmatory trial., Methods: SEL-I-METRY is a UK, single-arm, multi-centre, two-stage phase II trial. Participants with locally advanced or metastatic differentiated thyroid cancer with at least one measureable lesion and iodine refractory disease will be recruited from eight NHS Hospitals and treated with four-weeks of oral Selumetinib and assessed for sufficient I-123 uptake (defined as any uptake in a lesion with no previous uptake or 30% or greater increase in uptake). Those with sufficient uptake will be treated with I-131 and followed for clinical outcomes. Radiation absorbed doses will be predicted from I-123 SPECT/CT and verified from scans following the therapy. Sixty patients will be recruited to assess the primary objective of whether the treatment schedule leads to increased progression-free survival compared to historical control data., Discussion: The SEL-I-METRY trial will investigate the effect of Selumetinib followed by I-131 therapy on progression-free survival in radioiodine refractory patients with differentiated thyroid cancer showing increased radioiodine uptake following initial treatment with Selumetinib. In addition, information on toxicity and dosimetry will be collected. This study presents an unprecedented opportunity to investigate the role of lesional dosimetry in molecular radiotherapy, leading to greater personalisation of therapy. To date this has been a neglected area of research. The findings of this trial will be useful to healthcare professionals and patients alike to determine whether further study of this agent is warranted. It is hoped that the development of the infrastructure to deliver a multicentre trial involving molecular radiotherapy dosimetry will lead to further trials in this field., Trial Registration: SEL-I-METRY is registered under ISRCTN17468602 , 02/12/2015.

Introduction: Arthrodesis of a (diseased) ankle joint is usually performed to achieve pain relief and stability. One basic principle of arthrodesis techniques includes rigid fixation of the surfaces until union. It seems plausible that stable anchoring and homogeneous pressure distribution should be advantageous, however, it has not been investigated yet. The aim is to achieve uniform compression, as this is expected to produce favorable results for the bony fusion of the intended arthrodesis. Numerous implants with different biomechanical concepts can be used for ankle fusion. In this study, headless compression screws (HCS, DePuy Synthes, Zuchwil, Switzerland) were compared biomechanically to an alternative fixation System, the IOFix device (Extremity Medical, Parsippany, NJ, USA) in regard to the distribution of the compression force (area of contact) and peak compression in a sawbone arthrodesis-model (Sawbones® Pacific Research Laboratories, Vashon, WA, USA). This study aims to quantify the area of contact between the bone interface that can be obtained using headless compression screws compared to the IOFix. In current literature, it is assumed, that a large contact surface with sufficient pressure between the bones brings good clinical results. However, there are no clinical or biomechanical studies, that describe the optimal compression pressure for an arthrodesis. Material and methods: Two standardized sawbone blocks were placed above each other in a custom-made jig. IOFix and headless compression screws were inserted pairwise parallel to each other using a template for a uniform drilling pattern. All screws were inserted with a predefined torque of 0.5 Nm. Pressure transducers positioned between the two sawbone blocks were compressed for the measurement of peak compression force, compression distribution, and area of contact. Results: With the IOFix, the compression force was distributed over significantly larger areas compared to the contact area of the HCS screws, resulting in a more homogenous contact area over the entire arthrodesis surface. Maximum compression force showed no significant difference. Conclusion: The IOFix system distributes the compression pressure over a much larger area, resulting in more evenly spread compression at the surface. Clinical studies must show whether this leads to a lower pseudarthrosis rate. [ABSTRACT FROM AUTHOR]

Background: It is believed that loss of p53 function plays a crucial role in the progression of well to poorly differentiated thyroid cancers including anaplastic thyroid carcinoma (ATC). Given the poor prognosis of ATC due to its strong therapeutic resistance, there is a need to establish new therapeutic targets to extend the survival of ATC patients. Activating transcription factor 3 (ATF3) can inhibit the oncogenic activity of mutant p53 and, as a result, contribute to tumor suppression in several TP53-mutated cancers. Herein, we demonstrate that the ectopic overexpression of ATF3 leads to the suppression of oncogenic mutant p53 activity in chemo-resistant 8305 C thyroid cancer cells harboring R273C p53 gene mutation. Methods: The biological behavior of 8305 C cells was assessed pre- and post-transfection with pCMV6-ATF3 plasmid using MTT assay, fluorescent microscopy, cell cycle, and annexin V/PI flow cytometric analysis. The effect of ectopic ATF3 overexpression on the cellular level of p53 was examined by western blotting assay. The mRNA expression levels of TP53, TAp63, ΔNp63, and SHARP1 were evaluated in ectopic ATF3-expressing cells compared to controls. Results: The overexpression of ATF3 in 8305 C thyroid cancer cells significantly decreased cell viability and induced apoptosis and cell cycle arrest in vitro. The immunoblotting of p53 protein revealed that ATF3 overexpression significantly increased the level of mutant p53 in 8305C cells compared to mock-transfected control cells. Additionally, elevated mRNA levels of TAp63 and SHARP1 and a decreased mRNA level of ΔNp63 were observed in PCMV6-AC-ATF3-transfected 8305 C cells with significant differences compared to the mock and untreated cells. Conclusion: In light of our findings, it is evident that therapeutic strategies aimed at increasing ATF3 expression or enhancing the interaction between ATF3 and mutant p53 can be a promising approach for the treatment of p53-mutated metastatic thyroid cancer. [ABSTRACT FROM AUTHOR]

Background: Overdose deaths continue to rise within the United States, despite effective treatments such as buprenorphine and methadone for opioid use disorder (OUD). Mobile medical units with the ability to dispense buprenorphine have been developed to engage patients and eliminate barriers to accessing OUD treatment. This study reports survey responses of patients of a mobile medical unit dispensing buprenorphine in areas of Chicago, IL with high overdose rates. Methods: All patients who were dispensed buprenorphine via the mobile medical unit were invited to participate in a 7-item anonymous survey between May 24, 2023, and August 25, 2023. The survey included 5-point satisfaction scale, multiple-choice, and open-ended questions. Outcomes included satisfaction with buprenorphine dispensing from the mobile medical unit, satisfaction with filling buprenorphine at a pharmacy in the past, barriers experienced at pharmacies when filling buprenorphine, and whether the client would have started treatment that day if the mobile medical unit had not been present. Satisfaction scale and multiple-choice question responses were assessed using descriptive statistics. Wilcoxon signed-rank test was used to compare median satisfaction levels between receiving buprenorphine from the mobile medical unit versus filling a buprenorphine prescription at a community pharmacy. Open-ended questions were analyzed qualitatively using inductive thematic analysis. Results: 106 unique patients were dispensed buprenorphine from the mobile unit during the study period. Of these patients, 54 (51%) completed the survey. Respondents reported high satisfaction with the buprenorphine dispensing process as a part of a mobile medical unit. Of those who had previously filled buprenorphine at a pharmacy, 83% reported at least one barrier, with delays in prescription dispensing from a community pharmacy, lack of transportation to/from the pharmacy, and opioid withdrawal symptoms being the most common barriers. 87% reported they would not have started buprenorphine that same day if the mobile medical unit had not been present. Nearly half of survey participants reported having taken buprenorphine that was not prescribed to them. Qualitative analysis of open-ended survey responses noted the importance of convenient accessibility, comprehensive care, and a non-judgmental environment. Conclusions: Mobile medical units that dispense buprenorphine are an innovative model to reach patients with OUD who have significant treatment access barriers. This study found that patients who experienced barriers to accessing buprenorphine from a pharmacy were highly satisfied with the mobile medical unit's buprenorphine dispensing process. Programs seeking to develop mobile buprenorphine dispensing programs should consider patient priorities of accessibility, comprehensive care, and welcoming, non-judgmental environments. [ABSTRACT FROM AUTHOR]

Background: Among swine, reassortment of influenza virus genes from birds, pigs, and humans could generate influenza viruses with pandemic potential. Humans with acute infection might also be a source of infection for swine production units. This article describes the study design and methods being used to assess influenza A transmission between swine workers and pigs. We hypothesize that transmission of swine influenza viruses to humans, transmission of human influenza viruses to swine, and reassortment of human and swine influenza A viruses is occurring. The project is part of a Team Grant; all Team Grant studies include active surveillance for influenza among Hutterite swine farmers in Alberta, Canada. This project also includes non-Hutterite swine farms that are experiencing swine respiratory illness., Methods/design: Nurses conduct active surveillance for influenza-like-illness (ILI), visiting participating communally owned and operated Hutterite swine farms twice weekly. Nasopharyngeal swabs and acute and convalescent sera are obtained from persons with any two such symptoms. Swabs are tested for influenza A and B by a real time RT-PCR (reverse transcriptase polymerase chain reaction) at the Alberta Provincial Laboratory for Public Health (ProvLab). Test-positive participants are advised that they have influenza. The occurrence of test-positive swine workers triggers sampling (swabbing, acute and convalescent serology) of the swine herd by veterinarians. Specimens obtained from swine are couriered to St. Jude Children's Research Hospital, Memphis, TN for testing. Veterinarians and herd owners are notified if animal specimens are test-positive for influenza. If swine ILI occurs, veterinarians obtain samples from the pigs; test-positives from the animals trigger nurses to obtain specimens (swabbing, acute and convalescent serology) from the swine workers. ProvLab cultures influenza virus from human specimens, freezes these cultures and human sera, and ships them to St. Jude where sera will be examined for antibodies to swine and human influenza virus strains or reassortants. Full length sequencing of all eight genes from the human and swine influenza isolates will be performed so that detailed comparisons can be performed between them., Discussion: The declaration of pandemic influenza in June 2009, caused by a novel H1N1 virus that includes avian, swine and human genes, highlights the importance of investigations of human/swine influenza transmission.

Background: p53, the most frequently mutated gene in cancer, lacks effective targeted drugs. Methods: We developed monoclonal antibodies (mAbs) that target a p53 hotspot mutation E285K without cross-reactivity with wild-type p53. They were delivered using lipid nanoparticles (LNPs) that encapsulate DNA plasmids. Western blot, BLI, flow cytometry, single-cell sequencing (scRNA-seq), and other methods were employed to assess the function of mAbs in vitro and in vivo. Results: These LNP-pE285K-mAbs in the IgG1 format exhibited a robust anti-tumor effect, facilitating the infiltration of immune cells, including CD8+ T, B, and NK cells. scRNA-seq revealed that IgG1 reduces immune inhibitory signaling, increases MHC signaling from B cells to CD8+ T cells, and enriches anti-tumor T cell and B cell receptor profiles. The E285K-mAbs were also produced in the dimeric IgA (dIgA) format, whose anti-tumor activity depended on the polymeric immunoglobulin receptor (PIGR), a membrane Ig receptor, whereas that of IgG1 relied on TRIM21, an intracellular IgG receptor. Conclusions: Targeting specific mutant epitopes using DNA-encoded and LNP-delivered mAbs represents a potential precision medicine strategy against p53 mutants in TRIM21- or PIGR-positive cancers. [ABSTRACT FROM AUTHOR]

Background: Dolutegravir is an integrase strand transfer inhibitor that has been recommended for use in first-line antiretroviral regimens by the World Health Organisation and is currently being rolled out globally. There has been safety concerns with dolutegravir which has caused concern about its use in the general population. Dolutegravir first-line regimens have been used in South Africa since early 2020. Therefore, the aim of the present study was to assess the efficacy, safety, and tolerability of first-line dolutegravir-based antiretrovirals amongst adults living with HIV in Durban, South Africa. Methods: This was a mixed-methods study, which comprised a cross-sectional survey and longitudinal retrospective follow-up of medical records. The study was conducted between October 2020 and January 2022. Data were described using descriptive and summary statistics. Bivariate logistic regression was applied to socio-demographic and clinical variables and crude odds ratios with a 95% confidence interval was calculated. Pearson chi-square tests, paired sample T-tests, and cross-tabulations were performed on selected variables. Results: A total of 461 participants were enrolled in the study. There was a significant change in immunological outcomes (p < 0.001) after dolutegravir initiation. Furthermore, an assessment of laboratory parameters showed that there was a significant decrease in cholesterol (p < 0.001) and increase in creatinine (p < 0.001) levels. Increased weight was shown by 60.7% of the participants but was not associated with age, gender, CD4 counts, and previous antiretroviral usage. The study found that 43.6% of the participants experienced at least one side-effect. A total of 21.6% and 23.2% of the participants experienced neuropsychiatric and central nervous system side-effects, respectively. In the bivariate analyses, only gender was shown to be associated with side-effects, and only 1.7% of the participants discontinued the study due to side-effects. Conclusion: Our results suggest that dolutegravir is effective, safe, and well tolerated in the study population. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) affects about 200 million people worldwide, causing leakage of blood components into retinal tissues, leading to activation of microglia, the resident phagocytes of the retina, promoting neuronal and vascular damage. The microglial receptor, CX3CR1, binds to fractalkine (FKN), an anti-inflammatory chemokine that is expressed on neuronal membranes (mFKN), and undergoes constitutive cleavage to release a soluble domain (sFKN). Deficiencies in CX3CR1 or FKN showed increased microglial activation, inflammation, vascular damage, and neuronal loss in experimental mouse models. To understand the mechanism that regulates microglia function, recombinant adeno-associated viral vectors (rAAV) expressing mFKN or sFKN were delivered to intact retinas prior to diabetes. High-resolution confocal imaging and mRNA-seq were used to analyze microglia morphology and markers of expression, neuronal and vascular health, and inflammatory mediators. We confirmed that prophylactic intra-vitreal administration of rAAV expressing sFKN (rAAV–sFKN), but not mFKN (rAAV–mFKN), in FKNKO retinas provided vasculo- and neuro-protection, reduced microgliosis, mitigated inflammation, improved overall optic nerve health by regulating microglia-mediated inflammation, and prevented fibrin(ogen) leakage at 4 weeks and 10 weeks of diabetes induction. Moreover, administration of sFKN improved visual acuity. Our results elucidated a novel intervention via sFKN gene therapy that provides an alternative pathway to implement translational and therapeutic approaches, preventing diabetes-associated blindness. [ABSTRACT FROM AUTHOR]

Although the incidence of thyroid cancer is increasing year by year, most patients, especially those with differentiated thyroid cancer, can usually be cured with surgery, radioactive iodine, and thyroid-stimulating hormone suppression. However, treatment options for patients with poorly differentiated thyroid cancers or radioiodine-refractory thyroid cancer have historically been limited. Altered energy metabolism is one of the hallmarks of cancer and a well-documented feature in thyroid cancer. In a hypoxic environment with extreme nutrient deficiencies resulting from uncontrolled growth, thyroid cancer cells utilize "metabolic reprogramming" to satisfy their energy demand and support malignant behaviors such as metastasis. This review summarizes past and recent advances in our understanding of the reprogramming of glucose metabolism in thyroid cancer cells, which we expect will yield new therapeutic approaches for patients with special pathological types of thyroid cancer by targeting reprogrammed glucose metabolism. [ABSTRACT FROM AUTHOR]

Background: China has a high burden of influenza-associated illness among children. We aimed to evaluate the cost-effectiveness of introducing government-funded influenza vaccination to children in China (fully-funded policy) compared with the status quo (self-paid policy). Methods: A decision tree model was developed to calculate the economic and health outcomes, from a societal perspective, using national- and provincial-level data. The incremental cost-effectiveness ratio (ICER) [incremental costs per quality-adjusted life year (QALY) gained] was used to compare the fully-funded policy with the self-paid policy under the willingness-to-pay threshold equivalent to national and provincial GDP per capita. Sensitivity analyses were performed and various scenarios were explored based on real-world conditions, including incorporating indirect effect into the analysis. Results: Compared to the self-paid policy, implementation of a fully-funded policy could prevent 1,444,768 [95% uncertainty range (UR): 1,203,446–1,719,761] symptomatic cases, 92,110 (95% UR: 66,953–122,226) influenza-related hospitalizations, and 6494 (95% UR: 4590–8962) influenza-related death per season. The fully-funded policy was cost-effective nationally (7964 USD per QALY gained) and provincially for 13 of 31 provincial-level administrative divisions (PLADs). The probability of a funded vaccination policy being cost-effective was 56.5% nationally, and the probability in 9 of 31 PLADs was above 75%. The result was most sensitive to the symptomatic influenza rate among children under 5 years [ICER ranging from − 25,612 (cost-saving) to 14,532 USD per QALY gained]. The ICER of the fully-funded policy was substantially lower (becoming cost-saving) if the indirect effects of vaccination were considered. Conclusions: Introducing a government-funded influenza policy for children is cost-effective in China nationally and in many PLADs. PLADs with high symptomatic influenza rate and influenza-associated mortality would benefit the most from a government-funded influenza vaccination program. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid carcinoma (ATC) was a rare and extremely malignant endocrine cancer with the distinct hallmark of high proportion of cancer stem cell-like characteristics. Therapies aiming to cancer stem-like cells (CSCs) were emerging as a new direction in cancer treatment, but targeting ATC CSCs remained challenging, mainly due to incomplete insights of the regulatory mechanism of CSCs. Here, we unveiled a novel role of ISG15 in the modulation of ATC CSCs. Methods: The expression of ubiquitin-like proteins were detected by bioinformatics and immunohistochemistry. The correlation between ISG15 expression and tumor stem cells and malignant progression of ATC was analyzed by single-cell RNA sequence from the Gene Expression Omnibus. Flow cytometry combined with immunofluorescence were used to verify the enrichment of ISG15 and ISGyaltion in cancer stem cells. The effect and mechanism of ISG15 and KPNA2 on cancer stem cell-like characteristics of ATC cells were determined by molecular biology experiments. Mass spectrometry combined with immunoprecipitation to screen the substrates of ISG15 and validate its ISGylation modification. Nude mice and zebrafish xenograft models were utilized to demonstrate that ISG15 regulates stem cell characteristics and promotes malignant progression of ATC. Results: We found that among several ubiquitin proteins, only ISG15 was aberrantly expressed in ATC and enriched in CSCs. Single-cell sequencing analysis revealed that abnormal expression of ISG15 were intensely associated with stemness and malignant cells in ATC. Inhibition of ISG15 expression dramatically attenuated clone and sphere formation of ATC cells, and facilitated its sensitivity to doxorubicin. Notably, overexpression of ISGylation, but not the non-ISGylation mutant, effectively reinforced cancer stem cell-like characteristics. Mechanistically, ISG15 mediated the ISGylation of KPNA2 and impeded its ubiquitination to promote stability, further maintaining cancer stem cell-like characteristics. Finally, depletion of ISG15 inhibited ATC growth and metastasis in xenografted mouse and zebrafish models. Conclusion: Our studies not only provided new insights into potential intervention strategies targeting ATC CSCs, but also uncovered the novel biological functions and mechanisms of ISG15 and ISGylation for maintaining ATC cancer stem cell-like characteristics. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the relationship between the TyG (Triglyceride-glucose index) and the prognosis of patients with HOCM (hypertrophic obstructive cardiomyopathy) without diabetes. Research design and methods: A total of 713 eligible patients with HOCM were enrolled in this study and divided into two groups based on treatment: an invasive treatment group (n = 461) and a non-invasive treatment group (n = 252). The patients in both two groups were then divided into three groups based on their TyG index levels. The primary endpoints of this study were Cardiogenic death during long-term follow-up. Kaplan–Meier analysis was used to study the cumulative survival of different groups. Restricted cubic spline was used to model nonlinear relationships between the TyG index and primary endpoints. Myocardial perfusion imaging/Myocardial metabolic imaging examinations were performed to assess glucose metabolism in the ventricular septum of the HOCM patients. Results: The follow-up time of this study was 41.47 ± 17.63 months. The results showed that patients with higher TyG index levels had better clinical outcomes (HR, 0.215; 95% CI 0.051,0.902; P = 0.036, invasive treatment group; HR, 0.179; 95% CI 0.063,0.508; P = 0.001, non-invasive treatment group). Further analysis showed that glucose metabolism in the ventricular septum was enhanced in HOCM patients. Conclusions: The findings of this study suggest that the TyG index may serve as a potential protective factor for patients with HOCM without diabetes. The enhanced glucose metabolism in the ventricular septum of HOCM patients may provide a potential explanation for the relationship between the TyG index and HOCM prognosis. Highlights: The study aimed to investigate the relationship between the TyG index and prognosis in HOCM patients without diabetes. The TyG index was found to be a potential protective factor in HOCM patients without diabetes, with higher TyG index levels associated with better clinical outcomes. Enhanced glucose metabolism in the ventricular septum may explain the relationship between the TyG index and HOCM prognosis. The findings of this study may provide useful information for the clinical management of HOCM patients. [ABSTRACT FROM AUTHOR]

Background: The plants from Salvia genus contain widely distributed species which have been used in folk medicine as well as pharmaceutical and food industries. Methods: The chemical composition of 12 native Iranian Salvia species (14 plants) was identified using gas chromatography-mass spectrometry (GC–MS). Also, the inhibitory activity of all essential oils (EOs) was evaluated toward α-glucosidase and two types of cholinesterase (ChE) using spectrophotometric methods. The in vitro α-glucosidase inhibition assay was performed by the determination of p-nitrophenol (pNP) obtained from the enzymatic dissociation of p-nitrophenol-α-D-glucopyranoside (pNPG) as the substrate. In vitro ChE inhibitory assay was conducted based on the modified Ellman's procedure using the measurement of 5-thio-2-nitrobenzoic acid produced from the hydrolysis of thiocholine derivatives as the substrate, in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Results: Totally, 139 compounds were detected and caryophyllene oxide and trans-β-caryophyllene were the most abundant compounds in all EOs. The yield of EOs extracted from the plants were also calculated in the range of 0.06 to 0.96% w/w. Herein, α-glucosidase inhibitory activity of 8 EOs was reported for the first time and among all, S. spinosa L. was found to be the most potent inhibitor (90.5 inhibition at 500 μg/mL). Also, the ChE inhibitory activity of 8 species was reported for the first time and our results showed that the BChE inhibitory effect of all EOs was more potent than that of AChE. The ChE inhibition assay indicated that S. mirzayanii Rech.f. & Esfand. collected from Shiraz was the most potent inhibitor (72.68% and 40.6% at the concentration of 500 μg/mL, toward AChE and BChE, respectively). Conclusions: It seems that native Salvia species of Iran could be considered in the development of anti-diabetic and anti-Alzheimer's disease supplements. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid carcinoma has a very poor prognosis. We analyzed the effect of surgery, radiotherapy and chemotherapy on survival time and side effects in patients with ATC. Methods: We retrospectively analyzed all patients (n = 63) with histologically confirmed ATC who presented at our clinic between 1989 and 2020. We analyzed the survival with Kaplan–Meier curves and cox proportional hazard models and acute toxicities with logistic regression models. Results: Out of 63 patients, 62 received radiotherapy, 74% underwent surgery and 24% received combined chemotherapy. A median radiation dose of 49 Gy (range 4–66 Gy) was applied. In 32% of the cases opposing-field technique was used, in 18% 3D-conformal, in 27% a combination of opposing field and 3D-conformal technique and 21% obtained IMRT (intensity modulated radiotherapy) or VMAT (volumetric modulated arc radiotherapy). Median overall survival (OS) was 6 months. We identified five predictive factors relevant for survival: absence of distant metastases at the time of diagnosis (OS 8 months), surgery (OS 9.8 months), resection status R0 (OS 14 months), radiation dose of 50 Gy or higher (OS 13 months) and multimodal therapy (surgery, radiotherapy and chemotherapy) with a median OS of 9.7 months. Conclusion: In spite of the dismal outcome, longer survival can be achieved in some patients with ATC using surgery and radiotherapy with a high radiation dose. Compared to our previous study, there are no significant advantages in overall survival. Trial registration Retrospectively registered. [ABSTRACT FROM AUTHOR]

Background: Determining the core competence of advanced practice nurses is foundational for promoting optimal design and implementation of advanced practice nursing roles. Core competencies specific to the contexts of the advanced practice nurse in Hong Kong have been developed, but not yet validated. Thus, this study aims to assess the construct validity of advanced practice nurse core competence scale in Hong Kong. Methods: We performed a cross-sectional study using an online self-report survey. Exploratory factor analysis was used to examine the factor structure of a 54-item advanced practice nurse core competence scale through principal axis factoring with direct oblique oblimin rotation. A parallel analysis was conducted to determine the number of factors to be extracted. The Cronbach's α was computed to evaluate the internal consistency of the confirmed scale. The STROBE checklist was used as reporting guideline. Results: A total of 192 advanced practice nurse responses were obtained. Exploratory factor analysis led to the final 51-item scale with a three-factor structure, which accounted for 69.27% of the total variance. The factor loadings of all items ranged from 0.412 to 0.917. The Cronbach's alpha of the total scale and three factors ranged from 0.945 to 0.980, indicating robust internal consistency. Conclusion: This study identified a three-factor structure of the advanced practice nurse core competency scale: client-related competencies, advanced leadership competencies, and professional development and system-related competencies. Future studies are recommended to validate the core competence content and construct in different contexts. Moreover, the validated scale could provide a cornerstone framework for advanced practice nursing roles development, education, and practice, and inform future competency research nationally and internationally. [ABSTRACT FROM AUTHOR]

Introduction: Defects of the neck after palliative resection of exulcerated tumors could be reconstructed with different skin flaps. Case presentation: The present report describes the case of a 40-year-old Caucasian female patient with advanced anaplastic thyroid cancer. The exophytically growing, bad-smelling massive exulcerated tumor caused an esthetic defect, neck mobility restrictions, and mental state deterioration. Primary diagnosis, interventions, and outcomes: Palliative debulking of the tumor was performed. The 10 × 5 cm skin defect of the neck was successfully reconstructed with an internal mammary artery perforator island flap. The donor site was closed primarily. The patient had an uneventful clinical course; the cosmetic results and mental state were very pleasing. Conclusions: The present case illustrates that palliative resection of the tumor and plastic reconstruction of the neck defect promoted other treatments such as radiation or chemotherapy due to the improved local situation. [ABSTRACT FROM AUTHOR]

Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in treatment-naïve individuals living with HIV; these include first generation raltegravir, elvitegravir, and second generation dolutegravir and bictegravir. The most recent INSTI, cabotegravir, is approved for (1) treatment of HIV infection in adults to replace current antiretroviral therapy in individuals who maintain virologic suppression on a stable antiretroviral regimen without history of treatment failure and no known resistance to its components and (2) pre-exposure prophylaxis in individuals at risk of acquiring HIV-1 infection. Cabotegravir can be administered intramuscularly as a monthly or bi-monthly injection depending on the indication. This long-acting combination has been associated with treatment satisfaction in clinical studies and may be helpful for individuals who have difficulty taking daily oral medications. Worldwide, second generation INSTIs are preferred for treatment-naïve individuals. Advantages of these INSTIs include their high genetic barrier to resistance, limited drug-drug interactions, excellent rates of virologic suppression, and favorable tolerability. Few INSTI resistance-associated mutations have been reported in clinical trials involving dolutegravir, bictegravir and cabotegravir. Other advantages of specific INSTIs include their use in various populations such as infants and children, acute HIV infection, and individuals of childbearing potential. The most common adverse events observed in clinical studies involving INSTIs included diarrhea, nausea, insomnia, fatigue, and headache, with very low rates of treatment discontinuation versus comparator groups. The long-term clinical implications of weight gain associated with second generation INSTIs dolutegravir and bictegravir warrants further study. This review summarizes key clinical considerations of INSTIs in terms of clinical pharmacology, drug-drug interactions, resistance, and provides perspective on clinical decision-making. Additionally, we summarize major clinical trials evaluating the efficacy and safety of INSTIs in treatment-naïve patients living with HIV as well as individuals at risk of acquiring HIV infection. [ABSTRACT FROM AUTHOR]

The United States Food and Drug Administration (US FDA) has always been a forerunner in drug evaluation and supervision. Over the past 31 years, 1050 drugs (excluding vaccines, cell-based therapies, and gene therapy products) have been approved as new molecular entities (NMEs) or biologics license applications (BLAs). A total of 228 of these 1050 drugs were identified as cancer therapeutics or cancer-related drugs, and 120 of them were classified as therapeutic drugs for solid tumors according to their initial indications. These drugs have evolved from small molecules with broad-spectrum antitumor properties in the early stage to monoclonal antibodies (mAbs) and antibody‒drug conjugates (ADCs) with a more precise targeting effect during the most recent decade. These drugs have extended indications for other malignancies, constituting a cancer treatment system for monotherapy or combined therapy. However, the available targets are still mainly limited to receptor tyrosine kinases (RTKs), restricting the development of antitumor drugs. In this review, these 120 drugs are summarized and classified according to the initial indications, characteristics, or functions. Additionally, RTK-targeted therapies and immune checkpoint-based immunotherapies are also discussed. Our analysis of existing challenges and potential opportunities in drug development may advance solid tumor treatment in the future. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC. [ABSTRACT FROM AUTHOR]

Background: Onchocerca lupi is a filarial nematode affecting dogs, and occasionally cats and humans, in continental Europe, North Africa, the Middle East, and the USA. Adult worms are usually found in periocular nodules and enucleation is sometimes required if the infection fails to respond to other treatment options. Case presentation: Here, we report the presence of O. lupi in the UK for the first time. Of two dogs re-homed from continental Europe, one developed an ocular nodule seven years after arrival from Portugal. The conjunctival perilimbal mass in its left eye was surgically removed but despite anthelminthic treatment, a further nodule developed in the same eye six months later. In the second case - a dog imported from Romania 12 months earlier - a perilimbal mass was excised from the left eye and prior anthelminthic treatment was supplemented with oral prednisolone and doxycycline. However, nodules recurred, and the left globe was subsequently enucleated. Conjunctival hyperaemia then appeared in the right eye and neither additional anthelminthic treatment nor removal of worm masses failed to prevent the further development of lesions. Excised adult worms were identified in both cases as O. lupi based on morphological characteristics, as well as PCR and sequencing of cytochrome c oxidase subunit I and 12S rRNA gene fragments. Conclusion: O. lupi parasitosis can apparently remain cryptic in dogs for several years before any clinical signs manifest. Moreover, the progression of infection can be highly aggressive and recalcitrant to both surgical intervention and anthelminthic treatment. Increasingly, former stray dogs of unknown infection status are entering the UK, raising both veterinary and public health concerns. [ABSTRACT FROM AUTHOR]

Background: Equine herpesvirus-8 (EHV-8) is one of the most economically significant viruses that infect mammals of the genus Equus worldwide, which cause severe respiratory diseases and abortion in horses. However, there is no report of abortion caused by EHV-8 in donkeys. Case presentation: The present case report is about a 4-year-old donkey having an abortion and showing a serious respiratory issue on the 296th day of pregnancy. Bacteriological and molecular tests were used to screen possible bacterial/viral pathogens to detect the etiological agent. Salmonella abortus equi, EHV-1, EHV-4, and EAV were all negative in the current study. EHV-8, on the other hand, was the only agent that was isolated and identified. Conclusions: This was for the first time that EHV-8 had been isolated from a donkey in China. EHV-8 infection can cause abortion in donkeys; therefore, veterinarians and breeders should be aware of it. [ABSTRACT FROM AUTHOR]

Objective: Papillary Thyroid carcinoma accounts for more than 60% of adult thyroid carcinomas. Finding a helpful marker is vital to determine the correct treatment approach. The present study was aimed to evaluate the expression of the B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) gene in papillary carcinoma, adenoma, and adjacent healthy thyroid tissues. Pathology blocks of thyroid tissues at the pathology department of patients who have undergone thyroid surgery between 2015 and 2019 were examined; papillary carcinoma, adenoma, and healthy tissues were selected and sectioned. Total RNA was extracted, and the relative expression level of the BMI-1 gene was examined using the Real-Time qPCR method. Results: In the papillary and adenoma tissues, BMI-1 was overexpressed (1.047-fold and 1.042-fold) in comparison to healthy tissues (p < 0.05 for both comparisons). However, no statistically significant differences were observed between adenoma and papillary carcinoma tissues regarding BMI-1 gene expression. This study demonstrated a new biomarker for thyroid malignancies and found that the mRNA levels of the BMI-1 gene were higher in tumor tissues compared with healthy tissues. Further studies are needed to evaluate the BMI1 gene expression in other thyroid cancers. [ABSTRACT FROM AUTHOR]

Background: Infants fed contaminated breast milk are at an increased risk of exposure to lead. Breast milk to blood (M/B) ratios have not been investigated among women in Palestine. The aim of this study was to assess blood, breast milk, and M/B lead ratios in samples collected from Palestinian breastfeeding women. Associations between sociodemographic characteristics with breast milk lead levels and M/B lead ratios were also investigated. Methods: This study was conducted in a cross-sectional design in the period between October 2017 and April 2018. Breastfeeding women visiting maternity care centers in different regions of the West Bank of Palestine were recruited to the study by the nurses in the maternity care centers. Sociodemographic characteristics, venous blood, and breast milk samples were collected from each participant. Lead concentrations were analyzed using a validated inductively coupled plasma-mass spectrometric method. Mann–Whitney U test, Pearson's Chi-square, Fisher's exact, and Spearman's correlations were used to analyze the data. Odds ratios (OR) were computed using a multivariate logistic regression model. Results: Matching blood and milk samples were collected from 80 women. Lead concentrations in 11 (13.8%) of the breast milk samples were above the World Health Organization's recommended levels. Breast milk lead levels were more likely to be ≥5 μg/L in breastfeeding women who lived in urban areas (aOR 4.96; 95% CI 1.10, 22.38) compared to those who lived in rural areas. Breast milk to blood lead ratios were more likely to be ≥25% in breastfeeding women who lived in urban areas (aOR 7.06; 95% CI 1.68, 29.77), used eye kohl (aOR 14.29; 95% CI 1.32, 155.06), and used hair dye (aOR 5.33; 95% CI 1.58, 18.00) compared to those who lived in rural areas, did not use eye kohl, and did not use hair dye, respectively. Conclusions: Higher M/B lead ratios were predicted by living in urban areas, using eye kohl, and using hair dye. Decision makers in health authorities should address sources of exposure to lead in urban areas. Cosmetics containing lead should be assessed and regulated for lead content. [ABSTRACT FROM AUTHOR]

Background: To investigate the feasibility of intracranial pressure (ICP) monitoring after traumatic brain injury (TBI) by electromagnetic coupling phase sensing, we established a portable electromagnetic coupling phase shift (ECPS) test system and conducted a comparison with invasive ICP.Methods: TBI rabbits' model were all synchronously monitored for 24 h by ECPS testing and invasive ICP. We investigated the abilities of the ECPS to detect targeted ICP by feature extraction and traditional classification decision algorithms.Results: The ECPS showed an overall downward trend with a variation range of - 13.370 ± 2.245° as ICP rose from 11.450 ± 0.510 mmHg to 38.750 ± 4.064 mmHg, but its change rate gradually declined. It was greater than 1.5°/h during the first 6 h, then decreased to 0.5°/h and finally reached the minimum of 0.14°/h. Nonlinear regression analysis results illustrated that both the ECPS and its change rate decrease with increasing ICP post-TBI. When used as a recognition feature, the ability (area under the receiver operating characteristic curve, AUCs) of the ECPS to detect ICP ≥ 20 mmHg was 0.88 ± 0.01 based on the optimized adaptive boosting model, reaching the advanced level of current noninvasive ICP assessment methods.Conclusions: The ECPS has the potential to be used for noninvasive continuous monitoring of elevated ICP post-TBI. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) affects approximately 145,519 people in the UK. Speech impairments are common with a reported prevalence of 68%, which increase physical and mental demands during conversation, reliance on family and/or carers, and the likelihood of social withdrawal reducing quality of life. In the UK, two approaches to Speech and Language Therapy (SLT) intervention are commonly available: National Health Service (NHS) SLT or Lee Silverman Voice Treatment (LSVT LOUD®). NHS SLT is tailored to the individuals' needs per local practice typically consisting of six to eight weekly sessions; LSVT LOUD® comprises 16 sessions of individual treatment with home-based practice over 4 weeks. The evidence-base for their effectiveness is inconclusive.Methods/design: PD COMM is a phase III, multicentre, three-arm, unblinded, randomised controlled trial. Five hundred and forty-six people with idiopathic PD, reporting speech or voice problems will be enrolled. We will exclude those with a diagnosis of dementia, laryngeal pathology or those who have received SLT for speech problems in the previous 2 years. Following informed consent and completion of baseline assessments, participants will be randomised in a 1:1:1 ratio to no-intervention control, NHS SLT or LSVT LOUD® via a central computer-generated programme, using a minimisation procedure with a random element, to ensure allocation concealment. Participants randomised to the intervention groups will start treatment within 4 (NHS SLT) or 7 (LSVT LOUD®) weeks of randomisation.Primary Outcome: Voice Handicap Index (VHI) total score at 3 months. Secondary outcomes include: VHI subscales, Parkinson's Disease Questionnaire-39; Questionnaire on Acquired Speech Disorders; EuroQol-5D-5 L; ICECAP-O; resource utilisation; adverse events and carer quality of life. Mixed-methods process and health economic evaluations will take place alongside the trial. Assessments will be completed before randomisation and at 3, 6 and 12 months after randomisation. The trial started in December 2015 and will run for 77 months. Recruitment will take place in approximately 42 sites around the UK.Discussion: The trial will test the hypothesis that SLT is effective for the treatment of speech or voice problems in people with PD compared to no SLT. It will further test whether NHS SLT or LSVT LOUD® provide greater benefit and determine the cost-effectiveness of both interventions.Trial Registration: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 12421382. Registered on 18 April 2016. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) often has a long period from first symptom presentation to diagnosis. We examined the occurrence of symptoms, prescriptions and diagnostic tests in primary care electronic records over time prior to a diagnosis of AS. Methods: Nested case-control study using anonymised primary care electronic health records from Scotland. Cases were 74 adults with a first diagnosis of AS between 2000 and 2010. Controls were matched for age, sex and GP practice: (a) 296 randomly selected adults (b) 169 adults whose records contained codes indicating spinal conditions or symptoms. We extracted clinical features (symptoms, AS-related disorders, prescriptions and diagnostic tests). Conditional logistic regression was used to examine the association between clinical features (both individually and in combinations) and diagnosis of AS. We examined the associations between clinical features and diagnosis over time prior to diagnosis. Results: Several new composite pointers were predictive of AS: including distinct episodes of axial pain separated by more than 6 months (OR 12.7, 95% CI 4.7 to 34.6); the occurrence of axial pain with and tendon symptoms within the same year (OR 21.7, 95% CI 2.6 to 181.5); and the co-occurrence (within 30 days) of axial pain and a prescription for nonsteroidal anti-inflammatory drug (OR 10.4, 95%CI 4.9 to 22.1). Coded episodes of axial pain increased steadily over the 3 years before diagnosis. In contrast, large joint symptoms and enthesopathy showed little or no time trend prior to diagnosis. Conclusions: We identified novel composite pointers to a diagnosis of AS in GP records. These may represent valuable targets for diagnostic support systems. [ABSTRACT FROM AUTHOR]

Circulating tumor cells (CTCs) are a rare subset of cells found in the blood of patients with solid tumors, which function as a seed for metastases. Cancer cells metastasize through the bloodstream either as single migratory CTCs or as multicellular groupings—CTC clusters. The CTCs preserve primary tumor heterogeneity and mimic tumor properties, and may be considered as clinical biomarker, preclinical model, and therapeutic target. The potential clinical application of CTCs is being a component of liquid biopsy. CTCs are also good candidates for generating preclinical models, especially 3D organoid cultures, which could be applied in drug screening, disease modeling, genome editing, tumor immunity, and organoid biobanks. In this review, we summarize current knowledge on the value and promise of evolving CTC technologies and highlight cutting-edge research on CTCs in liquid biopsy, tumor metastasis, and organoid preclinical models. The study of CTCs offers broad pathways to develop new biomarkers for tumor patient diagnosis, prognosis, and response to therapy, as well as translational models accelerating oncologic drug development. [ABSTRACT FROM AUTHOR]

Background: Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene polymorphisms (*6 and *28) in Japanese individuals infected with human immunodeficiency virus (HIV)-1 to examine the relationship between their plasma trough concentration of DTG and gene polymorphisms. Recently, neuropsychiatric adverse events (NP-AEs) after the use of DTG have become a concern, so the association between UGT1A1 gene polymorphisms and selected NP-AEs was also investigated.Methods: The study subjects were 107 Japanese patients with HIV-1 infections who were receiving DTG. Five symptoms (dizziness, headache, insomnia, restlessness, and anxiety) were selected as NP-AEs. The subjects were classified by their UGT1A1 gene polymorphisms for the group comparison of DTG trough concentration and the presence or absence of NP-AEs.Results: The subjects consisted of eight (7%) *6 homozygotes, three (3%) *28 homozygotes, four (4%) for *6/*28 compound heterozygotes, 23 (21%) *6 heterozygotes, 18 (17%) *28 heterozygotes, and 51 (48%) patients carrying the normal allele. The plasma DTG trough concentration of the *6 homozygous patients was significantly higher than that of the patients carrying the normal allele (median, 1.43 and 0.82 μg/mL, respectively, p = 0.0054). The *6 and *28 heterozygous patients also showed significantly higher values than those shown by patients with the normal allele. Multivariate analysis revealed that carrying one or two UGT1A1*6 gene polymorphisms, one UGT1A1*28 polymorphism, and age of < 40 years were independent factors associated with high DTG trough concentrations. The median DTG trough concentration was significantly higher in the patients with NP-AEs (1.31 μg/mL) than in those without NP-AEs (1.01 μg/mL). Consistent with these results, subjects carrying UGT1A1*6, UGT1A1*28, or both alleles showed a higher cumulative incidence of having selected NP-AEs than those carrying the normal alleles (p = 0.0454).Conclusion: In addition to younger age, carrying UGT1A1*6 and/or UGT1A1*28 was demonstrated to be a factor associated with high DTG trough concentrations. Our results also suggest a relationship between plasma DTG trough concentrations and NP-AEs, and that carrying UGT1A1*6 and/or UGT1A1*28 alleles might be a risk factor for NP-AEs. [ABSTRACT FROM AUTHOR]

Background: After vaccination, vaccinees acquire some protection against infection and/or disease. Vaccination, therefore, reduces the number of infections in the population. Due to this herd protection, not everybody needs to be vaccinated to prevent infections from spreading.Methods: We quantify direct and indirect effects of influenza vaccination examining the standard Susceptible-Infected-Recovered (SIR) and Susceptible-Infected-Recovered-Susceptible (SIRS) model as well as simulation results of a sophisticated simulation tool which allows for seasonal transmission of four influenza strains in a population with realistic demography and age-dependent contact patterns.Results: As shown analytically for the simple SIR and SIRS transmission models, indirect vaccination effects are bigger than direct ones if the effective reproduction number of disease transmission is close to the critical value of 1. Simulation results for 20-60% vaccination with live influenza vaccine of 2-17 year old children in Germany, averaged over 10 years (2017-26), confirm this result: four to seven times as many influenza cases are prevented among non-vaccinated individuals as among vaccinees. For complications like death due to influenza which occur much more frequently in the unvaccinated elderly than in the vaccination target group of children, indirect benefits can surpass direct ones by a factor of 20 or even more than 30.Conclusions: The true effect of vaccination can be much bigger than what would be expected by only looking at vaccination coverage and vaccine efficacy. [ABSTRACT FROM AUTHOR]

Background: Screw fixation is a typical technique for isolated talonavicular arthrodesis (TNA), however, no consensus has been reached on how to select most suitable inserted position and direction. The study aimed to present a new fixation technique and to evaluate the clinical outcome of individual headless compression screws (HCSs) applied with three-dimensional (3D) image processing technology to isolated TNA. Methods: From 2007 to 2014, 69 patients underwent isolated TNA by using double Acutrak HCSs. The preoperative three-dimensional (3D) insertion model of double HCSs was applied by Mimics, Catia, and SolidWorks reconstruction software. One HCS oriented antegradely from the edge of dorsal navicular tail where intersected interspace between the first and the second cuneiform into the talus body along the talus axis, and the other one paralleled the first screw oriented from the dorsal-medial navicular where intersected at the medial plane of the first cuneiform. The anteroposterior and lateral X-ray examinations certified that the double HCSs were placed along the longitudinal axis of the talus. Postoperative assessment included the American Orthopaedic Foot & Ankle Society hindfoot (AOFAS), the visual analogue scale (VAS) score, satisfaction score, imaging assessments, and complications. Results: At the mean 44-months follow-up, all patients exhibited good articular congruity and solid bone fusion at an average of 11.26 ± 0.85 weeks (range, 10 ~ 13 weeks) without screw loosening, shifting, or breakage. The overall fusion rates were 100%. The average AOFAS score increased from 46.62 ± 4.6 (range, 37 ~ 56) preoperatively to 74.77 ± 5.4 (range, 64-88) at the final follow-up (95% CI: -30.86 ~ -27.34; p < 0.001). The mean VAS score decreased from 7.01 ± 1.2 (range, 4 ~ 9) to 1.93 ± 1.3 (range, 0 ~ 4) (95% CI: 4.69 ~ 5.48; p < 0.001). One cases (1.45%) and three cases (4.35%) experienced wound infection and adjacent arthritis respectively. The postoperative satisfaction score including pain relief, activities of daily living, and return to recreational activities were good to excellent in 62 (89.9%) cases. Conclusions: Individual 3D reconstruction of HCSs insertion model can be designed with three-dimensional image processing technology in TNA. The technology is safe, effective, and reliable to isolated TNA method with high bone fusion rates, low incidences of complications. [ABSTRACT FROM AUTHOR]

Background: To determine the diagnostic efficacy of ultrasonographic malignancy risk features (UMRFs) in follicular lesions (FL) in a population with low risk of malignancy in FL and to compare it with a similar analysis in a group of patients with unequivocal cytology (UC): benign lesion (BL) or malignant neoplasm (MN). Methods: Presence of UMRFs (hypoechogenicity, solid echostructure, taller-than-wide shape, pathological vascularization, irregular margins, microcalcifications and macrocalcifications) and their sets were assessed in 322 FL: 202 follicular lesions of undetermined significance (FLUS) and 120 suspicious for follicular neoplasm (SFN) and 300 nodules with UC: 200 BL and 100 MN, subsequently evaluated histopathologically. Results: Cancers were confirmed in 100% nodules in MN group (89.0% of them were papillary carcinomas - PTC), in 6.4% FLUS nodules (69.2% PTC), and in 10.8% SFN nodules (30.8% PTC). In the UC group all UMRFs occurred more frequently in cancers than in benign lesions. In the FL group only calcifications were found in cancers more frequently - macro and microcalcifications together: 34.6 vs. 11.5% (p = 0.001) and isolated macrocalcifications: 26.0 vs. 6.8% (p=0.001); the presence of those features increased the basic risk of malignancy in FL more than 2 times. The presence of at least 2 of the following URMFs: hypoechogenicity, solid echostructure, any type of calcifications and suspected shape, additionally improved sensitivity. Conclusions: Evaluation of UMRFs in FLs is less effective than in nodules with UC, and its effectiveness decreases parallel to the decrease in percentage of PTCs among malignant neoplasms and to the increase of the percentage of adenomas among benign nodules. The presence of macrocalcifications in such FLs significantly increases the basic risk of malignancy in these nodules. [ABSTRACT FROM AUTHOR]

Background: The RNA polymerase II transcriptional Mediator subunit Med12 is broadly implicated in vertebrate brain development, and genetic variation in human MED12 is associated with X-linked intellectual disability and neuropsychiatric disorders. Although prior studies have begun to elaborate the functional contribution of Med12 within key neurodevelopmental pathways, a more complete description of Med12 function in the developing nervous system, including the specific biological networks and cellular processes under its regulatory influence, remains to be established. Herein, we sought to clarify the global contribution of Med12 to neural stem cell (NSC) biology through unbiased transcriptome profiling of mouse embryonic stem (ES) cell-derived NSCs following RNAi-mediated Med12 depletion. Results: A total of 240 genes (177 up, 73 down) were differentially expressed in Med12-knockdown versus control mouse NS-5 (mNS-5) NSCs. Gene set enrichment analysis revealed Med12 to be prominently linked with "cell-to-cell interaction" and "cell cycle" networks, and subsequent functional studies confirmed these associations. Targeted depletion of Med12 led to enhanced NSC adhesion and upregulation of cell adhesion genes, including Syndecan 2 (Sdc2). Concomitant depletion of both Sdc2 and Med12 reversed enhanced cell adhesion triggered by Med12 knockdown alone, confirming that Med12 negatively regulates NSC cell adhesion by suppressing the expression of cell adhesion molecules. Med12-mediated suppression of NSC adhesion is a dynamically regulated process in vitro, enforced in self-renewing NSCs and alleviated during the course of neuronal differentiation. Accordingly, Med12 depletion enhanced adhesion and prolonged survival of mNS-5 NSCs induced to differentiate on gelatin, effects that were bypassed completely by growth on laminin. On the other hand, Med12 depletion in mNS-5 NSCs led to reduced expression of G1/S phase cell cycle regulators and a concordant G1/S phase cell cycle block without evidence of apoptosis, resulting in a severe proliferation defect. Conclusions: Med12 contributes to the maintenance of NSC identity through a functionally bipartite role in suppression and activation of gene expression programs dedicated to cell adhesion and G1/S phase cell cycle progression, respectively. Med12 may thus contribute to the regulatory apparatus that controls the balance between NSC self-renewal and differentiation, with important implications for MED12-linked neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Background: Older people living in Residential Aged Care Facilities (RACF) are a vulnerable, frail and complex population. They are more likely than people who reside in the community to become acutely unwell, present to the Emergency Department (ED) and require admission to hospital. For many, hospitalisation carries with it risks. Importantly, evidence suggests that some admissions are avoidable. A new collaborative model of care, the Aged Care Emergency Service (ACE), was developed to provide clinical support to nurses in the RACFs, allowing residents to be managed in place and avoid transfer to the ED. This paper examines the effects of the ACE service on RACF residents' transfer to hospital using a controlled pre-post design.Methods: Four intervention RACFs were matched with eight control RACFs based on number of total beds, dementia specific beds, and ratio of high to low care beds in Newcastle, Australia, between March and November 2011. The intervention consisted of a clinical care manual to support care along with a nurse led telephone triage line, education, establishing goals of care prior to ED transfer, case management when in the ED, along with the development of collaborative relationships between stakeholders. Outcomes included ED presentations, length of stay, hospital admission and 28-day readmission pre- and post-intervention. Generalised estimating equations were used to estimate mean differences in outcomes between intervention and controls RACFs, pre- and post-intervention means, and their interaction, accounting for repeated measures and adjusting for matching factors.Results: Residents had a mean age of 86 years. ED presentations ranged between 16 and 211 visits/100 RACF beds/year across all RACFs. There was no overall reduction in ED presentations (OR = 1.17, p = 0.56) with the ACE intervention. However, when compared to the controls, the intervention group reduced their ED length of stay by 45 min (p = 0.0575), and was 40 % less likely to be admitted to hospital, . The latter was highly significant (p = 0.0012).Conclusions: Transfers to ED and admission to hospital are common for residents of RACFs. This study has demonstrated that a complex multi-strategy intervention led by nursing staff can successfully reduce hospital admissions for older people living in Residential Aged Care Facilities. By defining goals of care prior to transfer to the ED, clinicians have the opportunity to better deliver care that patients require. Integrated care requires accountability from multiple stakeholders.Trial Registration: The Australian New Zealand Clinical Trials Registration number is ACTRN12616000588493 It was registered on 6(th) May 2016. [ABSTRACT FROM AUTHOR]

Background: Microeconomic evaluations of public health programmes such as immunisation typically only consider direct health benefits and medical cost savings. Broader economic benefits around childhood development, household behaviour, and macro-economic indicators are increasingly important, but the evidence linking immunization to such benefits is unclear. Methods: A conceptual framework of pathways between immunisation and its proposed broader economic benefits was developed through expert consultation. Relevant articles were obtained from previous reviews, snowballing, and expert consultation. Articles were associated with one of the pathways and quality assessed using modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Results: We found 20 studies directly relevant to one or more pathways. Evidence of moderate quality from experimental and observational studies was found for benefits due to immunisation in improved childhood physical development, educational outcomes, and equity in distribution of health gains. Only modelling evidence or evidence outside the immunization field supports extrapolating these benefits to household economic behaviour and macro-economic indicators. Conclusion: Innovative use of experimental and observational study designs is needed to fill evidence gaps around key pathways between immunisation and many of its proposed economic benefits. [ABSTRACT FROM AUTHOR]

Background: Seasonal influenza vaccine was once part of the routine immunization schedule that is routinely offered to all children in Japan, but it is now excluded from the schedule. This study aimed to investigate factors influential to parents' decision to have their children receive seasonal influenza vaccine, as well as types of seasonal influenza vaccine information that is given to parents. Methods: We conducted a cross-sectional online survey of 555 participants who have at least one child younger than 13 years of age. Respondents were asked to categorize the history of influenza vaccination of their youngest child as either 'annual', 'sometimes', or 'never'. Participants were also asked about potentially influential factors in their decision to have their children receive a seasonal influenza vaccine. Results: A total of 75% of respondents answered that their youngest child had received a seasonal influenza vaccine, and 57% of respondents answered that their child receives the vaccine every year. The higher income group was more likely than the lowest income group to have a history of influenza vaccine uptake. A recommendation from a pediatrician or school/nursery to have their child vaccinated was also positively associated with a history of influenza vaccine uptake. The most common reason for a pediatrician's recommendation was 'it leads to milder symptoms if infected'. Conclusions: The main finding of the study is a significant association between household income and influenza vaccination of the youngest child in the household. We also found that cost could be a barrier to vaccinating children in low income households and that information from pediatricians and schools/nurseries could motivate parents to have their children vaccinated. [ABSTRACT FROM AUTHOR]

Background: The formalized nurse practitioner (NP) role in British Columbia is relatively new with most roles implemented in primary care. The majority of primary care is delivered by physicians using the fee-for-service model. There is a shortage of general practitioners associated with the difficulties of recruitment and retention, particularly in rural and remote locations. The uptake of the primary care NP role has been slow due to challenges in understanding the extent of its contributions. This study aims to identify the outcomes associated with the NP role in collaborative primary care practice. Methods: Three case studies where NPs were embedded into rural fee-for-service practices were undertaken to determine the outcomes at the practitioner, practice, community, and health services levels. Interviews, documents, and before and after data, were analyzed to identify changes in practise, access, and acute care service utilization. Results: The results showed that NPs affected how care was delivered, particularly through the additional time afforded each patient visit, development of a team approach with interprofessional collaboration, and a change in style of practise from solo to group practise, which resulted in improved physician job satisfaction. Patient access to the practice improved with increased availability of appointments and practice staff experienced improved workplace relationships and satisfaction. At the community level, access to primary care improved for harder-to-serve populations and new linkages developed between the practice and their community. Acute care services experienced a statistically significant decrease in emergency use and admissions to hospital (P = 0.000). The presence of the NP improved their physician colleagues' desire to remain in their current work environment. Conclusions: This study identified the diversity of needs that can be addressed by the NP role. Namely, the importance of time to enhance patient care and its associated benefits, especially in the feefor-service model; the value of the NP's role in the community; the acceptance of the clinical competence of NPs by their physician colleagues; the outcomes generated at the practice level in terms of organizational effectiveness and service provision; and substantiated the impact of the role in improving primary care access and reducing acute care utilization. [ABSTRACT FROM AUTHOR]

Background Many patients with pneumonia and lower respiratory tract infection that could be treated as outpatients according to their clinical severity score, are in fact admitted to hospital. We investigated whether, with medical and social input, these patients could be discharged early and treated at home. Objectives: (1) To assess the feasibility of providing an early supported discharge scheme for patients with pneumonia and lower respiratory tract infection (2) To assess the patient acceptability of a study comprising of randomisation to standard hospital care or early supported discharge scheme. Methods Design: Randomised controlled trial. Setting: Liverpool, UK. Two University Teaching hospitals; one city-centre, 1 suburban in Liverpool, a city with high deprivation scores and unemployment rates. Participants: 200 patients screened: 14 community-dwelling patients requiring an acute hospital stay for pneumonia or lower respiratory tract infection were recruited. Intervention: Early supported discharge scheme to provide specialist respiratory care in a patient's own home as a substitute to acute hospital care. Main outcome measures: Primary - patient acceptability. Secondary - safety/mortality, length of hospital stay, readmission, patient/carer (or next of kin) satisfaction, functional status and symptom improvement. Results 42 of the 200 patients screened were eligible for early supported discharge; 10 were only identified at the point of discharge, 18 declined participation and 14 were randomised to either early supported discharge or standard hospital care. The total hospital length of hospital stay was 8.33 (1-31) days in standard hospital care and 3.4 (1-7) days in the early supported discharge scheme arm. In the early supported discharge scheme arm patient carers reported higher satisfaction with care and there were less readmissions and hospital-acquired infections. Limitations: A small study in a single city. This was a feasibility study and therefore not intended to compare outcome data. Conclusions An early supported discharge scheme for patients with pneumonia and lower respiratory tract infection was feasible. Larger numbers of patients would be eligible if future work included patients with dementia and those residing in care homes. [ABSTRACT FROM AUTHOR]

Background: Urinary tract infections (UTIs) are among the most common infectious diseases and drivers of antibiotic use and in-hospital days. A reduction of antibiotic use potentially lowers the risk of antibiotic resistance. An early and adequate risk assessment combining medical, biopsychosocial and functional risk scores has the potential to optimize site-of-care decisions and thus allocation of limited health-care resources. The aim of this factorial design study is twofold: first, for Intervention A, it investigates antibiotic exposure of patients treated with a protocol based on the type of UTI, procalcitonin (PCT) and pyuria. Second, for Intervention B, it investigates the usefulness of the prognostic biomarker proadrenomedullin (ProADM) integrated into an interdisciplinary assessment bundle for site-of-care decisions. Methods and design: This randomized controlled open-label trial has a factorial design (2 × 2). Randomization of patients will be based on a pre-specified computer-generated randomization list and independent for the two interventions. Adults with UTI presenting to the emergency department (ED) will be screened and enrolled after providing informed consent. For our first Intervention (A), we developed a protocol based on previous observational research to recommend initiation and duration of antibiotic use based on the clinical presentation of UTI, pyuria and PCT levels. For our second intervention (B), an algorithm was developed to support site-of care decisions based on the prognostic marker ProADM and distinct nursing factors on days 1 and 3. Both interventions will be compared with a control group conforming to the guidelines. The primary endpoints for the two interventions will be: (A) overall exposure to antibiotics and (B) length of physician-led hospitalization within a follow-up of 30 days. Endpoints are assessed at discharge from hospital, and 30 and 90 days after admission. We plan to screen 300 patients and enroll 250 for an anticipated estimated loss of follow-up of 20%. This will provide adequate power for the two interventions. Discussion: This trial investigates two strategies for improved individualized medical care in patients with UTI. The minimally effective duration of antibiotic therapy is not known for UTIs, which is important for reducing the selection pressure for antibiotic resistance, costs and drug-related side effects. Triage decisions must be improved to reflect the true medical, biopsychosocial and functional risks in order to allocate patients to the most appropriate care setting and reduce hospital-acquired disability. [ABSTRACT FROM AUTHOR]

Genetic factors may interact with lifestyle factors to modify obesity risk. FTO and PPARG2 are relevant obesogenes. Our aim was to explore the effect of Pro12Ala (rs1801282) of PPARG2 and rs9939609 of FTO on obesity risk and to examine their interaction with lifestyle factors in an elderly population. Subjects ( n = 978; aged 69 ± 6) were recruited from the SUN (Seguimiento Universidad de Navarra) Project. DNA was obtained from saliva, and lifestyle and dietary data were collected by validated self-reported questionnaires. Genotyping was assessed by RT-PCR plus allele discrimination. Subjects carrying the Ala allele of PPARG2 gene had a significantly increased obesity risk compared to non-carrier (Pro12Pro) subjects (OR, 1.66; 95 % CI, 1.01-2.74; p = 0.045). Greater obesity risk was also found in inactive or high carbohydrate intake subjects with the Ala12 allele of PPARG2 gene. Interestingly, subjects carrying the Ala allele of the PPARG2 gene and with a high CHO (>246 g/day) intake had an increased obesity risk compared to Pro12Pro subjects (OR, 2.67; 95 % CI, 1.3-5.46; p = 0.007; p for [CHO × PPARG2] interaction = 0.046). Moreover, in subjects with a high CHO intake, the co-presence of the Ala allele of PPARG2 gene and one minor A allele (rs9939609) of FTO gene did increase obesity risk (OR, 3.26; 95 % CI, 1.19-8.89; p = 0.021) when compared to non-carrier (Pro12Pro/TT) subjects. In conclusion, it appears that lifestyle factors may act as effect modifiers for obesity risk linked to Ala12 allele of the PPARG2 gene and the minor A allele of FTO gene in an elderly population. [ABSTRACT FROM AUTHOR]

The article offers information on system biology being a promising approach for resolving controversies in cancer research. It states that till the last decade of 20th century, biologists focused on the interior of the cell and the somatic mutation theory became dominant view in carcinogenesis. It mentions that the pathogenesis of human cancers is governed by set of genetic and biochemical rules that apply to most of human tumors.

The article presents a study related to inflammatory breast cancer (IBC). It investigates the effect of media on the expression of adhesion molecules E-cadherin and fibronectin of human IBC cell line SUM149, conditioned by human monocytes U937 secreted cytokines, chemokines and growth factors. The cytokines signaling pathway involved were also identified. It is stated interleukin-8 (IL-8) the secreted cytokine by U937 cells may play a vital role in fibronectin expression by SUM149 cells.