Impact of age on leptin and adiponectin independent of adiposity.
Age-related changes in leptin and adiponectin levels remain controversial, being affected by inconsistent normalisation for adiposity and body fat distribution in the literature. In a cross-sectional study on 210 Caucasians (127 women, eighty-three men, 18-78 years, BMI 16.8-46.8 kg/m²), we investigated the effect of age on adipokine levels independent of fat mass (FM measured by densitometry), visceral and subcutaneous adipose tissue volumes (VAT and SAT assessed by whole-body MRI). Adiponectin levels increased with age in both sexes, whereas leptin levels decreased with age in women only. There was an age-related increase in VAT (as a percentage of total adipose tissue, VAT%TAT), associated with a decrease in SAT(legs)%TAT. Adiposity was the main predictor of leptin levels, with 75.1 % of the variance explained by %FM in women and 76.6 % in men. Independent of adiposity, age had a minor contribution to the variance in leptin levels (5.2 % in women only). The variance in adiponectin levels explained by age was 14.1 % in women and 5.1 % in men. In addition, independent and inverse contributions to the variance in adiponectin levels were found for truncal SAT (explaining additional 3.0 % in women and 9.1 % in men) and VAT%TAT (explaining additional 13.0 % in men). In conclusion, age-related changes in leptin and adiponectin levels are opposite to each other and partly independent of adiposity and body fat distribution. Normalisation for adiposity but not for body fat distribution is required for leptin. Adiponectin levels are adversely affected by subcutaneous and visceral trunk fat.


Localisation and semiquantitative assessment of hepatic procollagen mRNA in primary biliary cirrhosis.
Chronic liver disease is characterised by excessive deposition of collagen and other extracellular matrix proteins, produced mainly, but not exclusively, by activated hepatic stellate cells in the perisinusoidal space. In primary biliary cirrhosis (PBC) fibrosis is concentrated mainly around the portal tracts. To examine the hypothesis that, in addition to hepatic stellate cells, portal tract fibroblasts might play a significant role in the deposition of collagen in PBC. Fifty liver biopsy specimens from patients with PBC were studied. An in situ hybridisation technique was adapted to localise and measure semiquantitatively type I procollagen mRNA in formalin fixed, paraffin wax embedded sections, using an 35S labelled cRNA probe specific for the alpha 1 chain of rat type I procollagen. Hepatic fibrogenic activity was also assessed using serum type III procollagen peptide (PIIINP). In PBC, type I procollagen gene expression was significantly increased. Signal was localised mainly in and around inflamed portal tracts, to cells which had the appearances of portal fibroblasts. Signal activity in these cells correlated with the degree of portal fibrosis and inflammation and also with serum PIIINP concentrations. Results are consistent with the hypothesis that the excessive extracellular matrix, deposited within the liver in PBC, is synthesised not only by hepatic stellate cells but also by portal tract fibroblasts. The semiquantitative assessment of procollagen mRNA in liver biopsy specimens may provide a useful method of evaluating the rate of synthesis of collagen and therefore disease activity in patients with PBC.


Local Structure of Glassy Lithium Phosphorus Oxynitride Thin Films: A Combined Experimental and Ab Initio Approach.
Lithium phosphorus oxynitride (LiPON) is an amorphous solid-state lithium ion conductor displaying exemplary cyclability against lithium metal anodes. There is no definitive explanation for this stability due to the limited understanding of the structure of LiPON. Herein, we provide a structural model of RF-sputtered LiPON. Information about the short-range structure results from 1D and 2D solid-state NMR experiments. These results are compared with first principles chemical shielding calculations of Li-P-O/N crystals and ab initio molecular dynamics-generated amorphous LiPON models to unequivocally identify the glassy structure as primarily isolated phosphate monomers with N incorporated in both apical and as bridging sites in phosphate dimers. Structural results suggest LiPON's stability is a result of its glassy character. Free-standing LiPON films are produced that exhibit a high degree of flexibility, highlighting the unique mechanical properties of glassy materials.


Anxiety in anesthesia providers during coronavirus disease 19 pandemic: Insights into perception of harm a cross-sectional study.
The influence of Coronavirus disease 2019 (COVID-19) pandemic on mental health has been widely studied; however, literature evaluating the mental health effects of the pandemic on small groups of people is scarce. We aim to evaluate the impact of the COVID-19 pandemic on anxiety levels of anesthesiology providers in an academic institution. We conducted a cross-sectional study including one hundred and five participants (Faculty anesthesiologists, anesthesia residents, certified registered and student nurse anesthetists). The generalized anxiety disorder questionnaire (GAD-7) was administered to participants. Approximately half of the 105 participants experienced various degrees of anxiety, with only 14.3% exhibiting moderate to severe symptoms of anxiety. Anxiety interfering with daily activities was reported in 54.9% of the participants. Anxiety-generating factors such as access to protective equipment and transmitting the disease to family members were identified. The COVID-19 pandemic is associated with different degrees of anxiety. The prevalence of severe anxiety is relatively low, probably due to differential individual perceptions, feelings of invulnerability, and resilience of anesthesia providers.


In vitro metabolism of the cardiotonic steroids gomphogenin and calactin.
The metabolism of gomphogenin and calactin was studied in vitro using respectively microsomes and the S9 fraction of homogenates from rat liver. These two substrates were previously shown to be in vitro and in vivo metabolites of gomphoside, a cardiotonic steroid belonging to a class of 5 alpha-cardenolide glycosides with doubly-linked hexosulose sugars. Structures of new metabolites were elucidated using 400 MHz 1H-NMR and chemical ionization mass spectrometry, while known compounds were identified by direct comparison. The major metabolite isolated from gomphogenin (2 alpha-hydroxyuzarigenin) metabolism was the oxidation product 2-oxo-uzarigenin which was further oxidized metabolically to 4 alpha-hydroxy-2-oxo-uzarigenin. Other metabolites were 2 alpha-hydroxyuzarigenone and its reduction product 3-epigomphogenin. Calactin was oxidized in vitro to 10-carboxyl-19-norgomphoside, the predominant metabolite, and underwent cleavage of the doubly-linked sugar to yield calotropagenin.


Compulsive buying: relationship with body mass index.
Compulsive buying has historically been associated with various self-regulatory disturbances, including eating pathology (e.g., binge eating). Therefore, a relationship between scores on a measure of compulsive buying, the Compulsive Buying Scale (CBS), and body mass index (BMI) in adulthood was hypothesized. Using a self-report survey methodology in a cross-sectional consecutive sample of convenience of 373 obstetrics/gynecology patients, correlations between CBS scores and BMI, both generally and with regard to race were examined. A modest general correlation between CBS scores and BMI (r = 0.17, P < 0.01) was found. However, when these data were examined by race, CBS scores and BMI were significantly related among Caucasian women (r = 0.25, P < 0.01), but not in African American women (r = 0.04, P = n.s.). Findings indicate that compulsive buying is associated with increasing BMI in adulthood, particularly among Caucasian women.


Plasma-Based Metabolomics Profiling of High-Risk Human Papillomavirus and their Emerging Roles in the Progression of Cervical Cancer.
High-risk human papillomavirus (HR-HPV) is the main etiological factor for cervical cancer. Accumulating evidence has suggested the active role of metabolites in the initiation and progression of cancers. This study explored the plasma metabolic profiles of HPV-16 positive (HPV16 (+)), HPV-18 positive (HPV18 (+)), and HPV negative (CTL) individuals using a nontargeted metabolomics approach. C8 ceramide-1-Phosphate (d18 : 1/8 : 0) was found to inhibit cervical cancer cell proliferation and migration in vitro, evidenced by CCK8 experiments, a cell migration test, RT-qPCR, and western blotting. The underlying mechanism demonstrated that C8 inhibited proliferation and migration in cervical cancer cells via the MAPK/JNK1 signaling pathway. These findings may contribute to the clinical treatment of HR-HPV-induced cervical cancer by intervening in its initiation and progression.


Sonochemical cycloadditions in ionic liquids. Lessons from model cases involving common dienes and carbonyl dienophiles.
This contribution describes a series of sonochemical cycloadditions involving either cyclopentadiene or 1,3-cyclohexadiene with carbonyl dienophiles in an imidazolium-based ionic liquid as reaction medium. In general, ultrasound does effectively improve these processes in terms of higher yields and/or shorter reaction times when compared with the corresponding silent reactions. Stereoselectivities, however, remain practically unaffected by sonication. The role of ionic liquids under ultrasonic activation is also discussed.


Synthesis of 4-pyrido-6-aryl-2-substituted amino pyrimidines as a new class of antimalarial agents.
A series of 2,4,6-trisubstituted pyrimidines were synthesized and evaluated for their in vitro antimalarial activity against Plasmodium falciparum. Of the 18 compounds synthesized, 14 compounds showed MIC in the range of 0.25-2 microg/mL. These compounds are in vitro several fold more active than pyrimethamine.


Diagnostic and prognostic roles of soluble CD22 in patients with Gram-negative bacterial sepsis.
Soluble CD22 (sCD22) is a fragment of CD22, a B cell-specific membrane protein that negatively regulates B-cell receptor signaling. To date, sCD22 has only been regarded as a tumor marker of B-cell malignancies. Its expression in infectious diseases has not yet been assessed. Serum concentrations of sCD22, procalcitonin (PCT) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assays in patients with intra-abdominal Gram-negative bacterial infection. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic accuracy of these biomarkers in this type of infection. The correlations between biomarkers and the Acute Physiology and Chronic Health Evaluation (APACHE) II scores were also analyzed. Concentrations of sCD22 were significantly elevated in patients with sepsis and the elevation is correlated with the severity of sepsis. sCD22 was also slightly elevated in patients with non-infected systemic inflammatory response syndrome or local infection. The diagnostic accuracy of sCD22 for sepsis was equivalent to that of PCT or IL-6. In addition, the correlation of sCD22 with APACHE II scores was stronger than that of PCT or IL-6. Serum sCD22 is a novel inflammatory mediator released during infection. This soluble biomarker plays a potential role in the diagnosis of Gram-negative bacterial sepsis, with a diagnostic accuracy as efficient as that of PCT or IL-6. Furthermore, sCD22 is more valuable to predict the outcomes in patients with sepsis than PCT or IL-6. The present study suggested that sCD22 might be potentially useful in supplementing current criteria for sepsis.


Cost-Effectiveness of Neoadjuvant-Adjuvant Treatment Strategies for Women With ERBB2 (HER2)-Positive Breast Cancer.
The neoadjuvant treatment options for ERBB2-positive (also known as HER2-positive) breast cancer are associated with different rates of pathologic complete response (pCR). The KATHERINE trial showed that adjuvant trastuzumab emtansine (T-DM1) can reduce recurrence in patients with residual disease compared with patients treated with trastuzumab; however, T-DM1 and other ERBB2-targeted agents are costly, and understanding the costs and health consequences of various combinations of neoadjuvant followed by adjuvant treatments in the United States is needed. To examine the costs and disease outcomes associated with selection of various neoadjuvant followed by adjuvant treatment strategies for patients with ERBB2-positive breast cancer. In this economic evaluation, a decision-analytic model was developed to evaluate various neoadjuvant followed by adjuvant treatment strategies for women with ERBB2-positive breast cancer from a health care payer perspective in the United States. The model was informed by the KATHERINE trial, other clinical trials with different regimens from the KATHERINE trial, the Flatiron Health Database, McKesson Corporation data, and other evidence in the published literature. Starting trial median age for KATHERINE patients was 49 years (range, 24-79 years in T-DM1 arm and 23-80 years in trastuzumab arm). The model simulated patients receiving 5 different neoadjuvant followed by adjuvant treatment strategies. Data analyses were performed from March 2019 to August 2020. There were 4 neoadjuvant regimens: (1) HP: trastuzumab (H) plus pertuzumab (P), (2) THP: paclitaxel (T) plus H plus P, (3) DDAC-THP: dose-dense anthracycline/cyclophosphamide (DDAC) plus THP, (4) TCHP: docetaxel (T) plus carboplatin (C) plus HP. All patients with pCR, regardless of neoadjuvant regimen, received adjuvant H. Patients with residual disease received different adjuvant therapies depending on the neoadjuvant regimen according to the 5 following strategies: (1) neoadjuvant DDAC-THP followed by adjuvant H, (2) neoadjuvant DDAC-THP followed by adjuvant T-DM1, (3) neoadjuvant THP followed by adjuvant DDAC plus T-DM1, (4) neoadjuvant HP followed by adjuvant DDAC/THP plus T-DM1, or (5) neoadjuvant TCHP followed by adjuvant T-DM1. Lifetime costs in 2020 US dollars and quality-adjusted life-years (QALYs) were estimated for each treatment strategy, and incremental cost-effectiveness ratios were estimated. A strategy was classified as dominated if it was associated with fewer QALYs at higher costs than the alternative. In the base-case analysis, costs ranged from $415 833 (strategy 3) to $518 859 (strategy 4), and QALYs ranged from 9.67 (strategy 1) to 10.73 (strategy 3). Strategy 3 was associated with the highest health benefits (10.73 QALYs) and lowest costs ($415 833) and dominated all other strategies. Probabilistic analysis confirmed that this strategy had the highest probability of cost-effectiveness (>70% at willingness-to-pay thresholds of $0-200,000/QALY) and was associated with the highest net benefit. These results suggest that neoadjuvant THP followed by adjuvant H for patients with pCR or followed by adjuvant DDAC plus T-DM1 for patients with residual disease was associated with the highest health benefits and lowest costs for women with ERBB2-positive breast cancer compared with other treatment strategies considered.


Impact of the government's restrictions and guidance in relation to "social distancing" on the lives of ethnic minority populations: A mixed methods study.
The impacts of the COVID-19 pandemic have not been equal, with a disproportionate impact among ethnic minority communities. Structural inequalities in social determinants of health such as housing and employment have contributed to COVID-19's impact on deprived communities, including many ethnic minority communities. To compare (1) how the UK government's "social distancing" restrictions and guidance were perceived and implemented by ethnic minority populations compared to white populations, (2) the impact of restrictions and guidance upon these groups. An explanatory sequential mixed methods study incorporated a quantitative survey and qualitative semi-structured interviews to explore individual perceptions and experiences of COVID-19 and the national restrictions. Survey participants (n = 1587) were recruited from North West England; 60 (4%) participants were from ethnic minority communities. Forty-nine interviews were conducted; 19 (39%) participants were from ethnic minority communities. Interviews were transcribed verbatim and analysed using a thematic approach. Data collection was between April and August 2020. Significant differences in demographics and household overcrowding were observed between white vs ethnic minority survey respondents, who were also significantly less confident in their knowledge of COVID-19, less likely to be high-risk drinkers, and marginally more likely to have experienced job loss and/or reduced household income. There were no group differences in wellbeing, perceptions, or nonfinancial impacts. Two inter-related themes included: (1) government guidance, incorporating people's knowledge and understanding of the guidance and their confusion/frustration over messaging; (2) the impacts of restrictions on keyworkers, home-schooling, working from home and changes in lifestyle/wellbeing. Further research is needed on the long-term impacts of COVID-19 on ethnic minority communities. If policy responses to COVID-19 are to benefit ethnic minority communities, there is a need for future studies to consider fundamental societal issues, such as the role of housing and economic disadvantage.


Impact of interpretation method on clinic visit length.
To determine the impact of interpretation method on outpatient visit length. Time-motion study. Hospital-based outpatient teaching clinic. Patients presenting for scheduled outpatient visits. Over a 6-week study period, a research assistant recorded the following information for consecutive patient visits: patient age, gender and insurance type; type of interpreter used (none, hospital interpreter, telephone interpreter or patient-supplied interpreter); scheduled visit length; provider type (nurse practitioner; attending physician; resident in postgraduate year 1, 2 or 3, or medical student); provider gender; amount of time the patient spent in the examination room with the provider (provider time); and total time the patient spent in the clinic from check-in to checkout (clinic time). When compared to patients not requiring an interpreter, patients using some form of interpreter had longer mean provider times (32.4 minutes [min] vs 28.0 min, P <.001) and clinic times (93.6 min vs 82.4 min, P =.002). Compared to patients not requiring an interpreter, patients using a telephone interpreter had significantly longer mean provider times (36.3 min vs 28.0 min, P <.001) and clinic times (99.9 min vs 82.4 min, P =.02). Similarly, patients using a patient-supplied interpreter had longer mean provider times (34.4 min vs 28.0 min, P <.001) and mean clinic times (92.8 min vs 82.4 min, P =.027). In contrast, patients using a hospital interpreter did not have significantly different mean provider times (26.8 min vs 28.0 min, P =.51) or mean clinic times (91.0 min vs 82.4 min, P =.16) than patients not requiring an interpreter. In our setting, telephone and patient-supplied interpreters were associated with longer visit times, but full-time hospital interpreters were not.


Assessing root canal fillings on a radiograph--an overview.
This article will discuss why a root filling that appears satisfactory on a radiograph may fail, and why one which appears unsatisfactory on a radiograph may succeed. In doing so, this article will also discuss the criteria of endodontic success and failure and its implications on the decision to retreat.


Pesticides on residential outdoor surfaces: environmental impacts and aquatic toxicity.
Pesticides are routinely applied to residential impervious outdoor surfaces for structural pest control. This residential usage has been linked to the occurrence of toxic levels of pesticides in urban water bodies. It is believed that run-off water transports particles that have sorbed hydrophobic pesticides. However, concentrations of particle-bound pesticides have not been directly measured on impervious surfaces, and the role of these particles as a source of contamination is unknown. Pesticides were detected in 99.4% of samples, with >75% of samples containing at least five pesticides. Assuming all particles were transferred with run-off, the run-off amount of pesticide during each rainfall would be >5 mg. We also used the US EPA Storm Water Management Model and estimated that 43 and 65% of the pesticides would be washed off during two rainfall events, with run-off concentrations ranging from 10.0 to 54.6 ng L(-1) and from 13.3 to 109.1 ng L(-1) respectively. The model-predicted pesticide run-off concentrations were similar to the levels monitored in urban run-off and sediments. Most (78%) particle samples contained aggregate toxicities above the Hyalella azteca LC50 . The results suggest that loose particles on residential impervious surfaces are not only carriers but also an important source of hydrophobic pesticides in urban run-off and contribute to downstream aquatic toxicities. © 2015 Society of Chemical Industry.


Jump-Chain Simulation of Markov Substitution Processes Over Phylogenies.
We draw attention to an under-appreciated simulation method for generating artificial data in a phylogenetic context. The approach, which we refer to as jump-chain simulation, can invoke rich models of molecular evolution having intractable likelihood functions. As an example, we simulate data under a context-dependent model allowing for CpG hypermutability and show how such a feature can mislead common codon models used for detecting positive selection. We discuss more generally how this method can serve to elucidate the ways by which currently used models for inference are susceptible to violations of their underlying assumptions. Finally, we show how the method could serve as an inference engine in the Approximate Bayesian Computation framework.


A trial deep learning-based model for four-class histologic classification of colonic tumor from narrow band imaging.
Narrow band imaging (NBI) has been extensively utilized as a diagnostic tool for colorectal neoplastic lesions. This study aimed to develop a trial deep learning (DL) based four-class classification model for low-grade dysplasia (LGD); high-grade dysplasia or mucosal carcinoma (HGD); superficially invasive submucosal carcinoma (SMs) and deeply invasive submucosal carcinomas (SMd) and evaluate its potential as a diagnostic tool. We collected a total of 1,390 NBI images as the dataset, including 53 LGD, 120 HGD, 20 SMs and 17 SMd. A total of 598,801 patches were trimmed from the lesion and background. A patch-based classification model was built by employing a residual convolutional neural network (CNN) and validated by three-fold cross-validation. The patch-based validation accuracy was 0.876, 0.957, 0.907 and 0.929 in LGD, HGD, SMs and SMd, respectively. The image-level classification algorithm was derived from the patch-based mapping across the entire image domain, attaining accuracies of 0.983, 0.990, 0.964, and 0.992 in LGD, HGD, SMs, and SMd, respectively. Our CNN-based model demonstrated high performance for categorizing the histological grade of dysplasia as well as the depth of invasion in routine colonoscopy, suggesting a potential diagnostic tool with minimal human inputs.


Respond, don't react: The influence of mindfulness training on performance monitoring in older adults.
A sizeable body of literature demonstrates positive effects of mindfulness training on brain, behavior, and psychological processes in both novice and expert practitioners as compared to non-meditators. However, only more recently has research begun to examine the specific mechanisms by which mindfulness exerts these effects. In the current study, we used event-related potentials (error-related negativity (ERN), error positivity (Pe)) to test the hypothesis that performance monitoring is one such mechanism. We conducted a randomized controlled trial in healthy older adults (n = 36), relevant because markers of performance monitoring are known to decline with normal aging. Compared to an active control condition, mindfulness participants showed an increase in the ERN, without an increase in the Pe. Participants in both groups reported a reduction in self-report of anxiety and self-judgment of one's own mental functioning, indicating the subjective impression of benefit from each intervention type. The current results are important insofar as they support the purported self-regulatory functions of mindfulness (i.e., learning to respond, not react), as well as demonstrating that such positive effects can be obtained in an older adult sample, both of which have important implications for intervention.


Influence of quality labels on the formation of preferences of lamb meat consumers. A Spanish case study.
Analysis of the attributes determining the formation of consumers' preferences when buying lamb meat is a key aspect in increasing the demand for this product. To this end, by means of conjoint analysis, we determined lamb meat consumers' preferences according to their frequency of consumption, and we used logistic simulation to analyse market shares of the most valued attributes. After segmenting the market into habitual and occasional consumers of lamb meat, our results seem to suggest that while regular consumers base their preferences mostly on origin, occasional consumers take other attributes into account, such as Protected Geographical Origin (PGI) and organic production. An analysis of market shares shows that PGI significantly influences consumer preferences, while ecological production has a less marked impact. This finding confirms the usefulness of PGI in the lamb meat market and highlights the urgent need to improve the communication strategy of the organic production sector as a synergistic effect to increase its acceptance among consumers.


Sexual risk behaviors and the legacy of colonial violence among Northern plains American Indian youth: A mixed methods exploratory study.
In this article, we honor the tribal remembering of two Northern Plains tribes to illustrate how the legacy of colonial violence frames the way in which substance use and mental health affect sexual risk behaviors among American Indian youth on the reservation today. We used a multi-phase, mixed quantitative and qualitative methods design within a community based participatory research framework to illustrate how the legacy of colonial violence frames epidemiological links between substance use, mental health, and sexual risk behavior among American Indian youth. We conducted semistructured interviews with 29 individuals and administered questionnaires to 298 American Indian youth living in a reservation environment. Our findings explicate how a legacy of colonial violence underlies epidemiological links between mental health and substance use with sexual risk behavior among youth. Salient facets of colonial violence included systematically altered living arrangements, the boarding school era, eroded traditional practices, and the entry of extractive industries onto native lands. The colonial violence enacted against the ancestors of Northern Plains tribal peoples materializes in the health of those living on the reservation today. Community interventions, which seek to address the role of substance use and mental health in sexual risk behavior, could benefit from delineating tribal perceptions regarding the legacy of colonial violence on public health outcomes through the use of a CBPR framework.


Effect of resection of lateral rectus muscle in undercorrected esotropia.
Bilateral lateral rectus resection was performed on both previously recessed medial rectus muscles in 23 patients with residual esotropia. The operation reduced the deviation in all patients, but successful treatment was achieved only in 52%. The advantages and disadvantages of this surgical approach are discussed.


Identifying personal beliefs of nursing staff about encouraging psychogeriatric nursing home residents in daily activities: A qualitative study.
To identify personal beliefs of Dutch nursing staff about encouraging psychogeriatric nursing home residents in daily activities. Qualitative study following COREQ guidelines. Fifteen semi-structured interviews with Dutch nursing staff of wards hosting psychogeriatric residents were conducted in Spring 2021. Data were systematically analysed through deductive coding analysis in NVivo. Most nurses indicated to encourage residents frequently to perform activities independently, although many also indicated to take over tasks habitually. Nurses seemed to show sufficient awareness, reflected by adequate knowledge of what encouraging residents entailed and insight in the risks of not encouraging residents. Nurses' motivation to encourage residents seemed high, reflected by expressing multiple advantageous and few disadvantageous beliefs and a high willingness to encourage residents. Managerial support was perceived ambiguous. Self-efficacy was perceived high, although little time, staffing shortages and resistance of residents reduced self-efficacy. Nurses were often unable to anticipate such situations and expressed the need of skills, e.g. patience.


Development of D-α-Tocopherol polyethylene glycol 1000 succinate fabricated nanostructural lipid carrier of sorafenib tosylate for metastatic colorectal targeting application: Stability, physical characterization, cytotoxicity, and apoptotic studies against SW48 cells PTEN.
The study aimed to create D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) nanostructured lipid carriers (NLC) of sorafenib tosylate (ST) as lymphatic delivery systems (LDDS) to fight Metastatic colorectal cancer. Initially, ST-SLN, ST-NLC, and ST-LNE were formulated considering oleic acid (OA), glycerol monolinoleate (GMO), glycerol monolinoleate (GML) as solid lipid and further characterised, and tested for stability. The most stable ST-NLC was fabricated with TPGS to produce ST-TPGS-NLC and evaluated by performing in vitro drug profiling, in vitro cytotoxicity, and apoptotic studies against human female colorectal adenocarcinoma cell lines (SW48 Cells PTEN). Stability studies on three lipidic nanoparticles (ST-SLN, ST-NLC, ST-LEN) showed particle size, polydispersity index, and zeta potential ranging from 165 nm to 298 nm, 0.125 to 0.288, and -31 mV to -16 mV. At 1600 minutes, more than 80% of ST-NLC1 was released, confirming the sustained release pattern of the formulation. ST-NLC and ST-TPGS-NLC have entrapment efficiencies above 50%. Pure ST's IC50 at 72 hr was 3.45 µg/mL, while 1.56 µg/mL was for ST-TPGS-NLC. The ST-TPGS-NLC reduced the number of livings SW48 Cells PTEN from 91% to 5%, compared to 75% to 8% of pure ST. The ST-TPGS-NLC is a promising LDDS for delivering ST for metastatic colorectal cancer.


Ajugol enhances TFEB-mediated lysosome biogenesis and lipophagy to alleviate non-alcoholic fatty liver disease.
Lipophagy is the autophagic degradation of lipid droplets. Dysregulated lipophagy has been implicated in the development of non-alcoholic fatty liver disease (NAFLD). Ajugol is an active alkaloid isolated from the root of Rehmannia glutinosa which is commonly used to treat various inflammatory and metabolic diseases. This study aimed to investigate the effect of ajugol on alleviating hepatic steatosis and sought to determine whether its potential mechanism via the key lysosome-mediated process of lipophagy. Our findings showed that ajugol significantly improved high-fat diet-induced hepatic steatosis in mice and inhibited palmitate-induced lipid accumulation in hepatocytes. Further analysis found that hepatic steatosis promoted the expression of LC3-II, an autophagosome marker, but led to autophagic flux blockade due to a lack of lysosomes. Ajugol also enhanced lysosomal biogenesis and promoted the fusion of autophagosome and lysosome to improve impaired autophagic flux and hepatosteatosis. Mechanistically, ajugol inactivated mammalian target of rapamycin and induced nuclear translocation of the transcription factor EB (TFEB), an essential regulator of lysosomal biogenesis. siRNA-mediated knockdown of TFEB significantly abrogated ajugol-induced lysosomal biogenesis as well as autophagosome-lysosome fusion and lipophagy. We conclude that lysosomal deficit is a critical mediator of hepatic steatosis, and ajugol may alleviate NAFLD via promoting the TFEB-mediated autophagy-lysosomal pathway and lipophagy.


Gingival crevicular fluid PGE2, IL-1beta, t-PA, PAI-2 levels in type 2 diabetes and relationship with periodontal disease.
To evaluate if type 2 diabetes mellitus increase gingival crevicular fluid (GCF) levels of prostaglandin E(2) (PGE(2)), interleukin-1beta (IL-1beta), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-2 (PAI-2). Seventeen type 2 diabetic patients with periodontal disease (DM), 17 otherwise healthy periodontally diseased patients (PD) and 17 systemically and periodontally healthy control subjects (H) were enrolled. Clinical periodontal measurements were recorded at six sites/tooth. GCF samples were analyzed by ELISA. Data were tested by statistical tests. DM group revealed lower IL-1beta levels than PD group (p<0.01). PGE(2), t-PA and PAI-2 levels were similar in DM and PD groups (p>0.05). PGE(2), t-PA levels were higher in DM and PD groups than H group (p<0.05). PAI-2 level was higher in DM group than H group (p<0.05). GCF total amount of PGE(2) in DM group exhibited significant correlations with all clinical periodontal measurements (p<0.05). Type 2 diabetes in this study seems not to increase GCF levels of the evaluated inflammatory mediators.


Susceptibility of clinical isolates of Candida spp. to terconazole and other azole antifungal agents.
Terconazole is a triazole ketal derivative with potent, broad-spectrum antifungal activity. We investigated the in vitro activity of terconazole, miconazole, and clotrimazole, against 94 clinical isolates of Candida spp.: C. albicans (n = 68), C. tropicalis (n = 18), and C. parapsilosis (n = 8). In vitro susceptibility testing was performed using a broth microdilution method. The minimal inhibitory concentrations of terconazole were less than those of miconazole against C. albicans and C. parapsilosis but higher against C. tropicalis. Terconazole was more active than clotrimazole against C. parapsilosis and less active against C. albicans and C. tropicalis. Terconazole inhibited the uptake of 14C-labeled glucose, leucine, and hypoxanthine into C. albicans and caused the rapid release of intracellular K+. Based on these studies, terconazole has promising anticandidal activity and warrants further in vitro and in vivo investigation.


The superior epigastric artery does not pass through Larrey's space (trigonum sternocostale).
The passage of the superior epigastric artery (SEA), the terminal branch of the internal thoracic artery (ITA), through the inferior orifice of the thorax differs in different reports. According to some, it passes through Larrey's space (trigonum sternocostale), therefore through a diaphragmatic orifice, but according to others it passes in front of the diaphragm and the transverse abdominal muscle. The aim of this study was to determine the position of the SEA in its thoracoabdominal segment. We carried out a series of 14 dissections (10 on embalmed cadavers and 4 on unembalmed cadavers), and a study of images from the Visible Human Project. Dissections always led to the same conclusions. After having dissected the trigonum sternocostale, we observed that no vascular element was present in the space, which was obstructed downwards by the parietal peritoneum and limited forwards by the aponeurosis of the transverse abdominal muscle. Inferior digitations of transversus thoracis were joined with the transversus abdominis. The SEA passed in front of the plane formed by these two muscles while the sternal and costal parts of the diaphragm were behind this plane. Whatever the level of the section of the Visible Human Project, there was always a musculoaponeurotic plane between Larrey's space and the superior epigastric artery and both veins. Larrey's space, or trigonum sternocostale, was limited medially by the lateral border of the sternal part of the diaphragm, laterally by the medial border of the costal part of the diaphragm, and anteriorly by the musculoaponeurotic plane formed by the transversus thoracis above and the transversus abdominis, below without a clear boundary between those muscles. The SEA, the terminal branch of the ITA, passed in front of this musculoaponeurotic plane.


The relative and absolute configuration of PF1140.
A potentially general approach for elucidating the absolute configuration of N-hydroxypyridone antibiotics has been developed. One member of this family of antibiotics, PF1140, was efficiently purified from a crude fungal extract following allylation of its N-hydroxyl group. Removal of the resultant allyl group permitted regeneration of the N-hydroxyl group as well as conversion into the corresponding pyridone derivative. The stereochemistry of PF1140 including the absolute configuration was established by X-ray crystallographic analysis of the S-2-methoxy-2-(1-naphthyl)propionic ester derivative.


Carotid artery intima-media thickness, heat shock proteins and oxidized LDL autoantibodies in systemic necrotizing vasculitis.
In this study we evaluate early atherosclerotic changes and determine whether anti-HSP-60, anti-HSP-65 and anti-oxLDL autoantibodies are elevated in systemic necrotizing vasculitis. Thirty-two patients having systemic necrotizing vasculitis were compared with normal controls and patients with systemic lupus erythematosus (SLE). The antibodies against human HSP-60, HSP-65 and oxLDL were measured by antihuman ELISA kit. All patients underwent non-invasive measurements of carotid artery intima-media thickness (IMT). In a comparison between carotid IMT extent between vasculitis patients and SLE, no significant differences were noted. Levels of anti-HSP-60, anti-HSP-65 IgG and anti-oxLDL autoantibodies were similar among patients compared to controls. IgM anti-HSP-60 antibody levels were significantly lower in patients compared to controls and a similar trend was found regarding IgM anti-HSP-65. As a group, patients having various necrotizing vasculitis have similar extent of early atherosclerotic changes regardless of the vasculitis type, and these levels are similar to those found in SLE.


Using a Classifier Fusion Strategy to Identify Anti-angiogenic Peptides.
Anti-angiogenic peptides perform distinct physiological functions and potential therapies for angiogenesis-related diseases. Accurate identification of anti-angiogenic peptides may provide significant clues to understand the essential angiogenic homeostasis within tissues and develop antineoplastic therapies. In this study, an ensemble predictor is proposed for anti-angiogenic peptide prediction by fusing an individual classifier with the best sensitivity and another individual one with the best specificity. We investigate predictive capabilities of various feature spaces with respect to the corresponding optimal individual classifiers and ensemble classifiers. The accuracy and Matthew's Correlation Coefficient (MCC) of the ensemble classifier trained by Bi-profile Bayes (BpB) features are 0.822 and 0.649, respectively, which represents the highest prediction results among the investigated prediction models. Discriminative features are obtained from BpB using the Relief algorithm followed by the Incremental Feature Selection (IFS) method. The sensitivity, specificity, accuracy, and MCC of the ensemble classifier trained by the discriminative features reach up to 0.776, 0.888, 0.832, and 0.668, respectively. Experimental results indicate that the proposed method is far superior to the previous study for anti-angiogenic peptide prediction.


Sleep-disordered breathing children: Measurement of nasal nitric oxide and fractional exhaled nitric oxide.
To assess the clinical significance of nasal nitric oxide (nNO) and fractional exhaled nitric oxide (FeNO) concentrations in children with sleep-disordered breathing (SDB). Enrolled in this study were 30 children with SDB and 15 healthy children. The nNO and FeNO concentrations were measured noninvasively using a NIOX MINO system (Aerocrine AB, Solna, Sweden). SPSS statistics 20.0 software (IBM SPSS statistics 20.0, Armonk, NY, USA) was used to analyze the data. The median (25th and 75th percentiles) nNO concentration of SDB children measured in parts per billion (ppb) was 111.0 (44.0; 349.0) ppb; FeNO concentration of SDB children was 12.0 (9.8; 14.0) ppb. The nNO concentration of healthy children was 52.0 (22.0; 139.0) ppb; FeNO concentration of healthy children was 12.0 (10.0; 16.0) ppb. Compared to healthy children, nNO concentration was significantly higher in children with SDB (Z = -2.215, P = 0.027). Correlation analysis showed that SDB children's nNO concentration directly correlated with apnea-hypopnea index (AHI; r = 0.429, P = 0.018), and inversely correlated with nadir oxygen saturation (SaO2; r = -0.482, P = 0.007). No other polysomnographic parameters significantly correlated with nNO concentration. Our data suggest that nNO concentration might be useful for diagnosis and evaluation of disease severity in SDB children. Furthermore, these results suggest that nNO concentration has a greater prognostic value than FeNO concentration.


An intron-encoded protein assists RNA splicing of multiple similar introns of different bacterial genes.
Four group II introns were found in an unusually intron-rich dnaN gene (encoding the beta subunit of DNA polymerase III) of the cyanobacterium Trichodesmium erythraeum, and they have strong similarities to two introns of the RIR gene (encoding ribonucleotide reductase) of the same organism. Of these six introns, only the RIR-3 intron encodes a maturase protein and showed efficient RNA splicing when expressed in Escherichia coli cells. The other five introns do not encode a maturase protein and did not show RNA splicing in E. coli. But these maturase-less introns showed efficient RNA splicing when the RIR-3 intron-encoded maturase protein was co-expressed from a freestanding gene in the same cell. These findings demonstrated that an intron-encoded protein could function as a general maturase for multiple introns of different genes. Major implications may include an intron-mediated co-regulation of the different genes and a resemblance of the evolutionary origin of spliceosomal introns.


Cytotoxic Effects of Verbascoside on MCF-7 and MDA-MB-231
Verbascoside, also known as acteoside/kusaginin, has attracted a great attention due to its pharmacological features. In this study, we aimed to determine the cytotoxic effects of pure verbascoside isolated from Phlomis nissolii L. plant in both MCF-7 and MDA-MB-231 cell lines in vitro. MCF-7 and MDA-MB 231 cells were treated with verbascoside (100, 48, 25, 10, 1, 0.5, and 0.1 μM) for 24, 48, and 72 hours. Cytotoxic effect of verbascoside in MCF-7 and MDA-MB-231 cells was assessed using TEBU-BIO cell counting kit 8. IC50 values for 24, 48, and 72 h verbascoside exposure of MCF-7 cells were determined as 0.127, 0.2174, and 0.2828 μM, respectively. R2 values were calculated as 0.9630, 0.8789 and 0.8752, respectively. Two-Way ANOVA multiple comparison test results showed that 100 μM verbascoside has the highest cytotoxic effect on MCF-7 breast cancer (BC) cells after 72 h of exposure. IC50 values for 24, 48 and 72 h verbascoside exposure of MDA-MB 231 cells were determined as 0.1597, 0.2584 and 0.2563 μM, respectively and R2 values were calculated as 0.8438, 0.5107 and 0.9203, respectively. Two-Way ANOVA multiple comparisons test results showed that 100 μM verbascoside has the highest cytotoxic effect on MDA-MB 231 BC cells after 24, 48 and 72 h of exposure.


"A Dad Can Get the Money and the Mom Stays at Home": Patriarchal Gender Role Attitudes, Intimate Partner Violence, Historical Oppression, and Resilience Among Indigenous Peoples.
Research has shown that gender role attitudes influence a number of health-related outcomes, including intimate partner violence (IPV). Yet the gender role attitudes of Indigenous peoples - a population that experiences persistent health and violence disparities - have received scant scholarly attention. Using the Framework of Historical Oppression, Resilience, and Transcendence (FHORT), the purpose of this mixed methodology was to qualitatively explore U.S. Indigenous peoples' gender role attitudes and quantitatively examine how key social determinants of health, including IPV perpetration, historical oppression, and resilience, relate to gender role attitudes. This research integrates qualitative and quantitative data from two Southeastern tribes with a total of 563 unique data sources. Regression analysis revealed male sex and IPV victimization were associated with higher patriarchal gender role attitudes, while historical oppression and resilience were associated with lower patriarchal gender role attitudes. Resilience was also associated with lower "victim blaming." Ethnographic team-based data analysis methods revealed qualitative themes of patriarchal gender role attitudes and gendered socialization processes. This work highlights how key aspects of the FHORT might explain Indigenous peoples' patriarchal gender role attitudes, suggesting the need to redress historical oppression and patriarchal roles through decolonization.


[Psychophysiologic manifestations, psychological and somatic risk factors and the physician-patient relationship in patients with heart diseases].
In daily medicine we often see patients complaining about thoracic pain. There is little doubt about the etiology in the most cases, but several patients continue posing diagnostic problems. There are different pathophysiological views to understand the situation of those patients, and it is important to determine their mental and psychological conditions. For this purpose, the focus on transference and countertransference phenomena has to be stressed. With these elements it will be possible to determine the diagnostic and therapeutic approach to those patients to reassure them and to justify investigations.


Nrf2-mediated protective effect of protein hydrolysates from Protaetia brevitarsis larvae against oxidative stress-induced hepatotoxicity.
In this study, we hypothesized that Protaetia brevitarsis larvae (PBL) protein hydrolysates, which have been previously reported to exhibit strong antioxidant activity, might protect liver cells against oxidative stress-induced injury. Thus, the cytoprotective effects and related mechanisms of PBL hydrolysates were investigated in AML12 liver cells. Among PBL hydrolysates prepared by three different proteases, the PBL flavouryzme hydrolysate showed significantly higher protective effect against H2O2-induced cytotoxicity than other hydrolysates in AML12 cells. Further mechanistic studies showed that pretreatment with PFH reduces cellular level of reactive oxygen species through induction of Nrf2-mediated antioxidant enzymes such as catalase and heme oxygenase-1. In addition, the free amino acid analysis revealed that PFH was rich in branched-chain amino acids, aromatic amino acids, and hydrophobic amino acids as compared to other hydrolysates, which could contribute to its hepatoprotective effect. These findings suggest that PFH represents a potential source of nutraceuticals that supports liver functions. The online version contains supplementary material available at 10.1007/s10068-023-01279-0.


Post-therapeutic circulating tumor cell-associated white blood cell clusters predict poor survival in patients with advanced driver gene-negative non-small cell lung cancer.
This study aimed to investigate the clinical utility of diverse aneuploid circulating tumor cell (CTC) subtypes and particularly CTC-associated white blood cell (CTC-WBC) clusters in predicting treatment response, prognosis and real-time monitoring disease progression in advanced driver gene-negative non-small lung cancer (NSCLC) patients. A total of 74 eligible patients were prospectively enrolled and serial blood samples were collected at pre-treatment(t0), after two cycles of therapy (t1) and at post-four-to-six treatment cycles (t2). Co-detection of diverse subtypes of aneuploid CTCs and CTC-WBC clusters was conducted in advanced NSCLC patients receiving first-line treatment. At baseline, CTCs were detected in 69 (93.24%) patients and CTC-WBC clusters were detected in 23 (31.08%) patients. Patients with CTCs < 5/6ml or with CTC-WBC clusters undetectable exhibited a better treatment response than patients with pre-therapeutic aneuploid CTCs ≥ 5/6ml or harboring CTC-WBC clusters (p = 0.034 and p = 0.012, respectively). Before treatment, patients bearing tetraploid CTCs ≥ 1/6ml showed significantly inferior progression-free survival (PFS) [hazard ratio (HR):2.420, 95% confidence interval (CI): 1.426-4.106; p = 0.001] and overall survival (OS) compared to patients with tetraploid CTCs < 1/6ml (HR:1.907, 95%CI: 1.119-3.251; p = 0.018). A longitudinal study demonstrated that post-therapeutic patients harboring CTC-WBC clusters displayed the reduced PFS and OS compared with those without CTC-WBC clusters, and subgroup analysis showed that the presence of CTC-WBC clusters indicated a worse prognosis in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. After adjusting for multiple significant factors, post-therapeutic CTC-WBC clusters were the only independent predictor of both PFS (HR:2.872, 95% CI: 1.539-5.368; p = 0.001) and OS (HR:2.162, 95% CI: 1.168-4.003; p = 0.014). In addition to CTCs, longitudinal detection of CTC-WBC clusters provided a feasible tool to indicate initial treatment response, dynamically monitor disease progression and predict survival in driver gene-negative advanced NSCLC patients.


Characterization of new recombinant noroviruses.
Noroviruses are important etiologic agents of acute gastroenteritis and show great genetic diversity. To characterize more fully previously detected strains that could not be assigned unequivocally to one particular genotype based on the RNA polymerase, we have sequenced a region in the capsid gene and, in some cases, in the junction between open reading frame 1 (ORF 1) and ORF 2. The results allowed us to identify several recombinant noroviruses: GGIIb viruses were detected for the first time in France in August 2000 and then spread through France and to Europe during the following winter. Here we present the characterization of three other probable GII recombinants which showed different phylogenetic positions depending on their ORF 1 and ORF 2 sequences. Analysis of the region located between ORF 1 and ORF 2 by a nucleotide identity window search showed a sudden shift in similarities. Moreover, recombination breakpoints were identified upstream and downstream of the beginning of ORF 2 by using a statistical test, thus confirming the involvement of this region in recombination. Unlike GGIIb, the three recombinants described here do not seem to have diffused widely in the community: one was found in a waterborne outbreak, and the other two were found in sporadic cases. Recombination is important for the evolution of RNA viruses and has already been described for noroviruses. Our results suggest that recombination is not a rare phenomenon among noroviruses, but not all these presumed recombinants that formed during RNA replication are able to spread widely.


An analysis of the transport of WGA-HRP in the cat's visual system.
The increasing use of WGA-HRP as a neuroanatomical tracer has led us to examine two aspects of its uptake and transport. Microelectrophoretic deposits of WGA-HRP were centered in lamina A of the LGd to determine whether or not there is a discrepancy between the size of the deposit site and the effective uptake zone. For this purpose, the size of the deposit site was compared to the area of labeled ganglion cells in the retina. It was found that the effective uptake zone is approximately one half the size of the geniculate area containing reaction-product. Deposits of WGA-HRP in the optic tract, optic radiations and corpus callosum were made in order to determine if this tracer is incorporated and transported by intact fibers. In no case were labeled axon terminals or neuronal somata observed. However, application of the conjugated enzyme to cut fibers of the corpus callosum resulted in robust labeling.


[Relational care at the heart of treatment].
Relational care is not limited to simple words or simple interaction with the patient. It is based on deeper reflection around the caregiving approaches and in this way can help patients And their way through their ordeals with a positive mindset.


Synthesis and antibacterial activity of linezolid analogues.
Several new compounds of oxazolidinone class were designed and synthesized referring to the structure-activity relationship studies and the synthesis of Linezolid, and their antibacterial activity was studied.


GABAergic mechanisms for shaping transient visual responses in the mouse superior colliculus.
An object that suddenly appears in the visual field should be quickly detected and responded to because it could be beneficial or harmful. The superficial layer of the superior colliculus (sSC) is a brain structure capable of such functions, as sSC neurons exhibit sharp transient spike discharges with short latency in response to the appearance of a visual stimulus. However, how transient activity is generated in the sSC is poorly understood. Here, we show that inhibitory inputs actively shape transient activity in the sSC. Juxtacellular recordings from anesthetized mice demonstrate that almost all types of sSC neurons, which were identified by post hoc histochemistry, show transient spike discharges, i.e., ON activity, immediately after visual stimulus onset. ON activity was followed by a pause before the visual stimulus was turned off. To determine whether the pause reflected the absence of excitatory drive or inhibitory conductance, we injected depolarizing currents juxtasomally, which enabled us to observe inhibition as decreased discharges. The pause was observed even under this condition, suggesting that inhibitory input caused the pause. We further found that local application of a mixture of GABAA and GABAB receptor antagonists additively diminished the pause. These results indicate that GABAergic inputs produce transient ON responses by attenuating excitatory activity through the cooperative activation of GABAA and GABAB receptors, allowing sSC neurons to act as a saliency detector.


The effect of increased cocaine use on drug treatment.
Trends in primary illicit drug use were monitored in an inpatient drug treatment program over a 10-year period, along with illicit drug used in a methadone maintenance program over a six-year period. The percentage of cocaine users admitted for inpatient treatment showed an increase for each six-month interval over the past three-year period. Cocaine was found to be the most frequently used illicit drug by methadone maintenance clients, and its continued use disrupted both inpatient and outpatient treatment. Implications for treatment are discussed.


UV dose-dependent increase in the Hoechst fluorescence intensity of both normal and BrdU-DNA.
If the DNA nucleoside thymidine is replaced by bromodeoxyuridine, the fluorescence of the nuclei of Hoechst-stained cells is quenched. The decrease of fluorescence intensity determined by flow cytometry and fluorometry is neutralized independent of the degree of BrdU substitution by an UV-exposure with a dose of 5-10 kJ/m2 to the unfiltered spectrum of a 100 W mercury high-pressure lamp. This dose is equivalent to that obtained in fluorescence microscopy after exposure for about 1 s. We suppose that this approximate matching of the intensities both of normal and BrdU in the DNA resulting in no further quenching. However, the fluorescence intensity of normal Hoechst-stained DNA also is increased by a previous exposure to UV light. We explain the time pattern of the Hoechst fluorescence in the course of an exposure with constant dose rate, by the superimposition of the well-known bleaching by an additional increase of the fluorescence intensity. Our results suggest that the UV-exposure of Hoechst dye creates a brightly fluorescing photoproduct which differs spectroscopically from the original dye. This product is stable in the dark and seems to fluorochrome DNA only if it is formed when the Hoechst dye is bound to DNA, thus increasing the nuclear fluorescence. Phosphorescence was not found.


An overview of research trends and genetic polymorphisms for noise-induced hearing loss from 2009 to 2018.
Recently, there has been increased studies in noise-induced hearing loss (NIHL). We aimed to make an overview of research trends and genetic polymorphisms for NIHL from 2009 to 2018 with VOSviewer software. A total of 2391 papers were identified for research trends analysis in NIHL and 33 studies identified for a brief review of genetic polymorphisms in human NIHL. The number of publications has been increasing over the past decade. The journal Hearing Research published the most articles (218). The USA contributed the largest number of papers (1042; 43.58%), with the most citations (18,987) and the highest H-index (60). The University of Washington was the most contributive institution. Liberman MC published the most articles (32), and Kujawa SG possessed the highest co-citations (584). Except for high-frequency keywords identified by the software, "prevalence," "oxidative stress," "hair cells," and "cochlear implant" were also the latest research frontiers. HSPA1A rs1043618, HSPA1L rs2227956, PON2 rs12026 and rs7785846, SOD2 rs2855116, KCNE1 rs2070358, KCNQ4 rs34287852, GJB2 rs3751385, PCDH15 rs7095441 and rs11004085, GRHL2 rs1981361, ITGA8 rs10508489, MYH14 rs667907, and POU4F3 rs891969 were the research hotspots and were replicated in independent samples. Inflammation response underlying NIHL has emerged and should be considered as a pioneering field in the future for the prevention of NIHL and conservation of hearing.


Rationality of FIGO 2018 IIIC restaging of cervical cancer according to local tumor size: A cohort study.
FIGO 2018 IIIC remains controversial for the heterogeneity of its prognoses. To ensure a better management of cervical cancer patients in Stage IIIC, a revision of the FIGO IIIC version classification is required according to local tumor size. We retrospectively enrolled cervical cancer patients of FIGO 2018 Stages I-IIIC who had undergone radical surgery or chemoradiotherapy. Based on the tumor factors from the Tumor Node Metastasis staging system, IIIC cases were divided into IIIC-T1, IIIC-T2a, IIIC-T2b, and IIIC-(T3a+T3b). Oncologcial outcomes of all stages were compared. A total of 63 926 cervical cancer cases were identified, among which 9452 fulfilled the inclusion criteria and were included in this study. Kaplan-Meier pairwise analysis showed that: the oncology outcomes of I and IIA were significantly better than of IIB, IIIA+IIIB, and IIIC; the oncology outcome of IIIC-(T1-T2b) was significantly better than of IIIA+IIIB and IIIC-(T3a+T3b); no significant difference was noted between IIB and IIIC-(T1-T2b), or IIIC-(T3a+T3b) and IIIA+IIIB. Multivariate analysis indicated that, compared with IIIC-T1, Stages T2a, T2b, IIIA+IIIB and IIIC-(T3a+T3b) were associated with a higher risk of death and recurrence/death. There was no significant difference in the risk of death or recurrence/death between patients with IIIC-(T1-T2b) and IIB. Also, compared with IIB, IIIC-(T3a+T3b) was associated with a higher risk of death and recurrence/death. No significant differences in the risk of death and recurrence/death were noted between IIIC-(T3a+T3b) and IIIA+IIIB. In terms of oncology outcomes of the study, FIGO 2018 Stage IIIC of cervical cancer is unreasonable. Stages IIIC-T1, T2a, and T2b may be integrated as IIC, and it might be unnecessary for T3a/T3b cases to be subdivided by lymph node status.


On the optimal choice of a recording electrode in electroneurography.
The influence of the type and size of recording electrodes on compound nerve action potentials was studied in order to establish optimal prerequisites for the application of quantitative analysis methods. A realistic volume conductor model was used to assess the dependence of the recorded signal on the position of the recording electrode with respect to the nerve. The analysis of both compound action potentials (CAPs) and single fibre action potentials (SFAPs) leads to the conclusion that near-nerve recording gives substantially more information. This applies in particular to the fine details in the CAP, such as notches in the main complex and the so-called late components. Subsequently, the influence of needle electrode bare tip length on the recorded signal was investigated by spatially averaging the potentials over the lead-off area. These results were combined with experimentally obtained noise levels for different stainless steel needle electrodes in order to determine the signal-to-noise ratio as a function of bare tip length. It was concluded that for near-nerve recording a needle tip of 1-2 mm gives optimal results in terms of wave shape preservation and signal-to-noise ratio.


Transient transfection and purification of SARS-CoV-2 spike protein from mammalian cells.
SARS-CoV-2 spike (S) protein ectodomain purification can be challenging, with engineered and natural variations often resulting in lower yields. Here, we present a detailed transfection and purification protocol for the SARS-CoV-2 S ectodomain. We describe how to trace protein yields during purification using highly sensitive and characteristic changes in S ectodomain intrinsic fluorescence upon thermal denaturation. Additionally, we detail several optimized aspects of the purification including timing and temperature. This protocol facilitates consistent, high-quality preparations of the SARS-CoV-2 S ectodomain. For complete details on the use and execution of this protocol, please refer to Stalls et al. (2022), Gobeil et al. (2022), Edwards et al. (2021), and Henderson et al. (2020).


[Comorbidity of depressive disorders and cardiovascular diseases. Implications for diagnosis, pharmaco- and psychotherapy].
Controlled studies and meta-analyses show not only that depression and cardiovascular disease often occur together, but that depressive illnesses are an independent risk factor in the development and the progression of coronary heart disease. It can be difficult to distinguish between reactive mood disturbance after myocardial infarction and depressive episodes that may have preceded the infarction and which require treatment. Due to this difficulty, depressive disorders are rarely diagnosed, and only a minority of patients receive adequate treatment. However, owing to the introduction of new antidepressants in recent years, the number of treatment options has increased. Specifically, selective serotonin reuptake inhibitors (SSRI) offer a valuable alternative to tricyclic antidepressants, which are problematic in heart disease. The authors describe on the one hand controlled studies of SSRIs and discuss differential therapeutic consequences. On the other hand, studies of psychotherapeutic interventions in comorbid patients with depression and coronary heart disease are reported. Finally, the authors discuss which psychotherapeutic interventions may be suitable.


Adenosine, adenosine receptors and glaucoma: an updated overview.
Glaucoma, a leading cause of blindness worldwide, is an optic neuropathy commonly associated with elevated intraocular pressure (IOP). The major goals of glaucoma treatments are to lower IOP and protect retinal ganglion cells. It has been revealed recently that adenosine and adenosine receptors (ARs) have important roles in IOP modulation and neuroprotection. This article reviews recent studies on the important roles of adenosine and ARs in aqueous humor formation and outflow facility, IOP and retinal neuroprotection. Adenosine and several adenosine derivatives increase and/or decrease IOP via A2A AR. Activation of A1 AR can reduce outflow resistance and thereby lower IOP, A3 receptor antagonists prevent adenosine-induced activation of Cl(-) channels of the ciliary non-pigmented epithelial cells and thereby lower IOP. A1 and A2A agonists can reduce vascular resistance and increase retina and optic nerve head blood flow. A1 agonist and A2A antagonist can enhance the recovery of retinal function after ischemia attack. Adenosine acting at A3 receptors can attenuate the rise in calcium and retinal ganglion cells death accompanying P2X(7) receptor activation. Evidence suggested that the adenosine system is one of the potential target systems for therapeutic approaches in glaucoma.


High intestinal parasite infection detected in children from Región Autónoma Atlántico Norte (R.A.A.N.) of Nicaragua.
There is a lack of epidemiological information concerning intestinal parasitic infections, and especially in soil-transmitted helminths, occurring in some departments of Nicaragua. Up to now, this is the first study involving two nearby areas (Puerto Cabezas and Siuna municipalities) of the Región Autónoma Atlántico Norte (R.A.A.N.). One stool sample was analyzed by Kato-Katz, formaldehyde-ethyl acetate concentration method and modified Ziehl-Neelsen technique, and a simple questionnaire concerning demographic, sanitary and behavioral data was distributed among 735 children and evaluated. Overall prevalence of infection reached 97.0%, being the highest prevalences detected in all Nicaragua. The higher protozoan prevalence appears in Siuna (94.5%), a rural interior municipality, with a typical tropical monsoon climate, while the higher helminths rates were reached in Puerto Cabezas (92.8%), the urbanized coastal capital, with a typical tropical rainforest climate. No statistical differences were found with regard to sex. However, the 6-11-year age-group children presented the highest prevalences. Most T. trichiura infections (59.4%) were of light intensity, while 51.7% of Ascaris lumbricoides were of moderate intensity. Multivariable logistic regression analysis indicated that those who drink rainwater and walk barefoot were 2.9 and 2.5 times more likely to have helminth infections, respectively. Results from one geographical setting might not be applied to other nearby with different climatic conditions. The use of anthelmintic drugs only will not be sufficient to bring prevalence to low levels. It is necessary to design geographically more specific intervention, with communication and interaction between different disciplines (e.g. parasitology, biochemistry, molecular biology, epidemiology, public health, etc.) being imperative to reduce STH infection.


Specific theorical and practical education on mechanical chest compression during advanced life support training courses - Results from a local experience.
Specific training modules focusing on mechanical chest compression and device use might be considered in a structured manner during the standard advanced life support (ALS) courses. The aim of this study was to evaluate the impact of a specific brief 15 min training on the use of a specific mechanical CPR device during Advanced Cardiac Life Support courses on its correct use and on attendees' satisfaction.


Multi-sectoral response to child maltreatment in Switzerland for different age groups: Varying rates of reported incidents and gaps in identification.
As many countries lack (multi-sectoral) data on the epidemiology of agency responses to child maltreatment, they do not know if children in different regions of the country have equal chances to receive help and protection. The Optimus Study, the first nationally representative Swiss study on multi-sectoral responses to child maltreatment, examines gaps in identifying children in need and reveals opportunities for improved support and protection. A stratified sample of 351 agencies (participation rate 81 %) in the social and health sector, public child protection, and the penal sector provided data on new cases between September 1 and November 30, 2016. The resulting study data on 7651 cases included information on the maltreatment incident, specifics of the report/referral, and child characteristics. The weighting procedure to produce national estimates was based on inverse sampling probabilities and inverse response rates. In the 3-month period, an estimated 10,335 cases were referred/reported to agencies in multiple sectors of the child protection system in Switzerland. This corresponded to 66 cases per 10,000 children. Rates were highest for adolescents (aged 13+), with 69 cases per 10,000 children. Lower rates for school-aged children coincided with a relatively low percentage of reports/referrals from the schools (8 %). Regional variance was extensive, with rates more than quadrupling from a low of 26 cases to a high of 107 cases per 10,000 children. Types of child maltreatment handled by agencies in the different sectors varied. Gender distribution was lopsided for sexual abuse, with many more girls experiencing incidents of sexual abuse, and unequal for incidents of neglect and psychological maltreatment. There are gaps in the identification of maltreated preschoolers. Promoting health checkups for this age group is a potential solution. However, school-aged children up to age 11 are underreported as well, as the schools contribute only marginally to child maltreatment reporting. The findings of the study are being used to initiate the implementation of continuous and multi-sectoral child maltreatment surveillance in Switzerland.


Two-pulse temporal resolution threshold in the peripheral visual field.
Using a 700-nm light-emitting diode, the minimum inter-pulse interval between two successively flashing pulses presented to 21 retinal loci along horizontal and vertical meridian were measured. The results showed inter-pulse interval changed as a W-shaped function of eccentricity on both meridians.


Aqueous humor penetration of gatifloxacin and moxifloxacin eyedrops given in different concentrations in a wick before cataract surgery.
To determine whether the penetration into the aqueous humor of gatifloxacin (Zymar) and moxifloxacin (Vigamox) eyedrops was affected by altering their concentrations in the dilating mixture in which the wick used to dilate the pupil before cataract surgery was soaked. Pasqua Hospital, Regina, Saskatchewan, Canada. This prospective randomized open-label study comprised 65 women and 35 men who were divided into 2 main groups. One group received 1 mL of the antibiotic in the dilating mixture and the other, 2 mL. Each group was divided into 2 subgroups, 1 for gatifloxacin and 1 for moxifloxacin. At the beginning of surgery, 0.1 mL of aqueous humor was aspirated, frozen, and couriered to the provincial laboratory for analysis by high-performance liquid chromatography. In the first group, the mean concentration of gatifloxacin in the aqueous humor was 0.30 microg/mL +/- 0.21 (SD) and of moxifloxacin, 0.97 +/- 0.63 microg/mL. When the volume of the antibiotic in the dilating mixture was doubled, the mean concentration increased to 0.34 +/- 0.25 microg/mL and 1.37 +/- 0.79 microg/mL, respectively. Only the increased penetration of moxifloxacin was statistically significant. Moxifloxacin penetrated the aqueous humor better than gatifloxacin when given in a wick soaked in the dilating mixture before cataract surgery. Only the penetration of moxifloxacin increased significantly when the volume of the antibiotic in the dilating mixture was doubled. In both groups, only moxifloxacin reached and exceeded the minimum inhibitory concentration levels for the most common ocular pathogens causing endophthalmitis.


Leptin and adiponectin synthesis and secretion in mature 3T3-L1 adipocytes are differentially down-regulated by arsenic and palmitic acid exposure throughout different stages of adipogenesis.
Arsenic is a risk factor for type 2 diabetes and cardiovascular disease. However, little is known about arsenic effects over adipocyte endocrine functionality, particularly for leptin and adiponectin, and about its interaction with dietary components, which are the main environmental regulators of adipose tissue functionality. The aim of this work was to evaluate leptin and adiponectin in mature 3T3-L1 adipocytes exposed to palmitate (simulating excess fat intake), arsenite, or both throughout two different stages of adipogenesis. 3T3-L1 adipocytes were exposed starting from the beginning of its differentiation process during 11 d or once adipocytes were mature for 72 h. Adipokines secretion was evaluated by ELISA, intracellular protein levels and secreted adiponectin multimers by Western blot and mRNA abundance by qPCR. Leptin and adiponectin secretion decreased by arsenite alone or in combination with palmitate due to reduced gene and protein expression of both adipokines. However, leptin was impaired more at the transcriptional level, whereas affections to adiponectin were more relevant at the intracellular protein amount level with changes in the multimers proportion. The gene expression of several of their transcription factors was altered. Additionally, the magnitude of the effects depends on the adipocyte cell stage at which exposure began; adiponectin was more affected when exposure started from differentiation and leptin once adipocytes were mature. These results in an in vivo model could be translated into less satiety and reduced insulin sensitivity.


Tracking phototactic responses and modeling motility of Synechocystis sp. strain PCC6803.
The unicellular cyanobacterium Synechocystis sp. Strain PCC 6,803 exhibits phototaxis by moving along a surface towards a light source. This process requires Type IV pili and a phytochrome-like photoreceptor coupled to a complex signal transduction pathway. Cells progress through different phases of interaction before the development of finger-like projections moving in the direction of the light that are characteristic of phototaxis. To probe the interaction between individual cells during the initial phase of phototaxis we tracked and analyzed a large number of cells. We observed that individual cells have limited motility, but when cells divide and/or aggregate to attain a certain minimal group size, enhanced motility and phototaxis is observed. At the later stages of motility, there is noticeable phototactic behavior which results in the appearance of the finger-like projections. Our results indicate that cells prefer to move over areas previously traversed by other cells and confine themselves to these areas and that cells alter local surface characteristics allowing for enhanced motility. Based on cell tracking data we present a preliminary random walk model showing the forces that might interact to create the typical phases of phototaxis and motility. In this model, we can simulate the formation of finger-like projections that are characteristic of phototaxis.


Hepatic radiofrequency under CT-fluoroscopy guidance.
This study was done to assess the effectiveness and advantages of computed tomography (CT) fluoroscopy as a guide for locating and treating lesions that are not amenable to ultrasound (US) guidance, and to evaluate the CT signs of immediate technical success and the short-term results. Over the past year, we selected 14 patients (four women and ten men; mean age 73, range 61-83 years) out of 103 candidates for hepatic radiofrequency ablation (RFA). The 14 lesions comprised seven residual tumours after combined embolisation and US-guided RFA of a large hepatocellular carcinoma (HCC), which were indistinguishable from necrosis or surrounding healthy parenchyma; two HCC nodules in locations that were inaccessible by US; five metastases (two from renal carcinoma, two from colorectal adenocarcinoma and one from lung carcinoma), of which one could not be distinguished from the surrounding healthy parenchyma on US and four were inaccessible by US. Lesion diameters were between 1.4 and 3.5 cm. The procedures were performed in the CT room with anaesthesiological assistance using a coaxial LeVeen needle electrode (14 gauge, 2-to 4-cm array diameter). Immediate technical success was evaluated by multidetector CT (MDCT), and follow-up was carried out with MDCT at 3 and 6 months and yearly thereafter. Immediate technical success was obtained in 13/14 patients; one case required further placement of the electrode due to incomplete ablation of a hypervascular lesion. In 2/3 metastatic lesions with portal vein supply, there were no recurrences at 3 and 6 months; in 1/3, we observed disease progression, with the appearance of additional nodules at 6 months. The two metastases with arterial supply showed no signs of recurrence at 3 months; one case developed a recurrence along the ablation margin, with the appearance of satellite nodules at 6 months. In two HCC nodules, there was immediate technical success and no recurrence at 3 and 6 months. Of the seven residual tumours of HCC, all treated with immediate technical success, we observed disease progression, with the appearance of satellite nodules at 3 months in one case, at 6 months in another and at 12 months in another; 3/7 patients were free of disease at 12-month follow-up; 1/7 died 5 months later due to causes unrelated to the procedure. CT fluoroscopy is overcoming the limitations of CT in locating and treating lesions with different hepatic vascularisation and those unamenable to US; furthermore, it reduces the length of the procedure, thanks to the faster and more accurate placement of the needle electrode. MDCT proved to be a reliable method in the assessment of immediate and short-term results of RFA.


Prospective assessment of perioperative course in 2648 patients after surgical treatment of benign prostatic obstruction.
TUR-prostate (TUR-P) is considered the reference method for surgical treatment of benign prostatic obstruction (BPO); Greenlight laser photoselective vaporization (PVP) and thulium laser vapoenucleation (ThuVEP) have also been established as treatments of BPO. Objective of this prospective observation was to compare a large numbers of patients treated in everyday routine. This prospective multicentre data collection assesses morbidity and perioperative course of consecutive men treated with BPO-related transurethral surgery between 2011 and 2014 in a German metropolis area with TUR-P, PVP or ThuVEP. Two thousand six hundred and forty-eight patients have been treated in the time period. All treatment options achieved immediate improvement of voiding parameters. Multivariate analyses proved shorter hospital stay after laser treatments as compared to resection (p < 0.001). In terms of hospital stay, the advantage of ThuVEP compared to TUR-P increased with prostate volume (p < 0.001). Patients with ongoing anticoagulation or bridging had prolonged hospital stay (p < 0.001). Overall adverse events were least frequent in PVP (p 0.016), as were Clavien 3b events (p < 0.001). Surgical treatment of BPO is effective and safe independent of the surgical procedure. Volume reduction is most effective in ThuVEP; PVP has the lowest rate of severe complications. Laser treatment is associated with shorter hospital stay. Surgery under ongoing anticoagulation prolonged the post-operative hospital stay.


A deep learning method for optimizing semantic segmentation accuracy of remote sensing images based on improved UNet.
Semantic segmentation of remote sensing imagery (RSI) is critical in many domains due to the diverse landscapes and different sizes of geo-objects that RSI contains, making semantic segmentation challenging. In this paper, a convolutional network, named Adaptive Feature Fusion UNet (AFF-UNet), is proposed to optimize the semantic segmentation performance. The model has three key aspects: (1) dense skip connections architecture and an adaptive feature fusion module that adaptively weighs different levels of feature maps to achieve adaptive feature fusion, (2) a channel attention convolution block that obtains the relationship between different channels using a tailored configuration, and (3) a spatial attention module that obtains the relationship between different positions. AFF-UNet was evaluated on two public RSI datasets and was quantitatively and qualitatively compared with other models. Results from the Potsdam dataset showed that the proposed model achieved an increase of 1.09% over DeepLabv3 + in terms of the average F1 score and a 0.99% improvement in overall accuracy. The visual qualitative results also demonstrated a reduction in confusion of object classes, better performance in segmenting different sizes of object classes, and better object integrity. Therefore, the proposed AFF-UNet model optimizes the accuracy of RSI semantic segmentation.


On the two iron centers of desulfoferrodoxin.
Desulfoferrodoxin from Desulfovibrio vulgaris, strain Hildenborough, is a homodimer of 28 kDa; it contains two Fe atoms per 14.0 kDa subunit. The N-terminal amino-acid sequence is homogeneous and corresponds to the previously described Rho gene, which encodes a highly charged 14 kDa polypeptide without a leader sequence. Although one of the two iron centers, FeA, has previously been described as a 'strained rubredoxin-like' site, EPR of the ferric form proves very similar to that of the pentagonal bipyramidally coordinated iron in ferric complexes of DTPA, diethylenetriaminepentaacetic acid: both systems have spin S = 5/2 and rhombicity E/D = 0.08. Unlike the Fe site in rubredoxin the FeA site in desulfoferrodoxin has a pH dependent midpoint potential with pKox = 9.2 and pKred = 5.3. Upon reduction (Em,7.5 = +2 mV) FeA exhibits an unusually sharp S = 2 resonance in parallel-mode EPR. The second iron, FeB, has S = 5/2 and E/D = 0.33; upon reduction (Em,7.5 = +90 mV) FeB turns EPR-silent.


Diesel Exhaust Exposure and Cause-Specific Mortality in the Diesel Exhaust in Miners Study II (DEMS II) Cohort.
With the exception of lung cancer, the health effects associated with diesel exhaust for other cancers and nonmalignant health outcomes are not well understood. We extended the mortality follow-up of the Diesel Exhaust in Miners Study, a cohort study of 12,315 workers, by 18 y (ending 31 December 2015), more than doubling the number of observed deaths to n=4,887, to evaluate associations between mortality and diesel exhaust exposure. Quantitative estimates of historical exposure to respirable elemental carbon (REC), a surrogate for diesel exhaust, were created for all jobs, by year and facility, using measurements collected from each mine, as well as historical measurements. Standardized mortality ratios (SMRs) and hazard ratios (HRs) were estimated for the entire cohort and by worker location (surface, underground). We observed an excess of death for cancers of the lung, trachea, and bronchus (n=409; SMR=1.24; 95% CI: 1.13, 1.37). Among workers who ever worked underground, where the majority of diesel exposure occurred, excess deaths were evident for lung, trachea, and bronchus cancers (n=266; SMR=1.26; 95% CI: 1.11, 1.42). Several nonmalignant diseases were associated with excess mortality among workers ever-employed underground, including ischemic heart disease (SMR=1.08; 95% CI: 1.00, 1.16), cerebrovascular disease (SMR=1.22; 95% CI: 1.04, 1.43), and nonmalignant diseases of the respiratory system (SMR=1.13; 95% CI: 1.01, 1.26). Continuous 15-y lagged cumulative REC exposure <1,280 μg/m3-y was associated with increased lung cancer risk (HR=1.93; 95% CI: 1.24, 3.03), but the risk declined at the highest exposures (HR=1.29; 95% CI: 0.74, 2.26). We also observed a significant trend in non-Hodgkin lymphoma (NHL) risk with increasing 20-y lagged cumulative REC (HRTertile3 vs. Tertile1=3.12; 95% CI: 1.00, 9.79; p-trend=0.031). Increased risks of lung cancer mortality observed in the original study were sustained. Observed associations between diesel exposure and risk of death from NHL and the excesses in deaths for diseases of the respiratory and cardiovascular system, including ischemic heart disease and cerebrovascular disease, warrant further study and provide evidence of the potential widespread public health impact of diesel exposure. https://doi.org/10.1289/EHP12840.


Isolation of oligodendroglial cells from cultured neural stem/progenitors.
The central nervous system (CNS) is composed of multiple cell types formed through a process of lineage commitment and phenotypic differentiation of stem-like progenitor cells into three key cell types: neurons, astrocytes, and oligodendrocytes. The ability to isolate and culture these CNS stem/progenitors has facilitated the characterization of the molecular mechanisms that regulate this process, in the hopes of providing therapeutically effective cells to treat disease and injury. Although astroglial, and to a lesser extent some neuronal, phenotypes are robustly generated when these cultured stem/progenitor cells are induced to differentiate, oligodendrocytes that form the myelin-rich sheath that allows nerves to conduct action potentials are only formed at a low frequency. This relatively low frequency has necessitated the development of methods for quantifying oligodendroglial phenotypes in vitro, with greater precision and accuracy than the standard technique of microscopic counting by hand. Here, we describe the isolation of neural stem cells and the application of intracellular flow cytometry to quantify oligodendroglial phenotypes in cultured CNS stem/progenitor cells using commercially available kits.


Improvement in the Surveillance System for Livestock Diseases and Antimicrobial Use Following Operational Research Studies in Sierra Leone January-March 2023.
In Sierra Leone, two operational research (OR) studies in 2019 and 2021 showed deficiencies in the data being captured by the Integrated Animal Disease Surveillance and Reporting (IADSR) system. This third OR study was conducted in 2023 to assess whether the second OR study's results and recommendations were disseminated with the key stakeholders, the uptake of the recommendations, improvements in data capture in the IADSR system, and to describe the data on livestock disease and antimicrobial use. In 2022, on seven occasions, the authors of the second OR study disseminated the study's findings. Of the four recommendations, the one on improving laboratory infrastructure for confirmation of animal disease was not implemented. The district animal health weekly surveillance reports received through the IADSR system were sustained at 88% between the second (2021) and third (2023) studies. In both studies, the proportion of sick animals receiving antibiotics (25%) remained the same, but the use of "critically important antimicrobials for veterinary use" declined from 77% (in 2021) to 69% (in 2023). The IADSR system has improved considerably in providing information on animal health and antibiotic use, and sequential OR studies have played a key role in its improvement.


Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma.
The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.


Patient mortality following new-onset heart failure stratified by cancer type and status.
Expected 1-year survival is essential to risk stratification of patients with heart failure (HF); however, little is known about the 1-year prognosis of patients with HF and cancer. Thus, the objective was to investigate the 1-year prognosis following new-onset HF stratified by cancer status in patients with breast, gastrointestinal, or lung cancer. All Danish patients with new-onset HF from 2000 to 2018 were included. Cancer status was categorized as history of cancer (no cancer-related contact within 5 years of HF diagnosis), non-active cancer (curative intended procedure administered) and active cancer. Standardized 1-year all-cause mortality was reported using G-computation. Age-stratified 1-year all-cause mortality was estimated using the Kaplan-Meier estimator. In total, 193 359 patients with HF were included, 7.3% had either a breast, gastrointestinal, or lung cancer diagnosis. Patients with cancer were older and more comorbid than patients without cancer. Standardized 1-year all-cause mortality (95% confidence intervals) was 24.6% (23.0-26.2%), 27.1% (25.5-28.6%), and 29.9% (25.9-34.0%) for history of breast, gastrointestinal and lung cancer, respectively, which was comparable to patients with non-active cancers. For active breast, gastrointestinal and lung cancer, standardized 1-year all-cause mortality was 36.2% (33.8-38.6%), 49.0% (47.2-50.9%), and 61.6% (59.7-63.5%), respectively. One-year all-cause mortality increased incrementally with age, except for active lung cancer. Standardized 1-year all-cause mortality was comparable for patients with history of cancer and non-active cancer regardless of cancer type, but varied comprehensively for active cancers. Prognostic impact of age was limited for active lung cancer. Thus, granular stratification of cancer is necessary for optimized management of new-onset HF.


Effect of Ramadan Fasting on Weight and Body Composition in Healthy Non-Athlete Adults: A Systematic Review and Meta-Analysis.
Ramadan involves one month of fasting from sunrise to sunset. In this meta-analysis, we aimed to determine the effect of Ramadan fasting on weight and body composition. In May 2018, we searched six databases for publications that measured weight and body composition before and after Ramadan, and that did not attempt to influence physical activity or diet. Data were collected from 70 publications (90 comparison groups, 2947 participants). There was a significant positive correlation between starting body mass index and weight lost during the fasting period. Consistently, there was a significant reduction in fat percentage between pre-Ramadan and post-Ramadan in people with overweight or obesity (-1.46 (95% confidence interval: -2.57 to -0.35) %, p = 0.010), but not in those of normal weight (-0.41 (-1.45 to 0.63) %, p = 0.436). Loss of fat-free mass was also significant between pre-Ramadan and post-Ramadan, but was about 30% less than loss of absolute fat mass. At 2⁻5 weeks after the end of Ramadan, there was a return towards, or to, pre-Ramadan measurements in weight and body composition. Even with no advice on lifestyle changes, there are consistent-albeit transient-reductions in weight and fat mass with the Ramadan fast, especially in people with overweight or obesity.


Characteristics of children and adolescents presenting to the emergency department with self-inflicted injury: Retrospective analysis of two teaching hospitals.
Data on Taiwanese adolescents with self-inflicted injuries are limited. We describe the epidemiology of children and adolescents visiting the emergency department for self-inflicted injuries in two geographically distinct teaching hospitals. Medical records of children 0-18 years old who visited the emergency department of Taipei Tzu Chi Hospital and Chi Mei Medical Center, Tainan between 2016 and 2019 coded with relevant diagnoses were reviewed. Visits with documented self-inflicted injury were included. During the 4-year period, 62 children made 74 emergency visits for self-inflicted injury. A total of 88% of visits were made by children with a psychiatric diagnosis, with depressive disorders being the most common (57%). Interpersonal relationship issue was cited as a trigger for self-harm in 49% of visits. Adjusted for annual visit volumes, self-harm visits per 10,000 pediatric emergency visits increased nearly 5 fold between 2016 and 2019, with the most prominent increase in the final year. Poisoning was the most common mechanism of injury and was frequently used by females, as compared to males who tended to jump from heights. Up to 96% of adolescents with previous self-harm seen at the emergency department had sought psychiatric help in the past year. Urban-rural inequity in mental health resource utilization was observed. Visits to the emergency department for self-inflicted injuries among children and adolescents increased, most remarkably in 2019, for both hospitals. Intentional poisoning with prescription and over-the-counter medications was the most common method. There was a high prevalence of psychiatric disorders in our study population. As the emergency department is likely the first point of medical contact for such visits, emergency personnel should be trained appropriately on managing such patients.


Natural Abenquines and Their Synthetic Analogues Exert Algicidal Activity against Bloom-Forming Cyanobacteria.
Abenquines are natural quinones, produced by some Streptomycetes, showing the ability to inhibit cyanobacterial growth in the 1 to 100 μM range. To further elucidate their biological significance, the synthesis of several analogues (4f-h, 5a-h) allowed us to identify some steric and electronic requirements for bioactivity. Replacing the acetyl by a benzoyl group in the quinone core and also changing the amino acid moiety with ethylpyrimidinyl or ethylpyrrolidinyl groups resulted in analogues 25-fold more potent than the natural abenquines. The two most effective analogues inhibited the proliferation of five cyanobacterial strains tested, with IC50 values ranging from 0.3 to 3 μM. These compounds may be useful leads for the development of an effective strategy for the control of cyanobacterial blooms.


The use of a new bilayer artificial dermis for vestibular extension.
In this study we evaluated the usefulness of a new bilayer artificial dermis (TERUDERMIS; Terumo Corporation, Japan) for vestibular extension. It is composed of a collagen sponge with the silicone layer which is sloughed off as the mucous membrane heals. We have used it for vestibular extension in 50 patients. The material was effective in nearly all patients in promoting haemostasis, relieving pain, inducing granulation, promoting rapid epithelialization, and preventing contracture. There were no side-effects. The greatest problem with such materials in the past has been contracture at the vestibular extension area. However, we found that the degree of contracture was similar to that seen with autogenous mucosa or free skin graft. Our results indicate that the material might be useful for vestibular extension.


Quinazoline alpha-adrenoreceptor blockers as an adjunct cancer treatment: From bench to bedside.
Drug repurposing has been increasingly used by both researchers and clinicians to identify new cancer treatments. The alpha-1 adrenoreceptor blockers are a class of drugs that have been used for many years in the treatment of hypertension and benign prostatic hyperplasia. Some of the drugs in this class, notably the quinazoline derivatives, have been found to display cytotoxic properties, identifying them as potential options in the treatment of cancer. This review will examine the currently available evidence that investigates the cytotoxic and anti-cancer properties of these agents, the mechanisms behind these properties and how the alpha-1 blockers fit within current cancer therapies. It aims to answer the question of whether these agents can go from the laboratory bench top into cancer clinics.


NTRK fusions in solid tumours: what every pathologist needs to know.
Fusions involving the Neurotrophic tropomyosin receptor kinase (NTRK) gene family (NTRK1, NTRK2 and NTRK3) are targetable oncogenic alterations that are found in a diverse range of tumours. There is an increasing demand to identify tumours which harbour these fusions to enable treatment with selective tyrosine kinase inhibitors such as larotrectinib and entrectinib. NTRK fusions occur in a wide range of tumours including rare tumours such as infantile fibrosarcoma and secretory carcinomas of the salivary gland and breast, as well as at low frequencies in more common tumours including melanoma, colorectal, thyroid and lung carcinomas. Identifying NTRK fusions is a challenging task given the different genetic mechanisms underlying NTRK fusions, their varying frequency across different tumour types, complicated by other factors such as tissue availability, optimal detection methods, accessibility and costs of testing methods. Pathologists play a key role in navigating through these complexities by determining optimal approaches to NTRK testing which has important therapeutic and prognostic implications. This review provides an overview of tumours harbouring NTRK fusions, the importance of identifying these fusions, available testing methods including advantages and limitations, and generalised and tumour-specific approaches to testing.