A review and study of aspirin utilization for the primary prevention of cardiovascular events in a psychiatric population.
In April 2016, the US Preventive Service Task Force (USPSTF) updated the aspirin guidelines for the primary prevention of cardiovascular disease (CVD) and colorectal cancer. This review assesses the importance of appropriate use of aspirin for the primary prevention of CVD and, specifically, how individuals with psychiatric disorders may benefit from such use. This study examined how current prescribing practices of aspirin in a state psychiatric hospital align with these new guidelines and how inappropriate prescribing may jeopardize patient safety. A retrospective chart review of 93 patients was performed to evaluate whether aspirin therapy would be recommended for primary prevention of CVD based on the new USPSTF guidelines. A secondary analysis of these data was performed using the 2009 USPSTF recommendations to strengthen the assumption that practitioners were no longer using the old guidelines. Drug interactions between aspirin and concurrently prescribed pharmacotherapy were classified based on of severity, and the past events of bleeding were quantified. Based on the 2016 guidelines, 25 of the 93 patients included in this study were identified as potential candidates who would benefit from aspirin use for the primary prevention of CVD; of whom 22 (88%) were not prescribed aspirin. The remaining 68 patients did not meet the criteria for aspirin use for primary prevention, although 11 (16.2%) of these patients were taking low-dose aspirin. Based on the 2009 guidelines, 49 of the 93 patients included in our study would have been identified as potential candidates who would benefit from the use of aspirin for the primary prevention of CVD; 41 (83.7%) of whom were not prescribed aspirin. The remaining 44 patients did not meet the previous criteria for aspirin use for primary prevention, although six (13.6%) of these individuals were taking low-dose aspirin daily. The results above indicate a difference between prescribing practices of aspirin use for the primary prevention of CVD. We identified a similar rate of underuse; however, there was a slight increase in the appropriate prescribing according to the 2016 guidelines compared with the 2009 guidelines (88 vs. 83.7%, respectively). Also, there was a higher incidence of unnecessary prescribing (overutilization) of aspirin for the primary prevention of CVD in 2016 compared with 2009 despite the more restrictive criteria (and smaller candidate pool) published in these newer guidelines. There were 47 drug interactions identified when patients' aspirin and concurrent medication regimens were reviewed for our entire sample population. These interactions could potentially lead to an adverse drug reaction in the future. Our safety analysis revealed that none of the patients who were prescribed aspirin had any bleeding events while on therapy within the period of this study. Inappropriate omission of aspirin (underutilization) was more prevalent in our psychiatric institution than overutilization; however, the overall percentage of both underuse and overuse were greater when patients were evaluated according to the 2016 guidelines and then compared with the 2009 statistics. Overutilization did not pose a serious risk for those on aspirin therapy in this sample, as there were no major episodes of bleeding. However, future harm from aspirin still exists based on the significant number of major and moderate potential drug interactions with aspirin and the increased risk of decreased adherence to critical psychiatric medications due to increased pill burden and regimen complexity. Our findings demonstrate that there is an opportunity to educate prescribers on the updated 2016 USPSTF guidelines to improve preventive care and patient safety, which include harm reduction by initiating aspirin in those who are at a risk of cardiovascular events, continuing aspirin in those who are currently receiving aspirin appropriately, and discontinuing aspirin in those who are not considered to be at a high risk of CVD and who may also be at a risk of experiencing an increased risk of bleeding.


Developing a Multichannel Bioreactor with a Collagen Scaffold, ECM, and Cryoprecipitate to Significantly Produce Platelets from Umbilical Cord Blood Stem Cells.
Background: Platelets play a key role in the treatment of thrombocytopenia. Nowadays, platelets (PLTs) are only obtained through blood donation. However, due to the limitations in their preparation and storage, they are produced in laboratories, especially through bioreactors that convert megakaryocytes from stem cells into large-scale injectable PLTs. Materials and Methods: In this study, the CD34 cells isolated from cord blood were differentiated into megakaryocytes. A 6-chamber bioreactor with a two-layer collagen scaffold, several ECM factors, and human cryoprecipitate were used to simulate the structure of the bone marrow. After the addition of megakaryocytes to the scaffold, PLTs were produced due to the flow pressure and the interaction between the scaffold structure and the ECM factors. Results: CD41 + cells were expanded 100 times as much as CD34 + cord blood stem cells. The mean PLT release from one megakaryocyte in the pure collagen scaffold was 17.42 PLTs. Once fibrin, fibronectin, hyaluronic acid, and cryoprecipitates were added to collagen, the mean PLT release was 21.4, 22.4, 23.9, and 27.37, respectively. With the simultaneous addition of three factors to collagen (CFFH) and then four factors (CFFHC), the number of PLTs reached 30.52 and then 34. Conclusion: Functional PLTs can be produced on a large scale with a multi-chamber bioreactor using a combination of ECM and cryoprecipitate with collagen scaffolding.


Accounting for Healthcare-Seeking Behaviours and Testing Practices in Real-Time Influenza Forecasts.
For diseases such as influenza, where the majority of infected persons experience mild (if any) symptoms, surveillance systems are sensitive to changes in healthcare-seeking and clinical decision-making behaviours. This presents a challenge when trying to interpret surveillance data in near-real-time (e.g., to provide public health decision-support). Australia experienced a particularly large and severe influenza season in 2017, perhaps in part due to: (a) mild cases being more likely to seek healthcare; and (b) clinicians being more likely to collect specimens for reverse transcription polymerase chain reaction (RT-PCR) influenza tests. In this study, we used weekly Flutracking surveillance data to estimate the probability that a person with influenza-like illness (ILI) would seek healthcare and have a specimen collected. We then used this estimated probability to calibrate near-real-time seasonal influenza forecasts at each week of the 2017 season, to see whether predictive skill could be improved. While the number of self-reported influenza tests in the weekly surveys are typically very low, we were able to detect a substantial change in healthcare seeking behaviour and clinician testing behaviour prior to the high epidemic peak. Adjusting for these changes in behaviour in the forecasting framework improved predictive skill. Our analysis demonstrates a unique value of community-level surveillance systems, such as Flutracking, when interpreting traditional surveillance data. These methods are also applicable beyond the Australian context, as similar community-level surveillance systems operate in other countries.


Viral infections in pediatric burn patients.
Bacterial and fungal infections are frequent complications of burns, but the frequency of viral infections has not been defined. In a retrospective survey of serum for viral antibodies in pediatric burn patients, 22% had fourfold increases in antibodies to cytomegalovirus (CMV); 8% had increases to herpes simplex virus and to Epstein-Barr virus; and 5% had increases to varicella-zoster virus. None of the patients had evidence of adenovirus or hepatitis B virus infection. On the basis of these observations, a prospective study of viral infections, using both serologic and viral culture techniques, was performed. This study showed that in 33% of the children CMV infection developed; in 25%, herpes simplex infection; and in 17%, adenovirus infection. In all of the most severely burned children CMV infections developed, and both primary and reactivation infections were observed. Unexplained fevers are common in pediatric burn patients, and this study shows that some of these may be due to CMV infection.


Changes in voice fundamental frequency following discharge of single motor units in cricothyroid and thyroarytenoid muscles.
This investigation was designed to measure voice Fo changes related to single motor unit (SMU) contractions in the cricothyroid and thyroarytenoid muscles. Four subjects (3 men and 1 woman) were recorded producing a prolonged vowel at modal pitch and loudness levels while simultaneous recordings of electromyograms (EMG) from the muscles were obtained. Voice Fo changes unrelated to SMU firings in the muscles were eliminated using an averaging method previously described by Baer (1979). Results indicate that the time between discharge of the SMU and the peak in Fo change ("Fo Latency") was variable and ranged from 5 to 20 ms for the thyroarytenoid and 6 to 75 ms for the cricothyroid muscle. Distinct oscillations in Fo were always present in recordings from the woman subject and from the men when they phonated at higher-than-modal pitch levels. The findings are discussed in relation to SMU contraction times, biomechanics of the vocal folds, and the presence of jitter in normal voices.


Network meta-analysis to evaluate the effectiveness of interventions to prevent falls in children under age 5 years.
This study aimed to simultaneously evaluate the effectiveness of a range of interventions to increase the possession of safety equipment or behaviours to prevent falls in children under 5 years of age in the home. A recently published systematic review identified studies to be included in a network meta-analysis; an extension of pairwise meta-analysis that enables comparison of all evaluated interventions simultaneously, including comparisons not directly compared in individual studies. 29 primary studies were identified, of which 16 were included in at least 1 of 4 network meta-analyses. For increasing possession of a fitted stair gate, the most intensive intervention (including education, low cost/free home safety equipment, home safety inspection and fitting) was the most likely to be the most effective, with an OR versus usual care of 7.80 (95% CrI 3.08 to 21.3). For reducing possession or use of a baby walker: education only was most likely to be most effective, with an OR versus usual care of 0.48 (95% CrI 0.31 to 0.84). Little difference was found between interventions for possession of window locks (most intensive intervention versus usual care OR=1.56 (95% CrI 0.02 to 89.8)) and for not leaving a child alone on a high surface (education vs usual care OR=0.89 (95% CrI 0.10 to 9.67)). There was insufficient evidence for network meta-analysis for possession and use of bath mats. These results will inform healthcare providers of the most effective components of interventions and can be used in cost-effectiveness analyses.


Sugar-sweetened beverage and sugar consumption and colorectal cancer incidence and mortality according to anatomic subsite.
Recent preclinical research strongly suggests that dietary sugars can enhance colorectal tumorigenesis by direct action, particularly in the proximal colon that unabsorbed fructose reaches. We aimed to examine long-term consumption of sugar-sweetened beverages (SSBs) and total fructose in relation to incidence and mortality of colorectal cancer (CRC) by anatomic subsite. We followed 121,111 participants from 2 prospective US cohort studies, the Nurses' Health Study (1984-2014) and Health Professionals Follow-Up Study (1986-2014), for incident CRC and related death. Cox proportional hazards regression was used to compute HRs and 95% CIs. During follow-up, we documented 2733 incident cases of CRC with a known anatomic location, of whom 901 died from CRC. Positive associations of SSB and total fructose intakes with cancer incidence and mortality were observed in the proximal colon but not in the distal colon or rectum (Pheterogeneity ≤ 0.03). SSB consumption was associated with a statistically significant increase in the incidence of proximal colon cancer (HR per 1-serving/d increment: 1.18; 95% CI: 1.03, 1.34; Ptrend = 0.02) and a more pronounced elevation in the mortality of proximal colon cancer (HR: 1.39; 95% CI: 1.13, 1.72; Ptrend = 0.002). Similarly, total fructose intake was associated with increased incidence and mortality of proximal colon cancer (HRs per 25-g/d increment: 1.18; 95% CI: 1.03, 1.35; and 1.42; 95% CI: 1.12, 1.79, respectively). Moreover, SSB and total fructose intakes during the most recent 10 y, rather than those from a more distant period, were associated with increased incidence of proximal colon cancer. SSB and total fructose consumption were associated with increased incidence and mortality of proximal colon cancer, particularly during later stages of tumorigenesis.


Sports Augmented Cognitive Benefits: An fMRI Study of Executive Function with Go/NoGo Task.
Exercise is believed to have significant cognitive benefits. Although an array of experimental paradigms have been employed to test the cognitive effects on exercising individuals, the mechanism as to how exercise induces cognitive benefits in the brain remains unclear. This study explores the effect of dynamic neural network processing with the classic Go/NoGo task with regular exercisers. We used functional magnetic resonance imaging to analyze the brain activation of areas involved in executive function, especially inhibitory control. Nineteen regular joggers and twenty-one subjects as a control group performed the task, and their brain imaging data were analyzed. The results showed that at the attentive visual period, the frontal and parietal areas, including the prefrontal cortex, putamen, thalamus, lingual, fusiform, and caudate, were significantly enhanced in positive activities than the control group. On the other hand, in the following inhibitory control processing period, almost the same areas of the brains of the exercise group have shown stronger negative activation in comparison to the control group. Such dynamic temporal response patterns indicate that sports augment cognitive benefits; i.e., regular jogging increases the brain's visual attention and inhibitory control capacities.


Research on customer churn prediction and model interpretability analysis.
In recent years, with the continuous improvement of the financial system and the rapid development of the banking industry, the competition of the banking industry itself has intensified. At the same time, with the rapid development of information technology and Internet technology, customers' choice of financial products is becoming more and more diversified, and customers' dependence and loyalty to banking institutions is becoming less and less, and the problem of customer churn in commercial banks is becoming more and more prominent. How to predict customer behavior and retain existing customers has become a major challenge for banks to solve. Therefore, this study takes a bank's business data on Kaggle platform as the research object, uses multiple sampling methods to compare the data for balancing, constructs a bank customer churn prediction model for churn identification by GA-XGBoost, and conducts interpretability analysis on the GA-XGBoost model to provide decision support and suggestions for the banking industry to prevent customer churn. The results show that: (1) The applied SMOTEENN is more effective than SMOTE and ADASYN in dealing with the imbalance of banking data. (2) The F1 and AUC values of the model improved and optimized by XGBoost using genetic algorithm can reach 90% and 99%, respectively, which are optimal compared to other six machine learning models. The GA-XGBoost classifier was identified as the best solution for the customer churn problem. (3) Using Shapley values, we explain how each feature affects the model results, and analyze the features that have a high impact on the model prediction, such as the total number of transactions in the past year, the amount of transactions in the past year, the number of products owned by customers, and the total sales balance. The contribution of this paper is mainly in two aspects: (1) this study can provide useful information from the black box model based on the accurate identification of churned customers, which can provide reference for commercial banks to improve their service quality and retain customers; (2) it can provide reference for customer churn early warning models of other related industries, which can help the banking industry to maintain customer stability, maintain market position and reduce corporate losses.


Preparation of Well-Constructed and Metal-Modified Covalent Organic Framework Nanoparticles for Biosensing Design with Cascade Catalytic Capability.
Uniform covalent organic framework nanoparticles (COF NPs) with a well-defined pore structure may provide a robust platform for scaffolding enzymes. Herein, bipyridine-based spherical COF NPs have been successfully prepared in this work through the Schiff base condensation reaction. Moreover, they are functionalized by metal modification and are further used for biosensor fabrication. Experimental results reveal that the metal-modified COF NPs also display impressive peroxidase-like catalytic activities, while they can load enzymes, such as glucose oxidase (GOx) and sarcosine oxidase (SOx), to develop a cascade catalysis system for design of various kinds of biosensors with very well performance. For example, the optimized GOx@Fe-COFs can achieve a sensitive detection of glucose with a low limit of detection (LOD) of 12.8 μM. Meanwhile, the enzymes also exhibit a commendable preservation of 80% enzymatic activity over a span of 14 days under ambient conditions. This work may pave the way for advancing cascade catalysis and the analysis of different kinds of biological molecules based on COF NPs.


[Androgenic and estrogenic modulation in the prostate: an approach in rodent experimental models with emphasis on structural biology].
The endocrine system is a complex network of glands and hormones that regulates many of the body's functions; including growth, development and maturation, as well as the way several organs operate. The prostate is an important target of hormones and its functional maturity and development are influenced by steroids levels. Our research group has been evaluating the potential effects of the steroidal agents on the Mongolian gerbil (Meriones unguiculatus) male and female prostate using different morphological and immunohistochemical methods. Our results have revealed the Mongolian gerbil prostate as an important tool for the morphofunctional studies of steroid hormones and its antagonist actions.


Screening organic chemicals in commerce for emissions in the context of environmental and human exposure.
Quantitative knowledge of organic chemical release into the environment is essential to understand and predict human exposure as well as to develop rational control strategies for any substances of concern. While significant efforts have been invested to characterize and screen organic chemicals for hazardous properties, relatively less effort has been directed toward estimating emissions and hence also risks. Here, a rapid throughput method to estimate emissions of discrete organic chemicals in commerce has been developed, applied and evaluated to support screening studies aimed at ranking and identifying chemicals of potential concern. The method builds upon information in the European Union Technical Guidance Document and utilizes information on quantities in commerce (production and/or import rates), chemical function (use patterns) and physical-chemical properties to estimate emissions to air, soil and water within the OECD for five stages of the chemical life-cycle. The method is applied to 16,029 discrete substances (identified by CAS numbers) from five national and international high production volume lists. As access to consistent input data remains fragmented or even impossible, particular attention is given to estimating, evaluating and discussing uncertainties in the resulting emission scenarios. The uncertainty for individual substances typically spans 3 to 4 orders of magnitude for this initial tier screening method. Information on uncertainties in emissions is useful as any screening or categorization methods which solely rely on threshold values are at risk of leading to a significant number of either false positives or false negatives. A limited evaluation of the screening method's estimates for a sub-set of about 100 substances, compared against independent and more detailed emission scenarios presented in various European Risk Assessment Reports, highlights that up-to-date and accurate information on quantities in commerce as well as a detailed breakdown on chemical function are critically needed for developing more realistic emission scenarios.


Inhibition of intestinal citrulline synthesis causes severe growth retardation in rats.
delta-N-(phosphonacetyl)-L-ornithine (PALO) is a powerful and specific inhibitor of ornithine transcarbamylase (1), but it does not readily enter intact cells and therefore does not inhibit citrulline synthesis in intact liver or intestine. We have used the glycylglycine derivative of PALO (Gly-Gly-PALO) to evaluate the importance of intestinal citrulline synthesis in supplying arginine for growth. We have shown that the peptide derivative of PALO is selectively taken up by gut cells via the peptide permease and is released intracellularly as the free inhibitor. When administered in drinking water to 6-wk-old rat pups on an arginine-deficient diet, serum citrulline was reduced from 85 +/- 4.2 to 44 +/- 2.2 microM and arginine from 240.1 +/- 19.0 to 52.1 +/- 4.1 microM. Ornithine increased from 100 +/- 6.2 to 273.5 +/- 21.3 microM. Addition of 0.1 mM Gly-Gly-PALO to drinking water caused a rapid and complete inhibition of growth in rats on arginine-deficient diets, and this growth inhibition could be partially prevented by simultaneous administration of 1% (wt/wt) arginine to the diet and completely prevented with 1% (wt/wt) citrulline. The specificity of the effects of Gly-Gly-PALO on intestinal citrulline synthesis was shown by the inability of the drug to be taken up or to inhibit citrulline synthesis in isolated rat hepatocytes, and the oral administration of the drug had no effect on serum ammonia concentrations. The relative importance of endogenous synthesis of arginine compared with dietary arginine for growth was shown by the ability of Gly-Gly-PALO to inhibit the growth of rats maintained on standard laboratory chow containing normal levels of arginine.


[Foot reflexology massage: a clinical study].
The aim of the study was to investigate the possible usefulness of foot reflexology on the recovery after a surgical intervention. 130 patients participated in the study. They underwent abdominal surgery under full anesthesia for different, but exclusively gynecological reasons. Foot reflexology investigated in this study was applied only for a few days for each patient. The following parameters were recorded: the subjective, self-assessed, general condition, pain intensity, movement of the bowels, micturition and sleep, beginning on the day before operation until day 10. Two other treatments served as controls, a simple massage of the foot or a personal conversation. The simple massage turned out to be a relaxing, positive experience, whereas foot reflexology had various effects, some of them were even negative. The conclusion was that foot reflexology is not recommended for acute, abdominal postsurgical situations in gynecology because it can occasionally trigger abdominal pain. This project is one of the few studies planned, conducted and performed by the nursing staff.


Urinary phytoestrogens and depression in perimenopausal US women: NHANES 2005-2008.
Fluctuating hormonal levels observed during the menopausal transition may increase vulnerability to depression in susceptible women. Thus, it is of interest to examine the effect of natural estrogens such as phytoestrogens on the risk of depression in perimenopausal women. Our analysis included 193 perimenopausal women of the National Health and Nutrition Survey (NHANES) 2005-2008 aged 45-55 years. Urinary concentrations of phytoestrogens (isoflavones and lignans) were measured by HPLC-APPI-MS/MS. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9). Logistic regression models examined the association of phytoestrogens concentrations (creatinine-standardized and log-transformed) with depression (yes/no). Unadjusted odds ratios (OR) of the associations between urinary phytoestrogen concentrations and perimenopausal depression were below 1; however, only lignans were significantly inversely associated with depression. The latter findings were not attenuated in multivariate analysis including age, race, body mass index, poverty income ratio, smoking, alcohol consumption, cancer, diabetes, and cardiovascular disease (lignans: OR=0.66; 95% confidence intervals (CI) 0.50-0.87, enterodiol: OR=0.63; 95% CI 0.51-0.78, enterolactone: OR=0.75; 95% CI 0.60-0.93). Our cross-sectional study design does not allow for causal inferences. Because information to precisely assess perimenopausal symptoms was missing, we defined perimenopause based on women's age. Lower lignans but not isoflavones concentrations were statistically significantly associated with an increased risk of depression in perimenopausal women. Because of medical risks associated with the use of hormone therapy, further investigation on the effect of lignans on the risk of depression in perimenopausal women is warranted.


Right and left ventricular volume and ejection fraction by tomographic gated blood-pool scintigraphy.
Tomographic techniques separate overlying structures, permitting measurements of absolute ventricular volumes. The purpose of this study was to determine absolute right and left ventricular volume and ejection fraction measurements with tomographic gated equilibrium blood-pool scintigraphy (TMUGA) compared to MRI and conventional planar scintigraphy. Eighteen patients were studied. Ventricular volumes for TMUGA and MRI were calculated by modified Simpson's rule. TMUGA regions were defined by constraints including phase analysis, intensity threshold and visual inspection. MRI studies were acquired with a fast gradient-echo, ECG-gated, breath-hold technique and boundaries were defined by a semiautomated contour method. Conventional gated first-pass radionuclide angiography (FP) and planar gated equilibrium blood-pool scintigraphy (PMUGA) were performed for RV EF and LV EF, respectively. TMUGA absolute right ventricular volumes showed excellent-correlation with MRI for both right ventricular volumes (r = 0.91, slope = 0.90, s.e.e. = 15.7) and left ventricular volumes (r = 0.96, slope = 0.88, s.e.e. = 18.2). For left ventricular ejection fraction, TMUGA also showed excellent correlation with MRI (r = 0.94, slope = 1.10, s.e.e. = 9.0) and planar MUGA (r = 0.97, slope = 1.23, s.e.e. = 6.2). For right ventricular ejection fraction, TMUGA showed good correlation with both MRI (r = 0.88, slope = 0.79, s.e.e. = 6.0) and first-pass planar scintigraphy (r = 0.86, slope = 1.2, s.e.e. = 7.9). Tomographic gated blood-pool scintigraphy absolute right and left ventricular volumes and ejection fractions show good correlation with accepted techniques. Further studies are necessary to define the reproducibility of this method.


v-src-induced cell shape changes in rat fibroblasts require new gene transcription and precede loss of focal adhesions.
The mechanism of v-src-induced morphological transformation is still obscure. We compared LA29 rat fibroblasts, which express a temperature-sensitive (ts) v-src mutant, with D1025 rat fibroblasts, transfected with a ts mutant of v-fps. Upon transformation, LA29 cells adopted an elongated shape with reduced focal adhesions and loss of actin stress fibers. In contrast, activation of v-fps in D1025 cells had little effect on morphology. In both cells, paxillin was strongly tyrosine phosphorylated upon activation of the kinases. This indicates that paxillin phosphorylation is not required, or not sufficient, for the v-src-induced disruption of focal adhesions. As previously described by others, v-src activated the ras-MAP kinase (MAPK) pathway, as indicated by tyrosine phosphorylation of the rasGAP-associated proteins p62 and p190 and MAPK phosphorylation. Since MAPK affects transcription, this suggested that novel gene transcription was required. This notion was confirmed using actinomycin D and cycloheximide, which did not impair activation of v-src kinase activity, but completely blocked v-src-induced morphological changes, as demonstrated using image analysis. Furthermore, we observed that v-src-induced changes in cell shape occurred before the reduction in number and size of focal adhesions. We conclude that v-src-induced transformation of rat fibroblasts depends on synthesis of a protein, which induces rapid changes in cell shape that precede the loss of focal adhesions.


Mutations in the arginine-rich protein gene, in lung, breast, and prostate cancers, and in squamous cell carcinoma of the head and neck.
Arginine-rich protein (ARP) is a highly conserved gene that maps to human chromosomal band 3p21.1. This gene contains an imperfect trinucleotide repeat which encodes a string of arginines. We previously detected a specific mutation (ATG50-->AGG) within this region of the gene in 10 of 21 sporadic renal cell carcinomas. Here, we report the detection of the same mutation in 5 of 21 squamous cell carcinomas of the head and neck, 1 of 2 small cell lung cancer cell lines, 6 of 18 non-small cell lung carcinomas, 9 of 22 breast tumors, and 5 of 13 prostate tumors. This mutation was seen in several early stage tumors and may thus be an early event in tumorigenesis. We also detected a mutation at codon 53 of this gene in both primary and metastatic tumors from one patient. Other nucleotide changes were observed in a few PCR subclones, but their frequency was the same in both tumor and control samples, suggesting that many of these changes were PCR or subcloning artifacts rather than mutations in the tumor cells themselves.


Local versus radical surgery for early rectal cancer with or without neoadjuvant or adjuvant therapy.
Total mesorectal excision is the standard of care for stage I rectal cancer. Despite major advances and increasing enthusiasm for modern endoscopic local excision (LE), uncertainty remains regarding its oncologic equivalence and safety relative to radical resection (RR). To assess the oncologic, operative, and functional outcomes of modern endoscopic LE compared to RR surgery in adults with stage I rectal cancer. We searched CENTRAL, Ovid MEDLINE, Ovid Embase, Web of Science - Science Citation Index Expanded (1900 to present), four trial registers (ClinicalTrials.gov, ISRCTN registry, the WHO International Clinical Trials Registry Platform, and the National Cancer Institute Clinical Trials database), two thesis and proceedings databases, and relevant scientific societies' publications in February 2022. We performed handsearching and reference checking and contacted study authors of ongoing trials to identify additional studies. We searched for randomized controlled trials (RCTs) in people with stage I rectal cancer comparing any modern LE techniques to any RR techniques with or without the use of neo/adjuvant chemoradiotherapy (CRT). We used standard Cochrane methodological procedures. We calculated hazard ratios (HR) and standard errors for time-to-event data and risk ratios for dichotomous outcomes, using generic inverse variance and random-effects methods. We regrouped surgical complications from the included studies into major and minor according to the standard Clavien-Dindo classification. We assessed the certainty of evidence using the GRADE framework. Four RCTs were included in data synthesis with a combined total of 266 participants with stage I rectal cancer (T1-2N0M0), if not stated otherwise. Surgery was performed in university hospital settings. The mean age of participants was above 60, and median follow-up ranged from 17.5 months to 9.6 years. Regarding the use of co-interventions, one study used neoadjuvant CRT in all participants (T2 cancers); one study used short-course radiotherapy in the LE group (T1-T2 cancers); one study used adjuvant CRT selectively in high-risk patients undergoing RR (T1-T2 cancers); and the fourth study did not use any CRT (T1 cancers). We assessed the overall risk of bias as high for oncologic and morbidity outcomes across studies. All studies had at least one key domain with a high risk of bias. None of the studies reported separate outcomes for T1 versus T2 or for high-risk features. Low-certainty evidence suggests that RR may result in an improvement in disease-free survival compared to LE (3 trials, 212 participants; HR 1.96, 95% confidence interval (CI) 0.91 to 4.24). This would translate into a three-year disease-recurrence risk of 27% (95% CI 14 to 50%) versus 15% after LE and RR, respectively. Regarding sphincter function, only one study provided objective results and reported short-term deterioration in stool frequency, flatulence, incontinence, abdominal pain, and embarrassment about bowel function in the RR group. At three years, the LE group had superiority in overall stool frequency, embarrassment about bowel function, and diarrhea. Local excision may have little to no effect on cancer-related survival compared to RR (3 trials, 207 participants; HR 1.42, 95% CI 0.60 to 3.33; very low-certainty evidence). We did not pool studies for local recurrence, but the included studies individually reported comparable local recurrence rates for LE and RR (low-certainty evidence). It is unclear if the risk of major postoperative complications may be lower with LE compared with RR (risk ratio 0.53, 95% CI 0.22 to 1.28; low-certainty evidence; corresponding to 5.8% (95% CI 2.4% to 14.1%) risk for LE versus 11% for RR). Moderate-certainty evidence shows that the risk of minor postoperative complications is probably lower after LE (risk ratio 0.48, 95% CI 0.27 to 0.85); corresponding to an absolute risk of 14% (95% CI 8% to 26%) for LE compared to 30.1% for RR. One study reported an 11% rate of temporary stoma after LE versus 82% in the RR group. Another study reported a 46% rate of temporary or permanent stomas after RR and none after LE. The evidence is uncertain about the effect of LE compared with RR on quality of life. Only one study reported standard quality of life function, in favor of LE, with a 90% or greater probability of superiority in overall quality of life, role, social, and emotional functions, body image, and health anxiety. Other studies reported a significantly shorter postoperative period to oral intake, bowel movement, and off-bed activities in the LE group. Based on low-certainty evidence, LE may decrease disease-free survival in early rectal cancer. Very low-certainty evidence suggests that LE may have little to no effect on cancer-related survival compared to RR for the treatment of stage I rectal cancer. Based on low-certainty evidence, it is unclear if LE may have a lower major complication rate, but probably causes a large reduction in minor complication rate. Limited data based on one study suggest better sphincter function, quality of life, or genitourinary function after LE. Limitations exist with respect to the applicability of these findings. We identified only four eligible studies with a low number of total participants, subjecting the results to imprecision. Risk of bias had a serious impact on the quality of evidence. More RCTs are needed to answer our review question with greater certainty and to compare local and distant metastasis rates. Data on important patient outcomes such as sphincter function and quality of life are very limited. Results of currently ongoing trials will likely impact the results of this review. Future trials should accurately report and compare outcomes according to the stage and high-risk features of rectal tumors, and evaluate quality of life, sphincter, and genitourinary outcomes. The role of neoadjuvant or adjuvant therapy as an emerging co-intervention for improving oncologic outcomes after LE needs to be further defined.


Identifying Topics for E-Cigarette User-Generated Contents: A Case Study From Multiple Social Media Platforms.
Electronic cigarette (e-cigarette) is an emerging product with a rapid-growth market in recent years. Social media has become an important platform for information seeking and sharing. We aim to mine hidden topics from e-cigarette datasets collected from different social media platforms. This paper aims to gain a systematic understanding of the characteristics of various types of social media, which will provide deep insights into how consumers and policy makers effectively use social media to track e-cigarette-related content and adjust their decisions and policies. We collected data from Reddit (27,638 e-cigarette flavor-related posts from January 1, 2011, to June 30, 2015), JuiceDB (14,433 e-juice reviews from June 26, 2013 to November 12, 2015), and Twitter (13,356 "e-cig ban"-related tweets from January, 1, 2010 to June 30, 2015). Latent Dirichlet Allocation, a generative model for topic modeling, was used to analyze the topics from these data. We found four types of topics across the platforms: (1) promotions, (2) flavor discussions, (3) experience sharing, and (4) regulation debates. Promotions included sales from vendors to users, as well as trades among users. A total of 10.72% (2,962/27,638) of the posts from Reddit were related to trading. Promotion links were found between social media platforms. Most of the links (87.30%) in JuiceDB were related to Reddit posts. JuiceDB and Reddit identified consistent flavor categories. E-cigarette vaping methods and features such as steeping, throat hit, and vapor production were broadly discussed both on Reddit and on JuiceDB. Reddit provided space for policy discussions and majority of the posts (60.7%) holding a negative attitude toward regulations, whereas Twitter was used to launch campaigns using certain hashtags. Our findings are based on data across different platforms. The topic distribution between Reddit and JuiceDB was significantly different (P<.001), which indicated that the user discussions focused on different perspectives across the platforms. This study examined Reddit, JuiceDB, and Twitter as social media data sources for e-cigarette research. These mined findings could be further used by other researchers and policy makers. By utilizing the automatic topic-modeling method, the proposed unified feedback model could be a useful tool for policy makers to comprehensively consider how to collect valuable feedback from social media.


Multiscale modeling with smoothed dissipative particle dynamics.
In this work, we consider two issues related to the use of Smoothed Dissipative Particle Dynamics (SDPD) as an intermediate mesoscale model in a multiscale scheme for solution of flow problems when there are local parts of a macroscopic domain that require molecular resolution. The first is to demonstrate that SDPD with different levels of resolution can accurately represent the fluid properties from the continuum scale all the way to the molecular scale. Specifically, while the thermodynamic quantities such as temperature, pressure, and average density remain scale-invariant, we demonstrate that the dynamic properties are quantitatively consistent with an all-atom Lennard-Jones reference system when the SDPD resolution approaches the atomistic scale. This supports the idea that SDPD can serve as a natural bridge between molecular and continuum descriptions. In the second part, a simple multiscale methodology is proposed within the SDPD framework that allows several levels of resolution within a single domain. Each particle is characterized by a unique physical length scale called the smoothing length, which is inversely related to the local number density and can change on-the-fly. This multiscale methodology is shown to accurately reproduce fluid properties for the simple problem of steady and transient shear flow.


Reaching adolescents who drink harmfully: Fitting intervention to developmental reality.
Alcohol use usually starts in early adolescence. While the greater proportion of young people develop adaptive patterns of drinking, many drink at harmful levels and may be at risk for future alcohol-related problems. Findings from the empirical literature suggest that universal prevention programs may delay onset of drinking among low-risk baseline abstainers; however, there is little evidence supporting their utility for at-risk adolescents. Further research is needed on how risk and protective factors interact to determine substance use trajectory, and intervention outcomes that take substance use trajectories into account may capture change more effectively than the use of absolute measures of substance use. Indicated prevention programs may benefit from modulations that account for adolescent individuation and identity formation. It is argued that motivational interviewing within a harm reduction framework is well suited to adolescents.


Relationships between body composition, body dimensions, and peak speed in cross-country sprint skiing.
In modern sprint cross-country skiing, strength and maximal speed are major determinants of performance. The aims of this study were to ascertain the anthropometric characteristics of world-class sprint skiers and to evaluate whether a specific body composition and/or body dimension characterizes a successful sprint skier. Our hypothesis was that body height and lean body mass are related to peak speed in double poling and diagonal stride. Fourteen male national and international elite skiers performed two peak speed tests in double poling and diagonal stride roller skiing on a treadmill and were analysed using dual-energy X-ray absorptiometry to determine body composition and body dimensions. Relative pole length was positively correlated with both techniques (double poling: r = 0.77, P < 0.01; diagonal stride: r = 0.60, P < 0.05) and was the only variable that was part of the multiple regression model for both double poling and diagonal stride peak speed. Body height was not correlated with any technique, whereas lean trunk mass (r = 0.75, P < 0.01), body mass index (r = 0.66, P < 0.01), total lean mass (r = 0.69, P < 0.01), and body mass (r = 0.57, P < 0.05) were positively related to double poling peak speed. Total lean mass (absolute: r = 0.58, P < 0.05; relative: r = 0.76, P < 0.001) and relative lean mass of the trunk, arms (both r = 0.72, P < 0.01), and legs (r = 0.54, P < 0.05) were positively related to diagonal stride peak speed. In conclusion, skiers should aim to achieve a body composition with a high percentage of lean mass and low fat mass. A focus on trunk mass through increased muscle mass appears to be important, especially for double poling. The use of longer poles (percent body height) seems to be advantageous for both double poling and diagonal stride peak speed, whereas body dimensions do not appear to be a predictive factor.


Composition of amino acids and related nitrogenous nutrients in feedstuffs for animal diets.
We analyzed the composition of amino acids (AAs) in oligopeptides, proteins, and the free pool, as well as creatine, agmatine, polyamines, carnosine, anserine, and glutathione, in animal- and plant-derived feedstuffs. Ingredients of animal origins were black soldier fly larvae meal (BSFM), chicken by-product meal, chicken visceral digest, feather meal, Menhaden fishmeal, Peruvian anchovy fishmeal, Southeast Asian fishmeal, spray-dried peptone from enzymes-treated porcine mucosal tissues, poultry by-product meal (pet-food grade), spray-dried poultry plasma, and spray-dried egg product. Ingredients of plant origins were algae spirulina meal, soybean meal, and soy protein concentrate. All animal-derived feedstuffs contained large amounts of all proteinogenic AAs (particularly glycine, proline, glutamate, leucine, lysine, and arginine) and key nonproteinogenic AAs (taurine and 4-hydroxyproline), as well as significant amounts of agmatine, polyamines, creatine, creatinine, creatine phosphate, and glutathione. These nitrogenous substances are essential to either DNA and protein syntheses in cells or energy metabolism in tissues (particularly the brain and skeletal muscle). Of note, chicken by-product meal, poultry by-product meal, and spray-dried poultry plasma contained large amounts of carnosine and anserine (potent antioxidants). Compared with most of the animal-derived feedstuffs, plant-derived feedstuffs contained much lower contents of glycine and proline, little 4-hydroxyproline, and no creatine, creatinine, creatine phosphate, carnosine or anserine. These results indicate the unique importance of animal-source feedstuffs in improving the feed efficiency, growth and health of animals (including fish and companion animals). Because soy protein concentrate is consumed by infants, children and adults, as are BSFM and algae for children and adults, our findings also have important implications for human nutrition.


Mass spectrometric detection of targeting peptide bioconjugation to Red clover necrotic mosaic virus.
Plant virus nanoparticle (PVN) formulations constructed from Red clover necrotic mosaic virus by drug infusion and targeting peptide conjugation can be employed as drug delivery tools. In this investigation, we studied the cross-linked structures formed by application of sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sSMCC) and succinimidyl-[(N-maleimidopropionamido)-hexaethylene glycol] ester (SMPEG) as heterobifunctional linkers in the bioconjugation process. The plant virus formulations using several targeting peptides cross-linked to the plant virus capsid were characterized by LC/MS(E) analysis, which produced at least 69% sequence coverage using trypsin and chymotrypsin digestion. The results showed evidence for several types of modification located in three domains of the capsid protein. Extensive linker modifications on lysines or cysteines were detected in all the domains, including both intended peptide-capsid cross-links and unintended intracapsid cross-links. Surprisingly, the most extensive peptide modification was observed in the R domain, which is thought to be quite inaccessible to peptides and cross-linking reagents in solution, since it is on the interior of the virus. These results show that heterobifunctional linkers may not be the most efficient method for attachment of peptides to plant virus capsids. As an alternative conjugation strategy, maleimide peptides were used to conjugate with the virus in a one-step reaction. Analysis by LC/MS(E) showed that these one-step maleimide coupling reactions were more specific, such as modifications of C154 and to a lesser extent C267, and provide a means for achieving more effective PVN formulations.


A diet moderately enriched in phytosterols lowers plasma cholesterol concentrations in normocholesterolemic humans.
Twelve normolipidic healthy human subjects were fed a diet with or without additional soybean phytosterols for 4 weeks in a crossover design. The order of the treatments was randomized. Phytosterols were added to the diet blended in butter. The dietary ratio cholesterol:phytosterols was 0.7 during the control period (436 mg cholesterol/day and 29 mg phytosterols/day) and 1.88 during the phytosterols period (410 mg cholesterol/day and 740 mg phytosterols/day). Blood cholesterol was 10% lower after subjects consumed the phytosterol-enriched diet than when they consumed the control diet (p < 0.001), which was due to a 15% LDL cholesterol decrease (p < 0.001). The HDL cholesterol:LDL cholesterol ratio was markedly enhanced (+25%) (p < 0.01). These findings suggest that a significant lowering of plasma total and LDL cholesterol can be effected by a modest dietary intake of soybean phytosterols.


Topically active carbonic anhydrase inhibitors. 4. [(Hydroxyalkyl)sulfonyl]benzene and [(hydroxyalkyl)sulfonyl]thiophenesulfonamides.
For several decades a tantalizing goal for the treatment of primary open-angle glaucoma has been the development of a topically active carbonic anhydrase inhibitor. Recent results from several research groups indicate that considerable progress has been made toward this objective. In this report, we present the design and synthesis of (hydroxyalkyl)sulfonyl-substituted benzene- and thiophenesulfonamides. These compounds exhibit inhibition of carbonic anhydrase II in the nanomolar range and lower intraocular pressure in the alpha-chymotrypsinized rabbit model of ocular hypertension after topical instillation.


CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection.
The discovery of the CD1 antigen presentation pathway has expanded the spectrum of T-cell antigens to include lipids, but the range of natural lipid antigens and functions of CD1-restricted T cells in vivo remain poorly understood. Here we show that the T-cell antigen receptor and the CD1c protein mediate recognition of an evolutionarily conserved family of isoprenoid glycolipids whose members include essential components of protein glycosylation and cell-wall synthesis pathways. A CD1c-restricted, mycobacteria-specific T-cell line recognized two previously unknown mycobacterial hexosyl-1-phosphoisoprenoids and structurally related mannosyl-beta1-phosphodolichols. Responses to mannosyl-beta1-phosphodolichols were common among CD1c-restricted T-cell lines and peripheral blood T lymphocytes of human subjects recently infected with M. tuberculosis, but were not seen in naive control subjects. These results define a new class of broadly distributed lipid antigens presented by the CD1 system during infection in vivo and suggest an immune mechanism for recognition of senescent or transformed cells that are known to have altered dolichol lipids.


VIRALpro: a tool to identify viral capsid and tail sequences.
Not only sequence data continue to outpace annotation information, but also the problem is further exacerbated when organisms are underrepresented in the annotation databases. This is the case with non-human-pathogenic viruses which occur frequently in metagenomic projects. Thus, there is a need for tools capable of detecting and classifying viral sequences. We describe VIRALpro a new effective tool for identifying capsid and tail protein sequences, which are the cornerstones toward viral sequence annotation and viral genome classification. The data, software and corresponding web server are available from http://scratch.proteomics.ics.uci.edu as part of the SCRATCH suite. email@example.com or email@example.com Supplementary data are available at Bioinformatics online.


Hypothalamic orexins/hypocretins as regulators of breathing.
It was suggested half a century ago that electrical impulses from the lateral hypothalamic area stimulate breathing. It is now emerging that these effects may be mediated, at least in part, by neurons containing orexin neuropeptides (also known as hypocretins). These cells promote wakefulness and consciousness, and their loss results in narcolepsy. Recent data also show that orexin neurons directly project to respiratory centres in the brainstem, which express orexin receptors, and where injection of orexin stimulates breathing. Because orexin neurons receive inputs that signal metabolic, sleep/wake and emotional states, it is tempting to speculate that they may regulate breathing according to these parameters. Knockout of the orexin gene in mice reduces CO2-induced increases in breathing by approximately 50% and increases the frequency of spontaneous sleep apneas. The relationship between orexins and breathing may be bidirectional: the rate of breathing controls acid and CO2 levels, and these signals alter the electrical activity of orexin neurons in vitro. Overall, these findings suggest that orexins are important for the regulation of breathing and may potentially play a role in the pathophysiology and medical treatment of respiratory disorders.


The Promise of Optogenetics for Bioproduction: Dynamic Control Strategies and Scale-Up Instruments.
Progress in metabolic engineering and synthetic and systems biology has made bioproduction an increasingly attractive and competitive strategy for synthesizing biomolecules, recombinant proteins and biofuels from renewable feedstocks. Yet, due to poor productivity, it remains difficult to make a bioproduction process economically viable at large scale. Achieving dynamic control of cellular processes could lead to even better yields by balancing the two characteristic phases of bioproduction, namely, growth versus production, which lie at the heart of a trade-off that substantially impacts productivity. The versatility and controllability offered by light will be a key element in attaining the level of control desired. The popularity of light-mediated control is increasing, with an expanding repertoire of optogenetic systems for novel applications, and many optogenetic devices have been designed to test optogenetic strains at various culture scales for bioproduction objectives. In this review, we aim to highlight the most important advances in this direction. We discuss how optogenetics is currently applied to control metabolism in the context of bioproduction, describe the optogenetic instruments and devices used at the laboratory scale for strain development, and explore how current industrial-scale bioproduction processes could be adapted for optogenetics or could benefit from existing photobioreactor designs. We then draw attention to the steps that must be undertaken to further optimize the control of biological systems in order to take full advantage of the potential offered by microbial factories.


Quinacrine inhibits Candida albicans growth and filamentation at neutral pH.
Candida albicans is a common cause of catheter-related bloodstream infections (CR-BSI), in part due to its strong propensity to form biofilms. Drug repurposing is an approach that might identify agents that are able to overcome antifungal drug resistance within biofilms. Quinacrine (QNC) is clinically active against the eukaryotic protozoan parasites Plasmodium and Giardia. We sought to investigate the antifungal activity of QNC against C. albicans biofilms. C. albicans biofilms were incubated with QNC at serially increasing concentrations (4 to 2,048 μg/ml) and assessed using a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay in a static microplate model. Combinations of QNC and standard antifungals were assayed using biofilm checkerboard analyses. To define a mechanism of action, QNC was assessed for the inhibition of filamentation, effects on endocytosis, and pH-dependent activity. High-dose QNC was effective for the prevention and treatment of C. albicans biofilms in vitro. QNC with fluconazole had no interaction, while the combination of QNC and either caspofungin or amphotericin B demonstrated synergy. QNC was most active against planktonic growth at alkaline pH. QNC dramatically inhibited filamentation. QNC accumulated within vacuoles as expected and caused defects in endocytosis. A tetracycline-regulated VMA3 mutant lacking vacuolar ATPase (V-ATPase) function demonstrated increased susceptibility to QNC. These experiments indicate that QNC is active against C. albicans growth in a pH-dependent manner. Although QNC activity is not biofilm specific, QNC is effective in the prevention and treatment of biofilms. QNC antibiofilm activity likely occurs via several independent mechanisms: vacuolar alkalinization, inhibition of endocytosis, and impaired filamentation. Further investigation of QNC for the treatment and prevention of biofilm-related Candida CR-BSI is warranted.


The relationship between liver-kidney impairment and viral load after nephropathogenic infectious bronchitis virus infection in embryonic chickens.
To examine the relationship of impairments of the liver and kidney with viral load after nephropathogenic infectious bronchitis virus (NIBV) infection in embryonic chickens, 120 specific-pathogen-free Leghorn embryonated chicken eggs were randomly divided into two groups (infected and control), with three replicates per group and 20 eggs in each replicate. The eggs in the infected and control groups were challenged with 0.2 mL of 105.5 ELD50 NIBV and sterile saline solution, respectively. The embryonic chickens' plasma and liver and kidney tissues were collected at 1, 3, and 5 days post-inoculation (dpi), the liver and kidney functional parameters were quantified, and the tissue viral loads were determined with real-time PCR. The results showed that plasma potassium, sodium, chlorine, magnesium, calcium, and phosphorus levels were increased. The infected group exhibited significantly higher plasma uric acid, blood urea nitrogen, and creatinine levels than the control group at 3 dpi. The plasma concentrations of aspartate aminotransferase and alanine aminotransferase were significantly increased in the infected group. The total protein, albumin, and globulin levels in the infected group were significantly lower than those in the control group. The liver-kidney viral load in the infected group peaked at 3 dpi, at which time the kidney viral load was significantly higher than that of the liver. Our results indicated that NIBV infection caused liver and kidney damage in the embryonic chickens, and the results also demonstrated that the liver and kidney damage was strongly related to the tissue viral load following NIBV infection in embryonic chickens.


The TM2 6' position of GABA(A) receptors mediates alcohol inhibition.
Ionotropic GABA(A) receptors (GABA(A)Rs), which mediate inhibitory neurotransmission in the central nervous system, are implicated in the behavioral effects of alcohol and alcoholism. Site-directed mutagenesis studies support the presence of discrete molecular sites involved in alcohol enhancement and, more recently, inhibition of GABA(A)Rs. We used Xenopus laevis oocytes to investigate the 6' position in the second transmembrane region of GABA(A)Rs as a site influencing alcohol inhibition. We asked whether modification of the 6' position by substitution with larger residues or methanethiol labeling [using methyl methanethiosulfonate (MMTS)] of a substituted cysteine, reduced GABA action and/or blocked further inhibition by alcohols. Labeling of the 6' position in either α2 or β2 subunits reduced responses to GABA. In addition, methanol and ethanol potentiation increased after MMTS labeling or substitution with tryptophan or methionine, consistent with elimination of an inhibitory site for these alcohols. Specific alcohols, but not the anesthetic etomidate, competed with MMTS labeling at the 6' position. We verified a role for the 6' position in previously tested α2β2 as well as more physiologically relevant α2β2γ2s GABA(A)Rs. Finally, we built a novel molecular model based on the invertebrate glutamate-gated chloride channel receptor, a GABA(A)R homolog, revealing that the 6' position residue faces the channel pore, and modification of this residue alters volume and polarity of the pore-facing cavity in this region. These results indicate that the 6' positions in both α2 and β2 GABA(A)R subunits mediate inhibition by short-chain alcohols, which is consistent with the presence of multiple counteracting sites of action for alcohols on ligand-gated ion channels.


Recent advances in thiopeptide antibiotic biosynthesis.
Thiopeptides, or thiazolylpeptides, are a family of highly modified peptide antibiotics first discovered several decades ago. Dozens of thiopeptides have since been identified, but, until recently, the biosynthetic genes responsible for their production remained elusive. The biosynthetic systems for a handful of thiopeptide metabolites were identified in the first portion of 2009. The surprising finding that these metabolites arise from the enzymatic tailoring of a simple, linear, ribosomally-synthesized precursor peptide led to a renewed appreciation of the architectural complexity accessible by posttranslational modification. This recent progress toward understanding thiopeptide antibiotic biosynthesis benefits the discovery of novel thiopeptides by either directed screening techniques or by mining available microbial genome sequences. Furthermore, access to the biosynthetic machinery now opens an avenue to the biosynthetic engineering of thiopeptide analogs. This Highlight discusses the genetic and biochemical insights revealed by these initial reports of the biosynthetic gene clusters for thiopeptide metabolites.


Nutritional value of a highly digestible sorghum cultivar for meat-type chickens.
The nutritional value of a newly discovered sorghum mutant cultivar (P851171), with high in vitro protein digestibility, was compared to those of corn and two normal sorghums (P721N and 611Y) in two chick feeding trials. Although 8-20 day protein efficiency ratios and net protein ratios of all three sorghums were inferior to those of corn, P851171 and 611Y had markedly greater mean true amino acid digestibilities (TAAD) than either corn or P721N. In a subsequent 42-day experiment, all three sorghums supported weight gains equal to those of the corn-fed chicks. Feeding suboptimal levels of dietary protein resulted in reduced weight gains and no observed benefits of P851171 or 611Y. Furthermore, chicks fed P851171 exhibited poorer feed/gain values as compared to those fed the other cereals. It is possible that the starch content/carbohydrate profile of P851171 was inferior to that of the other sorghums, which offset its superior TAAD and resulted in poorer broiler performance.


Corifollitropin α followed by menotropin for poor ovarian responders' trial (COMPORT): a protocol of a multicentre randomised trial.
Poor response to ovarian stimulation affects a significant proportion of infertile couples undergoing in vitro fertilisation (IVF) treatment. Recently, the European Society of Human Reproduction and Embryology developed new criteria to define poor ovarian response, the so-called Bologna criteria. Although preliminary studies in these patients demonstrated very low pregnancy rates, a recent pilot study has shown promising results in women <40 years old fulfilling the criteria, after treatment with corifollitropin α followed by highly purified menotropin (hpHMG) in a gonadotropin-releasing hormone (GnRH) antagonist setting. Corifollitropin α followed by menotropin for poor ovarian responders' trial (COMPORT) is a randomised trial aiming to investigate whether this novel protocol is superior to treatment with recombinant follicle-stimulating hormone (FSH) in an antagonist setting for young poor responders. COMPORT is a multicentre, open label, phase III randomised trial using a parallel two-arm design. 150 patients <40 years old fulfilling the 'Bologna criteria' will be randomised to corifollitropin α followed by hpHMG (group A) or recombinant FSH (group B) in a GnRH antagonist protocol for IVF/intracytoplasmic sperm injection (ICSI). The primary outcome is the ongoing pregnancy rate (defined as the presence of intrauterine gestational sac with an embryonic pole demonstrating cardiac activity at 9-10 weeks of gestation). Secondary outcomes are clinical and biochemical pregnancy rates and number of oocytes retrieved. Central randomisation will be performed using a computer-generated list and allocation concealment will be secured with the use of sealed-opaque envelopes. A sample size of 150 women is essential to detect a difference of 19.5% in ongoing pregnancy rates between group A (28%) and group B (8.5%) with a power of 85% and a level of significance at 0.05 using a two-sided Fisher's exact test.


Glucocorticoid management of adrenal insufficiency in the United Kingdom: assessment using real-world data.
Background and objectives Glucocorticoids are used to manage adrenal insufficiency (AI). We describe treatments used in the United Kingdom and real-world clinical outcomes for each treatment. Methods We used 2010-2016 primary care data from The Health Improvement Network (THIN). Descriptive analyses were conducted, and differences in variables between patients prescribed immediate-release hydrocortisone (IR HC), prednisolone or modified-release hydrocortisone (MR HC) were assessed using Fisher's exact test. Results Overall, 2648 patients were included: 1912 on IR HC (72%), 691 on prednisolone (26%) and 45 (2%) on MR HC. A total of 1174 (44.3%) had primary and 1150 (43.4%) had secondary AI. Patients on prednisolone were older (P < 0.001) and had a greater history of smoking (292/691, P < 0.001) and CVD (275/691, P < 0.001). Patients on MR HC had more PCOS (3/45, P = 0.001) and diabetes (27/45, P = 0.004). The number of GP visits/patient/year was 6.50 in IR HC, 9.54 in prednisolone and 9.11 in MR HC cohorts. The mean number of A&E visits and inpatient and outpatient hospital admissions ranged from 0.42 to 0.93 visits/patient/year. The mean number of adrenal crises/patient/year was between 0.02 and 0.03 for all cohorts. Conclusion IR HC is most commonly used for the management of AI in the United Kingdom, followed by prednisolone. Few patients receive MR HC. The prednisolone and MR HC cohorts displayed a greater prevalence of vascular risk factors compared with IR HC. The occurrence of AC and primary and secondary resource use were similar between treatment cohorts, and they indicate significant resource utilisation. Improved treatment and management of patients with AI is needed.


The quality of turning in Parkinson's disease: a compensatory strategy to prevent postural instability?
The ability to turn while walking is essential for daily living activities. Turning is slower and more steps are required to complete a turn in people with Parkinson's disease (PD) compared to control subjects but it is unclear whether this altered strategy is pathological or compensatory. The aim of our study is to characterize the dynamics of postural stability during continuous series of turns while walking at various speeds in subjects with PD compared to control subjects. We hypothesize that people with PD slow their turns to compensate for impaired postural stability. Motion analysis was used to compare gait kinematics between 12 subjects with PD in their ON state and 19 control subjects while walking continuously on a route composed of short, straight paths interspersed with eleven right and left turns between 30 and 180°. We asked subjects to perform the route at three different speeds: preferred, faster, and slower. Features describing gait spatio-temporal parameters and turning characteristics were extracted from marker trajectories. In addition, to quantify dynamic stability during turns we calculated the distance between the lateral edge of the base of support and the body center of mass, as well as the extrapolated body center of mass. Subjects with PD had slower turns and did not widen the distance between their feet for turning, compared to control subjects. Subjects with PD tended to cut short their turns compared to control subjects, resulting in a shorter walking path. Dynamic stability was smaller in the PD, compared to the healthy group, particularly for fast turning angles of 90°. The slower turning speeds and larger turning angles in people with PD might reflect a compensatory strategy to prevent dynamic postural instability given their narrow base of support.


[Chemical protection of the body against irradiation with high-energy protons].
Comparison of chemical protection against electromagnetic radiations (X- and gamma-rays) and high-energy proton radiations give evidence that the mechanism of antiradiation effects of radioprotectors and other biological protectors against different radiations is identical. On the basis of the data published in the literature it has been shown that the degree of radiation protection of animals and other biological objects in comparable doses differs insignificantly during exposures to proton and standard irradiations.


Prevalence and consequences of disaster-related illness and injury from Hurricane Ike.
To explore the extent to which disasters may be a source of injury and disability in community populations, we examined the prevalence and short-term consequences of disaster-related illness and injury for distress, disability, and perceived needs for care. A random population survey was conducted 2-6 months after Hurricane Ike struck Galveston Bay on September 13, 2008. The sample was composed of 658 adults representative of Galveston and Chambers Counties, Texas. The prevalences of personal injury (4%) and household illness (16%) indicated that approximately 7,700 adults in the two-county area were injured, and another 31,500 adults experienced household-level illness. Risk for injury/illness increased with area damage and decreased with evacuation. In bivariate tests, injury or illness or both were related to all outcome measures. In multivariate analyses that controlled for co-occurring stressors representing trauma, loss, adversities, and community effects, injury or illness or both were associated with global stress, posttraumatic stress, dysfunction, days of disability, and perceived needs for care, but not with depression or anxiety. The associations of injury with distress and disability suggest that community programs should reach out to injured persons for early mental health and functional assessments and, where indicated, intervene in ways that reduce further disability and need for complex rehabilitative services. The results also point to the potential effectiveness of evacuation incentives with regard to the prevention of disaster-related injury and disability.


Polynucleotide sequence divergence among strains of Escherichia coli and closely related organisms.
Polynucleotide sequence similarity tests were carried out to determine the extent of divergence present in a number of Escherichia coli strains, obtained from diverse human, animal, and laboratory sources, and closely related strains of Shigella, Salmonella, and the Alkalescens-Dispar group. At 60 C, relative reassociation of deoxyribonucleic acid (DNA) from the various strains with E. coli K-12 DNA ranged from 100 to 36%, with the highest level of reassociation found for three strains derived from K-12, and the lowest levels for two "atypical" E. coli strains and S. typhimurium. The change in thermal elution midpoint, which indicates the stability of DNA duplexes, ranged from 0.1 to 14.5 C, with thermal stability closely following the reassociation data. Reassociation experiments performed at 75 C, at which temperature only the more closely related DNA species form stable duplexes, gave similar indications of relatedness. At both temperatures, Alkalescens-Dispar strains showed close relatedness to E. coli, supporting the idea that they should be included in the genus Escherichia. Reciprocal binding experiments with E. coli BB, 02A, and K-12 yielded different reassociation values, suggesting that the genomes of these strains are of different size. The BB genome was calculated to be 9% larger than that of K-12, and that of 02A 9% larger than that of BB. Calculation of genome size for a series of E. coli strains yielded values ranging from 2.29 x 10(9) to 2.97 x 10(9) daltons. E. coli strains and closely related organisms were compared by Adansonian analysis for their relatedness to a hypothetical median strain. E. coli 0128a was the most closely related to this median organism. In general, these data compared well with the data from reassociation experiments among E. coli strains. However, anomalous results were obtained in the cases of Shigella flexneri, S. typhimurium, and "atypical" E. coli strains.


Fenpropathrin induces neurotoxic effects in common carp (Cyprinus carpio L.).
Fenpropathrin (FEN) is a synthetic pyrethroid that has been frequently detected in aquatic environments, yet the neurotoxic impacts and underlying mechanisms on nontarget organisms are lacking. In this experiment, common carp were exposed to 0.45 and 1.35 μg/L FEN for 14 d and exhibited abnormal locomotor behaviour. Biochemical and molecular analysis results indicated that FEN altered the contents of tight junction proteins (claudin-1, occludin, and ZO-1), disturbed Na+-K+-ATPase and AChE activities, caused abnormal expression of neurotransmitters (ACh, DA, GABA, 5-HT, and glutamate) and caused histological damage in the brain, suggesting that FEN may damage the blood-brain barrier and induce neurotoxicity in carp. Furthermore, FEN also promoted an increase in ROS, changed SOD and CAT activities, and generally upregulated the contents of MDA, 8-OHdG, and protein carbonyl in the brain, indicating that FEN can induce oxidative stress and cause damage to lipids, DNA, and proteins. Moreover, inflammation-related indicators (TNF-α, IL-1β, IL-6, and IL-10), mitophagy-related genes (PINK1, parkin, ulk1, beclin1, LC3, p62, tfeb, and atg5), and apoptosis-related parameters (p53, bax, bcl-2, caspase-3, caspase-8, and caspase-9) were also significantly changed, suggesting that inflammation, mitophagy, and apoptosis may participate in FEN-induced neurotoxicity in carp. This study refines the understanding of the toxicity mechanism of FEN and thus provides data support for the risk assessment of FEN.


Rapamycin attenuates pulmonary allergic vasculitis in murine model by reducing TGF-β production in the lung.
Rapamycin has been reported to inhibit mesenchymal cell proliferation in a murine model of pulmonary fibrosis. In the present study, we examined the effects of rapamycin on vascular remodeling including intraluminal myofibroblast proliferation in a murine model of allergic vasculitis with eosinophil infiltration. C57BL/6 mice were sensitized with ovalbumin (OVA) and alum. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice was administered with rapamycin (1mg/kg) intraperitoneally, in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and concentrations of IL-4, IL-5, IL-13 and TGF-β in the BAL fluid (BALF) were measured. Semi-quantitative analysis of pathological changes in the pulmonary arteries was evaluated according to the severity of vasculitis. The number of eosinophils in BALF was reduced significantly in the mice treated with rapamycin compared to the positive control. There was a significant decrease in the TGF-β concentration of the BALF in the rapamycin-treated group compared to that of the positive control. The pathological scores were reduced significantly in the rapamycin-treated group compared to the positive control group. Intraluminal myofibroblasts in pulmonary arteries were reduced dramatically in the rapamycin-treated group compared to the positive control group. Rapamycin suppressed pulmonary vascular remodeling in a murine model of allergic vasculitis with eosinophil infiltration through reducing eosinophil infiltration and TGF-β production in the lung and inhibition against biological action of TGF-β.


[Local control and the esthetic results in the conservative treatment of breast cancer. An analysis of 397 consecutive cases].
Conservative therapy has been the therapy of choice for patients with breast cancer in early stage. The results of 397 patients treated with conservative therapy and radiotherapy over the breast and lymph node areas (when necessary) are analyzed. The results obtained in the different risk groups and according to the irradiation mode of the tumoral bed are compared. The likelihood of remaining local disease free at 7 years was 94.9 (95% CI: 90.7-99.1). No significant differences were observed regarding the mode of overprinting the tumoral bed: external radiotherapy or brachytherapy, regarding control and aesthetic result; also, no differences were observed between the different risk groups. The existence of a subgroup of patients with contraindication for conservative therapy is currently not demonstrated.


An altered mode of calcium coordination in methionine-oxidized calmodulin.
Oxidation of methionine residues in calmodulin (CaM) lowers the affinity for calcium and results in an inability to activate target proteins fully. To evaluate the structural consequences of CaM oxidation, we used infrared difference spectroscopy to identify oxidation-dependent effects on protein conformation and calcium liganding. Oxidation-induced changes include an increase in hydration of alpha-helices, as indicated in the downshift of the amide I' band of both apo-CaM and Ca(2+)-CaM, and a modification of calcium liganding by carboxylate side chains, reflected in antisymmetric carboxylate band shifts. Changes in carboxylate ligands are consistent with the model we propose: an Asp at position 1 of the EF-loop experiences diminished hydrogen bonding with the polypeptide backbone, an Asp at position 3 forms a bidentate coordination of calcium, and an Asp at position 5 forms a pseudobridging coordination with a calcium-bound water molecule. The bidentate coordination of calcium by conserved glutamates is unaffected by oxidation. The observed changes in calcium ligation are discussed in terms of the placement of methionine side chains relative to the calcium-binding sites, suggesting that varying sensitivities of binding sites to oxidation may underlie the loss of CaM function upon oxidation.


Effectiveness of Autologous Whole-Blood Injections in Patients with Refractory Chronic Spontaneous Urticaria.
Nonsedating antihistamines are the treatment of choice for chronic spontaneous urticaria (CSU), while omalizumab and immunosuppressants have also been approved as an add-on treatment. Autologous whole-blood injection (AWBI) has been used in previous studies with ambiguous results. The aim of our study was to evaluate changes in the Urticaria Activity Score (UAS7), Dermatology Life Quality Index (DLQI), and Chronic Urticaria Quality of Life (CU-Q2oL) score, and also the association of serologic markers with disease severity measures after AWBI. In this observational study, AWBIs were performed (8 courses on a weekly basis) in adults with refractory CSU, who refused an add-on treatment with either omalizumab or immunosuppressants. UAS7, DLQI, and CU-Q2oL questionnaires and serum concentrations of total IgE, C-reactive protein (CRP), and D-dimer were evaluated before and after the intervention. Nineteen patients (12 females; mean age 54 ± 20.8 years) completed the protocol. Following AWBI, significant improvements in the UAS7 (34.26 ± 8.04 vs. 12.52 ± 10.83, p < 0.001), DLQI (11.63 ± 5.51 vs. 3.47 ± 2.85, p < 0.001), and CU-Q2oL score (32.97 ± 18.71 vs. 10.94 ± 7.71, p < 0.001) were recorded. A negative correlation between the baseline D-dimer levels and UAS7 and DLQI variations (p = 0.002 and p = 0.001, respectively) was noted. D-dimer levels ≥292 ng/mL have been associated with poor responsiveness (sensitivity 75%; specificity 83.3%). No correlation with either total immunoglobulin E or CRP levels was observed. AWBI appears to be a safe, alternative, add-on therapeutic option in refractory CSU, particularly in patients with low plasma levels of D-dimer.


Ethnography: contributions to nursing research.
Health and illness behaviour occur within a cultural context. Ethnographic methodology facilitates an investigation of the context in which people's health beliefs and practices evolve as well as serving to identify the cultural components of health and illness. Ethnography is primarily an inductive mode of research which may utilize several methods of data collection. Participant observation, used in conjunction with interviewing, is the most frequently used data-gathering technique. Sampling procedures in ethnography must be addressed in relation to persons interviewed and/or observed, events to be seen, topics to be considered and time frames to be established. The ethnographic method creates difficulties in establishing reliability as techniques for gathering data are highly individualistic and involve a complex admixture of observations, structured and unstructured interviews, and other procedures. The lengthy stay in a community, as well as the extensive and in-depth data-collection procedures contribute to validity of the findings and their interpretation. Data analysis is time consuming and complex. Ethnography is concerned with the context of discovery, rather than verification, and leads to narrative descriptions and interpretations of cultural phenomena. Ethnography is a means for gaining access to the health beliefs and practices of a culture. In a practice profession such as nursing, improved understanding of the meaning of clients' behaviour will enhance nursing judgements and improve nursing care.


The Primary Process and Key Concepts of Economic Evaluation in Healthcare.
Economic evaluations in the healthcare are used to assess economic efficiency of pharmaceuticals and medical interventions such as diagnoses and medical procedures. This study introduces the main concepts of economic evaluation across its key steps: planning, outcome and cost calculation, modeling, cost-effectiveness results, uncertainty analysis, and decision-making. When planning an economic evaluation, we determine the study population, intervention, comparators, perspectives, time horizon, discount rates, and type of economic evaluation. In healthcare economic evaluations, outcomes include changes in mortality, the survival rate, life years, and quality-adjusted life years, while costs include medical, non-medical, and productivity costs. Model-based economic evaluations, including decision tree and Markov models, are mainly used to calculate the total costs and total effects. In cost-effectiveness or costutility analyses, cost-effectiveness is evaluated using the incremental cost-effectiveness ratio, which is the additional cost per one additional unit of effectiveness gained by an intervention compared with a comparator. All outcomes have uncertainties owing to limited evidence, diverse methodologies, and unexplained variation. Thus, researchers should review these uncertainties and confirm their robustness. We hope to contribute to the establishment and dissemination of economic evaluation methodologies that reflect Korean clinical and research environment and ultimately improve the rationality of healthcare policies.


Validation of an NSP-based (negative selection pattern) gene family identification strategy.
Gene family identification from ESTs can be a valuable resource for analysis of genome evolution but presents unique challenges in organisms for which the entire genome is not yet sequenced. We have developed a novel gene family identification method based on negative selection patterns (NSP) between family members to screen EST-generated contigs. This strategy was tested on five known gene families in Arabidopsis to see if individual paralogs could be identified with accuracy from EST data alone when compared to the actual gene sequences in this fully sequenced genome. The NSP method uniquely identified family members in all the gene families tested. Two members of the FtsH gene family, three members each of the PAL, RF1, and ribosomal L6 gene families, and four members of the CAD gene family were correctly identified. Additionally all ESTs from the representative contigs when checked against MapViewer data successfully identify the gene locus predicted. We demonstrate the effectiveness of the NSP strategy in identifying specific gene family members in Arabidopsis using only EST data and we describe how this strategy can be used to identify many gene families in agronomically important crop species where they are as yet undiscovered.


Independent influences of sex steroids of systemic and central origin in a rat model of Parkinson's disease: A contribution to sex-specific neuroprotection by estrogens.
This review considers evidence which reveals considerable complexity and sex differences in the response of the nigrostriatal dopaminergic (NSDA) system to hormonal influences. This pathway degenerates in Parkinson's disease (PD) and sex hormones contribute to sex differences in PD, where men fare worse than women. Here we discuss evidence from animal studies which allows us to hypothesize that, contrary to expectations, the acclaimed neuroprotective property of physiological concentrations of estradiol arises not by promoting NSDA neuron survival, but by targeting powerful adaptive responses in the surviving neurons, which restore striatal DA functionality until over 60% of neurons are lost. Estrogen generated locally in the NSDA region appears to promote these adaptive mechanisms in females and males to preserve striatal DA levels in the partially injured NSDA pathway. However, responses to systemic steroids differ between the sexes. In females there is general agreement that gonadal steroids and exogenous estradiol promote striatal adaptation in the partially injured NSDA pathway to protect against striatal DA loss. In contrast, the balance of evidence suggests that in males gonadal factors and exogenous estradiol have negligible or even harmful effects. Sex differences in the organization of NSDA-related circuitry may well account for these differences. Compensatory mechanisms and sexually dimorphic hard-wiring are therefore likely to represent important biological substrates for sex dimorphisms. As these processes may be targeted differentially by systemic steroids in males and females, further understanding of the underlying processes would provide valuable insights into the potential for hormone-based therapies in PD, which would need to be sex-specific. Alternatively, evidence that estrogen generated locally is protective in the injured male NSDA pathway indicates the great therapeutic potential of harnessing central steroid synthesis to ameliorate neurodegenerative disorders. A clearer understanding of the relative contributions and inter-relationships of central and systemic steroids within the NSDA system is an important goal for future studies.


Early IL-10 predominant responses are associated with progression to chronic hepatitis C virus infection in injecting drug users.
The critical events in clearance or persistence of hepatitis C virus (HCV) infection are unknown but likely to be determined early in acute infection. Type 1 and type 2 cytokine production was assessed by HCV peptide ELISpot and multiplex in vitro cytokine production assays in longitudinally collected samples from 20 untreated participants enrolled in the Australian Trial in Acute Hepatitis C (ATAHC); a prospective cohort of acute HCV infection (77% injecting drug users, IDU). Significantly higher interleukin-10 (IL-10) production (P = 0.048), in the relative absence of interferon-gamma (IFN-γ) and IL-2 production, was present early in HCV infection in those who progressed to chronic infection. In contrast, viral clearance was associated with a greater magnitude and broader specificity of IFN-γ (magnitude P < 0.001, breadth P = 0.004) and IL-2 responses, in the relative absence of IL-10. Early IL-10 production was correlated with higher HCV RNA level at baseline (P = 0.046) and week 12 (P = 0.018), while IFN-γ and IL-2 production was inversely correlated with HCV RNA level at baseline (IFN-γ P = 0.020, IL-2 P = 0.050) and week 48 (IFN-γ P = 0.045, IL-2 P = 0.026). Intracellular staining (ICS) indicated the HCV-specific IFN-γ response was primarily from CD8(+) T cells and NK cells, whereas IL-10 production was predominantly from monocytes, with a subset of IL-10 producing CD8(+) T cells present only in those who progressed to chronic infection. IL-10, an immunoregulatory cytokine, appears to play a key role in progression to chronic HCV infection.


Transforming growth factor alpha in chemically transformed hamster oral keratinocytes.
The cheek pouch of the Syrian hamster is an excellent tissue for the experimental induction of oral cancer by carcinogenic chemicals. Lysate prepared from a cell line (HCPC-1) derived from one of these hamster oral tumors greatly increased the growth of these oral tumor cells in vitro. We now show that the mitogenic substance, transforming growth factor alpha (TGF-alpha), is present in all of the chemically transformed hamster oral tumors examined (in vitro and in vivo). In no adult normal tissue of the Syrian hamster can we detect expression of TGF-alpha. TGF-alpha could be partly or wholly responsible for the mitogenic activity detected in the lysate of the chemically transformed hamster oral keratinocytes. Both normal and chemically transformed hamster oral keratinocytes express the receptor to epidermal growth factor. The consistent detection of TGF-alpha and epidermal growth factor receptor mRNAs in these hamster oral tumor cells suggests that an autocrine growth mechanism might be operative. This hamster cheek pouch oral cancer model can be used for the molecular analysis of how TGF-alpha and epidermal growth factor receptor might be involved in the malignant transformation of epithelial tissues.


Silver sulfadiazine loaded breathable hydrogel sponge for wound healing.
Objectives Patients with serious injury need special care and treatment to control the infection, as wound sepsis is one of the major causes of death. Silver sulfadiazine (SSD) is widely used as an antimicrobial agent which promotes healing and re-epithelialization. However, due to certain drawbacks such as inflammation and cytotoxicity, the need for novel drug delivery modality emerges. The objective of this study was to develop natural polymeric (chitosan and gelatin) hydrogel sponges containing SSD and evaluate its efficacy in wound healing using animal models. Methods SSD containing hydrogel sponges were prepared by solvent casting technique. Scanning electron microscopy (SEM) and Differential scanning calorimetry (DSC) were used to evaluate morphological characteristics of the hydrogel sponges. Anti-thrombogenic property, drug release studies, drug release kinetics, antimicrobial property, and wound healing effect were also studied in detail. Results The optimized batch of hydrogel sponges (CG4) consists of 1% SSD wt., 10% wt. Gelatin, 1% wt. Chitosan and honey 7.5% wt. as plasticizer. At the 12th hour, in vitro and ex vivo drug release was found to be 76.994±0.67% and 24.22±0.57% respectively. CG4 batch had enhanced in vitro antimicrobial activity as compared to conventional marketed cream. The developed SSD hydrogel sponges showed a faster rate of wound healing as compared to a marketed cream. Animals treated with CG4 formulation showed complete angiogenesis and re-epithelialization by 8th day, whereas 12 days were required for complete wound healing with marketed cream. Conclusions The prepared hydrogel sponges can serve as a potential alternative for wound healing dressing as compared to the marketed product.


Perception regarding the quality of care of Care Network for People with Disabilities.
verify the perception of Care Network users for People with Disabilities in Minas Gerais regarding the quality of care. This is an observational, descriptive and cross-sectional study of 871 informants, users and caregivers of Care Network for People with Disabilities in Minas Gerais. Interviews were carried out based on three instruments, the User Interview Roadmap and Brazil's Economic Classification Criteria for sociodemographic, clinical and care characterization, as well as the Quality of Care Scale to assess the quality of care for the interviewees. the majority of users were male, single, unworked and had income of a minimum wage. A higher proportion of elementary school is incomplete, white in color, with household income greater than one and up to two minimum wages. The average age of 98.9% of the users was 28.6 years, of which 50.0% was up to 14 years. The majority reported having a type of disability with no associated comorbidity. Regarding the quality of care referred to, at least a quarter of the interviewees evaluated negatively the Access, Social Needs and Received Information axes. It will be necessary to improve the waiting time to receive care and also the services offer where the user resides, to facilitate access to consultations, to contribute intersectorally in leisure and social activities and to improve communication with users to increase the quality of care.


Utilization of a rodent model to examine the neurological effects of early life adversity on adolescent pain sensitivity.
All children experience pain, and although many recover quickly, some go on to develop chronic pain. Adolescent chronic pain is a growing epidemic. It is unknown why some adolescents recover without incident and others experience persistent pain. Although unexplored, early life adversity may contribute to the development and maintenance of chronic pain. This study investigated the effects and underlying neurobiological mechanisms of an early life stressor on nociceptive (pain) sensitivity and emotional function in male and female Sprague-Dawley rats. Using maternal separation (MS) as an established model of early life stress, we addressed two aims: investigation of the effects of MS on behavior (anxiety and pain sensitivity), and investigation of the effects of MS on mRNA and pathophysiological changes associated with an acutely painful stimulus. Our results indicate that MS increased anxiety-like behavior and altered nociceptive responsivity in adolescent rats, with decreased mechanical withdrawal thresholds indicative of heightened and prolonged pain-related behavior. The MS groups also demonstrated increased expression of genes involved in regulating the stress and fight-or-flight response, mood, and neuroplasticity; as well as increased levels of inflammatory markers. We conclude that nociception, both at the behavioral and molecular level, is altered in response to the MS stressor.


[Confidentiality and the medical record. Ethical-legal considerations].
Confidentiality is a key aspect in the relationship between health professionals and patients. It involves the cession by the patient of a reserved part of herself and the ethical principles of autonomy and non-maleficency that are closely linked to its preservation. There are also numerous legal regulations that make professional secrecy obligatory, in some cases imposing hard sanctions that are often not known about. As the medical record is the document where the relationship with the patient is recorded, it requires extraordinary protection due to the especially sensitive nature of the information it contains. It should be compulsory that the professional who works with it should know some basic aspects of the fundamental laws that regulate it in different aspects. This article reviews questions that at times are only known in the abstract, but that are contained in the legal regulations, such as ownership of the medical record, subjective annotations, its custody and rectification or who can have access to it and why.


[Cost-effectiveness analysis of a preventive program for gallbladder disease in Chile].
Chilean women have one of the highest mortality rates from gallstone disease in the world. There is no primary prevention for the disease and the benefits of prophylactic cholecystectomy in high risk groups have not been studied. To analyze the cost and effectiveness of a screening program for gallbladder disease in the Chilean women population. A decision analytic model is used to compare lifetime cost and effectiveness of standard care with three screening strategies. The first two strategies consider "universal ultrasound screening" for all women 40 years old and laparoscopic cholecystectomy for those with gallstones ("elective intervention") or with calculous > or = 3 cm ("high risk intervention"). The third strategy is based on "selective screening" for obese women. The lifetime probability of a 40 years old Chilean woman of dying from gallbladder disease is reduced by 70% in the universal screening/elective intervention, by 63% in the high risk intervention and by 18% in the selective screening strategy. Her lifetime expectancy increases by 5.25, 4.64 and 1.24 months respectively. The incremental cost-effectiveness ratio of each screening strategy is US$ 180, US$ 147 and US$ 481 respectively. A screening program for gallbladder disease in a high risk population achieves significant benefits at a low incremental cost and acceptable cost-effectiveness.


Improving protection effects of eucalyptol via carboxymethyl chitosan-coated lipid nanoparticles on hyperglycaemia-induced vascular endothelial injury in rats.
Hyperglycaemia is responsible for the major pathophysiological factor of diabetes-associated vascular endothelial injury, which mainly resulted from the disturbance of equilibrium between ROS generation and elimination. Eucalyptol was verified with exact anti-oxidation effects via stimulating the secretion of endogenous antioxidant enzymes against ROS. However, the volatility, instability and poor water solubility of eucalyptol limited its pharmacological activities in vivo. In this study, we developed carboxymethyl chitosan-coated lipid nanoparticles for eucalyptol (CMC/ELN) to facilitate oral administration. A thin lipid film dispersion method was used to prepare the ELN. After CMC coating, the diameter of ELN increased from 166 nm to 177 nm and charge reversal was observed. The nanocarrier enhanced the protective effects of eucalyptol both in the high level of glucose (HG)-damaged HUVECs and endothelial injury in type I diabetes mellitus (T1DM) rat model. Furthermore, the mechanism of eucalyptol on the promotion of Nrf2 and HO-1 and reduction on Keap1 expression have been verified both in the in vitro and in vivo model. Besides, the pharmacokinetics data were verified the promotion of the oral eucalyptol absorption by the nanocarrier. Taken together, we established an optimal oral delivery system that promoted oral administration of eucalyptol to exert protective effects on hyperglycaemia-induced vascular endothelial injury.