The influence of carbaryl on the uptake of (3H)-noradrenaline (3H)-NA by rat hypothalamic slices.
The uptake of (3H)-NA by rat hypothalamic slices was investigated following carbaryl poisoning. The insecticide was administered to rats orally in a single dose of 50% LD50 and of 20% LD50, and in repeated dosing for 14 days (5% LD50 daily). The kinetics of (3H)-NA uptake was defined by the modified Lineweaver-Burk plots (Rmax was used instead of Vmax and Km was replaced with t05 max). The results indicated that in all the experiments carbaryl elevated the (3H)-NA uptake by hypothalamic slices in a dosage dependent fashion (insignificantly at the 20% LD50 dose level, p greater than 0.05) as evidenced by the increased Rmax values. However, carbaryl simultaneously decreased the kinetics of the process in the hypothalamus since t0.5max values were enhanced (insignificantly at the 5% LD50 dose level, p greater than 0.05). Carbaryl produced a dose-dependent increase of t0.5max values. The changes in the (3H)-NA uptake may be related to the increase of NA level in the hypothalamus following exposure to carbaryl observed by other authors.


Quantitative DNase footprint titration: a tool for analyzing the energetics of protein-DNA interactions.
A major goal in biomedical research is to determine the mechanisms responsible for gene regulation. However, the promoters and operators that control transcription are often complex in nature, containing multiple-binding sites with which DNA-binding proteins can interact cooperatively. Quantitative DNase footprint titration is one of the few techniques capable of resolving the microscopic binding affinities responsible for the macroscopic assembly process. Here, we present a step-by-step protocol for carrying out a footprint titration experiment. We then describe how to quantify the resultant images to generate individual-site binding curves. Finally, we derive basic equations for binding at each site and present an overview of the fitting process, applying it to the anticipated results. Users should anticipate that the footprinting experiment will take 3-5 d starting from DNA template isolation to image acquisition and quantitation.


Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2(+) Breast Cancer.
Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2(+) breast cancer, particularly when combined with carboplatin.


Therapeutics against influenza.
Despite 75 years of research into prevention and treatment of influenza, the viruses that cause this disease continue to rank as some of the most important pathogens afflicting humans today. Progress in development of therapeutics for influenza has been slow for much of that time, but has accelerated in pace over the last two decades. Two classes of antiviral medications are used in humans at present, but each has limitations in scope and effectiveness of use. New strategies involving these licensed agents, including alternate forms of delivery and combination therapy with other drugs, are currently being explored. In addition, several novel antiviral compounds are in various clinical phases of development. Together with strategies designed to target the virus itself, new approaches to interrupt host-pathogen interactions or modulate detrimental aspects of the immune response have been proposed. Therapy for influenza will likely undergo substantial changes in the decades to come, evolving with our knowledge of pathogenesis as new approaches become viable and are validated clinically.


Clinical features and treatment of hematopoietic stem cell transplantation-associated gastric antral vascular ectasia.
Gastric antral vascular ectasia (GAVE) may occur after hematopoietic stem cell transplantation (HSCT) and cause severe and prolonged gastric bleeding. The underlying pathology of transplant-associated GAVE (HSCT-GAVE) is poorly understood and an effective therapeutic strategy has not been established yet. We retrospectively reviewed the medical records of 230 consecutive allogeneic transplant recipients in our institution between January 1997 and June 2002. We identified five patients who developed HSCT-GAVE (2.2%). Four patients had bleeding from HSCT-GAVE and one patient had HSCT-GAVE discovered incidentally. The clinical features of these patients were similar in that they all received conditioning treatment with busulfan and had history of thrombotic microangiopathy. Furthermore, treatment with a beta-blocker apparently improved the outcome of HSCT-GAVE in three patients.


The site-specific cleavage of synthetic Holliday junction analogs and related branched DNA structures by bacteriophage T7 endonuclease I.
Various branched DNA structures were created from synthetic, partly complementary oligonucleotides combined under annealing conditions. Appropriate mixtures of oligonucleotides generated three specific branched duplex DNA molecules: (i) a Holliday junction analog having a fixed (immobile) crossover bounded by four duplex DNA branches, (ii) a similar Holliday junction analog which is capable of limited branch migration and, (iii) a Y-junction, with three duplex branches and fixed branch point. Each of these novel structures was specifically cleaved by bacteriophage T7 gene 3 product, endonuclease I. The cleavage reaction "resolved" the two Holliday structure analogs into pairs of duplex DNA products half the size of the original molecules. The point of cleavage in the fixed-junction molecules was predominantly one nucleotide removed to the 5' side of the expected crossover position. Multiple cleavage positions were mapped on the Holliday junction with the mobile, or variable, branch point, to sites consistent with the unrestricted movement of the phosphodiester crossover within the region of limited dyad symmetry which characterizes this molecule. Based on the cleavage pattern observed with this latter substrate, the enzyme displayed a modest degree of sequence specificity, preferring a pyrimidine on the 3' side of the cleavage site. Branched molecules that were partial duplexes (lower order complexes which possessed single-stranded as well as duplex DNA branches) were also substrates for the enzyme. In these molecules, the cleaved phosphodiester bonds were in duplex regions only and predominantly one nucleotide to the 5' side of the branch point. The phosphodiester positions 5' of the branch point in single-stranded arms were not cleaved. Under identical reaction conditions, individually treated oligonucleotides were completely refractory. Thus, cleavage by T7 endonuclease I displays great structural specificity with an efficiency that can vary slightly according to the DNA sequence.


Impact of COVID-19 pandemic in the activity of a Therapeutic Apheresis unit in Italy.
The recent Coronavirus Disease 2019 (COVID-19) outbreak has led to profound and rapid changes in the Italian and Veneto Region Healthcare System. This context also includes the quick reorganization which the Apheresis Unit (AU) of the Padova University Hospital, i.e. the Regional Reference Center for Therapeutic Apheresis (TA), had to face. The study retrospectively evaluated the TA activity (procedures performed, patients treated and consultations) during the COVID-19 pandemic, from March to April 2020, comparing the activity in the same time period in 2018 and 2019. In the period analyzed, a significant reduction in both the total number of procedures performed and of patients treated, respectively by 17 % and 16 % for the procedures and by 19 % and 20 % for patients treated compared to the same period of 2018 and 2019, respectively, was observed. A concomitant reduction in requests for TA consultation for new patients (both outpatients and inpatients) was observed, equal to 32 % and 21 % compared to 2018 and 2019, respectively. Many reasons determined the observed reduction in the TA activity during the recent COVID-19 outbreak. The AU itself was quickly reorganized in terms of location and supplies to allow for the appropriate COVID-19 patients care. Many non urgent cases, after multidisciplinary discussion between Clinicians and Apheresis Specialists, were deferred, maintaining close phone and e-mail contact with patients.


The effects of a simulated refinery effluent on the grass shrimp, Palaemonetes pugio.
Duplicate static bioassays were conducted using a simulated refinery effluent on the grass shrimp (Palaemonetes pugio, Hippolyte sp.) with the LC-50 values recorded at 4-, 8-, 24-, 48-, and 96-hr intervals. The stimulated refinery effluent contained phenol (0.10 mg/L), sulfide (0.17 mg/L), chromium (0.25 mg/L), ammonia (10 mg/L), No. 2 fuel oil (10 mg/L), and kaolinite (20 mg/L). This arbitrary reference mixture (ARM) contains approximately the concentration of compounds recommended by EPA for 1977. Of the six ARM components, No. 2 fuel oil was the most toxic followed in decreasing order by sulfide, ammonia, phenol, chromium, and kaolinite. Temperature was the most important environmental variable affecting short term toxicity of the ARM to the grass shrimp. Light intensity, photo-period, and salinity had no significant effect. There was no difference in sensitivity of grass shrimp collected from five locations along the gulf and eastern coasts of the United States. Similarly, there was no difference in the response of two grass shrimp genera, Palaemonetes and Hippolyte to the ARM and there was no differences among the three species of Palaemonetes tested. In comparing the sensitivities of the two genera of grass shrimp and the pinfish (Lagodon rhombroides) to the ARM, the grass shrimp were more sensitive.


Parasagittal zones in the cerebellar cortex differ in excitability, information processing, and synaptic plasticity.
At the molecular and circuitry levels, the cerebellum exhibits a striking parasagittal zonation as exemplified by the spatial distribution of molecules expressed on Purkinje cells and the topography of the afferent and efferent projections. The physiology and function of the zonation is less clear. Activity-dependent optical imaging has proven a useful tool to examine the physiological properties of the parasagittal zonation in the intact animal. Recent findings show that zebrin II-positive and zebrin II-negative zones differ markedly in their responses to parallel fiber inputs. These findings suggest that cerebellar cortical excitability, information processing, and synaptic plasticity depend on the intrinsic properties of different parasagittal zones.


Sustainable preparation of high-calorific value and low-N and S energy products through the low-temperature alkali fusion of coal gasification fine ash.
Coal gasification fine ash (CGFA) is characterized by high yield, high carbon content, and difficult recovery. This results in waste of coal resources and serious environmental pollution. To address this issue, a novel green deashing process is proposed in this study to modify CGFA into deashed carbon (DAC) with a high calorific value and an ash content of less than 5% through a low-temperature alkaline fusion process. Compared with traditional alkaline fusion (which is carried out at 600-1000 °C), low-temperature alkaline fusion treatment can efficiently remove ash minerals in the temperature range of 300-450 °C, which is beneficial to the efficient recovery of residual carbon in DA, while simultaneously improving the physicochemical properties and energy characteristics of DAC, thereby improving its combustion performance. At an alkali fusion temperature of 350 °C, a NaOH:DA ratio of 4.5:1, and a reaction time of 40 min, the resulting DAC product had ash content of 2.28%, combustible material recovery (CMR) of 82.03%, higher heating value (HHV) of 31.07 MJ kg-1, and SBET of 445.43 m2 g-1. In comparison, it was found that low-temperature alkali fusion significantly improved the deashing of CGFA when compared to existing deashing technologies. These results strongly suggest that this innovative deashing method can modify CGFA into a high-calorific value and low-N and S fuel, thereby providing a cost-effective and sustainable utilization method for CGFA.


[Sleep disorders and the consumption of hypnotics on the island of Mallorca].
To estimate the frequency and characteristic of sleep disorders and consumption of hypnotic drugs in a population attended by primary care physicians (PC). Interviewing a population of 602 patients at the office exit of 87 PC physicians in 32 institution in Mallorca 1994. Questionnaire on sleep: hypnotic drugs and scale hospital anxiety-depression, others. 17.4% (95% CI: 14.4%-20.5%) sleepless (DSM-III-R), 27.0% (95% CI: 23.5%-30.6%) complained from poor sleep quality and 16.4% (95% CI: 13.4%-19.4%) usually consumed hypnotic drugs (56.7%, for longer than one year). The high frequency of both sleep disorders and chronic consumption of hypnotic drugs represents a relevant health problem.


Pulmonary tuberculosis and pneumocystis jirovecii concurrent pneumonia in HIV infected patients at a resource limited setting in Eastern India: A case series.
Pneumocytis jirovecii pneumonia (PJP) and Pulmonary TB (PTB) both are common opportunistic infections among HIV infected individuals. But concurrent infections pose a diagnostic challenge owing to similar clinical features. Data suggests a high prevalence of such concurrent infections in developing countries but limited diagnostic modalities especially in resource constraint setup limits accurate diagnosis. At our centre we came across 6 newly diagnosed PTB patients among HIV infected ones had persistent shortness of breath (SOB) and hypoxia despite starting anti-tuberculous treatment (ATT). We excluded concomitant bacterial pneumonia by imaging, sputum examination and blood culture. Serum lactate dehydrogenase (LDH) was estimated and hypoxia by arterial blood gas (ABG). We found all 6 patients had elevated serum LDH, hypoxia and imaging suggestive of PJP were offered sputum for Geisma stain and standard treatment for PJP in form of Bactrim-double strength and steroid. 1 patient had PJ cysts in sputum. 5 patient's classical radiologic findings in form of ground glass opacities in lower lobes along with bilateral infiltrates and 1 had honeycombing. Serum LDH was elevated all 6 subjects. 5 were newly diagnosed HIV and 4 had CD4 count below 50 cells/mm3 and 2 had below 200 cells/mm3.1 patient had developed bilateral pneumothorax as complication. 4 patients responded to treatment and 2 (33.3%) died of respiratory failure during treatment. We were able to diagnose only severe PJP cases as concurrent infection with PTB as there was no availability of broncho alveolar lavage (BAL) as well as direct fluorescent antigen (DFA) test for PJ detection. A high index of suspicion for PJP even in PTB patients with low CD4 count will guide to appropriate therapy for both infections and eventually reduces morbidity and mortality.


Serum amyloid a protein in clinical cancer diagnosis.
The serum amyloid A (SAA) protein is an acute phase protein that is synthesized under the regulation of inflammatory cytokines during both acute and chronic inflammation. It is suggested that the SAA increases correlate with many types of carcinogenesis and neoplastic diseases. Th changes in SAA in serum could therefore indicate the progress and malignancy of the disease, as well as the host responses. The present paper reviewed the rationale of using SAA as potential cancer biomarker in clinical diagnosis, including the contribution and involvement of SAA in cancer growth and development. Then we discussed the current applications of SAA in diagnosis and tracing of different types of cancers. Finally the proteomics techniques, especially the SELDI-TOF MS to identify SAA in serum from patients were appreciated as an important manner in clinical diagnosis.


Validity of intrapartum diagnosis of fetal thrombocytopenia.
Performing a platelet count in fetal scalp blood was hitherto the only method to predict whether the infant of a mother with idiopathic thrombocytopenic purpura will be thrombocytopenic. Fifteen such cases are reported. Falsely low platelet counts were found in almost half of these fetal scalp samples. In two patients this could have altered the obstetric management.


A review of the removal of microplastics in global wastewater treatment plants: Characteristics and mechanisms.
Wastewater treatment plants (WWTPs) are considered to be the main sources of microplastic contaminants in the aquatic environment, and an in-depth understanding of the behavior of microplastics among the critical treatment technologies in WWTPs is urgently needed. In this paper, the characteristics and removal of microplastics in 38 WWTPs in 11 countries worldwide were reviewed. The abundance of microplastics in the influent, effluent, and sludge was compared. Then, based on existing data, the removal efficiency of microplastics in critical treatment technologies were compared by quantitative analysis. Particularly, detailed mechanisms of critical treatment technologies including primary settling treatment with flocculation, bioreactor system, advanced oxidation and membrane filtration were discussed. Thereafter, the abundance load and ecological hazard of the microplastics discharged from WWTPs into the aquatic and soil environments were summarized. The abundance of microplastics in the influent ranged from 0.28 particles L-1 to 3.14 × 104 particles L-1, while that in the effluent ranged from 0.01 particles L-1 to 2.97 × 102 particles L-1. The microplastic abundance in the sludge within the range of 4.40 × 103-2.40 × 105 particles kg-1. In addition, there are still 5.00 × 105-1.39 × 1010 microplastic particles discharged into the aquatic environment each day Moreover, among the critical treatment technologies, the quantitative analysis revealed that filter-based treatment technologies exhibited the best microplastics removal efficiency. Fibers and microplastics with large particle sizes (0.5-5 mm) were easily separated by primary settling. Polyethene and small-particle size microplastics (<0.5 mm) were easily trapped by bacteria in the activated sludge of bioreactor system. The negative impact of microplastics from wastewater treatment plant was worthy of attention. Moreover, unknown transformation products of microplastics and their corresponding toxicity need in-depth research.


Quantification and determination of household food waste and its relation to sociodemographic characteristics in Croatia.
Every year in the EU alone, almost 90 million tonnes of food is lost. The sectors contributing the most to this amount are households, accounting for 53% of total food waste. Bearing in mind the fact those two-thirds of this amount refers to the occurrence of waste which is theoretically avoidable, the greatest attention should be paid to the generation of food waste in households. In Croatia, there is no data on the quantities of food waste produced, but only estimates on the amount of such waste. The aim of this research paper was to determine the type and amount of household food waste and the differences in production of waste relative to the socio-demographic characteristics of household members. The research was carried out by 115 Croatian households, who self-reported the amount of food waste during seven days. According to the results, on average, 2.57 portions of food waste were reported as the amount of discarded food per household member per day, equivalent to 0.21 kg of food waste mass. In general, the typical Croatian household generates 75 kg of food waste per person on average. The age of respondents positively affected the prevention of waste, while the income level and the number of children under the age of 18 in the household had an adverse impact.


Antibacterial and antibiofilm activities of novel antimicrobial peptide DP7 against the periodontal pathogen Porphyromonas gingivalis.
Accumulating evidence suggests that Porphyromonas gingivalis is closely associated with the development of various chronic inflammatory diseases, particularly periodontitis. This study investigated the antibacterial activity and action mechanism of a novel antimicrobial peptide (AMP), DP7, against P. gingivalis. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for DP7 were determined via a broth microdilution method, revealing an MIC of 8 μg ml-1 and MBC of 32 μg ml-1 . Growth inhibition and killing assays confirmed the bactericidal effect of DP7, and treatment with DP7 at MBC eliminated P. gingivalis within 8 h. DP7 had a low cytotoxic effect against human cells. Transmission electron microscopy revealed that DP7 destroyed the bacterial membrane, and confocal laser scanning microscopy revealed its inhibitory effect on P. gingivalis biofilms. Quantitative reverse transcription-polymerase chain reaction revealed DP7-mediated inhibition of several virulence factor genes, partially explaining its antibacterial mechanism. DP7, a novel AMP with low mammalian cytotoxicity, inhibits both planktonic and biofilm forms of P. gingivalis by destroying the bacterial membrane and reducing virulence factor gene expression. DP7 has potential clinical application in the prevention and treatment of P. gingivalis-associated diseases.


Microbial flora alterations in jejunum and colon after chemical bowel preparation before Kasai hepatoportojejunostomy.
There is little reported evidence on the effect of preoperative chemical bowel preparation by the administration of oral antibiotics in patients with biliary atresia (BA). This study was designed to examine and compare the alterations of microbial flora in feces cultures before and after the administration of oral antibiotics, and to examine fluid cultures from the tip of the jejunal limb at bile duct reconstruction by Kasai hepatoportoenterostomy (HPJ), and to evaluate the effects of preoperative oral antibiotics on postoperative cholangitis. Between January 2003 and July 2005, 6 infants with BA underwent surgical correction, and were treated preoperatively with polymyxin B (80 000 U/kg/day in 3 divided doses for 2 days) and metronidazole (10 mg/kg/day in 2 divided doses for 2 days). Quantitative feces cultures, both before administration of oral antibiotics and at Kasai HPJ, were obtained in patients with BA. Furthermore, fluid cultures from the tip of the jejunal limb at bile duct reconstruction by Kasai HPJ were obtained to examine alterations of bacteria and fungi. Bacterial colonization of the tip of the jejunal limb did not occur at the Kasai HPJ. The most commonly encountered organisms were ENTEROCOCCUS and intestinal bacterial flora. Fungus was not detected in the feces before or after the administration of oral antibiotics. CANDIDA was detected in the tip of the jejunal limb after Kasai HPJ in only one patient. The authors propose that colonic-type flora are generally found in the feces before and after the administration of oral antibiotics, and no bacteria are detected in the bilioenteric conduits.


Detection and species identification of Campylobacter in stool samples of children and animals from Vellore, south India.
Campylobacter spp. are an important cause of bacterial gastroenteritis frequently isolated from animal, poultry and environmental samples. In this study, we investigated the zoonotic potential of Campylobacter spp. by comparing prevalence rates and species in 394 children with diarrhoea and 652 animals in Vellore using PCR-based tools. Eighteen children (4.5%) had campylobacteriosis, a majority of whom had co-pathogens (15/18) and most were infected with Campylobacter jejuni (16/18). A few C. coli and mixed infections with both species were also seen. Among the animal samples, 16/25 chicken samples (64%) were positive and all were found to be C. jejuni.


Prediction of Occult Contralateral Nodal Metastasis in Surgical Treated p16 Negative Oropharyngeal Squamous Cell Carcinoma.
It is well known that p16 negative oropharyngeal squamous cell carcinoma (OPSCC) has a high probability of spreading to the ipsilateral neck. However, no consensus exists as to whether to perform elective treatment for clinical nodal negative in contralateral neck. A total of 85 patients with p16 negative OPSCC who underwent primary tumor excision and bilateral neck dissections between 2005 and 2018 were analyzed retrospectively. Clinicopathologic variables were used to identify factors predicting occult contralateral nodal metastasis (OCNM). A nomogram was developed to assess the risk of OCNM and the model was validated internally by using bootstrap resampling. The overall prevalence of pathologically positive contralateral nodes was 30.6% (26/85) in our cohort, and the rate of OCNM was 18.3% (11/60). The presence of ipsilateral clinical extranodal extension (cENE) was significantly associated with contralateral neck metastasis (odds ratio, 5.662; 95% CI, 2.079-15.415) with increased risk of OCNM (odds ratio, 4.271; 95% CI, 1.045-17.458). Moreover, the concordance index of the proposed nomogram model without ipsilateral cENE was 0.623 and could increase to 0.717 with the inclusion of ipsilateral cENE in the calculation. The risk of OCNM in p16 negative OPSCC with ipsilateral cENE is notable. Ipsilateral cENE-based nomogram might assist in individual decision-making regarding contralateral nodal negative neck management and help avoid the over- and under-treatment of p16 negative OPSCC.


Anticipatory HR deceleration as a function of perceived control and probability of aversive loud noise: a deployment of attention account.
Five groups of 10 undergraduate subjects each participated in an experiment to examine the effects of perceived control over, and the probability of occurrence of, noxious (white-noise) stimulation on anticipatory heart rate (HR) deceleration. All groups performed an arithmetic task, the numbers for which were changed on each of the 20 trials, but three groups were defined as active groups since they were instructed that the occurrence of noxious stimulation was contingent upon their performance on the task. The actual probability of occurrence of noxious stimulation (i.e., either 0.9, 0.5 or 0.1) was manipulated between these three groups. A fourth (passive) group (0.5 probability of occurrence) was instructed as to the non-contingent relationship between performance and the aversive white noise. The last group was a control group which only performed the task, and thus both provided an estimate of the rate of return to baseline following the expected HR acceleration to the task and eliminated the need for a within-subject control period to assess HR deceleration. The results indicated that all active and passive groups produced significant HR decelerations, relative to the control group, prior to the noxious stimulus. However, all active groups (regardless of probability levels) displayed significantly greater, and required more trials to maximally develop, anticipatory deceleration than the passive group. In addition, the results for the active groups revealed a direct relationship between the probability of occurrence of noxious stimulation and the magnitude of anticipatory deceleration. It is argued that the results cannot be adequately accommodated by the preparatory-adaptive-response theory. A deployment-of-attention account is suggested since it appears both to account for the obtained pattern of results completely and to generate additional testable predictions for the future.


Possible contribution of better maternal psychological well-being to the acquisition of sleeping through the night in infants during the early postpartum period.
The objective of this study was to elucidate whether better maternal psychological well-being contributes to the acquisition of "sleeping through the night" (STN) in infants during the early postpartum period. Fifty-two primiparous mothers completed the General Health Questionnaire-28 (GHQ-28) in the third trimester (prenatal) and when the conceptional ages of their babies reached 8-9 weeks (hereafter, 2 months), 12-13 weeks (3 months), and 16-17 weeks (4 months). They also recorded babies' nocturnal sleep patterns in a timetable for 5 consecutive days each month postpartum. "Regular STN" was defined when the mean of longest nocturnal sleep duration for 5 consecutive days was > 8 h or between 6 and 8 h with < 1.0 nocturnal awakenings. According to these criteria, a total of 14 infants (27 %) acquired regular STN at 4 months (referred to as "STN infants"), with STN infants showing a marked increase in longest nocturnal sleep duration and a decrease in nocturnal awakenings from 2 to 3 months of age. The mothers of STN infants demonstrated steady reductions in postnatal GHQ-28 scores and had significantly lower prenatal GHQ-28 scores compared with the mothers of non-STN infants (3.7 ± 3.0 vs. 6.4 ± 4.1, p = 0.027). In random forest models for binomial classification, both prenatal and postnatal (at 4 months) GHQ-28 scores were identified as significant covariates for distinguishing STN infants, and other important covariates, including weeks of delivery, stepfamily, birth weight of the infant, and maternal co-sleeping at bedtime, were selected. Among these covariates, maternal co-sleeping at bedtime had relatively stronger correlations with both STN infants (r = - 0.440) and prenatal maternal GHQ-28 scores (r = 0.377). In conclusion, because prenatal maternal psychological well-being was thought to predict the acquisition of STN in infants, infants born from mothers with better psychological well-being appear to have some advantages in acquiring STN. These cross-lagged correlations suggest that the pathway from mothers to infants may be mediated by certain parenting behaviors, such as maternal co-sleeping at bedtime.


Correction: Heart sounds: a pilot randomized trial to determine the feasibility and acceptability of audio recordings to improve discharge communications for cardiology inpatients protocol.
[This corrects the article DOI: 10.1136/openhrt-2019-001062.].


Statins and clinical outcomes with COVID-19: Meta-analyses of observational studies.
People with cardiovascular disease or risk factors are at increased risk when exposed to SARS-CoV-2. Most are treated with statins, but the impact of these drugs on clinical outcomes of COVID-19 remains unclear. This report is therefore based on meta-analyses of retrospective observational studies aimed at investigating the impact of previous statin therapy in patients hospitalized for COVID-19. In studies reporting on the clinical outcomes of COVID-19 in statin users vs non-users, two endpoints have been used-in-hospital death rates, and disease severity as assessed by admission to intensive care units (ICUs)-with a special focus on patients with diabetes. Regarding mortality, 13 studies were included in the meta-analysis for a total of 10,829 statin users (2517 deaths) and 31,893 non-users (7516 deaths): univariate analysis showed no statistically significant reduction in deaths (OR: 0.97, 95% CI: 0.92-1.03), although between-study heterogeneity was high (I² = 97%). As for disease severity, 11 studies were selected for a total of 3462 statin users (724 endpoints) and 10,560 non-users (1763 endpoints): here again, univariate analysis showed no reduction in severity (OR: 1.09, 95% CI: 0.99-1.22; I² = 93%). Collectively, in 10 studies using multivariable analysis adjusted for the more prevalent baseline risk factors among statin users, lower OR values were reported than with univariate analyses (0.73 ± 0.31 vs 1.44 ± 0.84, respectively; P = 0.0028; adjusted OR: P = 0.0237 vs non-users). Limited but conflicting findings were observed for diabetes patients. Although no significant reductions in either in-hospital mortality or COVID-19 severity were reported among statin users compared with non-users after univariate comparisons, such reductions were observed after adjusting for confounding factors. These highly heterogeneous observational findings now require confirmation by ongoing randomized clinical trials.


Improved postoperative analgesia with preoperative piroxicam.
Piroxicam like other Non-Steroidal Anti-Inflammatory drugs can be used to provide postoperative analgesia. With a half-life of 50 hr given preoperatively its' analgesic effect should continue postoperatively. This study compared the effects of 20 mg piroxicam given at different times in the perioperative period on postoperative analgesic requirement. Following ethical committee approval and written informed consent, 60 ASA I and II patients presenting for inpatient gynaecological laparoscopic surgery were given either 20 mg piroxicam or a placebo po two hours preoperatively, immediately before induction of anaesthesia or one hour postoperatively in a randomised double bind manner. Postoperative Visual Analogue Pain Scores were lower on admission to the recovery ward in patients given piroxicam preoperatively (Group 1), than in the other two treatment groups (groups 2 and 3). Pain scores were 2.72 vs 4.25 vs 6.67 respectively (P < 0.001). Pain scores did not differ at any other times. Time to first analgesic request was greater in the group 1 than in the other two treatment groups; 141 (61) min vs 115 (147) in Group 2 and 30 (36) min in Group 3. Nine patients in Group 1 requested further analgesia compared with 15 in Group 2 and 16 in Group 3. There were no piroxicam-induced side-effects. Piroxicam given two hours preoperatively reduced pain scores, time to first analgesia and postoperative analgesic requirements compared with administration prior to induction or one hour postoperatively.


Analysis of the relationship between GLUT family in the progression and immune infiltration of head and neck squamous carcinoma.
Head and neck squamous cell carcinoma (HNSCC) causes much health and economic burden, and the therapeutic results must be improved. Glucose metabolism is an essential component of tumor metabolism and is instrumental in its development. Glucose transporter types (GLUTs) can uptake glucose from the extracellular matrix (ECM), regulating cellular metabolism in several cancers. However, the function of different GLUT proteins in HNSCC remains unclear. To clarify the role of GLUTs in HNSCC, several open-access online databases (Oncomine, GEPIA, Kaplan-Meier, cBioPortal, GeneMANIA, and TIMER) were used to evaluate the differential expression, clinical significance, genetic alteration, and relative immune cell infiltration. The expression of GLUTs was detected in clinical patient samples by immunohistochemistry. The mRNA level of SLC2A1/3 significantly increased in HNSCC, while SLC2A4 reduced. SLC2A3 was related to the advanced clinical stage and short overall survival (OS) in HNSCC. Also, higher SLC2A1/2 mRNA expression was related to shorter OS in HNSCC patients. The expression of GLUTs was related to diverse immune cells, including B cells, CD4+ T cells, CD8+ T cells, dendritic cells (DCs), macrophages, and Treg cells in HNSCC. Moreover, the high expression of GLUTs was demonstrated by immunohistochemistry in patient tissues. GLUTs might have a potential role in HNSCC's progression and development. Therefore, the current findings might offer a novel perception for selecting GLUT family prognostic markers and treatment for HNSCC patients.


Initial Approach to the Patient with Multiple Newly Diagnosed Brain Metastases.
Brain metastases are the most common intracranial tumor in adults, with increasing incidence owing to prolonged survival times. Roughly half of patients diagnosed with new brain metastases have greater than 1 brain metastasis at the time of diagnosis, raising the question of how to optimize patient care with multiple brain metastases. The authors review studies relevant to the care of patients with brain metastasis, with emphasis on those relevant to the care of patients with multiple brain metastases. They discuss evolving strategies involving multiple modalities and the benefit of surgical management in patients with a large symptomatic brain metastasis.


Influence of Baseline HbA1c and Antiplatelet Therapy on 1-Year Vein Graft Outcome.
The influence of baseline HbA1c levels on vein graft outcomes post coronary artery bypass grafting (CABG) remains unclear. The purpose of this study was to assess the association between baseline HbA1c and 1-year vein graft patency, and the effects of antiplatelet therapy on the 1-year vein graft patency after CABG in patients with baseline HbA1c <6.5% vs ≥6.5%. We examined the subgroups with baseline HbA1c <6.5% vs ≥6.5% from the DACAB trial (NCT02201771), in which 500 patients were randomly allocated to receive ticagrelor plus aspirin (T+A), ticagrelor alone (T), or aspirin alone (A) for 1 year after CABG. The primary outcome was the vein graft patency (FitzGibbon grade A) at 1 year. A total of 405 patients with available baseline HbA1c data were included in this subgroup analysis. Of them, there were 233 patients (678 vein grafts) with baseline HbA1c <6.5% and 172 patients (512 vein grafts) with baseline HbA1c ≥6.5%. Compared with the HbA1c <6.5% subgroup, the HbA1c ≥6.5% subgroup showed worse 1-year vein graft patency (adjusted odds ratio [OR] for nonpatency: 1.69, 95% confidence interval [CI]: 1.08-2.64). T+A showed higher vein graft patency than A in both HbA1c <6.5% (adjusted OR for nonpatency: 0.34, 95% CI: 0.15-0.75) and HbA1c ≥6.5% subgroups (adjusted OR for nonpatency: 0.45, 95% CI: 0.19-1.09), without an interaction effect (P for interaction = 0.335), whereas T did not show more significant improvement than A in both subgroups. In the DACAB trial, lower baseline HbA1c was associated with higher vein graft patency 1 year after CABG. T+A improved 1-year vein graft patency vs A, irrespective of baseline HbA1c.


Estimating mortality associated with seasonal influenza among adults aged 65 years and above in China from 2011 to 2016: A systematic review and model analysis.
Estimation of influenza disease burden is crucial for optimizing intervention strategies against seasonal influenza. This study aimed to estimate influenza-associated excess respiratory and circulatory (R&C) and all-cause (AC) mortality among older adults aged 65 years and above in mainland China from 2011 to 2016. Through a systematic review, we collected influenza-associated excess R&C and AC mortality data of older adults aged 65 years and above for specific cities/provinces in mainland China. Generalized linear models were fitted to estimate the corresponding excess mortality for older adults by province and nationwide, accounting for the potential variables of influenza virus activity, demography, economics, meteorology, and health service. All statistical analyses were conducted using R software. A total of 9154 studies were identified in English and Chinese databases, and 11 (0.1%) were included in the quantitative synthesis after excluding duplicates and screening the title, abstract, and full text. Using a generalized linear model, the estimates of annual national average influenza-associated excess R&C and AC mortality among older adults aged 65 years and above were 111.8 (95% CI: 92.8-141.1) and 151.6 (95% CI: 127.6-179.3) per 100,000 persons, respectively. Large variations in influenza-associated excess R&C and AC mortality among older adults were observed among 30 provinces. Influenza was associated with substantial excess R&C and AC mortality among older adults aged 65 years and above in China from 2011 to 2016. This analysis provides valuable evidence for the introduction of the influenza vaccine into the National Immunization Program for the elderly in China.


Staphylococcal scalded skin syndrome in an extremely premature neonate: a case report with a brief review of literature.
Staphylococcus aureus can cause a spectrum of exfoliative skin conditions including staphylococcal scalded skin syndrome (SSSS) which can present as a severe and life threatening illness in extremely premature neonates. We describe a case of an extremely premature neonate with SSSS and discuss relevant pathology and issues in clinical management.


Utility of modified Glasgow prognostic score for head and neck squamous cell carcinoma: Systematic review and meta-analysis.
Whether the modified Glasgow prognostic score (mGPS) is useful for patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. An electronic database search on EMBASE, PubMed, and the Cochrane Library from inception to 30 June 2022 was performed for study selection and data extraction. The associations between the mGPS and survival outcomes were evaluated using a random-effects meta-analysis and expressed as pooled hazard ratios (HRs) and 95% CIs. We included 11 studies involving a total of 2017 patients with HNSCC. A higher mGPS was associated with poorer progression-free survival (HR = 2.39, 95% CI 1.69-3.38), overall survival (HR = 2.40, 95% CI 1.94-2.98), disease-specific survival (HR = 2.57, 95% CI 1.71-3.88), and disease-free survival (HR = 2.67, 95% CI 1.51-4.73, all p ≤ 0.001) in HNSCC. The mGPS can function as a valid prognostic biomarker for patients diagnosed as having HNSCC.


The valley system of the Jihlava river and Mohelno reservoir with enhanced tritium activities.
The Dukovany nuclear power plant (NPP Dukovany) releases liquid effluents, including HTO, to the Mohelno reservoir, located in a deep valley. Significantly enhanced tritium activities were observed in the form of non-exchangeable organically bound tritium in the surrounding biota which lacks direct contact with the water body. This indicates a tritium uptake by plants from air moisture and haze, which is, besides the uptake by roots from soil, one of the most important mechanisms of tritium transfer from environment to plants. Results of a pilot study based on four sampling campaigns in 2011-2015 are presented and discussed, with the aim to provide new information on tritium transport in the Mohelno reservoir - Jihlava River - plants ecosystems.


A giant radiopaque mass in the masticatory space.
A 2-year-old boy presented with a giant mass in the masticatory space. The mass exhibited a lobulating ossification, with no attachment to the adjacent normal bone. An enucleation was performed under the tentative diagnosis of extra-articular synovial chondromatosis, benign ossifying neoplasm, non-neoplastic heterotopic ossification, or low-grade malignancy. Upon microscopic examination, the excised mass was composed of multiple osteocartilaginous areas. We hereby present detailed clinicopathological findings.


Hypertension outcomes of adrenalectomy in patients with primary aldosteronism: a systematic review and meta-analysis.
The hypertension cure rate of unilateral adrenalectomy in primary aldosteronism (PA) patients varies widely in existing studies. We conducted an observational meta-analysis to summarize the pooled hypertension cure rate of unilateral adrenalectomy in PA patients. Comprehensive electronic searches of PubMed, Embase, Cochrane, China National Knowledge Internet (CNKI), WanFang, SinoMed and Chongqing VIP databases were performed from initial state to May 20, 2016. We manually selected eligible studies from references in accordance with the inclusion criteria. The pooled hypertension cure rate of unilateral adrenalectomy in PA patients was calculated using the DerSimonian-Laird method to produce a random-effects model. Forty-three studies comprising approximately 4000 PA patients were included. The pooled hypertension cure rate was 50.6% (95% CI: 42.9-58.2%) for unilateral adrenalectomy in PA. Subgroup analyses showed that the hypertension cure rate was 61.3% (95% CI: 49.4-73.3%) in Chinese studies and 43.7% (95% CI: 38.0-49.4%) for other countries. Furthermore, the hypertension cure rate at 6-month follow-up was 53.3% (95% CI: 36.0-70.5%) and 49.6% (95% CI: 40.9-58.3%) for follow-up exceeding 6 months. The pooled hypertension cure rate was 50.9% (95% CI: 40.5-61.3%) from 2001 to 2010 and 50.2% (95% CI: 39.0-61.5%) from 2011 to 2016. The hypertension cure rate for unilateral adrenalectomy in PA is not optimal. Large clinical trials are required to verify the utility of potential preoperative predictors in developing a novel and effective prediction model.


Relationship of the maxillary posterior teeth and maxillary sinus floor in different skeletal growth patterns: A cone-beam computed tomographic study of 1600 roots.
This study evaluated the distance from the posterior root apices to the maxillary sinus floor (MSF) and the frequency of roots touching or protruding through the MSF using cone-beam computed tomography (CBCT). This study included 100 subjects divided into different vertical and anteroposterior skeletal growth patterns. On CBCT images, the distance from the posterior root apices to MSF was measured and the frequency of roots touching or protruding through the MSF was evaluated using NNT software (version 22.214.171.124; ImageWorks, Elmsford, NY, USA). No statistically significant differences were found in the distance from the posterior root apices to the MSF among vertical skeletal groups (P>0.05). The palatal roots of the first molar and the palatal, mesio-buccal and disto-buccal roots of the second molars had significantly less distance from MSF in skeletal class II than in class III (P<0.05). The high-angle group had the highest frequencies of roots touching or protruding into the maxillary sinus (49.8%); the lowest proportion of these roots was found in skeletal class III (28.3%) and the highest proportion in class II (50.3%). Males had shorter distances from the posterior root apices to the MSF and higher frequencies of roots protruding through or touching the MSF than females. Anteroposterior skeletal growth patterns and sex affected the distances from the maxillary posterior roots to the MSF. The frequency of roots protruding into or touching the sinus was affected by both vertical and anteroposterior skeletal groups and sex. These findings have implications for dental practice.


Development and evaluation of a Japanese prediction model for low anterior resection syndrome after rectal cancer surgery.
Low anterior resection syndrome (LARS) is the most common complication after rectal cancer resection. We aimed to identify LARS' predictive factors and construct and evaluate a predictive model for LARS. This retrospective study included patients with rectal cancer more than 1 year after laparoscopic or robotic-assisted surgery. We administered a questionnaire to evaluate the degree of LARS. In addition, we examined clinical characteristics with univariate and multivariate analysis to identify predictive factors for major LARS. Finally, we divided the obtained data into a learning set and a validation set. We constructed a predictive model for major LARS using the learning set and assessed the predictive accuracy of the validation set. We reviewed 160 patients with rectal cancer and divided them into a learning set (n = 115) and a validation set (n = 45). Univariate and multivariate analyses in the learning set showed that male (odds ratio [OR]: 2.88, 95% confidence interval [95%CI] 1.11-8.09, p = 0.03), age < 75 years (OR: 5.87, 95%CI 1.14-47.25, p = 0.03) and tumors located < 8.5 cm from the AV (OR: 7.20, 95%CI 2.86-19.49, p < 0.01) were significantly related to major LARS. A prediction model based on the patients in the learning set was well-calibrated. We found that sex, age, and tumor location were independent predictors of major LARS in Japanese patients that underwent rectal cancer surgery. Our predictive model for major LARS could aid medical staff in educating and treating patients with rectal cancer before and after surgery.


Inactivation of Saccharomyces cerevisiae in solution by low-amperage electric treatment.
The objectives of this study were to investigate the potential application of a low-amperage direct electric current as a non-thermal process for inactivation of Saccharomyces cerevisiae. Electric current was generated using a direct current power supply connected to a traditional electrochemical cell with two platinum electrodes immersed in conducting solution containing a population of S. cerevisiae. This treatment provoked inactivation of the yeast cells. The microbial destruction illustrated by D-values calculated from survival curves was shown to be proportional to the current amperage (i) (D varies from 1547 min to 140 min when i varies from 0.1 to 1 A, respectively). The efficacy of the treatment was shown to be better at pH < 7. Statistical analysis showed no significant effect (P > 0.05) of ionic strength on yeast lethality induced by electrolysis. The lethal effect of the electric treatment on S. cerevisiae in phosphate buffer was shown to be due to neither ohmic heating nor toxic hydrogen peroxide. A synergistic effect of temperature and electrolysis was observed when the temperature became lethal for the yeast. The method described for yeast lethality induced by electrolysis has potential for soft sterilization, particularly when combined with the synergistic effect of moderate heat.


A High-Performance Alginate Hydrogel Binder for Aqueous Zn-Ion Batteries.
The binder is an indispensable battery component that maintains the integrity of the electrode. Polyvinylidene fluoride (PVDF) is most commonly used as a binder in rechargeable batteries; however, it is associated with the toxic and expensive N-methyl-2-pyrrolidone organic solvent. Here, through the cross-linking of sodium alginate (SA) with metal cations, a high-performance hydrogel binder is developed that maintains the stability of MnO2 cathodes in an aqueous electrolyte. Owing to the strong adhesion, high hydrophilicity, and good mechanical stability resulting from the strong bonding of Ca2+ with SA, a commercial microsized MnO2 cathode with a Ca-SA binder delivered a capacity above 300 mAh/g at 1 C, which was larger than those of Mn-SA and Zn-SA (∼200 mAh/g) and PVDF (∼150 mAh/g) binders, and a capacity of 250 mAh/g at 3 C for over 200 cycles. These encouraging results could unlock the enormous potential of aqueous binders for practical applications in aqueous batteries.


The puzzle of cocaine's effects following maternal use during pregnancy: are there reconcilable differences?
This is a selective review of the clinical and epidemiological literature. It attempts to reconcile disparate and contradictory findings dealing with the morphologic, growth, and neurobehavioral effects reported to occur in neonates and young children exposed prenatally to cocaine. A history of cocaine use in the United States is briefly presented followed by impressionistic observations of some of the events that transpired during the cocaine epidemic of the 1980s. Based on the collective research findings, it is tentatively suggested that the teratogenic effects of prenatal cocaine may be produced only in those infants exposed to the highest doses reported in the literature. It remains unknown, however, whether or not these effects may be dependent on the concurrent abuse of alcohol and/or cigarettes. As to growth and neurobehavioral outcomes, effects attributable primarily to cocaine alone and not other substances of abuse appear to be only marginal and transitory. The data to support these conclusions are particularly tenuous and are thus offered only as working hypotheses. Because of the intractable methodological and interpretive problems inherent in human developmental research on substance abuse, any attempt to draw definitive conclusion is admittedly premature. Because these methodological problems also complicate the efforts of ongoing studies, answers to these persistent questions may not be readily forthcoming.


Statistical analysis of twin populations using dissimilarity measurements in hippocampus shape space.
By analyzing interpoint comparisons, we obtain significant results describing the relationship in "hippocampus shape space" of clinically depressed, high-risk, and control populations. In particular, our analysis demonstrates that the high-risk population is closer in shape space to the control population than to the clinically depressed population.


Bamboo construction materials: Carbon storage and potential to reduce associated CO2 emissions.
The construction industry is one of the largest contributors of CO2 emissions. To achieve the goal of carbon peaking by 2030 and carbon neutrality by 2060, China needs to develop carbon reduction pathways for the construction industry. Bamboo is believed to be one of the most appropriate candidates for afforestation to reduce CO2 concentration and alleviate the effects of climate change. It is also an ideal building material with high tensile and compressive strengths. However, the carbon emissions and storage of bamboo building materials have not been well understood. This study aims to quantify the CO2 emissions and carbon storage of bamboo building materials and to analyse the potential to reduce these carbon emissions. Results show that the planting phase contributes the largest amount of carbon uptake whilst the production phase contributes the largest amount of carbon emissions. 'Carbonisation' is found to be the production process with the highest carbon emissions, followed by 'antimould, anticorrosion and drying treatment' and 'glue application'. Three strategies that are useful in reducing carbon emissions are proposed and validated. After the implementation of the proposed strategies, the average and median amount of carbon emissions changed from 1291.63 and 1290.75 kg to 1088.36 and 1090.29 kg. Taking all phases into account, one cubic meter of bamboo assembled components can reduce 249.92 kg CO2 from the atmosphere. Compared to dimensioned lumber, engineered lumber, cement, steel, timber, hempcrete, bamboo building materials have the highest CO2 emissions and carbon storage. The carbon storage of bamboo assembled components per tonne is around 140 kg more than that of timber per tonne. This study is expected to assist not only researchers in understanding the carbon reduction potential of bamboo building materials but also practitioners in promoting bamboo building-based carbon reduction pathways.


Functional traits and phylogeny explain snake distribution in the world's largest dry forest ecoregion, the Gran Chaco.
Macroecological studies describe large-scale diversity patterns through analyses of species distribution patterns and allows us to elucidate how species differing in ecology, physical requirements, and life histories are distributed in a multidimensional space. These patterns of distributions can be explained by vegetation, and climatic factors, and are determined by historical and current factors. The continuous accumulation of information on the distribution patterns of species is essential to understand the history and evolution of the biota. In this study, we aimed to identify functional and evolutionary drivers that explain the geographic patterns of vertical stratification. We compiled morphological, ecological, and distribution data of 140 species of Chacoan snakes and constructed null models to map their geographic pattern. We used a range of environmental variables to assess which drivers are influencing these biogeographic patterns. Lastly, we used evolutionary data to build the first map of the phylogenetic regions of Chacoan snakes. We found a latitudinal pattern, with a marked verticality in the snake assemblies in the Chaco. Verticality and long-tailed species richness increased in areas with high stratified habitats and stable temperature. Fossoriality is driven mainly by soil conditions, especially soils with fewer sand particles and less stratified habitat. Phylogenetic regions in the Chaco showed a marked latitudinal pattern, like that observed in the geographic pattern of verticality. The distribution pattern of Chacoan snakes also reflects their evolutionary history, with a marked phylogenetic regionalization.


Impact of a 1-day urodynamic course on knowledge, perceptions, and attitudes of urology residents.
No evidence-informed educational curriculum is available for designing urodynamics (UDS) courses. We evaluated the learning outcomes of a short-lasting urodynamic course for urology residents. Urology residents of postgraduate years 4 and 5 (n = 13 and n = 1316, respectively) attended a 1-day urodynamic course. Learning objectives included patient preparation, indication and technique, terminology, trace interpretation, and impact on patient management. Instructional methods consisted of short lectures (3 h) and case-based discussions (7.5 h). Learners' reactions, modifications of perceptions and attitudes, and acquisition of knowledge and skills were assessed by three written tests with a single group, pretest, posttest 1, and posttest 2 design. Tests were conducted precourse, 1 week after, and 4 months after the course. All participants felt more confident in several urodynamic competencies after the course, including patient preparation, urodynamic indication and technique, terminology, trace interpretation, and impact for patient management. These perceptions remained unchanged after 4 months. Most became stricter in the indication of UDS, including 20 (87.0%) at posttest 1 and 8 (66.7%) at posttest 2. The mean number of correct answers in the knowledge evaluation was 52.2% versus 61.4% versus 56.7%, respectively at pretest, posttest 1, and posttest 2; p = 0.535). All participants rated the course as very useful or useful in both posttest evaluations. Our study demonstrates that a 1-day urodynamic course can promote lasting improvements in self-reported perceptions, attitudes, and urodynamic-related competencies of urology residents. Further studies using evidence-informed educational principles are needed to determine the effect of specific educational interventions on urodynamic competencies in different contexts.


Crosstalk between the PI3K/mTOR and MEK/ERK pathways involved in the maintenance of self-renewal and tumorigenicity of glioblastoma stem-like cells.
The molecular signaling pathways orchestrating the biology of cancer stem-like cells (CSLCs), including glioblastoma, remain to be elucidated. We investigated in this study the role of the MEK/extracellular signal-regulated kinase (ERK) pathway in the control of self-renewal and tumorigenicity of glioblastoma CSLCs, particularly in relation to the PI3K/mTOR (mammalian target of rapamycin) pathway. Targeted inactivation of MEK alone using pharmacological inhibitors or siRNAs resulted in reduced sphere formation of both cell line- and patient-derived glioblastoma CSLCs, accompanied by their differentiation into neuronal and glial lineages. Interestingly, this effect of MEK inactivation was apparently augmented in the presence of NVP-BEZ235, a dual inhibitor of PI3K and mTOR. As a potential explanation for this observed synergy, we found that inactivation of either the MEK/ERK or PI3K/mTOR pathway triggered activation of the other, suggesting that there may be mutually inhibitory crosstalk between these two pathways. Significantly, inactivation of either pathway led to the reduced activation of p70S6K, and siRNA-mediated knockdown of p70S6K resulted in the activation of both pathways, which no longer maintained the cross-inhibitory relationship. Finally, combinational blockade of both pathways in glioblastoma CSLCs suppressed their tumorigenicity, whether transplanted subcutaneously or intracranially, more efficiently than blockade of either alone. Our findings suggest that there is p70S6K-mediated, cross-inhibitory regulation between the MEK/ERK and PI3K/mTOR pathways, in which each contribute to the maintenance of the self-renewal and tumorigenic capacity of glioblastoma CSLCs. Thus, combinational disruption of these pathways would be a rational and effective strategy in the treatment of glioblastoma.


Developmental and genetic audiogenic seizure models: behavior and biological substrates.
Audiogenic seizure (AGS) models of developmental or genetic origin manifest characteristic indices of generalized seizures such as clonus or tonus in rodents. Studies of seizure-resistant strains in which AGS is induced by intense sound exposure during postnatal development provide models in which other neural abnormalities are not introduced along with AGS susceptibility. A critical feature of all AGS models is the reduction of neural activity in the auditory pathways from deafness during development. The initiation and propagation of AGS activity relies upon hyperexcitability in the auditory system, particularly the inferior colliculus (IC) where bilateral lesions abolish AGS. GABAergic and glutaminergic mechanisms play crucial roles in AGS, as in temporal lobe models of epilepsy, and participate in AGS modulatory and efferent systems including the superior colliculus, substantia nigra, basal ganglia and structures of the reticular formation. Catecholamine and indolamine systems also influence AGS severity. AGS models are useful for elucidating the underlying mechanisms for formation and expression of generalized epileptic behaviors, and evaluating the efficacy of modern treatment strategies such as anticonvulsant medication and neural grafting.


Observations of biofilm growth on human dentin and potential destruction after exposure to antibiotics.
This study was performed to observe biofilm formation on dentin and to then observe effects of clinically achievable antimicrobial drug concentrations on these biofilms. Wild-strain endodontic bacteria were anaerobically cultured from necrotic pulps of extracted human teeth and used to grow biofilms on sterilized dentin slices in an anaerobic chamber for 12 days. Then these biofilms were exposed to ampicillin, doxycycline, clindamycin, azithromycin, or metronidazole. Each day for 8 days, specimens were fixed using 2% glutaraldehyde and examined with a scanning electron microscope (SEM). The SEM images revealed the presence of a mature biofilm after 8 days of growth and that none of the antibiotics tested was effective in eliminating the biofilm even after 8 days of exposure. Biofilms are formed in a few days and are resistant to antimicrobial drugs.


Why coastal upwelling is expected to increase along the western Iberian Peninsula over the next century?
Former studies about coastal upwelling along the Western Iberian Peninsula (WIP) using historical data indicated contradictory results, showing either its strengthening or reduction, while previous studies using Global Climate Models (GCMs) indicated that global warming is likely to intensify this phenomenon although predicting different rates and not justifying the patterns found. Taking advantage of the recent high spatial resolution Regional Climate Models (RCMs) projections from EURO-CORDEX project (Representative Concentration Pathway, RCP 8.5), detailed higher accuracy estimations of the spatio-temporal trends of Upwelling Index (UI) along the WIP coast were performed in this study, integrating the coastal mesoscale effects within the framework of climate change. Additionally, this research brings new insights about the origin of the WIP coastal upwelling intensification over the next century. These new projections clarified the upwelling strengthening rates predicted along the coast of the WIP from 2006 to 2099 revealing more prominent changes in the northern limit of the region (25-30m3s-1km-1 per decade between 41.5 and 42.5°N). Trends observed at high latitudes of the region were found to be induced by the displacement of the Azores High, which will intensify (0.03hPa per decade) and drift northeastward (10km per decade) during the 21st century.


The potential of esculin in ameliorating Type-2 diabetes mellitus induced neuropathy in Wistar rats and probing its inhibitory mechanism of insulin aggregation.
Diabetic neuropathy encompasses multiple pathological disturbances, many of which coincide with the pathophysiological mechanisms of neurodegenerative disorders. In the present study, various biophysical techniques like Rayleigh light scattering assay, Thioflavin T assay, far-UV Circular Dichroism spectroscopy, Transmission electron microscopy have unveiled the anti-fibrillatory effect of esculin upon human insulin fibrillation. MTT cytotoxicity assay demonstrated the biocompatibility of esculin and in-vivo studies such as behavioral tests like hot plate test, tail immersion test, acetone drop test, plantar test were performed for validating diabetic neuropathy. Assessment of levels of serum biochemical parameters, oxidative stress parameters, pro-inflammatory cytokines as well as neuron specific markers was done in the current study. Rat brains were subjected to histopathology and their sciatic nerves were subjected to transmission electron microscopy to analyze myelin structure alterations. All these results reveal that esculin ameliorates diabetic neuropathy in experimental diabetic rats. Conclusively, our study demonstrates the anti-amyloidogenic potential of esculin in the form of inhibition of human insulin fibrillation, making it a promising candidate in combating neurodegenerative disorders in the near future and the results of various behavioral, biochemical, and molecular studies reveal that esculin possesses anti-lipidemic, anti-inflammatory, anti-oxidative and neuroprotective properties which help in ameliorating diabetic neuropathy in streptozotocin induced diabetic Wistar rats.


A nursing theory of personal system empathy: interpreting a conceptualization of empathy in King's interacting systems.
This article presents a theory of empathy discovered through rational hermeneutic interpretation within King's personal system. Personal system concepts from King's general systems framework include perception, self, growth and development, body image, space, time, and learning. Propositions for each concept in the personal system were explicated and a theory of nursing empathy was developed. This nursing theory proposes that empathy organizes perceptions; facilitates awareness of self and others; increases sensitivity; promotes shared respect, mutual goals, and social awareness; cultivates understanding of individuals within a historical and social context; and affects learning.


The place of excision repair cross complementation 1 (ERCC1) in surgically treated non-small cell lung cancer.
Platinum-based regimens are the cornerstones of therapy in adjuvant and neoadjuvant management of early stage non-small cell lung cancer (NSCLC). However, the survival benefit associated with platinum-based chemotherapy is marginal and therefore adequate patient selection is essential. Excision repair cross complementation 1 (ERCC1) is a key-enzyme in the repair of platinum-DNA adducts that has been demonstrated to influence the response to platinum-based therapy. We performed a systematic review of the literature from 1996 to September 2007 on studies that assessed the role of ERCC1 in resected NSCLC. Overall, nine studies were identified. ERCC1 expression has been assessed by mRNA expression (n=5) and/or by protein expression (immunohistochemistry) (n=5). One study assessed ERCC1 status by both methods. In these studies, patients with early stage NSCLC treated by surgery alone survived longer if ERCC1 levels are high (favourable prognostic value of high ERCC1 level). Conversely, patients treated by surgery and who receive chemotherapy, either as adjuvant therapy or for disease relapse, have a better overall survival when ERCC1 levels are low (favourable predictive value of low ERCC1 level). ERCC1 expression might assist in selecting patients who will respond to adjuvant (neoadjuvant) platinum-based chemotherapy. However, further investigation is necessary in order to prospectively confirm these results and to ascertain the most appropriate method of assessment. Thoracic surgeons should participate in this field of research.


Abnormal brain glucose metabolism patterns in patients with advanced non-small-cell lung cancer after chemotherapy:A retrospective PET study.
This study was designed to investigate the acute or chronic post-chemotherapy effect and different chemotherapy cycles effect on brain glucose metabolism. A total of seventy-three patients who received chemotherapy after being diagnosed with advanced non-small-cell lung cancer (NSCLC) and underwent 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan at Nuclear Medicine Department of the Fifth Hospital of Sun Yat-sen University between September 2017 and August 2022 were included. Seventy-two healthy control patients who underwent whole-body 18F-FDG PET/CT scans at our department, without any evidence of malignancy and confirmed by follow-up visits, were included. Advanced NSCLC patients were classified into six arms: short-to-long course (chemotherapy cycles under 4, between 5 and 8 and more than 8) in acute chemotherapy effect (AC) group (scanned 18F-FDG PET/CT within 6 months post-chemotherapy) or chronic chemotherapy effect (CC) group (the interval between scanning and the last chemotherapy session more than six months). Statistical Parametric Mapping (SPM) analysis between patients' groups and healthy controls' brain 18F-FDG PET was performed (uncorrected p ˂ 0.001 with cluster size above 20 contiguous voxels). There were no significant differences between patients' groups and healthy controls in age, gender and body mass index (BMI). SPM PET analyses revealed anomalous brain metabolic activity in different groups (p ˂ 0.001). Short-course + AC group exhibited hypermetabolism in the cerebellum and widespread hypometabolism in bilateral frontal lobe predominantly. Only hypometabolic brain regions were observed in middle-course + AC patients. Long-course + AC group displayed a greater number of abnormalities. Notably, these metabolic abnormalities tended to decrease in CC groups versus AC groups across all courses. Our study revealed that patients with advanced NSCLC who underwent chemotherapy exhibited persistent abnormal brain metabolism patterns during continuous chemotherapy and these abnormalities tended to recover after completion of chemotherapy over time, but without correlation to an increasing number of chemotherapy cycles. 18F-FDG PET/CT may serve as a possible modality for evaluating brain function and guiding appropriate treatment timing.


An audio-visual review model enhanced one-year retention of cardiopulmonary resuscitation skills and knowledge: A randomized controlled trial.
As the majority of out-of-hospital cardiac arrest occur at patients' homes, implementing high-quality cardiopulmonary resuscitation by family members is critical in improving patient outcomes. However, the survival rate remains low due to low bystander cardiopulmonary resuscitation rate and rapid skill deterioration in individuals who complete the training. To evaluate the effectiveness of audio-visual review model and audio-visual-practice review model on cardiopulmonary resuscitation skill retention 12 months after training. A randomized, double-blind, placebo controlled, and three-arm parallel study. A total of 641 family members of patients at high risk of out-of-hospital cardiac arrest enrolled in the study and 448 participants completed the follow-up. Family members from Beijing, China were recruited. All families underwent initial cardiopulmonary resuscitation training. Their cardiopulmonary resuscitation skill and knowledge were assessed immediately after training. Trainees who were rated "adequate skill and knowledge" were assigned randomly into one of three groups. The control group was given a cardiopulmonary resuscitation instruction booklet and a placebo-DVD without any reminders. Both audio-visual and audio-visual-practice groups were reinforced by a telephone reminder every 3 months. The audio-visual-practice group was also asked to simultaneously practice the skills while watching the instructional-DVD. The trainees' cardiopulmonary resuscitation skills and knowledge were re-assessed 12 months after training. The retention rates of cardiopulmonary resuscitation skills in both audio-visual-practice (N = 177) and audio-visual (N = 157) groups were higher than that in control group (N = 114) 12 months after training (all P-values < 0.001). The cardiopulmonary resuscitation skill retention rate in audio-visual-practice group was higher than that in audio-visual group (49.7% vs 36.9%, P = 0.019), but no difference was found in intention-to-treat analysis (32.1% vs 27.1%, P = 0.230). Both audio-visual-practice and audio-visual groups had higher correct rates on all skill elements than that in control group (all P-values < 0.05). The cardiopulmonary resuscitation knowledge scores in both audio-visual-practice and audio-visual groups were higher than that in control group (all P-values < 0.001). However, no significant difference was found between audio-visual-practice and audio-visual groups (P = 0.243). Both audio-visual-practice and audio-visual review models demonstrated better long-term retention of cardiopulmonary resuscitation skills for families of people at higher risk of out-of-hospital cardiac arrest. (Registration number: chiCTR-TRC-12002149).


Chronological changes in brain MRI, SPECT, and EEG in neurosarcoidosis with stroke-like episodes.
Neurosarcoidosis with recurrent stroke-like episodes has been reported only rarely in the literature. We repeatedly measured brain magnetic resonance images (MRI), SPECT, and electroencephalograms (EEG) in a 32-year-old male patient with this condition. In the acute stage of the episodes, he showed semi-coma followed by severe dysphasia; left-frontal EEG delta wave activities and left-sided hyperperfusion SPECT were noted. Gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) MRI findings were aggravated diffusely in the convalescent stage of the disease rather than in the acute stage. The EEG and SPECT findings were clearly reflective of an early stage of acute encephalomeningitis caused by the neurosarcoidosis, and thus are more useful than MRI for evaluation of the acute inflammatory process in this condition.


Influence of patient, physician, and hospital characteristics on the receipt of guideline-concordant care for inflammatory breast cancer.
Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer for which treatments vary, so we sought to identify factors that affect the receipt of guideline-concordant care. Patients diagnosed with IBC in 2004 were identified from the Breast and Prostate Cancer Data Quality and Patterns of Care Study, containing information from cancer registries in seven states. Variation in guideline-concordant care for IBC, based on National Comprehensive Cancer Network (NCCN) guidelines, was assessed according to patient, physician, and hospital characteristics. Of the 107 IBC patients in the study without distant metastasis at the time of diagnosis, only 25.8% received treatment concordant with guidelines. Predictors of non-concordance included patient age (≥70 years), non-white race, normal body mass index (BMI 18.5-25 kg/m(2)), patients with physicians graduating from medical school >15 years prior, and smaller hospital size (<200 beds). IBC patients survived longer if they received guideline-concordant treatment based on either 2003 (p=0.06) or 2013 (p=0.06) NCCN guidelines. Targeting factors associated with receipt of care that is not guideline-concordant may reduce survival disparities in IBC patients. Prompt referral for neoadjuvant chemotherapy and post-operative radiation therapy is also crucial.


Sleep and affective disorders. A minireview.
The most predictable electroencephalographic sleep changes of major depression are a shortened first NREM sleep period, a prolonged first REM period (with increased density of rapid eye movements), sleep continuity disturbance, and diminished slow wave sleep (with shifting of delta activity from the first to the second NREM sleep period). The more rapid appearance of the first REM sleep period occurs in relation to sleep onset but not apparently in relation to clock time. The changes occurring in the first NREM-REM cycle of the night appear to be relatively specific to major (particularly endogenous) depression. Depressed men appear to have diminished nocturnal penile tumescence compared with healthy controls, but depressed patients generally do not have a higher incidence of sleep apnea or nocturnal myoclonus. The sleep physiologic changes of depression appear to persist into clinical remission, suggesting that they are trait-like. Published studies appear to support the conclusion that there is a close link between the regulation of sleep and the regulation of mood in affective illness.


Induction of Th1 and Th2 in the protection against SARS-CoV-2 through mucosal delivery of an adenovirus vaccine expressing an engineered spike protein.
A series of recombinant human type 5 adenoviruses that express the full-length or membrane-truncated spike protein (S) of SARS-CoV-2 (AdCoV2-S or AdCoV2-SdTM, respectively) was tested the efficacy against SARS-CoV-2 via intranasal (i.n.) or subcutaneous (s.c.) immunization in a rodent model. Mucosal delivery of adenovirus (Ad) vaccines could induce anti-SARS-CoV-2 IgG and IgA in the serum and in the mucosal, respectively as indicated by vaginal wash (vw) and bronchoalveolar lavage fluid (BALF). Serum anti-SARS-CoV-2 IgG but not IgA in the vw and BALF was induced by AdCoV2-S s.c.. Administration of AdCoV2-S i.n. was able to induce higher anti-SARS-CoV-2 binding and neutralizing antibody levels than s.c. injection. AdCoV2-SdTM i.n. induced a lower antibody responses than AdCoV2-S i.n.. Induced anti-S antibody responses by AdCoV2-S via i.n. or s.c. were not influenced by the pre-existing serum anti-Ad antibody. Novelty, S-specific IgG1 which represented Th2-mediated humoral response was dominantly induced in Ad i.n.-immunized serum in contrast to more IgG2a which represented Th1-mediated cellular response found in Ad s.c.-immunized serum. The activation of S-specific IFN-ɣ and IL-4 in splenic Th1 and Th2 cells, respectively, was observed in the AdCoV2-S i.n. and s.c. groups, indicating the Th1 and Th2 immunity were activated. AdCoV2-S and AdCoV2-SdTM significantly prevented body weight loss and reduced pulmonary viral loads in hamsters. A reduction in inflammation in the lungs was observed in AdCoV-S via i.n. or s.c.-immunized hamsters following a SARS-CoV-2 challenge. It correlated to Th1 cytokine but no inflammatory cytokines secretions found in AdCoV-S i.n. -immunized BALF. These results indicate that intranasal delivery of AdCoV2-S vaccines is safe and potent at preventing SARS-CoV-2 infections.


Model predictive control of DC/DC boost converter with reinforcement learning.
Power electronics is seeing an increase in the use of sophisticated self-learning controllers as single board computers and microcontrollers progress faster. Traditional controllers, such as PI controllers, suffer from transient instability difficulties. The duty cycle and output voltage of a DC/DC converter are not linear. Due to this non-linearity, the PI controller generates variable levels of voltage fluctuations depending on the operating region of the converter. In some cases, non-linear controllers outperform PI controllers. The non-linear model of a non-linear controller is determined by data availability. So, a self-calibrating controller that collects data and optimizes itself as the operation goes on is necessary. Iteration and oscillation can be minimized with a well-trained reinforcement learning model utilizing a non-linear policy. A boost converter's output power supply capacity changes with a change in load, due to which the maximum duty cycle limit of a converter also changes. A support vector calibrated by reinforcement learning can dynamically change the duty cycle limit of a converter under variable load. This research highlights how reinforcement learning-based non-linear controllers can improve control and efficiency over standard controllers. The proposed concept is based on a microgrid system. Simulation and experimental analysis have been conducted on how reinforcement learning-based controller works for DC-DC boost converter.


Developmental expression of voltage-dependent calcium currents in identified mouse motoneurons.
Previous work has shown that during chick embryonic development, large changes occur in the density of specific, motoneuronal calcium currents just prior to the period of naturally occurring motoneuron cell death. Here we report on calcium currents in mouse motoneurons isolated from embryos at the time of peak cell death and also during a subsequent developmental stage when supernumerary synapses are being eliminated. In mouse motoneurons, the density of high-voltage-activated calcium current increases significantly after the phase of cell death, during the period of synapse elimination.


Evaluation of the admission procedure and academic performance on the Medical Faculty in Ljubljana, Yugoslavia.
The data about the applicants and medical students who matriculated at the Medical Faculty of Ljubljana during the period from 1962-63 to 1969-70 by admission procedure were reviewed. A higher proportion of women than men was accepted, but men went on from year to year more regularly (P less than 0.05). Women graduated significantly later (P less than 0.05). More than half the students came from Ljubljana and its surrounding area. Academic success was correlated with general success in secondary school and with the raw scores at the admission examinations. Pearson's correlation coefficients were calculated and their values varied greatly between men and women, as well as among single cohorts. The multiple regression analysis showed that the best predictor for academic performance was the average success in secondary school (gymnasium) and in addition, the raw scores in biology and foreign language obtained at the admission examination. The results also showed the standardized regression coefficients beta and these variables should therefore be retained in the admission procedure in future. The cumulated coefficient of determination could explain about 11% to 15% of the variability of dependent variables--i.e., average academic success (mean mark of all examinations) and average academic success standardized to the duration of study. The psychological test was of the least importance and could be omitted in future admission procedures. The mean mark in mathematics in secondary school and the mean mark in somatology (the study of the anatomy and physiology of the body) at the admission examination correlated highly with other admission criteria and could also be omitted in future.


What is usual care for low back pain? A systematic review of health care provided to patients with low back pain in family practice and emergency departments.
International clinical practice guidelines for low back pain (LBP) contain consistent recommendations including universal provision of information and advice to remain active, discouraging routine referral for imaging, and limited prescription of opioids. This systematic review describes usual care provided by first-contact physicians to patients with LBP. Studies that reported the assessments and care provided to people with LBP in family practice and emergency departments (EDs) from January 2000 to May 2019 were identified by searches of PubMed, EMBASE, and CINAHL. Study quality was assessed with reference to representativeness of samples, potential misclassification of patients, potential misclassification of outcomes, inconsistent data and precision of the estimate, and the findings of high-quality studies were prioritized in the data synthesis. We included 26 studies that reported data from almost 195,000 patients: 18 from family practice, and 8 from EDs. Less than 20% of patients with LBP received evidence-based information and advice from their family practitioner. Around 1 in 4 patients with LBP received referral for imaging in family practice and 1 in 3 in EDs. Up to 30% of patients with LBP were prescribed opioids in family practice and up to 60% in EDs. Large numbers of patients who saw a physician for LBP received care that is inconsistent with evidence-based clinical practice guidelines. Usual care included overuse of imaging and opioid prescription and underuse of advice and information. Suboptimal care may contribute to the massive burden of the condition worldwide.


Congenital epigastric evisceration: a case report.
A rare case of abdominal wall defect at the epigastric midline is presented. This newborn boy had only the greater omentum eviscerated, and no other abnormalities could be detected. This case does not seem to relate to the abdominal wall defects reported so far in the literature. This singular case contributes to enlarge the spectrum of congenital defects of the abdominal wall.


Cholinesterase from the common prawn (Palaemon serratus) eyes: catalytic properties and sensitivity to organophosphate and carbamate compounds.
The main purpose of this study was to describe the kinetic properties of the cholinesterase (ChE) enzyme present in the eyes of the prawn Palaemon serratus, an abundant, ecological and commercially relevant species of European coastal environments. The obtained results suggest that the studied enzyme is a ChE and not a non-specific esterase, due to its apparent affinity for choline esters and the high sensitivity to eserine sulphate. This ChE displays a distinct preference for the substrate acetylthiocholine, showing a triphasic behaviour, with activation at low concentrations and inhibition by excess of substrate. Moreover, irreversible ChE inhibition by several organophosphate and carbamate compounds was characterized. All the irreversible inhibitions were homogeneous following a second-order rate reaction. The bimolecular rate constant (k(i)) values of ChE inhibition by the tested pesticides were also estimated and compared with available data from other invertebrate and vertebrate species. In conclusion, the results of the present study showed that prawn eyes possess only one ChE with typical properties of acetylcholinesterase, which is highly sensitive to the tested anti-cholinesterase compounds.


Concentrations of neonicotinoid insecticides in honey, pollen and honey bees (Apis mellifera L.) in central Saskatchewan, Canada.
Neonicotinoid insecticides (NIs) and their transformation products were detected in honey, pollen and honey bees, (Apis mellifera) from hives located within 30 km of the City of Saskatoon, Saskatchewan, Canada. Clothianidin and thiamethoxam were the most frequently detected NIs, found in 68 and 75% of honey samples at mean concentrations of 8.2 and 17.2 ng g(-1) wet mass, (wm), respectively. Clothianidin was also found in >50% of samples of bees and pollen. Concentrations of clothianidin in bees exceed the LD50 in 2 of 28 samples, while for other NIs concentrations were typically 10-100-fold less than the oral LD50. Imidaclorpid was detected in ∼30% of samples of honey, but only 5% of pollen and concentrations were <LOD in bees. Transformation products of Imidaclorpid, imidaclorpid-Olefin and imidacloprid-5-Hydroxy were detected with greater frequency and at greater mean concentrations indicating a need for more focus on potential effects of these transformation products than the untransformed, active ingredient NIs. Results of an assessment of the potential dietary uptake of NIs from honey and pollen by bees over winter, during which worker bees live longer than in summer, suggested that, in some hives, consumption of honey and pollen during over-wintering might have adverse effects on bees.


Polygenic risk score in comparison with C-reactive protein for predicting incident coronary heart disease.
Despite interest in the use of polygenic risk scores (PRS) for predicting coronary heart disease (CHD) risk, the clinical utility of PRS compared to conventional risk factors has not been demonstrated. We compared the performance of PRS with that of high-sensitivity C-reactive protein (hsCRP) in two well-established cohorts. The study population included individuals of European ancestry free of baseline CHD from ARIC (N = 13,113) and the Framingham Offspring Study (FHS) (N = 2,696). The primary predictors included a validated PRS consisting of >6.6 million single nucleotide polymorphisms and hsCRP. The outcome was incident CHD, defined as non-fatal or fatal myocardial infarction. We compared the performance of both predictors after adjusting for the Pooled Cohort Equations in multivariable-adjusted Cox regression models. We assessed discrimination and reclassification using c-statistics and net reclassification improvement. Incident CHD occurred in 565 ARIC and 153 FHS participants. In multivariable-adjusted models, both PRS and hsCRP were associated with incident CHD (p < 0.05 in both cohorts). In models incorporating both predictors, strengths of association were similar. For instance, in ARIC, the hazard ratio per SD increment was 1.38 (95% CI, 1.27-1.50, p = 2.94 × 10-14) for PRS and 1.41 (1.30-1.55, p = 3.10 × 10-15) for hsCRP. Neither predictor significantly increased model discrimination or net reclassification when compared with models containing the Pooled Cohort Equations alone. In two independent cohorts, PRS performed similarly to hsCRP for the prediction of CHD risk. These findings suggest PRS does not have unique clinical utility beyond this widely-available, inexpensive measure of risk in unselected middle-aged populations.


Role of pyroglutamic acid in cumulus cells of women with polycystic ovary syndrome.
Polycystic ovary syndrome is a complex heterogeneous endocrine disorder associated with established metabolic abnormalities and is a common cause of infertility in females. Glutathione metabolism in the cumulus cells (CCs) of women with PCOS may be correlated to the quality of oocytes for infertility treatment; therefore, we used a metabolomics approach to examine changes in CCs from women with PCOS and oocyte quality. Among 135 women undergoing fertility treatment in the present study, there were 43 women with PCOS and 92 without. CCs were collected from the two groups and levels of pyroglutamic acid were measured using LC-MS/MS followed by qPCR and Western blot analysis to examine genes and proteins involved in pyroglutamic acid metabolism related to glutathione synthesis. Women with PCOS showed increased levels of L-pyroglutamic acid, L-glutamate, and L-phenylalanine and decreased levels of Cys-Gly and N-acetyl-L-methionine. Gene expression of OPLAH, involved in pyroglutamic synthesis, was significantly increased in women with PCOS compared with those without. Gene expression of GSS was significantly decreased in women with PCOS and synthesis of glutathione synthetase protein was decreased. Expression of nuclear factor erythroid 2-related factor 2, involved in resistance to oxidative stress, was significantly increased in women with PCOS. CCs of women with PCOS showed high concentrations of pyroglutamic acid and reduced glutathione synthesis, which causes oxidative stress in CCs, suggesting that decreased glutathione synthesis due to high levels of pyroglutamic acid in CCs may be related to the quality of oocytes in women with PCOS.


Machine learning instructed microfluidic synthesis of curcumin-loaded liposomes.
The association of machine learning (ML) tools with the synthesis of nanoparticles has the potential to streamline the development of more efficient and effective nanomedicines. The continuous-flow synthesis of nanoparticles via microfluidics represents an ideal playground for ML tools, where multiple engineering parameters - flow rates and mixing configurations, type and concentrations of the reagents - contribute in a non-trivial fashion to determine the resultant morphological and pharmacological attributes of nanomedicines. Here we present the application of ML models towards the microfluidic-based synthesis of liposomes loaded with a model hydrophobic therapeutic agent, curcumin. After generating over 200 different liposome configurations by systematically modulating flow rates, lipid concentrations, organic:water mixing volume ratios, support-vector machine models and feed-forward artificial neural networks were trained to predict, respectively, the liposome dispersity/stability and size. This work presents an initial step towards the application and cultivation of ML models to instruct the microfluidic formulation of nanoparticles.


Influence of food limitation on the effects of fenvalerate pulse exposure on the life history and population growth rate of Daphnia magna.
Laboratory ecotoxicity tests may not adequately evaluate the effects of pesticides, because they often do not include more environmentally relevant conditions, such as pulsed toxicant exposures and low food conditions. Therefore, we tested the effects of a pulse of the pyrethroid insecticide fenvalerate (FV) on the life history and population growth rate (r) of the cladoceran Daphnia magna. The daphnids were subjected to a 24-h pesticide pulse exposure (0.03, 0.1, 0.3, 0.6, 1.0, and 3.2 microg/L) under high and low food conditions and were monitored for 21 d. Chemical analysis showed that at t = 1 h, the nominal FV concentrations were reduced by 50 to 66%. Fenvalerate decreased survival and growth in the week following pulse exposure. Age at first reproduction increased, with consequent adverse effects on cumulative reproduction per living female and, therefore, on r. Thus, a short-term exposure of FV caused a long-term reduction on r as a result of increased mortality and a delay in development. Low food conditions exacerbated the effects of the FV exposure on juvenile survival and growth during the first week. This caused a much stronger reduction in r under low food conditions. We concluded that a pulsed FV exposure may result in long-term reduction of r that can be predicted only with more environmentally relevant toxicity tests, as described in the present study.


The isolation of coupled mitochondria from Physarum polycephalum and their response to Ca2+.
A method for the isolation of coupled mitochondria from the acellular slime mould Physarum polycephalum is described. The mitochondria oxidize respiratory substrates at rates comparable to those of mitochondria from other microorganisms and show similar responses to respiratory inhibitors. ADP/O values approach similar values to those obtained with mitochondria from higher organisms: 3 with NAD-linked substrates, 2 with succinate, and 1 with ascorbate-TMPD. Mitochondria actively take up low concentrations of Ca2+ with stimulation of their respiration. With succinate or pyruvate-malate as substrates respiratory responses are depressed by Ca2+ concentrations in excess of 200 micron in the presence or absence of phosphate. Exogenous NADH is unique in supporting the uptake of large amounts of Ca2+ in the presence of phosphate and in showing an unusual 'uncoupled' response in the absence of phosphate. A sigmoidal relationship occurs between initial velocity of Ca2+ uptake and Ca2+ concentration with a maximum velocity of approx. 15 nmol/s per mg protein and half maximum velocity occurring at approx. 50 micron Ca2+.


Retinoblastoma protein binding properties are dependent on 4 cysteine residues in the protein binding pocket.
The retinoblastoma gene product (pRB) participates in regulating mammalian cell replication. The mechanism responsible for pRB's growth regulatory activity is uncertain. However, pRB is known to bind viral transforming proteins including the papilloma virus E7 protein, cellular proteins, and DNA. pRB contains a critical domain termed the "binding pocket" which is required for binding activities. This binding pocket contains 8 cysteine residues. A naturally occurring mutation affecting one of these cysteines is known to eliminate pRB's protein and DNA binding activities. To investigate the cysteine residues in pRB's binding pocket, each residue was mutated to alanine, phenylalanine, or serine. These mutant genes were used to prepare pRBs harboring specific amino acid substitutions. Individual mutations at positions 407, 553, 666, and 706 depressed pRB binding to E7 protein, DNA, and a conformation-specific anti-pRB antibody, XZ133. Combinations of these inhibitory mutations exhibited additive inhibitory effects on pRB's binding properties. Mutations at positions 438, 489, 590, 712, and 853 did not affect pRB binding to E7 protein, DNA, or the XZ133 antibody. Combination of these five neutral mutations yielded a pRB species with full E7 protein, DNA, and XZ133 binding activities. These studies indicate that the cysteine residues at positions 407, 553, 666, and 706 contribute to the E7 protein and DNA binding properties of pRB and appear to do so by maintaining pRB's normal conformation.


Standardizing terminology for minimally invasive pancreatic resection.
There is a growing body of literature pertaining to minimally invasive pancreatic resection (MIPR). Heterogeneity in MIPR terminology, leads to confusion and inconsistency. The Organizing Committee of the State of the Art Conference on MIPR collaborated to standardize MIPR terminology. After formal literature review for "minimally invasive pancreatic surgery" term, key terminology elements were identified. A questionnaire was created assessing the type of resection, the approach, completion, and conversion. Delphi process was used to identify the level of agreement among the experts. A systematic terminology template was developed based on combining the approach and resection taking into account the completion. For a solitary approach the term should combine "approach + resection" (e.g. "laparoscopic pancreatoduodenectomy); for combined approaches the term must combine "first approach + resection" with "second approach + reconstruction" (e.g. "laparoscopic central pancreatectomy" with "open pancreaticojejunostomy") and where conversion has resulted the recommended term is "first approach" + "converted to" + "second approach" + "resection" (e.g. "robot-assisted" "converted to open" "pancreatoduodenectomy") CONCLUSIONS: The guidelines presented are geared towards standardizing terminology for MIPR, establishing a basis for comparative analyses and registries and allow incorporating future surgical and technological advances in MIPR.