Relation between serum monocyte chemoattractant protein-1 and coronary collateral development.
The degree of coronary collateral development is not same in every patient with similar degree of coronary stenosis. In animal studies monocyte chemoattractant protein-1 (MCP-1) has been found to be related to collateral vessel development. In this study we investigated whether a higher serum MCP-1 level is related to better coronary collateral vessel development in patients with stable coronary artery disease. Eighty-three patients with stable angina pectoris, who have at least one coronary stenosis equal to or greater than 70% at coronary angiography, were prospectively enrolled. Serum MCP-1 and vascular endothelial growth factor (VEGF) levels were studied. Coronary collateral development was graded according to the Rentrop method. Patients with grade 2-3 collateral developments were included in good collateral group and formed group I. The patients with grade 0-1 collateral developments were included in poor collateral group and formed group II. The serum MCP-1 level was significantly higher in good collateral group (288 ± 277 pg/ml vs. 132 ± 64 pg/ml; P<0.001). There was also a positive correlation between serum MCP-1 level and Rentrop score (r=0.39, P<0.001). The patients in the good collateral group also had a significantly higher number of coronary arteries with significant stenosis (1.7 ± 0.7 vs. 1.4 ± 0.6, P=0.049), and higher VEGF levels (322 ± 147 pg/ml vs. 225 ± 161 pg/ml, P=0.007). In multivariate analysis, only serum MCP-1 level (P=0.014, odds ratio: 1.01, 95% confidence interval: 1.002-1.019) was independently related to good coronary collateral development. Higher serum MCP-1 level is related to better coronary collateral development.


Phrenic nerve injury associated with high free right internal mammary artery harvesting.
The right phrenic nerve is at risk of injury during high mobilization of the right internal mammary artery (RIMA). The incidence and implications of this injury have not been previously defined. Prospectively collected data on all patients who underwent RIMA harvesting between January 1995 and February 2002 were analyzed. Thirty-one patients with right phrenic nerve injury were identified and the medical charts reviewed. Phrenic nerve injury was diagnosed when a postoperative chest roentgenogram showed the right hemidiaphragm to be two or more intercostal spaces higher than the left, or transection of the nerve was seen intraoperatively. Investigations included fluoroscopy and spirometry in upright and supine positions. Diaphragm plication was offered for symptom control. Subsequent follow-up was undertaken to determine the incidence of spontaneous recovery of diaphragm function and the benefits of diaphragm plication. Seven hundred and eighty-three patients underwent high mobilization of the RIMA with proximal detachment for use as a free graft. Thirty-one patients with right hemidiaphragm dysfunction were identified in the postoperative period providing an injury incidence of 4% (confidence interval, 2.6% to 5.3%). Of these, 12 patients underwent diaphragm plication (4 early and 8 late), 14 patients achieved spontaneous recovery, and 5 patients were lost to follow-up. The supine to upright forced vital capacity ratios at the time of phrenic nerve dysfunction, after diaphragm plication, and after spontaneous recovery were 0.79, 0.90, and 0.96 respectively. The incidence of phrenic nerve injury associated with high RIMA harvesting was 4% but spontaneous recovery may be anticipated in two thirds (14 of 22) of patients in whom the injury is identified postoperatively. High RIMA harvesting should be used with caution in patients with preoperative pulmonary dysfunction in whom phrenic nerve injury would be poorly tolerated.


Assessment of vaccination service delivery and quality: a cross-sectional survey of over 1300 health facilities from 29 districts in Sindh, Pakistan conducted between 2017-18.
Routine childhood immunization coverage in Pakistan remains sub-par, in part, due to suboptimal utilization of existing vaccination services. Quality of vaccine delivery can affect both supply and demand for immunization, but data for immunization center quality in Pakistan is sparse and in Sindh province in Southern Pakistan, no comprehensive health facility assessment has ever been conducted at a provincial level. We assessed health facilities, specifically immunization centers, and their associated health workers throughout the province to summarize quality of immunization centers. METHODS: An exhaustive list of health facilities obtained from Sindh's provincial government was included in our analysis, comprising a total of 1396 public, private, and public-private health facilities. We adapted a health facility and health worker assessment survey developed by BASICS and EPI-Sindh to record indicators pertaining to health facility infrastructure, processes and human resources. Using expert panel ranking, we developed critical criteria (the presence of a cold box/refrigerator, vaccinator and vaccination equipment at the immunization center) to indicate the bare minimum items required by immunization centers to vaccinate children. We also categorized other infrastructure, process, and human resource items to determine high, low and moderate function requirements to ascertain quality. We evaluated presence of critical criteria, calculated scores for high, moderate and low function requirements, and displayed frequencies of infrastructure, process and human resource indicators for all immunization centers across Sindh. We analyzed results at the division level and utilized a two-sample independent clustered t-test to test differences in average function requirement scores between facilities that met critical criteria and those that did not. Out of the 1396 health facilities assessed across Sindh province from October 2017 to January 2018, 1236 (88.5%) were operational while 1209 (86.6%) offered vaccination services (immunization centers). Only 793 (65.6%; 793/1209) immunization centers met the critical criteria of having all the following items: vaccinator, a cold box or refrigerator and vaccine supplies. Of the 416 (34.4%; 416/1209) immunization centers that did not meet the critical criteria, most of the centers did not have a cold box or refrigerator (28.3%; 342/1209), followed by lack of vaccines (19.9%; 240/1209), and a vaccinator (13.0%; 157/1209). Of the 2153 healthcare workers interviewed, 1875 (87.1%) were vaccinators, of which 1745 (81.0%; 1745/2153) were male, and had an average of 12.4 years of schooling. A total of 1805 (96.3%; 1805/1875), 1655 (88.3%; 1655/1875) and 1387 (74.0%; 1387/1875) of the vaccinators were trained in vaccination, cold chain and inventory management respectively. One out of three immunization centers in Sindh lack the critical components essential for quality vaccination services. While the majority of health workers (>80%) were trained on vaccination and cold chain management, the proportion trained on inventory management was comparatively low. Our findings therefore suggest that suboptimal immunization center quality is partly due to inadequate infrastructure and inefficient processes contributed to an extent, by low levels of inventory management training among vaccinators. Our study presents critical research findings with high-impact policy implications for identifying and addressing gaps to improve vaccination uptake within a low-middle income country setting.


Clinical experience with implantable devices for control of tachyarrhythmias.
Pacing is becoming an accepted form of treatment for reentry tachycardias. The different pacing modalities available and experience with a patient-activated antitachycardia pacemaker are presented in this paper. This system has bidirectional communication between pacemaker and pacemaker-activator and between pacemaker and prescription formulator (which is a sophisticated portable stimulator used for non-invasive electrophysiological evaluation of the system). This pacemaker was implanted in 18 patients with drug-resistant tachycardias. Six patients had ventricular tachycardia, 3 had A-V nodal reentrant tachycardia, 4 had the concealed accessory pathway, and 5 had the WPW syndrome. In the 3 months before implantation the mean number of admissions for termination of tachycardia was 2.1 per patient-month. During a follow-up period of 3-26 months only 6 patients were admitted once for termination of tachycardia (0.02 admissions per patient-month). The reasons for admission of these 6 patients were: defective pacemaker activator in 2 patients, inadequate control of tachycardia in 2 patients, inappropriate use of the device in 1, and inadequate intake of medication in 1. All these problems were solved easily. Eight pacemaker activators required reprogramming, which was done in 5 patients on an out-patient basis. The interval scanning mode was used in 9 patients. Nine patients required more than 2 stimuli for reproducible termination. A step-wise increase in number of stimuli was used in 5 patients. This system has proven to be a safe and effective form of treatment of drug-resistant supraventricular and ventricular tachycardias and has resulted in marked improvement of the quality of life of these patients.


Itraconazole in the treatment of sporotrichosis: a Korean experience.
We describe three cases of sporotrichosis which were successfully treated with itraconazole 100mg daily. Itraconazole was effective and well tolerated in one patient with lymphocutaneous sporotrichosis who discontinued potassium iodide therapy because of side-effects and in two patients with fixed cutaneous sporotrichosis.


The impact of retirement on the drinking patterns of older adults: a review.
Due to the aging of the population, there is renewed focus on the public health issues of middle-aged and older adults. One area of such focus is unhealthy drinking, and researchers seek to understand the unique developmental risk and protective factors among those entering older adulthood. Retirement has been hypothesized as a contributing factor in the onset and maintenance of unhealthy drinking in late life. This review describes the relevant theories and critically reviews empirical evidence that explores the relationship between alcohol and retirement drawn from both the industrial and organizational psychology and substance misuse literatures. Using four research databases, thirteen studies published in the last 25years that investigated the relationship of retirement and alcohol use and met specific selection criteria were reviewed. The literature suggests that retirement may not have a strong direct impact on drinking behaviors or problems, but attributes of the process (e.g. retirement voluntariness) of transition to retirement and individual attributes, such as having a history of problem drinking, may facilitate or inhibit drinking. Future research should delve into the social context of drinking in retirement with a goal of understanding the aspects and conditions of retirement that increase risk of alcohol problems. Investigation should also examine heterogeneity in retirement drinking patterns with a goal of identifying subpopulations that are at greater risk.


Short- and Long-term Outcomes of Group B Streptococcus Invasive Disease in Mozambican Children: Results of a Matched Cohort and Retrospective Observational Study and Implications for Future Vaccine Introduction.
Invasive group B Streptococcus disease (iGBS) in infancy, including meningitis or sepsis, carries a high risk of mortality and neurodevelopmental impairment (NDI). We present data on iGBS from 2 decades of surveillance in Manhiça, Mozambique, with a focus on NDI. Morbidity surveillance databases in a rural Mozambican district hospital were screened for iGBS cases. From February 2020 to March 2021, surviving iGBS patients (n = 39) plus age- and sex-matched children without iGBS (n = 119) were assessed for neurocognitive development, vision, and hearing. The role of GBS in stillbirths and infant deaths was investigated using minimally invasive tissue sampling (MITS). Ninety iGBS cases were included, with most children being <3 months of age (85/90). The in-hospital case fatality rate was 14.4% (13/90), increasing to 17.8% (3 additional deaths) when considering mortality during the 6 months postdiagnosis. Fifty percent of the iGBS exposed infants and 10% of those unexposed showed any NDI. Surviving GBS conferred a 11-fold increased adjusted odds of moderate/severe NDI (odds ratio, 2.8 [95% confidence interval, .92-129.74]; P = .06) in children aged 0-5 years. For older children (6-18 years), no differences in NDI were found between exposed and unexposed. Motor domain was the most affected among young GBS survivors. Three stillbirths and 4 early neonatal deaths (of the 179 MITS performed) were attributed to iGBS. In absence of preventive strategies, such as intrapartum antibiotics, iGBS remains a significant cause of perinatal and infant disease and death. GBS also causes major longer-term neurodevelopmental sequelae, altogether justifying the need for maternal GBS vaccination strategies to increase perinatal and infant survival.


Quality evaluation by capillary electrophoresis of amphotericin B injection after filtration through various membrane filters.
The determination of amphotericin B, an antifungal agent, was developed using micellar electrokinetic capillary chromatography (MEKC) with a diode array detector. Repeatability and intermediate precision of MEKC analysis were acceptable. A high correlation was found between amphotericin B levels in pharmaceutical solutions obtained by MEKC and those by high-performance liquid chromatography (HPLC) (r = 0.994). This MEKC method is therefore useful for the determination of amphotericin B. The concentration of amphotericin B did not significantly change after filtration through polyethersulfone (PES, 0.2 microm) and polyvinylidene difluoride (PVDF, 0.45 microm) membrane filters. When the Fungizone injection was filtered through PES (0.2 microm) and added to 5% dextrose for injection (500 mL), particulate matters larger than 10 microm decreased by 64% to a level under the standard defined by United States Pharmacopoeia (USP XXIII). PVDF filtration (0.45 microm) did not have this effect. Our results suggest that filtration of Fungizone injection through PES (0.2 microm) membrane filters is recommended for the preparation of intravenous amphotericin B fluid.


Regulation by glucagon of serine: pyruvate/alanine: glyoxylate aminotransferase gene expression in cultured rat hepatocytes.
The effects of glucagon on serine: pyruvate/alanine: glyoxylate aminotransferase (SPT/AGT) gene expression were studied in primary cultured rat hepatocytes. When hepatocytes had been precultured for 16-18 h under serum- and hormone-free conditions, the addition of glucagon caused (after a lag period of about 2 h) a remarkable increase in the cellular level of SPT/AGT mRNA by 4 h in a time- and dose-dependent manner. The induced mRNA was that for mitochondrial SPT/AGT, as judged by ribonuclease protection analysis. A nuclear run-on assay revealed that activation of transcription is responsible for the increase in mitochondrial SPT/AGT mRNA and that the maximal rate of transcription occurs 1.5 h after glucagon addition. The effect of glucagon was mimicked by 8-bromo-cAMP and suppressed by N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide, an inhibitor of cAMP-dependent protein kinase (protein kinase A), while both 12-O-tetradecanoylphorbol-13-acetate and A23187 were without effect in elevating the SPT/AGT mRNA level, suggesting that the cAMP/protein kinase A system is involved in the regulation of SPT/AGT gene expression. In hepatocytes precultured for 16-18 h under serum- and hormone-free conditions, the glucagon-induced transcription was severely inhibited by cycloheximide. When the preculture was for 2 h, on the other hand, the activation of transcription by glucagon was more rapid, and the inhibition by cycloheximide was less than that observed with cells precultured for 16-18 h, suggesting that a short-lived protein factor is involved in the hormonal regulation. The glucagon-induced expression of the SPT/AGT gene was also turned off by dexamethasone.


A traumatic corneoscleral epithelial cyst.
We describe a case of a patient with a corneoscleral epithelial cyst originating from a traumatic scleral rupture. Ultrasound biomicroscopy (UBM) and in vivo confocal microscopy (IVCM) were used to diagnose this rare condition. A lamellar corneoscleral graft was performed with histopathological examination of the excised cyst. The treatment of corneoscleral epithelial cysts is discussed.


Magnetic copper silicate and boronic acid-conjugated AuNCs@keratin-based electrochemical/fluorescent dual-sensing for carcinoembryonic antigen.
Boronic Acid Sensitivity, selectivity, and reliability are of great importance for tumor diagnosis. Herein, we proposed a novel electrochemical and fluorescent dual-sensing strategy to detect carcinoembryonic antigens (CEA). To this end, monodisperse spindle-like magnetic copper silicate (FeOx@C@CS) was prepared with multiple active sites to immobilize the CEA antibody. Moreover, magnetic properties improved the anti-interference ability and sensitivity to endow the assay for complex samples. In addition, boronic acid-conjugated gold nanocluster (AuNCs@keratin-BA) was prepared as an electrochemical and fluorescent dual-signal indicator. Thus, the sandwich structure of FeOx@C@CS/CEA/AuNCs@keratin-BA was formed for electrochemical/fluorescent dual-modality assay. Under optimal conditions, the quantitation range of 12.5 fg mL-1-37.5 pg mL-1 and detection limit of 4.3 fg mL-1 were obtained for the electrochemical strategy. The fluorescence detection owned the linear range of 0.05 pg mL-1-7.5 pg mL-1 with a detection limit of 0.025 pg mL-1. Dual-modality assay improved the accuracy and efficiency of CEA detection to meet the requirement of tumor diagnosis, while chemical identification and signal transduction lay an important foundation for engineering advanced nanomaterials for clinical applications.


Identification of Lactobacillus ruminus SPM0211 isolated from healthy Koreans and its antimicrobial activity against some pathogens.
The intestinal microbiota are important to the host with regard to resistance they impart against bacterial infections and their involvement in mediating metabolic functions. Lactic acid producing bacteria such as Lactobacillus play an important physiological role in these matters. The aim of the present study was to isolate Lactobacillus sp. that inhibits enteric pathogens. Initially, 17 isolates from healthy Koreans were collected on Lactobacillus selective medium. Resistance of the isolates to antibiotics including rifampicin, streptomycin, clindamycin and vancomycin was measured. One of the isolate was identified as Lactobacillus ruminus on the basis of bacterial cell morphology, cultural characteristic and biochemical characteristics, 16S rRNA sequence analysis and PCR-RAPD. Antimicrobial activity of the bacterium against Vancomycin Intermediate Resistant Staphylococcus aureus (VISA) and Vancomycin-Resistant Enterococci (VRE) was measured. About 10(4) cells of VISA or VRE were mixed with 1, 5, and 9 mL of L. ruminus SPM 0211 and the final volume was adjusted to 10 mL with brain heart infusion (BHI) broth. The cell suspension was incubated for 3, 6, 9, and 24 h, serially diluted and then plated on BHI agar plates. As numbers of L. ruminus SPM 0211 were increased, viable cell count of VISA and VRE decreased. The strongest antimicrobial activity of SPM 0211 was observed after 9 h incubation in any mixture, almost completely inhibiting the growth of these two bacteria. The results suggest that the freshly isolated L. ruminus SPM 0211 may be used as a pro-biotic microbe that prevents the colonization of enteric pathogens and can thereby promote good gastrointestinal health.


Study of alpha-particle emission probabilities and energies in the decay of 240Pu.
In the frame of EUROMET Project No 325 "Analysis of Plutonium Alpha-Particle Spectra", the isotopic composition of a 238, 239, 240Pu mixture was measured by mass spectrometry and by high-resolution alpha-particle spectrometry. The latter revealed a discrepancy with published data of the alpha-particle emission probabilities (Palpha) and the energies (Ealpha) of the two major peaks of 240Pu. New values have been derived: Palpha1 = 0.7256 (6), Palpha2 = 0.2735 (7) and Ealpha1 = 5168.54 (14)keV, Ealpha2 = 5124.10 (15)keV, relative to reference peaks of 238Pu and 239Pu.


Gilbert's syndrome--a frequent cause of unconjugated hyperbilirubinemia in children after orthotopic liver transplantation.
Gilbert's syndrome is one major cause for unconjugated hyperbilirubinemia in healthy individuals with the prevalence being approximately 3.2-8.6%. It is caused by a mutation in the promoter region of the UGT1A1-gene with a prolonged TAA-repeat coding for the enzyme bilirubin UDP-glucuronosyltransferase (A(TA)(7) TAA allele). After OLT, Gilbert's disease of the transplanted liver can cause unconjugated hyperbilirubinemia. Therefore, we looked for the presence of A(TA)(7) TAA alleles in pediatric liver transplant recipients with unconjugated hyperbilirubinemia. Laboratory results of 106 pediatric liver transplant recipients (aged 0-17 yr) were evaluated for elevated total bilirubin over 2.0 mg/dL (conjugated bilirubin <30%). In these patients, DNA of the liver graft was extracted from paraffin-embedded liver biopsy samples formerly taken for diagnostic reasons. The DNA was analyzed for A(TA)(7) TAA alleles in the promoter region of the UGT1A1-gene. In 4 of 106 pediatric liver transplant recipients we found unconjugated hyperbilirubinemia with total bilirubin above 2.0 mg/dL (conjugated bilirubin <30%). The analysis of the promoter region of the UGT1A1-gene of the liver grafts showed three homozygous A(TA)(7) TAA alleles (homozygous Gilbert's syndrome) and one heterozygous A(TA)(7) TAA allele (heterozygous Gilbert's syndrome). This study shows that pediatric liver transplant recipients with unconjugated hyperbilirubinemia are very likely to have received a liver graft from a donor with Gilbert's syndrome.


How does industrial restructuring influence carbon emissions: City-level evidence from China.
This study addresses the question of why industrial restructuring towards light industries or services sometimes fails to achieve carbon emission mitigation goals. By employing a new perspective of dividing industry segments into emission-dominating and non-emission-dominating ones based on Logarithmic Mean Divisia Index (LMDI) decomposition method, this paper analyses city-level carbon dioxide emission reduction performance under three distinctive industrial restructuring directions. Results indicate that carbon dioxide emission dominating segments are relatively fixed across cities, regardless of the various city types in China. The key point to achieve emission reduction through industrial restructuring is to identify and control the emission-dominating segments, instead of economic-leading ones. Besides, emission reduction performance of industrial restructuring from emission-dominating industry segments to services is better than that to non-emission-dominating ones. More importantly, industrial restructuring not involving output scale controlling of emission-dominating segments, or that recklessly rushing towards services are likely to fail the emission mitigation goal. This paper presents a strong international reference that merits cities facing policy hesitation over industrial restructuring directions while in pursuit of emission mitigation. It suggests that cities first focus on identifying the carbon dioxide dominating segments, of which the output scale should be controlled. For cities whose emission-dominating segments are not economic-leading ones, it is necessary to carry out industrial restructuring towards services or non-emission-dominating segments; while for cities heavily dependent on emission-dominating segments, energy efficiency should also be improved.


A systematic integrative review of the literature on midwives and student midwives engaged in problematic substance use.
The objective of this systematic integrative review was to review the literature in relation to problematic substance use (PSU) in midwifery populations. Associated aims were to aggregate existing knowledge about midwives and student midwives' personal engagement in PSU, to generate a holistic conceptualisation and synthesis of the existing literature regarding midwives and student midwives personally engaged in PSU and to present new understandings and perspectives to inform the development of future research questions. This review is the first of its kind. Systematic searches were conducted in CINAHL, Academic Search Complete, MEDLINE, PSYCInfo, Scopus and the Cochrane Library. Findings were grouped into themes and subthemes relating to both midwives and student midwives and then analysed critically in relation to the wider literature. A quality assessment was conducted using the Mixed Methods Appraisal Tool (MMAT). The PRISMA statement was used to guide reporting. Included studies were conducted in Scotland, Ireland, Australia and New Zealand. Studies included a total of 6,182 participants. A total of 3 studies were included. All included study types comprised quantitative survey designs, yet one also included a mixed methods design with the use of semi structured interviews. Two overarching themes emerged relating to both midwives and student midwives engaged in problematic substance use. For midwives, three subthemes are described: harmful daily alcohol consumption, working hours and harmful daily alcohol consumption and features associated with harmful daily alcohol consumption. For student midwives, two subthemes are presented: escape avoidance and alcohol, tobacco and cannabis use. There is limited evidence available in relation to problematic substance use in midwifery populations in comparison to that available for other healthcare populations. Further research is required, and could usefully focus upon midwives and student midwives as distinct professions to be separated out from the wider healthcare workforce. Problematic substance use among the healthcare workforce is associated with an increase in medical errors and inadequate care. Those affected can be reluctant to seek help, experience psychological distress and even contemplate suicide. Whilst evidence remains lacking for midwifery populations, they form a part of the general healthcare workforce and are exposed to similar workplace stressors. As such, it is likely that they too would be affected in similar ways.


Free radicals in medicine. II. Involvement in human disease.
This review explores evidence that free radicals might be involved in various human disease processes. Such involvement is difficult to prove because direct evidence is often lacking and is based on animal models of the disease process. Evidence for free radical involvement includes demonstrating abnormal free radical production in the disease, finding that deliberately applying free radical-producing systems into the cellular locus responsible for the disease reproduces its manifestations, and showing that free radical scavengers control facets of the disease process. Confirmation of free radical involvement in a particular disease may have clinical relevance, inasmuch as clinically applicable techniques are currently being developed to remove free radicals from cellular sites where they are injurious and, in other situations such as chemotherapy, techniques or drugs that produce free radicals are available to destroy harmful cells.


Pathways to care for first-episode psychosis in an early detection healthcare sector: part of the Scandinavian TIPS study.
Early detection programmes aim to reduce the duration of untreated psychosis (DUP) by public education and by prompt access to treatment via active outreach detection teams. To determine whether those with first-episode psychosis in an early detection healthcare area with existing referral channels differ from those who access care via detection teams. Those with first-episode psychosis recruited via detection teams were compared with those accessing treatment via conventional channels, at baseline and after 3 months of acute treatment. Patients recruited via detection teams are younger males with a longer DUP, a less dramatic symptom picture and better functioning; however they recover more slowly, and have more symptoms at 3-month follow-up. After establishing low threshold active case-seeking detection teams, we found clear differences between those patients entering treatment via detection teams v. those obtaining treatment via the usual channels. Such profiling may be informative for early detection service development.


Community-based treatment for youth with co- and multimorbid disruptive behavior disorders.
Little is known about the types of psychotherapeutic practices delivered to youth with comorbid and multimorbid diagnoses in community settings. The present study, based on therapists' self-reported practices with 569 youth diagnosed with a disruptive behavior disorder (ODD or CD), examined whether specific therapeutic practice applications varied as a function of the number and type of comorbid disorders. While type of comorbid disorder (AD/HD or internalizing) did not predict therapists' practices, youth with more than two diagnoses (multimorbid) received treatment characterized by a more diverse set and a higher dosage of practices.


Non-solid lung nodules on low-dose computed tomography: comparison of detection rate between 3 visualization techniques.
To compare various visualization techniques for the detection of non-solid nodules in low-dose lung cancer screening computed tomography (CT) scans. An enriched sample of 216 male lung cancer screening subjects aged 60.4 ± 6.0 years was used. Two blinded independent readers searched for non-solid nodules on 5-mm multiplanar reconstructions, 1-mm slices and 7-mm maximum intensity projections (trial protocol). The reference standard was a consensus diagnosis of all non-solid nodules reported at least once. Twenty-three individuals (10.6%) had in total 34 non-solid nodules. Interobserver agreement was good (Cohen kappa 0.89-0.95). For both observers, we found no differences between the 3 viewing techniques (P > 0.13). In low-dose lung cancer screening CT scans, we were unable to find a viewing technique superior to that used in the trial by experienced observers who focused on non-solid nodule detection.


Population genetics of 8 Y chromosome STR loci in Macedonians and Macedonian Romani (Gypsy).
Eight Y chromosome short tandem repeat (STR) polymorphisms (DYS19, DYS385, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393) were analyzed in Macedonians (n = 84) and Macedonian Romani ethnic group (n = 68). Observed allelic frequency distribution and locus diversity values in Macedonians correspond closer to neighboring southeastern European populations than (mostly) western European populations, whereas observed allelic frequency distribution and locus diversity values in Macedonian Romani, as expected based on their Asian (Indian) origin, differ from both neighboring southeastern and (mostly) western European populations. Sixty-six (78.57%) haplotypes appeared in single copies in Macedonians and 15 (22.06%) in Macedonian Romani. The most frequent Macedonian haplotypes (DYS19-DYS385-DYS389I-DYS389II-DYS390-DYS391-DYS392-DYS393) 16-14/15-13-31-24-11-11-13 and 13-16/18-13-30-24-10-11-13 were found in 7 and 6 copies, respectively. The most frequent Macedonian Romani haplotype 15-15/17-14-29-22-10-11-12 was found in 18 males. Total haplotype diversity was 0.9885 +/- 0.0058 (Macedonians) and 0.9008 +/- 0.0242 (Macedonian Romani).


SNP Regulation of microRNA Expression and Subsequent Colon Cancer Risk.
MicroRNAs (miRNAs) regulate messenger RNAs (mRNAs) and as such have been implicated in a variety of diseases, including cancer. MiRNAs regulate mRNAs through binding of the miRNA 5' seed sequence (~7-8 nucleotides) to the mRNA 3' UTRs; polymorphisms in these regions have the potential to alter miRNA-mRNA target associations. SNPs in miRNA genes as well as miRNA-target genes have been proposed to influence cancer risk through altered miRNA expression levels. MiRNA-SNPs and miRNA-target gene-SNPs were identified through the literature. We used SNPs from Genome-Wide Association Study (GWAS) data that were matched to individuals with miRNA expression data generated from an Agilent platform for colon tumor and non-tumor paired tissues. These samples were used to evaluate 327 miRNA-SNP pairs for associations between SNPs and miRNA expression levels as well as for SNP associations with colon cancer. Twenty-two miRNAs expressed in non-tumor tissue were significantly different by genotype and 21 SNPs were associated with altered tumor/non-tumor differential miRNA expression across genotypes. Two miRNAs were associated with SNP genotype for both non-tumor and tumor/non-tumor differential expression. Of the 41 miRNAs significantly associated with SNPs all but seven were significantly differentially expressed in colon tumor tissue. Two of the 41 SNPs significantly associated with miRNA expression levels were associated with colon cancer risk: rs8176318 (BRCA1), ORAA 1.31 95% CI 1.01, 1.78, and rs8905 (PRKAR1A), ORGG 2.31 95% CI 1.11, 4.77. Of the 327 SNPs identified in the literature as being important because of their potential regulation of miRNA expression levels, 12.5% had statistically significantly associations with miRNA expression. However, only two of these SNPs were significantly associated with colon cancer.


Coumarins hinged directly on benzimidazoles and their ribofuranosides to inhibit hepatitis C virus.
A new compound library that contained 20 hinged benzimidazole-coumarin hybrids and their β-d-ribofuranosides was established. The anti-hepatitis C virus (HCV) activity of all novel coumarin derivatives, which were obtained by use of organic synthetic methods, was tested. Two of these hybrids exhibited appealing EC50 values of as low as 3.0 and 5.5 μM. The best selectivity index was 14. The incorporation of a d-ribofuranose into the hinged hybrids provided the corresponding nucleosides with the β configuration, one of which inhibited HCV replication with an EC50 value of 20 μM. Additionally, the structure-activity relationship is elucidated on the basis of the functional groups that were attached to the nuclei of benzimidazole, coumarin, and ribofuranose of the hybrids.


Thromboxane receptor activation mediates isoprostane-induced increases in amyloid pathology in Tg2576 mice.
Alzheimer's disease (AD) amyloid plaques are composed of amyloid-beta (Abeta) peptides produced from proteolytic cleavage of amyloid precursor protein (APP). Isoprostanes, markers of in vivo oxidative stress, are elevated in AD patients and in the Tg2576 mouse model of AD-like Abeta brain pathology. To determine whether isoprostanes increase Abeta production, we delivered isoprostane iPF(2alpha)-III into the brains of Tg2576 mice. Although treated mice showed increased brain Abeta levels and plaque-like deposits, this was blocked by a thromboxane (TP) receptor antagonist, suggesting that TP receptor activation mediates the effects of iPF(2alpha)-III on Abeta. This hypothesis was supported by cell culture studies that showed that TP receptor activation increased Abeta and secreted APP ectodomains. This increase was a result of increased APP mRNA stability leading to elevated APP mRNA and protein levels. The increased APP provides more substrate for alpha and beta secretase proteolytic cleavages, thereby increasing Abeta generation and amyloid plaque deposition. To test the effectiveness of targeting the TP receptor for AD therapy, Tg2576 mice underwent long-term treatment with S18886, an orally available TP receptor antagonist. S18886 treatment reduced amyloid plaques, insoluble Abeta, and APP levels, thereby implicating TP receptor signaling as a novel target for AD therapy.


Underdetermination.
When trying to assess the implications of recent deep shifts in the philosophy of science for the broader arena of medicine, the theme that most readily comes to mind is underdetermination. In scientific research one always hopes for determination: that the world should determine the observations we make of it; that evidence should determine the theories we adopt; that the practice of science should determine results independent of the sort of society in which that practice takes place. In this essay, doubts cast on each of these ideas by recent work in philosophy of science will be discussed and the consequences for philosophy of medicine will be indicated.


The effect of housing tiestall dairy cows in deep-bedded pens during an 8-week dry period on gait and step activity.
Increasing locomotor activity can improve leg health and decrease the prevalence of lameness in dairy cows. The dry period offers an opportunity to provide alternative housing to tiestall (TSL) cows that can increase locomotor activity. The objective was to determine whether housing TSL dairy cows in a deep-bedded loose pen (LP) during the 8-wk dry period affected gait and step activity. Twenty cows, paired by parity and calving date, were assigned at dry-off to a deep-bedded LP or a TSL. Step activity was measured by leg-mounted pedometers. Cows were walked 1×/wk on a test corridor, and video recordings of gait were taken. Six aspects of gait were scored on a 0-to-5 scale (interval: 0.1 unit): tracking up, joint flexion, back arch, asymmetric step, swing, and reluctance to bear weight. Overall gait was also scored using a 1-to-5 scale (interval: 0.5 unit). Data for gait were analyzed based on the change in gait between dry-off and calving. Daily step data were averaged per week of the dry period. Analyses were performed using a mixed model with treatment, term, and block as fixed effects and cow nested within treatment and block as a random effect for step data. The same model, omitting the fixed effect of week, was used for gait variable analyses. There was no difference in step activity between LP and TSL cows (842.1 ± 88.86 vs. 799.5 ± 76.92 steps/d, LP vs. TSL, respectively). Only joint flexion yielded a treatment difference, with LP cows improving over time and TSL cows worsening (-0.4 ± 0.15 vs. 0.2 ± 0.15). Possibly owing to individual variation in motivation to perform locomotor activity, higher levels of step activity, independent of treatment, tended to be correlated with improvements in swinging out, tracking up, joint flexion, and overall gait score. The increased space allotted to LP cows may have allowed for a larger range of motion for each step, and the denser lying surface may have provided a cushioning effect when transitioning between rising and lying, all of which can improve joint health, reflected in improved joint flexion. Further investigation is warranted into the potential benefits of alternative housing on cow comfort, movement opportunity, and cow condition.


Comparison of quantitative ultrasound measurements in calcaneus with DXA and SXA at other skeletal sites: a population-based study on 280 children aged 11-16 years.
We performed ultrasound measurements (QUS) of the calcaneus in a population-based setting on 280 healthy children, aged 11-16 years, from a small urban area in southern Sweden. The results are compared with dual-energy X-ray absorptiometry (DXA) measurements in the total body, the lumbar spine and the hip, as well as single-energy X-ray absorptiometry (SXA) of the forearm. Normative data and correlations between the three different techniques were determined. We found significant correlations between QUS and age (r = 0.34-0.54), height (r = 0.13-0.56) and weight (r = 0.30-0.60), and between QUS and bone mineral density (BMD) measurements (r = 0.44-0.70). Boys increased all their bone mineral variables with age, whereas girls showed a decreasing trend from age 15 years. QUS had a significantly higher increase in standardized value with age than Ward's triangle BMD, but a significantly lower increase in standardized value with age than distal radius (cortical site) BMD. At other BMD sites we did not find any significant differences compared with QUS regarding changes with age. The measurements obtained by QUS, DXA and SXA, respectively, were divided into, quartiles. Of all subjects in the lowest quartile for QUS measurements, only 34-50% were also in the lowest quartiles for DXA and SXA measurements. In conclusion, QUS measurements of the calcaneus in children show similar results as for adult regarding the correlation with DXA and SXA; they also have a significant correlation with anthropometric data. QUS did not identify the same individuals with low bone mass as the X-ray techniques.


Thyroid carcinoma in Graves' disease: A meta-analysis.
The incidence of thyroid carcinoma is increasing worldwide. Graves' disease is the most common hyperthyroid disease. Studies have suggested an increased risk of thyroid malignancy in Graves' disease: there has not yet been a meta-analysis to allow quantitative comparison. The purpose of this study was to determine the risk of thyroid carcinoma in Graves' disease, and to gather information on the histological subtypes of carcinoma and the co-existence of thyroid nodules. Several databases and article reference lists were searched. Inclusion criteria included appropriate diagnostic criteria for thyroid conditions and a diagnoses of carcinoma based on histology. 33 studies were selected, all reporting on surgically-resected specimens. The event rate of thyroid carcinoma in Graves' disease was 0.07 (95% CI 0.04 to 0.12). There was no data to allow comparison with patients without hyperthyroid diseases. There was no increase in the odds of developing carcinoma in Graves' disease compared to toxic multinodular goitre and toxic uninodular goitre. 88% of thyroid carcinomas in Graves' disease were papillary, with solitary papillary micro-carcinoma (diameter 10 mm or less) comprising 23% of all detected thyroid carcinomas. Patients with Graves' disease and co-existing thyroid nodules were almost 5 times more likely to be diagnosed with thyroid carcinoma than those without nodules. Thyroid malignancy in Graves' disease requiring surgical treatment should be considered as likely as in other hyperthyroid diseases needing surgical treatment. Clinicians should consider screening selected patients with Graves' disease for nodules whilst being aware of potentially over-diagnosing papillary micro-carcinoma.


Mutagenicity and irreversible binding of the hepatocarcinogen, 2,4-diaminotoluene.
Mutagenicity of 2,4-diaminotoluene (DAT) in the Salmonella mutagenicity assay was increased with liver fractions from phenobarbital (PB) or beta-naphthoflavone (BNF) treated rats. Substitutions of the hydrogens in the methyl group of 2,4-DAT with deuterium resulted in a decrease in mutagenicity. Incubation of rat liver microsomes with tritiated 2,4-DAT in the presence of NADPH led to the formation of irreversibly bound products to microsomal protein. The rates of binding were not increased using microsomes from PB or BNF-treated rats and was not altered by deuterium substitution in the methyl group. Addition of superoxide dismutase, glutathione (GSH) or rat liver supernatant reduced 2,4-DAT irreversible binding, whereas 2,4-DAT mutagenicity was unaffected by superoxide dismutase addition. Injection of tritiated 2,4-DAT 100 mg/kg to rats lead to its irreversible binding to liver protein and ribosomal RNA and to kidney protein in vivo, again protein binding was not increased after prior treatment with PB or BNF. No irreversible interaction of tritiated 2,4-DAT with DNA either in vitro or in vivo could be demonstrated.


Pressure wrist pulse signal analysis by sparse decomposition using improved Gabor function.
In traditional Chinese medicine and Ayurvedic medicine, wrist pulse wave fluctuations are an important indicator for distinguishing different health states. Owing to the development of modern sensing technology, computational methods have been used in the analysis of pulse wave signals. The description and quantification of the peaks in the pulse wave is significant for the identification of health status. In this study, we decomposed the pressure pulse waveform of the radial artery into several components by sparse decomposition with an improved Gabor function. To better represent the position, shape, and relationship of the peaks, we designed an improved Gabor function structure based on the characteristics of the pulse waveform to generate a time-frequency dictionary. Compared with conventional representation methods, the shape of the Gabor function is more variable. In addition, owing to the limitation of windowing, the Gabor function can reduce the influence on other positions when it represents a specific position. Feature vectors consisting of decomposed components can be used for computerized pulse signal analysis and disease diagnosis. In the binary classification of healthy and diseased pulse signals, the proposed method achieved the best results for health/diabetes, health/cardiac disease, health/hypertension, and health/nephropathy with accuracies of 93.54%, 73.42%, 88.42%, and 82.28%, respectively. The multi-classification performance of the different types of features was evaluated by six classifiers, and the proposed method obtained the highest classification performance with support vector machine-radial basis function for both balanced and imbalanced data. The results indicated that the proposed method enabled to obtain a smaller representation error and exhibited superior performance in distinguishing between the signals collected from patients and healthy individuals. Moreover, for the multi-classification of the pulse signals, the proposed method performed better than the state-of-the-art methods.


Impact of pea protein-inulin conjugates prepared via the Maillard reaction using a combination of ultrasound and pH-shift treatments on physical and oxidative stability of algae oil emulsions.
Algal oil is an aquatic plant source of polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), which may exhibit health benefits when consumed in sufficiently high quantities. But its application as a healthy lipid in functional foods is often limited by its tendency to rapidly oxidize and produce rancid off-flavors. In this study, algal oil-in-water emulsions were prepared using pea protein isolate (PPI)-inulin conjugates as emulsifiers. These conjugates were prepared via the Maillard reaction using a combination of ultrasound and pH-shift treatments. The algal oil phase was mixed with lemon oil (0 to 1.2 wt%) prior to homogenization to improve its sensory characteristics. The addition of 0.6 wt% of lemon oil did not significantly affect the formation and physical stability of the emulsions but it did mask the unpleasant odor of algae oil. The conjugate-stabilized emulsions exhibited shear thinning behavior and had a higher viscosity than PPI-stabilized emulsions. They also had a higher surface load and formed thicker interfacial layers. The conjugates, especially the conjugates prepared by the combined treatments, also significantly improved the physical and oxidative stability of the emulsions. These effects were attributed to an increase in the steric repulsion between the oil droplets due to the hydrophilic inulin chains, as well as to an increase in the antioxidant activity of the interfacial layers due to the presence of more antioxidant proteins. Overall, our results show that the quality attributes and shelf life of DHA-fortified algae oil emulsions can be significantly improved using a plant-based protein-inulin conjugate.


Platr4 is an early embryonic lncRNA that exerts its function downstream on cardiogenic mesodermal lineage commitment.
The mammalian genome encodes thousands of long non-coding RNAs (lncRNAs), many of which are developmentally regulated and differentially expressed across tissues, suggesting their potential roles in cellular differentiation. Despite this expression pattern, little is known about how lncRNAs influence lineage commitment at the molecular level. Here, we demonstrate that perturbation of an embryonic stem cell/early embryonic lncRNA, pluripotency-associated transcript 4 (Platr4), directly influences the specification of cardiac-mesoderm-lineage differentiation. We show that Platr4 acts as a molecular scaffold or chaperone interacting with the Hippo-signaling pathway molecules Yap and Tead4 to regulate the expression of a downstream target gene, Ctgf, which is crucial to the cardiac-lineage program. Importantly, Platr4 knockout mice exhibit myocardial atrophy and valve mucinous degeneration, which are both associated with reduced cardiac output and sudden heart failure. Together, our findings provide evidence that Platr4 is required in cardiac-lineage specification and adult heart function in mice.


Development and Validation of the User Version of the Mobile Application Rating Scale (uMARS).
The Mobile Application Rating Scale (MARS) provides a reliable method to assess the quality of mobile health (mHealth) apps. However, training and expertise in mHealth and the relevant health field is required to administer it. This study describes the development and reliability testing of an end-user version of the MARS (uMARS). The MARS was simplified and piloted with 13 young people to create the uMARS. The internal consistency and test-retest reliability of the uMARS was then examined in a second sample of 164 young people participating in a randomized controlled trial of a mHealth app. App ratings were collected using the uMARS at 1-, 3,- and 6-month follow up. The uMARS had excellent internal consistency (alpha = .90), with high individual alphas for all subscales. The total score and subscales had good test-retest reliability over both 1-2 months and 3 months. The uMARS is a simple tool that can be reliably used by end-users to assess the quality of mHealth apps.


Educational differences in labor market marginalization among mature-aged working men: the contribution of early health behaviors, previous employment histories, and poor mental health.
Social inequalities in labor force participation are well established, but the causes of these inequalities are not fully understood. The present study aims to investigate the association between educational qualification and labor market marginalization (LMM) among mature-aged working men and to examine to what extent the association can be explained by risk factors over the life course. The study was based on a cohort of men born between 1949 and 1951 who were examined for Swedish military service in 1969/70 and employed in 2000 (n = 41,685). Data on educational qualification was obtained in 2000 and information on the outcome of LMM (unemployment, sickness absence, and disability pension) was obtained between 2001 and 2008. Information on early health behaviors, cognitive ability, previous employment histories, and mental health was collected from conscription examinations and nationwide registers. Evidence of a graded association between years of education and LMM was found. In the crude model, compared to men with the highest level of education men with less than 12 years of schooling had more than a 2.5-fold increased risk of health-related LMM and more than a 1.5-fold increased risk of non-health-related LMM. Risk factors measured across the life course explained a large part of the association between education and health-related LMM (33-61%) and non-health-related LMM (13-58%). Educational differences remained regarding LMM among mature-aged workers, even after considering several important risk factors measured across the life course. Previous health problems and disrupted employment histories explained the largest part of the associations.


Bioluminescent imaging in bone.
Monitoring gene expression in vitro and in vivo, is crucial when analyzing osteogenesis and developing effective bone gene therapy protocols. Until recently, molecular analytical tools were only able to detect protein expression either in vitro or in vivo. These systems include histology and immunohistochemistry, fluorescent imaging, PET (micro-PET), CT (micro-CT), and bioluminescent imaging. The last is the only system to date that can enable efficient quantitative monitoring of gene expression both in vitro and in vivo. Effective bioluminescent imaging in bone can be achieved by using transgenic mice harboring the luciferase reporter gene, downstream of an osteogenesis specific promoter. The aim of this chapter is to comprehensively describe the various protocols needed for the detection of bioluminescence in bone development and repair.


Comparing the Acute Toxicity of Imidacloprid with Alternative Systemic Insecticides in the Aquatic Insect Chironomus dilutus.
Acute (96-h) toxicities of 5 systemic insecticides (chlorantraniliprole, cyantraniliprole, flupyradifurone, flubendiamide, and sulfoxaflor) were tested on larval Chironomus dilutus and compared with the neonicotinoid imidacloprid. Three insecticides were less acutely toxic than imidacloprid (2.5-25 times lower). However, chlorantraniliprole and cyantraniliprole were 1.5 to 1.8 times more toxic to C. dilutus. Thus, these ryanodine receptor agonists could pose a higher risk to aquatic insects than their neonicotinoid predecessors, warranting further studies. Environ Toxicol Chem 2020;39:587-594. © 2019 SETAC.


Multinational study exploring patients' perceptions of side-effects induced by chemo-radiotherapy.
We aimed to prospectively assess the incidence, severity and patients' perceptions of side-effects induced by radiotherapy and concomitant weekly cisplatin. This multinational survey included patients with a diagnosis of gynaecological or head and neck cancer scheduled to receive radiotherapy and concomitant weekly cisplatin. Patients completed a questionnaire prior to anti-cancer treatment and after 3 weeks of treatment. Baseline frequency and severity of symptoms were compared to frequency and severity after 3 weeks of treatment, and patients were asked to rank the five most severe symptoms experienced. An increase in the severity as well as in the mean number of symptoms (18 compared to 24) was observed during treatment. Patients ranked 7 of the 10 most feared baseline symptoms as non-physical, whereas 8 of the 10 most feared symptoms after 3 weeks of treatment were physical. Nausea was ranked as the 5th most severe symptom during treatment, despite 98% of patients receiving antiemetic prophylaxis. Patients with head and neck cancer or gynaecological cancer suffer from a number of primarily non-physical symptoms before starting combined chemo-radiotherapy. After 3 weeks of treatment patients score 8 of the 10 most feared symptoms as physical. Future trials focusing on the prevention of side-effects in patients receiving radiotherapy and concomitant chemotherapy are highly warranted.


Cognitive-communication disorder following right hemisphere damage: Narrative production.
Cognitive-communication disorder (CCD) results from the association of language and cognition impairment that may follow right hemisphere (RH) damage and impair the quality of life of affected persons. We studied a set of 1,625 narratives produced by a cohort of 125 individuals (50 with a single right vascular lesion in the MCA territory and 75 cognitively healthy controls) using a task of picture-based discourse production. Discourse production was analyzed in its macro-and microlinguistic aspects to characterize better the linguistic mechanisms underlying RH patients' performance. The RH group produced more words and elocutions than controls, with a lower rate of informational content and a higher percentage of global coherence errors (all p-values <0.0001). Individuals with RH lesions showed formal lexical and syntactic aspects of discourse mostly preserved. Alterations in the macrostructure of discourse prevailed over microstructural alterations in our sample, according to most literature studies. The group of individuals with RH lesions produced narratives containing more words and utterances, with a lesser degree of lexical information and more global coherence errors.


CD8+ T cells, NK cells and IFN-gamma are important for control of tumor with downregulated MHC class I expression by DNA vaccination.
One of the major hurdles facing cancer immunotherapy is that cancers may downregulate expression of MHC class I molecules. The development of a suitable tumor model with downregulated MHC class I expression is critical for designing vaccines and immunotherapeutic strategies to control such tumors. We developed an E7-expressing murine tumor model with downregulated MHC class I expression, TC-1 P3 (A15). Using this model, we tested DNA and vaccinia vaccines for their ability to control tumors with downregulated MHC class I expression. We found that vaccination with DNA encoding E7 linked to Mycobacterial heat shock protein 70 (HSP70) generated a significant antitumor effect against TC-1 P3 (A15), while vaccination with E7/HSP70 vaccinia did not generate an appreciable antitumor effect. Lymphocyte depletion experiments revealed that both CD8+ T cells and NK cells were essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Furthermore, tumor protection experiments using IFN-gamma knockout mice revealed that IFN-gamma was essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Our results demonstrate that vaccination with E7/HSP70 DNA results in a significant antitumor effect against a neoplasm with downregulated MHC class I expression and the importance of CD8+ T cells, NK cells, and IFN-gamma in generating this antitumor effect.


COVID-19: Pathophysiology and implications for cystic fibrosis, diabetes and cystic fibrosis-related diabetes.
The novel SARS-CoV-2 coronavirus (COVID-19) has become a global health crisis since its initial outbreak in Wuhan, China in December 2019. On January 30, 2020, the WHO recognized the COVID-19 outbreak as a Public Health Emergency, and on March 11, 2020, it was declared a pandemic. Although all age groups have been affected, patients with cystic fibrosis (CF) and patients with type 1 or type 2 diabeteshave been categorized as highly vulnerable to SARS-CoV-2 infection. Thus far, studies have found that the incidence of SARS-CoV-2 in the CF population is lower than the general population. We review the underlying protective mechanisms which may reduce inflammation and lung damage in CF patients, thus decreasing their risk of severe COVID-19. While the effect of SARS-CoV-2 in those with diabetes related to CF is unknown, other forms of diabetes have been associated with more severe disease. To further understand the potential impact of SARS-CoV-2 in cystic fibrosis-related diabetes, we provide a comprehensive overview of the potential factors contributing to COVID-19 severity in other forms of diabetes, including direct viral effect on the pancreas and indirect effects related to hyperglycemia and immune dysregulation.


The association between built environment features and physical activity in the Australian context: a synthesis of the literature.
There is growing evidence indicating that the built environment is a determinant of physical activity. However, despite the well-established health benefits of physical activity this is rarely considered in urban planning. We summarised recent Australian evidence for the association built environment-physical activity among adults. This summary aims to inform policy makers who advocate for the consideration of health in urban planning. A combination of built environment and physical activity terms were used to systematically identify relevant peer reviewed and grey literature. A total of 23 studies were included, providing 139 tests of associations between specific built environment features and physical activity. Of the total, 84 relationships using objective measures of built environment attributes were evaluated, whereas 55 relationships using self-reported measures were evaluated. Our results indicate that walkable neighbourhoods with a wide range of local destinations to go to, as well as a diverse use of land, encourage physical activity among their residents. This research provides a summary of recent Australian evidence on built environments that are most favourable for physical activity. Features of walkability and availability of destinations within walking distance should be accounted for in the development or redevelopment of urban areas. Our findings emphasise the importance of urban planning for health via its impact on population levels of physical activity.


Viral Genomics to Inform Infection-control Response in Occupational Coronavirus Disease 2019 (COVID-19) Transmission.
Healthcare workers are at increased risk of occupational transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report 2 instances of healthcare workers contracting SARS-CoV-2 despite no known breach of personal protective equipment. Additional specific equipment cleaning was initiated. Viral genomic sequencing supported this transmission hypothesis and our subsequent response.


Improved Treatment Engagement Among Patients with Diabetes Treated with Insulin Glargine 300 U/mL Who Participated in the COACH Support Program.
Persistence with basal insulin therapy can be suboptimal, despite recent improvements in insulin formulations and delivery systems. Patient support programs may help increase adherence. This study evaluated the impact of the Toujeo® COACH support program, which provides patients with continuing and individualized education and advice on lifestyle changes, by assessing its effect on number of refills and days on therapy. The study population included 1724 patients with diabetes who filled a first prescription for insulin glargine 300 U/mL (Gla-300) between April and December 2015 and received a welcome call from a Guide, and 1724 matched control patients from the Symphony Health Integrated Dataverse® prescription claims database. Control patients received Gla-300 but did not enroll in the program. These patients were matched based on age, gender, location, prior use of insulin, insulin dose, number of concomitant drugs, and copay tier. The COACH and control groups comprised 52% men and 48% women; 22% were aged 18-47 years, 23% were 48-55 years, 27% 56-61 years, and 28% ≥ 62 years. Most (99%) had used insulin in the year before receiving the welcome call. At 6 months, patients in the COACH group had refilled their prescription 3.2 times on average, compared with 2.4 times for control patients (P < 0.0001); at 9 months, the average number of refills was 4.7 and 3.6, respectively (P < 0.0001). The average number of days on therapy at 6 months was 102.2 days in the COACH group and 81.5 days in the control group (P < 0.0001); at 9 months, the average number of days on therapy was 151.9 and 121.6, respectively (P < 0.0001). Patients in the COACH program were significantly more likely to refill their prescriptions and stay on therapy. Patient support programs such as the COACH program could be an effective way to help improve diabetes care. Sanofi US, Inc. and McKesson Corporation.


Neurological lameness in the cat: common causes and clinical approach.
Neurological causes of lameness are infrequently seen in cats but they are an important consideration when an obvious orthopaedic cause cannot be identified. Monoparetic cats are also frequently presented for veterinary investigation with the main complaint being lameness. Neurological causes of lameness may be difficult to determine without access to advanced imaging modalities, electrodiagnostics or cerebrospinal fluid analysis. This review, aimed at all veterinarians who treat cats, sets out to describe the specific approach to cats with lameness that cannot be attributed to an orthopaedic cause. It describes the diagnosis and management of the most common neurological conditions responsible for lameness or monoparesis in cats.


The use of patient-specific instrumentation improves the accuracy of acetabular component placement.
Preoperative assessment of acetabular pathology, planning of bone preparation, and implant placement using current imaging, templating, and surgical techniques are imprecise, frequently resulting in component malposition. This study compared the accuracy of 2 surgical approaches: (1) standard preoperative imaging and instrumentation and (2) a novel 3-dimensional computed tomography scan-based preoperative planning software linked to patient- and implant-specific instrumentation (PSI) for placing acetabular components. The PSI group resulted in a significant improvement (P < .05) in the average deviation of implant position (actual vs planned) for version, inclination, and total offset. Fewer clinically relevant screw perforations were observed in the PSI group. This study shows proof of concept and justifies a clinical trial comparing PSI technology with standard surgical techniques.


Is the concentration of gamma-aminobutyric acid in the nerve terminal regulated via product inhibition of glutamic acid decarboxylase?
Fractions of synaptosomes were used to study the regulation of gamma-aminobutyric acid (GABA) synthesis. The isolated synaptosomes were superfused in media of various compositions. [3H]GABA and GABA released into the medium or remaining in the synaptosomes were analyzed by liquid scintillation and HPLC techniques. Different conditions, designed to increase the GABA efflux rate were used: the rate of superfusion was varied and the concentrations of K+ and Ca2+ were altered. Stimulation of GABA efflux was paralleled with an increased synthesis of GABA, since, in spite of the increased GABA efflux, a relatively constant intraterminal level was found. The findings suggest that the intraterminal concentration of GABA and thus also its synthesis is regulated via product inhibition. In addition, [3H]GABA, exogenous, and GABA, endogenous, responded to external stimulae (Ca2+, veretradine, various GABA concentrations and the glutaminase inhibitor diazo-nor-leucine) in a way which was compatible with them being localized in and/or released from different compartments.


Pilot prospective evaluation of (18)F-FPPRGD2 PET/CT in patients with cervical and ovarian cancer.
We report the effect of antiangiogenic therapy on the biodistribution of (18)F-FPPRGD2 (a surrogate biomarker of integrin αvβ3 expression), and the potential of (18)F-FPPRGD2 to predict the prognosis in patients with cervical cancer and ovarian cancer in this clinical scenario. Data from six women, age range 30 - 59 years (mean ± SD 44.0 ± 12.5 years), who had undergone a (18)F-FPPRGD2 PET/CT scan and bevacizumab-containing therapy were prospectively collected and analyzed. We compared baseline (18)F-FPPRGD2 and (18)F-FDG uptake in the lesions and tumor-to-background (T/B) ratios. The maximum and mean (18)F-FPPRGD2 standardized uptake values (SUVmax and SUVmean) were recorded for 13 normal organs, as well as in all the identified malignant lesions on the pretreatment scan and the 1-week post-treatment scan. We also measured changes in (18)F-FPPRGD2 uptake from before to 1 week after treatment, and compared them to the changes in (18)F-FDG uptake from before to 6 weeks after treatment. Treatment outcomes were correlated with these changes. The uptake in lesions and T/B ratio of (18)F-FPPRGD2 were lower than those of (18)F-FDG (SUVmax 3.7 ± 1.3 vs. 6.0 ± 1.8, P < 0.001; SUVmean 2.6 ± 0.7 vs. 4.2 ± 1.3, P < 0.001; T/B ratio based on SUVmax 2.4 ± 1.0 vs. 2.6 ± 1.0, P < 0.04; T/B ratio based on SUVmean 1.9 ± 0.6 vs. 2.4 ± 1.0, P < 0.003). One patient did not return for the follow-up scan and in another patient no lesions were identified on the pretreatment scan. (18)F-FPPRGD2 uptake in lesions in the remaining four patients had significantly changed 1 week after treatment (SUVmean 3.3 ± 1.0 vs. 2.7 ± 1.0, P < 0.001), while uptake in all normal tissues analyzed was not affected by treatment. One patient with clinical disease progression had a decrease in lesional (18)F-FPPRGD2 SUVmean of 1.6 % and in (18)F-FDG SUVmean of 9.4 %. Two patients with a clinical complete response to treatment had decreases in lesional (18)F-FPPRGD2 SUVmean of 25.2 % and 25.0 % and in (18)F-FDG SUVmean of 6.1 % and 71.8 %. One patient with a clinical partial response had a decrease in lesional (18)F-FPPRGD2 SUVmean of 7.9 % and in (18)F-FDG SUVmean of 76.4 %. This pilot study showed that (18)F-FPPRGD2 and (18)F-FDG provide independent information about the biology of ovarian and cervical cancers. Bevacizumab-containing therapy does not affect (18)F-FPPRGD2 uptake in normal organs, but does result in statistically significant changes in lesions. In addition, (18)F-FPPRGD2 may have potential for early prediction of response to such treatments. These preliminary findings have to be confirmed in larger studies.


Inconsistency of a model aimed at predicting bacteremia in hospitalized patients.
Clinical prediction rules can help physicians determine the necessity for blood cultures in specific patients and/or in whom empiric antibiotic treatment should be administered. Before adopting a prediction rule its validity must be evaluated in different settings. We revealed independent predictors of true bacteremia and developed a risk score based on them in one group of adult hospitalized patients (n = 474; derivation set). An attempt was made to validate this risk score in a second group of in-patients at the same hospital (n = 438; validation set). The derivation set included 540 blood culture episodes and the validation set 516. A blood culture episode was defined as one or more of all blood specimens withdrawn for culture from one patient over one 24 hour period. Independent multivariate predictors of true bacteremia were: temperature of 39 degrees C or higher, current immunosuppressive therapy, serum alkaline phosphatase > 100 IU and hospitalization in an intensive care unit. In the low risk group, defined by the absence of the said predictors, the rates of true bacteremia were 5.1 and 4.6% for the derivation and validation sets, respectively. As raised temperature is the main clinical feature guiding physicians to suspect bacteremia, we examined the probability of true bacteremia in patients with a temperature of less than 38 degrees C and found it to be 5.6% in the two sets. The model identified high risk subset patient groups demonstrating true bacteremia in 38% of all episodes in the derivation set and the comparatively low rate of 12.1% (p < 0.01) for the validation set.(ABSTRACT TRUNCATED AT 250 WORDS)


Risk factors for idiopathic myelitis at admission and predictors for late diagnostic change.
Immune-mediated myelopathy (IMM) diagnosis is challenging, and its etiology may remain unclear despite extensive investigation. We evaluated diagnostic changes in IMM patients during follow-up. We included 80 patients, 61.3% female, with median follow-up time 62.5 months. Diagnoses at discharge were: 48.8% Multiple Sclerosis-IMM (MS-IMM), 32.5% I-IMM, 11.3% Neuromyelitis Optica Spectrum Disorders-IMM (NMOSD-IMM), 1.3% MOG encephalomyelitis (MOGAD), and 6.2% Others IMM (O-IMM). Twenty-two patients (27.5%) changed diagnosis (median 15.5 months): 68.8% MS-IMM, 12.5% NMOSD-IMM, 3.8% MOGAD, 10.0% I-IMM, and 5.0% O-IMM. Most patients that changed diagnosis were I-IMM. Predictive factors for diagnostic change in I-IMM were: autonomous gait (p = 0.029), lesions suggestive of MS (p = 0.039), higher number of lesions (p = 0.043), lesions length < 3 vertebral bodies (p = 0.033), cervical involvement (p = 0.038), and lower EDSS at admission (p = 0.013). Etiologic reclassifications in IMM are common, therefore patients require an appropriate follow-up time to increase diagnostic accuracy.


Binary fluoride and As(V) adsorption in water using pleco fish bone chars.
The present work studied individual and binary adsorption of fluorides and As(V) in water on pleco fish bone chars (BC), as well as the effect of BC mass variation on the adsorption capacity of fluoride and As(V) in water for human consumption. The results of individual adsorption indicated that the adsorption of fluoride and As(V) on BC depends on solution pH. The adsorption capacity of fluorides at an initial concentration of 30 mg L-1 increases approximately 3 times, from 5.9 to 15.3 mg g-1, when decreasing the pH of the solution from 9 to 5, however, for the case of As(V) an antagonistic effect is observed, the adsorption capacity increases 7 times when raising the pH from 5 to 9, from 18.4 to 132.1 µg g-1 at an initial As(V) concentration of 300 µg L-1. Besides, in the binary adsorption, BC showed a higher affinity to adsorb fluoride since its adsorption capacity decreased from 16.55 to 12.50 mg g-1 as the As(V) concentration increased from 0 to 800 µg L-1 in solution. In contrast, As(V) adsorption was severely affected, decreasing from 140.2 to 32.7 µg g-1 when the fluoride concentration in the solution increased from 0 to 100 mg L-1. On the other hand, in the adsorption of groundwater contaminated with fluoride and As(V), it was determined that increasing the mass of BC from 0.5 to 20 g increases the removal percentage, reaching 99.3 and 75.7% removal for fluoride and As(V), respectively, due to the fact that increasing the mass of the adsorbent leads to a larger area and a greater number of sites that allow the adsorption of these contaminants. The thermodynamic study revealed the spontaneity of fluoride and As(V) adsorption, better affinity for fluoride but higher adsorption rate of As(V) on BC. Characterization techniques such as XRD and EDS allowed identifying hydroxyapatite as the mineral phase of BC, which is responsible for the adsorption of BC. By studying the effect of solution pH on the adsorption capacities and the characterization of BC such as XRD, EDS and TGA, it was determined that the mechanisms of fluoride adsorption are by electrostatic attractions and ion exchange, and for As(V) it is by coprecipitation and ion exchange. It was concluded that BC from pleco fish could be an alternative for treating water contaminated by fluorides and As(V).


Identification of the multifunctional calmodulin-dependent protein kinase in the cytosol, sarcoplasmic reticulum, and sarcolemma of rabbit skeletal muscle.
A multifunctional calmodulin-dependent protein kinase (calmodulin kinase) was purified from the cytosol of rabbit skeletal muscle as a subunit of 58 kDa. A 58-kDa protein in sarcoplasmic reticulum (SR) and sarcolemma (SL) of rabbit skeletal muscle was endogenously phosphorylated in a calmodulin-dependent manner. The 58-kDa protein in SR and SL was considered to be identical to the subunit of cytosol calmodulin kinase on the basis of immunoreactivity, calmodulin binding, and autophosphorylation studies and on the patterns of protease-treated phosphopeptides. Calmodulin kinase showed broad substrate specificity and phosphorylated troponins I and T.


Interleukin-6 is a positive regulator of tumor necrosis factor alpha-induced adipose-related protein in 3T3-L1 adipocytes.
Tumor necrosis factor (TNF) alpha-induced adipose-related protein (TIARP) is a novel TNFalpha-stimulated protein in adipocytes. Besides TNFalpha, interleukin (IL)-6 has recently been shown to be another adipocytokine implicated in insulin resistance. Therefore, the impact of IL-6 on TIARP gene expression in 3T3-L1 adipocytes was determined by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, TIARP mRNA expression was stimulated up to 3.8-fold by IL-6 in a dose-dependent fashion with significant stimulation detectable at effector concentrations as low as 3 ng/ml and maximal effects seen at 100 ng/ml IL-6. Induction of TIARP mRNA by IL-6 was time-dependent with significant upregulation occurring as early as 2 h after effector addition and maximal effects observed at 4 h. In parallel, TIARP protein synthesis was upregulated with maximal effects seen after 8 h of IL-6 treatment. Furthermore, the Janus kinase 2 inhibitor AG490 decreased TIARP mRNA expression. The increase of TIARP mRNA could be reversed by withdrawal of IL-6 for 24 h. Furthermore, TIARP mRNA induction by IL-6 was also seen in brown adipocytes but not in muscle and liver cells. Taken together, these results show that TIARP is acutely regulated in adipose tissue not only by TNFalpha but also by IL-6 which has been shown to be another important cytokine implicated in the pathogenesis of insulin resistance.


Environmental life cycle assessment of rice production in northern Italy: a case study from Vercelli.
The study's objective is to assess the environmental performance of rice production in Northern Italy, in particular in Piedmont, the first Italian and European district for the rice-growing area, and thus identify the most critical hotspots and agricultural processes. In particular, as a case study, a farm located in Vercelli (VC) has been chosen. Subsequently, the study results were compared with other different cultivation practices to evaluate the most sustainable choice. The application of the LCA has been performed, highlighting the phases of rice production that have the most significant impact. Then, uncertainty and sensitivity analyses have been made to estimate the robustness of the results and assess the influence of changing some input variables on emission reduction. Finally, multivariate statistical, specifically a principal component analysis (PCA), was conducted to aid the interpretation of the output dataset of this case study. LCA, uncertainty analysis, and sensitivity analysis were performed with SimaPro 9.2.0, using ReCiPe 2016 Midpoint (H) methodology, and PCA with R software. The hotspot with the highest environmental load is irrigation, which compared to the other phases impacts more in 15 out of 18 categories, including 12 with impacts greater than + 75%. This is because irrigation causes direct impacts, related to the methanogenesis in rice fields, but also indirect impacts related mainly to the production of the energy mix required to move the large masses of irrigation water. Therefore, different water management systems were compared and results show that the irrigation systems based on intermittent paddy submergence (DSI) could result in - 40% lower impacts, resulting to be the preferable technique over the other irrigation systems analyzed, including the traditional one used in this study. In order to reduce the environmental impacts related to the irrigation process, a water management system characterized by intermittent flooding of the paddy field (DSI) could be used as it reduces the environmental impacts the most (- 40%), while the least suitable system is one characterized by continuous flooding without drought periods, as it causes the highest impacts. The online version contains supplementary material available at 10.1007/s11367-022-02109-x.


Overwhelming postsplenectomy infection.
A characteristic case of overwhelming postsplenectomy infection in a previously healthy, 25-year-old man is presented. The patient progressed from influenza-like symptoms to irreversible septic shock and death within 24 hours. His spleen had been removed nine years earlier because of abdominal trauma. Aggressive therapy, including IV fluids, antibiotics, vasopressers, steroids, heparin, packed red blood cells, platelets, cryoprecipitates, and fresh frozen plasma, failed to alter the course of this fulminant septic syndrome. The cause, treatment, and certain prevention options are presented.


Combination of low-dose bupivacaine and opioids provides satisfactory analgesia with less intraoperative hypotension for spinal anesthesia in cesarean section.
This meta-analysis was undertaken to compare the three most common drug regimens of bupivacaine in spinal anesthesia for cesarean section: high-dose bupivacaine (≥10 mg, HB), low-dose bupivacaine (<10 mg, LB) and combination of low-dose bupivacaine and opioids (LBO). Databases of MEDLINE, EMBASE, and Cochrane Library were searched (updated on October 30, 2011). Primary endpoints were the incidence of intraoperative hypotension and analgesia efficacy. Pooled risk ratio (RR) or standard mean difference and their 95% confidence intervals (95% CI) were calculated. A RR <1 indicates that LB or LBO regimen is associated with less intraoperative complications and better anesthesia or analgesia efficacy. A total of 11 randomized controlled trials including 605 parturients were analyzed. Results of this meta-analysis showed that compared with HB regimen, LB regimen decreased the incidence of intraoperative hypotension (RR = 0.64, 95% CI: 0.42-0.96) with less satisfactory analgesia (fixed model, RR = 1.50, 95% CI: 1.14-1.98). LBO regimen significantly reduced the incidence of intraoperative hypotension (RR = 0.52, 95% CI: 0.33-0.82) with reliable analgesia efficacy (RR = 2.56, 95% CI: 0.77-8.48). Compared with conventional HB regimen and LB regimen, LBO regimen not only reduced intraoperative hypotension but also provided reliable analgesia. Therefore, LBO regimen should be considered as the preferred drug combination for spinal anesthesia in cesarean section.


Computational Visual Stress Level Analysis of Calcareous Algae Exposed to Sedimentation.
This paper presents a machine learning based approach for analyses of photos collected from laboratory experiments conducted to assess the potential impact of water-based drill cuttings on deep-water rhodolith-forming calcareous algae. This pilot study uses imaging technology to quantify and monitor the stress levels of the calcareous algae Mesophyllum engelhartii (Foslie) Adey caused by various degrees of light exposure, flow intensity and amount of sediment. A machine learning based algorithm was applied to assess the temporal variation of the calcareous algae size (∼ mass) and color automatically. Measured size and color were correlated to the photosynthetic efficiency (maximum quantum yield of charge separation in photosystem II, [Formula: see text]) and degree of sediment coverage using multivariate regression. The multivariate regression showed correlations between time and calcareous algae sizes, as well as correlations between fluorescence and calcareous algae colors.


The pentylenetetrazole-kindling model of epilepsy in SAMP8 mice: behavior and metabolism.
This work describes a novel epilepsy model, combining pentylenetetrazole (PTZ) kindling with the senescence-accelerated mouse P8 (SAMP8) a model for aging. The 2- and 8-month-old SAMP8 mice were treated with PTZ, phenobarbital plus PTZ or saline every 48 h during a period of 40 days. Both 2- and 8-month-old PTZ-kindled mice showed a behavioral pattern that was very similar to severe chronic epilepsy with secondary generalized seizures. Two out of six 8-month-old animals died in the PTZ group. Interestingly, atypical absence seizures were limited to the 8-month-old PTZ group. Furthermore, 8-month-old mice were more sensitive to the sedative effect of phenobarbital. The concentrations of several amino acids were examined by HPLC. Lower levels of amino acids were found in the 8-month-old compared to the 2-month-old control animals. No biochemical changes were observed between the groups of 2-month-old animals, while in the 8-month-old animals both treatment groups showed significantly higher concentrations of GABA, glutamine and glutathione. Thus, it could be shown that cerebral metabolism of 8-month-old SAMP8 mice was more sensitive to PTZ and phenobarbital than metabolism of 2-month-old mice. Furthermore, it is suggested that glutamate metabolism in brains of 8-month-old SAMP8 mice is altered and that excessive glutamate is transformed, in considerable amounts, into glutamate related metabolites, possibly in astrocytes.


A rare presentation of hepatolithiasis in an adolescent patient: A case report.
Hepatolithiasis (intrahepatic stones) is rare in adolescent patients and requires complex management strategies to prevent recurrent infections and progression to hepatic fibrosis. Surgical management is often required. In cases of unclear etiology, further work-up is indicated to provide insight into future management. In this report we describe an extensive stone analysis. A 20-year-old Caucasian female presented with known hepatolithiasis and multiple prior recurrent bouts of abdominal pain requiring hospitalization. Magnetic resonance cholangiopancreatography (MRCP) demonstrated an abnormal left-sided hepatic biliary ductal system dilatation. She was treated surgically with a formal left hepatectomy and preservation of the caudate lobe. The right ductal system had no stones or evidence of inflammation, and her bile and stones cultures were negative for organism growth. An extensive analysis demonstrated stone composition primarily of cholesterol. Adolescent presentations of hepatolithiasis are rare and considerations in the differential diagnosis include primary sclerosing cholangitis, bile acid transporter defects, and other known genetic diseases. This case is unique because only the left half of the intrahepatic ductal system had evidence of stone disease and the bile was sterile. A detailed stone analysis demonstrating cholesterol supersaturation provides additional context though the etiology remains unclear in this case and will require lifelong follow-up. Early-onset hepatolithiasis is rare and requires expert management, and in some cases definitive surgical management with life-long follow-up. Extensive stone analysis and genetic testing can be performed to help identify disease etiology in unique cases.


A new method of bile duct cannulation allowing bile collection and re-infusion in the conscious rat.
A technique is described for collection of bile from the surgically-prepared, conscious rat after a postoperative recovery period of 7 days. This model can also be used to study enterohepatic recirculation.


Machine Learning Enables Accurate and Rapid Prediction of Active Molecules Against Breast Cancer Cells.
Breast cancer (BC) has surpassed lung cancer as the most frequently occurring cancer, and it is the leading cause of cancer-related death in women. Therefore, there is an urgent need to discover or design new drug candidates for BC treatment. In this study, we first collected a series of structurally diverse datasets consisting of 33,757 active and 21,152 inactive compounds for 13 breast cancer cell lines and one normal breast cell line commonly used in in vitro antiproliferative assays. Predictive models were then developed using five conventional machine learning algorithms, including naïve Bayesian, support vector machine, k-Nearest Neighbors, random forest, and extreme gradient boosting, as well as five deep learning algorithms, including deep neural networks, graph convolutional networks, graph attention network, message passing neural networks, and Attentive FP. A total of 476 single models and 112 fusion models were constructed based on three types of molecular representations including molecular descriptors, fingerprints, and graphs. The evaluation results demonstrate that the best model for each BC cell subtype can achieve high predictive accuracy for the test sets with AUC values of 0.689-0.993. Moreover, important structural fragments related to BC cell inhibition were identified and interpreted. To facilitate the use of the model, an online webserver called ChemBC (http://chembc.idruglab.cn/) and its local version software (https://github.com/idruglab/ChemBC) were developed to predict whether compounds have potential inhibitory activity against BC cells.


Thick filament activation is different in fast- and slow-twitch skeletal muscle.
The contractile properties of fast-twitch and slow-twitch skeletal muscles are primarily determined by the myosin isoform content and modulated by a variety of sarcomere proteins. X-ray diffraction studies of regulatory mechanisms in muscle contraction have focused predominately on fast- or mixed-fibre muscle with slow muscle being much less studied. Here, we used time-resolved X-ray diffraction to investigate the dynamic behaviour of the myofilament proteins in relatively pure slow-twitch-fibre rat soleus (SOL) and pure fast-twitch-fibre rat extensor digitorum longus (EDL) muscle during twitch and tetanic contractions at optimal length. During twitch contractions the diffraction signatures indicating a transition in the myosin heads from ordered OFF states, where heads are held close to the thick filament backbone, to disordered ON states, where heads are free to bind to thin filaments, were found in EDL and not in SOL muscle. During tetanic contraction, changes in the disposition of myosin heads as active tension develops is a quasi-stepwise process in EDL muscle whereas in SOL muscle this relationship appears to be linear. The observed reduced extensibility of the thick filaments in SOL muscle as compared to EDL muscles indicates a molecular basis for this behaviour. These data indicate that for the EDL, thick filament activation is a cooperative strain-induced mechano-sensing mechanism, whereas for the SOL, thick filament activation has a more graded response. These different approaches to thick filament regulation in fast- and slow-twitch muscles may be adaptations for short-duration, strong contractions versus sustained, finely controlled contractions, respectively. KEY POINTS: Fast-twitch muscle and slow-twitch muscle are optimized for strong, short-duration contractions and for tonic postural activity, respectively. Structural events (OFF to ON transitions) in the myosin-containing thick filaments in fast muscle help determine the timing and strength of contractions, but these have not been studied in slow-twitch muscle. The X-ray diffraction signatures of structural OFF to ON transitions are different in fast extensor digitorum longus (EDL) and slow soleus (SOL) muscle, being completely absent during twitches in soleus muscle and blunted during tetanic contractions SOL as compared to EDL Quasi-stepwise thick filament structural OFF to ON transitions in fast twitch muscle may be an adaptation for rapid, ballistic movements, whereas more graded OFF to ON structural transitions in slow-twitch muscle may be an adaptation for slower, finer motions.


Effects of Repetitive Transcranial Magnetic Stimulation at the Cerebellum on Working Memory.
Transcranial magnetic stimulation is a widely used brain intervention technique in clinical settings. In recent years, the role of the cerebellum in learning and memory has become one of the hotspots in the field of cognitive neuroscience. In this study, we recruited 36 healthy college or graduate students as subjects and divided them into groups, with 10 to 14 subjects in each group. We performed 5 Hz and 20 Hz repeated transcranial magnetic stimulation and sham stimulation on the Crus II subregion of the cerebellum in different groups, then let them complete the 2-back working memory task before and after the stimulation. We simultaneously recorded the electroencephalogram in the experiment and analyzed the data. We found that after repeated transcranial magnetic stimulation of the cerebellum at 5 Hz and 20 Hz, the N170 and P300 event-related potential components in the prefrontal cortex showed significant differences compared to those in the sham stimulation group. Using phase-locked values to construct brain networks and conduct further analysis, we discovered that stimulation frequencies of 5 Hz and 20 Hz had significant effects on the local and global efficiency of brain networks in comparison to the sham stimulation group. The results showed that repeated transcranial magnetic stimulation on cerebellar targets can effectively affect the subjects' working memory tasks. Repeated transcranial magnetic stimulation at 5 Hz and 20 Hz could enhance the excitatory responses of the frontal lobes. After stimulation at 5 Hz and 20 Hz, the efficiency of the brain network significantly improved.


Mass Spectrometry-Based Analysis of DNA Modifications: Potential Applications in Basic Research and Clinic.
Stable-isotope-dilution tandem mass spectrometry is the most advanced technique used for quantitative determination of a wide spectrum of endogenously generated DNA nucleobase modifications. It is regarded as a gold standard for such analyses. Here, we consider the requirements for reliable identification and quantification of DNA adducts/modifications, whether endogenously derived or not, and discuss how their quantification can provide information on the mechanism of action and the biological relevance of individual nucleobase modifications. A clinical application of such measurements will only be possible after a full validation of the assay and once we have gained a better understanding of the exact role that these DNA modifications play in disease pathogenesis. Once these prerequisites are satisfied, DNA modification measurements may be helpful as clinical parameters for treatment monitoring, for risk group identification and for the development of prevention strategies.


Prognostic utility of longitudinal quantification of PET myocardial blood flow early post heart transplantation.
Myocardial blood flow (MBF) quantification by Rubidium-82 positron emission tomography (PET) has shown promise for cardiac allograft vasculopathy (CAV) surveillance and risk stratification post heart transplantation. The objective was to determine the prognostic value of serial PET performed early post transplantation. Heart transplant (HT) recipients at the University of Ottawa Heart Institute with 2 PET examinations (PET1 = baseline, PET2 = follow-up) within 6 years of transplant were included in the study. Evaluation of PET flow quantification included stress MBF, coronary vascular resistance (CVR), and myocardial flow reserve (MFR). The primary composite outcome was all-cause death, re-transplant, myocardial infarction, revascularization, allograft dysfunction, cardiac allograft vasculopathy (CAV), or heart failure hospitalization. A total of 121 patients were evaluated (79% male, mean age 56 ± 11 years) with consecutive scans performed at mean 1.4 ± 0.7 and 2.6 ± 1.0 years post HT for PET1 and PET2, respectively. Over a mean follow-up of 3.0 (IQR 1.8, 4.6) years, 26 (22%) patients developed the primary outcome: 1 death, 11 new or progressive angiographic CAV, 2 percutaneous coronary interventions, 12 allograft dysfunction. Unadjusted Cox analysis showed a significant reduction in event-free survival in patients with PET1 stress MBF < 2.1 (HR: 2.43, 95% CI 1.11-5.29 P = 0.047) and persistent abnormal PET1 to PET2 CVR > 76 (HR: 2.19, 95% CI 0.87-5.51 P = 0.045). There was no association between MFR and outcomes. Low-stress MBF and persistent increased CVR on serial PET imaging early post HT are associated with adverse cardiovascular outcomes. Early post-transplant and longitudinal assessment by PET may identify at-risk patients for increased surveillance post HT.


PCR-electrospray ionization mass spectrometry for direct detection of pathogens and antimicrobial resistance from heart valves in patients with infective endocarditis.
Microbiological diagnosis is pivotal to the appropriate management and treatment of infective endocarditis. We evaluated PCR-electrospray ionization mass spectrometry (PCR/ESI-MS) for bacterial and candidal detection using 83 formalin-fixed paraffin-embedded heart valves from subjects with endocarditis who had positive valve and/or blood cultures, 63 of whom had positive valvular Gram stains. PCR/ESI-MS yielded 55% positivity with concordant microbiology at the genus/species or organism group level (e.g., viridans group streptococci), 11% positivity with discordant microbiology, and 34% with no detection. PCR/ESI-MS detected all antimicrobial resistance encoded by mecA or vanA/B and identified a case of Tropheryma whipplei endocarditis not previously recognized.


Treatability of organic matter derived from surface and subsurface waters of drinking water catchments.
The treatability of NOM present in runoff and subsurface waters from discrete zero-order catchments (ZOCs) with three land management practices (Australian native vegetation, pine plantation, grasslands) on varying soil textures of a closed drinking water reservoir-catchment was investigated. Subsurface water samples were collected by lysimeters and shallow piezometers and surface waters by installation of barriers that diverted waters to collection devices. For small sample volumes collected, a 'micro' jar testing procedure was developed to assess the treatability of organics by enhanced coagulation using alum, under standardised conditions. DOM present in water samples was quantified by measurement of DOC and UV absorbance (at 254 nm) and characterized using these and F-EEM. The mean alum dose rate (mg alum per mg DOC removed or Al/DOC) was found to be lower for DOM from sandy soil ZOCs (21.1 ± 11.0 Al/DOC) than from clayey soil ZOCs (38.6 ± 27.7 Al/DOC). ZOCs with Pinus radiata had prominent litter layers (6.3 ± 2.6 cm), and despite differences in soil textures showed similarity in DOM character in subsurface waters, and in alum dose rates (22.2 ± 5.5 Al/DOC). For sandy soil ZOCs, the lowest alum dose rates (16.5 ± 10.6 Al/DOC) were for waters from native vegetation catchment while, for clayey soil ZOCs, waters from pine vegetation had the lowest alum dose rates (23.0 ± 5.0 Al/DOC). Where ZOCs have a prominent O horizon, soil minerals had no apparent influence on the treatability of DOM.