Autocrine/paracrine role of the angiopoietin-1 and -2/Tie2 system in cell proliferation and chemotaxis of cultured fibroblastic synoviocytes in rheumatoid arthritis.
Hypervascularity is a characteristic synovial feature of rheumatoid arthritis (RA). We previously reported that Tie1 and Tie2, endothelium-specific tyrosine kinase receptors essential for angiogenesis, are expressed not only by vascular cells, but also by a subpopulation of synovial lining and stromal cells in the inflamed RA synovium. The present study used immunohistochemistry and in situ hybridization to examine whether angiopoietin-1 and -2 (Ang1 and Ang2), ligands for Tie2, are also expressed in the RA synovium. Ang1 and Ang2 were expressed in all of 15 RA synovial samples, and their distribution pattern was similar to that of Tie2. Intense staining was noted in synovial lining and stromal cells, as well as in small vessels in areas of papillary projection and high cell density. Double immunohistochemistry revealed coexpression of Ang1, Ang2, and Tie2 in synovial components exhibiting proliferating cell nuclear antigen immunoreactivity. In addition, Ang1 and Ang2 were preferentially expressed in vimentin-positive fibroblastic cells. To address the functional role of Ang/Tie signaling in RA pathophysiology, we carried out [(3)H]thymidine incorporation and transwell chemotaxis assays using cultured fibroblastic synoviocytes obtained from 2 RA patients. Incubation with various concentrations of recombinant Ang1 or Ang2 did not alter DNA synthesis, but the ligands enhanced chemotactic migration of RA fibroblastic synoviocytes. Our results suggest that the autocrine/paracrine signaling of the Ang/Tie2 system is important for the up-regulated angiogenesis in the RA synovium, as well as for synoviocyte behavior, by regulating chemotactic cell movement.


Uncovering ART adherence inconsistencies: An assessment of sustained adherence among adolescents in South Africa.
Antiretroviral treatment (ART) adherence rates are lower among adolescents living with HIV (ALHIV) than among adults and children, but more evidence is needed on long-term sustained ART adherence among ALHIV. This study assesses rates of sustained ART adherence in a cohort of adolescents in South Africa. A prospective cohort of adolescents (10-19 years) living with HIV (baseline sample N = 1 046, 55% female, mean age 13.6) in the Eastern Cape Province in South Africa were interviewed at baseline (2014-15) and followed-up twice (2015-16, 2017-18). All adolescents ever initiated on treatment in 52 government health facilities were traced (with 90% uptake, 94% retention at Wave 2, and 97% retention at Wave 3, 3.4% mortality) and their clinic records were extracted where available. We investigate sustained ART adherence among adolescents interviewed at all three waves of data collection (N = 933). To quantify adherence at each study wave, we used self-reported past-week adherence (including weekdays and weekends). Self-reported adherence was validated using HIV-1 RNA viral load (>50 copies/mL cut-off) reported in clinic records, in a random-intercept logistic regression. At baseline, approximately 66% (N = 615) of adolescents reported past-week ART adherence, and of these 45.3% reported adherence at both baseline and follow-up. Only 37.1% of the sample reported sustained past-week ART adherence over the three waves of the study. Most adolescents (N = 587, 62.9%) report inconsistent adherence across time (including 6.4% disengaged from care). Older (P = 0.007) and adolescents with horizontally acquired HIV (P = 0.002) were more likely to report inconsistent adherence across time. Controlling for socio-demographic characteristics, past-week adherence was associated with non-detectable viral load (aOR 1.72, 95%CI 1.14-2.59, P = 0.009). Overall, of the adolescents with viral load measurements at study Wave 1 and Wave 2, 50.6% maintained undetectable viral load for the preceding year. Adolescents living with HIV reported very low rates of sustained ART adherence. Adherence reported at a single time may mask high rates of variability in adherence over time. These findings highlight the urgent need for enhanced and effective interventions to assist ALHIV with ART adherence through the challenging years of adolescence.


Blinded randomised controlled study of the effect of a discharge communication template on proton pump inhibitor prescribing.
To evaluate whether the inclusion of advice in the hospital discharge letter regarding published guidelines for the review of PPI therapy can increase the number of patients that have documented PPI therapy review, consistent with the published guidelines, following hospital discharge. Patients on PPIs at discharge from hospital were randomised to either have their hospital discharge letter completed as per usual practice or to have additional information on PPI review included that was aligned to published local guidelines. Patients' GP records were reviewed at 3 to 6 months post discharge to determine if a PPI review had occurred and if that review adhered to the guidelines. Including specific, guideline based, PPI discharge instructions in the hospital discharge summary did not significantly increase the number of patients receiving post-discharge review consistent with the guidelines. Post discharge only 5/26 (19%) patients in the control group and 6/25 (24%) in the intervention group had their PPI therapy reviewed in accordance with the guidelines. We were not able to demonstrate a beneficial change in PPI prescribing practice from the inclusion of PPI prescribing advice in the discharge letter.


Structure of repeating units of a polysaccharide(s) from the lipopolysaccharide of Azospirillum brasilense SR80.
A high-molecular mass polysaccharide fraction was obtained by mild acid hydrolysis of the lipopolysaccharide of diazotrophic rhizobacterium Azospirillum brasilense SR80 followed by GPC on Sephadex G-50 Superfine. Studies by composition and methylation analyses, Smith degradation, and 1D and 2D (1)H and (13)C NMR spectroscopy demonstrated the presence of two structurally distinct repeating units having the following structures: It seems likely, although not proved, that these are repeats of two distinct polysaccharides rather than they build blocks within the same polysaccharide chain. The former structure is new, whereas the latter is closely related to the O-polysaccharide structure of A. brasilense Jm6B2 established earlier, which differs in partial (~60%) 3-O-methylation of d-rhamnose only [Boiko, A. S.; Dmitrenok, A. S.; Fedonenko, Yu. P.; Zdorovenko, E. L.; Konnova, S. A.; Knirel, Y. A.; Ignatov, V. V. Carbohydr. Res.2012, 355, 92-95].


Monitoring of antifungal drugs in biological samples using ultrasonic-assisted supramolecular dispersive liquid-liquid microextraction based on solidification of a floating organic droplet.
A new method for the simultaneous determination of the three antifungal drugs using ultrasonic-assisted supramolecular dispersive liquid-liquid microextraction based on solidification of a floating organic droplet (UASMDLLME-SFO) was proposed. The supramolecular solvents produced from reversed micelles of 1-dodecanol (extraction solvent) in tetrahydrofuran (THF) were injected into the aqueous sample solution. Reverse micelle coacervates were produced in situ through self-assembly processes. The antifungal drugs were extracted from the aqueous sample into a supramolecular solvent. Sonication accelerated the mass transfer of the target analytes into the supramolecular solvent phase and enhanced the dispersion process. Some parameters affecting the extraction efficiency such as type and volume of the extraction solvent, pH, volume of the disperser solvent and ultrasound extraction time were investigated. Under optimum conditions, the limits of detections for ketoconazole, clotrimazole and miconazole ranged from 0.08 to 1.3μgL(-1) and the relative standard deviations (RSDs, n=5)<6% were obtained. The method was successfully applied for preconcentration of the three drugs in biological and water samples.


Subcutaneous etonogestrel implant combined with endometrial ablation for the treatment of adenomyosis: two case reports.
Adenomyosis is a common disease that affects many premenopausal women. Two patients with adenomyosis, aged 51 and 42 years, presented with dysmenorrhea and increased menstrual volume. They refused laparoscopy or laparotomy surgery and were not eligible for the levonorgestrel-releasing intrauterine system (LNG-IUS). The first patient underwent endometrial ablation and subcutaneous etonogestrel (ENG)-releasing implant placement at the same time. Her symptoms of dysmenorrhea and heavy menstruation improved significantly. When serum follicle-stimulating hormone (FSH) and estradiol (E2) levels suggested menopause, the ENG-releasing implant was removed. However, her abdominal pain recurred and was relieved by medication. For the second patient, an ENG-releasing implant was placed first, and her dysmenorrhea and heavy menstrual volume were relieved. However, the bleeding pattern changed from regular bleeding to prolonged bleeding, which troubled the patient. Endometrial ablation was performed 4 months later to solve the problem. Both patients had improved symptoms and were satisfied with the treatment. For patients with adenomyosis who refuse surgery and are not candidates for the use of LNG-IUS, an ENG-releasing implant combined with endometrial ablation may be an effective alternative.


Budget projections and clinical impact of an immuno-oncology class of treatments: Experience in four EU markets.
Immunotherapies have revolutionized oncology, but their rapid expansion may potentially put healthcare budgets under strain. We developed an approach to reduce demand uncertainty and inform decision makers and payers of the potential health outcomes and budget impact of the anti-PD-1/PD-L1 class of immuno-oncology (IO) treatments. We used partitioned survival modelling and budget impact analysis to estimate overall survival, progression-free survival, life years gained (LYG), and number of adverse events (AEs), comparing "worlds with and without" anti-PD-1/PD-L1s over five years. The cancer types initially included melanoma, first and second line non-small cell lung cancer (NSCLC), bladder, head and neck, renal cell carcinoma, and triple negative breast cancer [1]. Inputs were based on publicly available data, literature, and expert advice. The model [2] estimated budget and health impact of the anti-PD-1/PD-L1s and projected that between 2018-2022 the class [3] would have a manageable economic impact per year, compared to the current standard of care (SOC). The first country adaptations showed that for that period Belgium would save around 11,100 additional life years and avoid 6,100 AEs. Slovenia - 1,470 LYGs and 870 AEs avoided; Austria - respectively 4,200, 3,000; Italy - 19,800, 6,800. For Austria, the class had a projected share of about 4.5 % of the cancer care budget and 0.4 % of the total 2020 healthcare budget. For Belgium, Slovenia, and Italy - respectively 15.1 % and 1.1 %, 12.6 %, 0.6 %, and 6.5 %, 0.5 %. The Health Impact Projection (HIP) is a horizon scanning model designed to estimate the potential budget and health impact of the PD-(L)1 inhibitor class at a country level for the next five years. It provides valuable data to payers which they can use to support their reimbursement plans. The model is a strategic tool which allows decisionmakers to assess the implications of policy decisions, such as additional investment, or accelerated access to IOs. It can drive tangible population health benefits by eliminating the questions around PD-(L)1 inhibitor spending and its related outcomes.


[Tertiary crowding in the lower front teeth. Two observations].
Tertiary crowding, especially in the lower dentition, is shortly discussed. Two cases are illustrated that show the uncertainty regarding the often stated influence of the third molars in this respect.


Prevalence and associated factors of depression, anxiety, and stress among Hubei pediatric nurses during COVID-19 pandemic.
The COVID-19 pandemic is putting healthcare workers across the world in an unprecedented situation. The purpose of this study was to evaluate the levels of depression, anxiety, and stress among Hubei pediatric nurses during the COVID-19 pandemic and to analyze the potential factors associated with them. A self-designed online questionnaire survey, which consisted of the demographic and selected features, the occupational protection knowledge, attitudes, and practices of COVID-19, and the Chinese version of Depression, Anxiety, and Stress Scale, were used to assess the levels of depression, anxiety, and stress among Hubei pediatric nurses during COVID-19 pandemic. The logistic regression analyses were performed to analyze the potential factors associated with depression, anxiety, and stress. A total of 617 pediatric nurses were included in the survey. A considerable proportion of pediatric nurses reported symptoms of depression (95 [15.4%]), anxiety (201 [32.6%]), and stress (111 [18.0%]). Results of multivariable logistic regression analyses indicated that the good occupational protection practices (for depression: OR = 0.455, 95%CI: 0.281 to 0.739; for anxiety: OR = 0.597, 95%CI: 0.419 to 0.851; for stress: OR = 0.269, 95%CI: 0.166 to 0.438) and the personal protective equipment (PPE) meeting work requirements (for depression: OR = 0.438, 95%CI: 0.246 to 0.778; for anxiety: OR = 0.581, 95%CI: 0.352 to 0.959; for stress: OR = 0.504, 95%CI: 0.283 to 0.898) were independent protective factors against depression, anxiety, and stress, respectively. Yet, working in an isolation ward or fever clinic was an independent risk factor associated with depression, anxiety, and stress, respectively (for depression: OR = 1.809, 95%CI: 1.103 to 2.966; for anxiety: OR = 1.864, 95%CI: 1.221 to 2.846; for stress: OR = 2.974, 95%CI: 1.866 to 4.741). Having suspected or confirmed COVID-19 patients in the departments (OR = 1.554, 95%CI: 1.053 to 2.294) and coming in contact with the patient's bodily fluids or blood (OR = 1.469, 95%CI: 1.031 to 2.095) were independent risk factors for anxiety, while >3 times of training for COVID-19 related information was an independent protective factor for depression (OR = 0.592, 95%CI: 0.360 to 0.974). Moreover, >10 years of working was an independent risk factor for stress (OR = 1.678, 95%CI: 1.075 to 2.618). During the COVID-19 outbreak, a considerable proportion of Hubei pediatric nurses had psychological problems. The pediatric nurses endorsing the higher number of risk factors should be given special attention and necessary psychological intervention. Improving the levels of PPE so as to meet the work requirements and intensifying occupational protection practices might help safeguard pediatric nurses from depression, anxiety, and stress.


Trends in U.S. Pediatric Otolaryngology Fellowship Training.
Interest in pediatric otolaryngology fellowship training is growing. The workforce implications of this growing interest are unclear and understudied. To analyze trends in pediatric otolaryngology training, determine where fellows who graduated over the past 10 years are currently practicing, and test the hypothesis that graduates from Accreditation Council for Graduate Medical Education (ACGME)–accredited programs were more likely to have academic tertiary positions with faculty appointments. We conducted a web-based analysis of pediatric otolaryngology fellowship graduates. The names of all 274 applicants who were matched to pediatric otolaryngology fellowships from May 31, 2003, to May 31, 2014, were obtained from the SF Match website. Accreditation status of each program for each match year was obtained from the ACGME website. We then performed an Internet search for the current practice location of each matched applicant. Analysis was conducted from January 1, 2015, to May 1, 2015. Practice setting per year of fellowship match and accreditation status of program. For the 2003 to the 2014 match years, there was an increase from 5 to 22 accredited pediatric otolaryngology fellowship programs overall; simultaneously, the number of yearly matched applicants increased from 14 to 35. More graduates with ACGME accreditation practice at academic settings compared with graduates without ACGME accreditation although the difference was not statistically significant (67.1% vs. 50.7%; P = .15). Graduates from accredited programs, however, were significantly more likely to practice at a hospital-based setting compared with those from nonaccredited programs (81.7% vs. 65.5%; P = .003). Fellows trained in the last 10 years are relatively well distributed across the country. The number of pediatric otolaryngology fellowship applicants as well as total number of matched applicants and ACGME-accredited positions has risen in the last 10 years. It appears that a higher proportion of fellows trained in accredited programs work in academic positions in hospital-based practices. The long-term effect on the pediatric otolaryngology workforce of training more fellows in accredited fellowships remains to be seen.


Boron-Locked Starazine - A Soluble and Fluorescent Analogue of Starphene.
A starlike heterocyclic molecule containing an electron-deficient nonaaza-core structure and three peripheral isoquinolines locked by three tetracoordinate borons, namely isoquinoline-nona-starazine (QNSA), is synthesized by using readily available reactants through a rather straightforward approach. This new heteroatom-rich QNSA possesses a quasi-planar π-backbone structure, and bears phenyl substituents on borons which protrude on both sides of the π-backbones endowing it with good solubility in common organic solvents. Contrasting to its starphene analogue, QNSA shows intense fluorescence with a quantum yield (PLQY) of up to 62 % in dilute solution.


Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation.
Our previous studies showed that the green tea-derived polyphenolic compound (-)-epigallocatechin-3 gallate (EGCG) reduces amyloid-β (Aβ) production in both neuronal and mouse Alzheimer's disease (AD) models in concert with activation of estrogen receptor-α/phosphatidylinositide 3-kinase/protein kinase B (ERα/PI3K/Akt) signaling and anti-amyloidogenic amyloid precursor protein (APP) α-secretase (a disintegrin and metallopeptidase domain-10, ADAM10) processing. Since the gallate moiety in EGCG may correspond to the 7α position of estrogen, thereby facilitating ER binding, we extensively screened the effect of other gallate containing phenolic compounds on APP anti-amyloidogenic processing. Octyl gallate (OG; 10 µM), drastically decreased Aβ generation, in concert with increased APP α-proteolysis, in murine neuron-like cells transfected with human wild-type APP or "Swedish" mutant APP. OG markedly increased production of the neuroprotective amino-terminal APP cleavage product, soluble APP-α (sAPPα). In accord with our previous study, these cleavage events were associated with increased ADAM10 maturation and reduced by blockade of ERα/PI3k/Akt signaling. To validate these findings in vivo, we treated Aβ-overproducing Tg2576 mice with OG daily for one week by intracerebroventricular injection and found decreased Aβ levels associated with increased sAPPα. These data indicate that OG increases anti-amyloidogenic APP α-secretase processing by activation of ERα/PI3k/Akt signaling and ADAM10, suggesting that this compound may be an effective treatment for AD.


Increased Serum LIGHT Levels Correlate with Disease Progression and Severity of Interstitial Pneumonia in Patients with Dermatomyositis: A Case Control Study.
Activated CD8+ T cells play an important role in the pathogenesis of dermatomyositis (DM) with interstitial pneumonia (IP). Serum CD8+ T-cell activator, LIGHT, and Th1/Th2/Th17 cytokines were measured in DM-IP patients and compared with clinical parameters to investigate their usefulness. The correlations between the clinical findings and serum LIGHT and Th1/Th2/Th17 cytokine levels were investigated in 21 patients with DM-IP (14 with rapidly progressive IP [RPIP] and 7 with chronic IP [CIP], including 4 fatal cases of IP). The median serum LIGHT level was 119 (16-335.4) pg/ml, which was higher than that in healthy control subjects and DM patients without IP. The median serum IL-6 level was 14.7 (2.4-154.5) pg/ml (n = 13). The other cytokines were detected in only a few patients. The median serum LIGHT level in DM-RPIP patients (156 [49.6-335.4] pg/ml) was significantly higher than that in DM-CIP patients (94.3 [16-164.2] pg/ml) (P = 0.02). The serum IL-6 level did not correlate with either progression or outcome of DM-IP. ROC curve analysis determined a serum LIGHT level of ≥120 pg/ml to be the cut-off value for the rapid progression of DM-IP. Serum LIGHT levels correlated significantly with %DLco (R = 0.55, P = 0.04) and total ground-glass opacity scores (R = 0.72, P = 0.0002). The serum LIGHT level significantly decreased to 100.5 (12.4-259.3) pg/ml 4 weeks after treatment initiation (P = 0.04). The serum LIGHT level may be a promising marker of disease progression and severity in patients with DM-IP.


Frequency of COVID-19 IgG Antibodies among Special Police Squad Lahore, Pakistan.
To find out the sero-prevalence of COVID-19 IgG antibodies among policemen performing duties at high risk areas of Lahore, Pakistan. Cross-sectional, observational study. Chughtai Lab Lahore from 20th to 30th May 2020. One hundred and fifty-four young policemen (mean age 27.1 ±3.8 years) were included in the study after written consent. Squad officers who had any sign of acute respiratory infection were excluded from the study. The participants were asked to fill a questionnaire regarding nature of exposure with the infected cases, kind of personal protective equipment they are provided with and living arrangements. Three ml of blood samples were collected from the participants and immediately sent to the lab for analysis. COVID-19 IgG antibodies were analysed using chemiluminescence immunoassay method on Architect Ci8200 (Abbott). SPSS 23.0 was used for data analysis. All participants were males and mean age was 27.1 ±3.8 years. Out of 154 squad members, 24 were reactive for COVID-19 IgG antibodies and performing duties at the areas of high virus exposure. None of COVID-19 IgG reactive cases exhibited symptoms and most of them performed duties at high risk areas with only masks provided as personal protective equipment. Only 10% of the participants who were exposed to confirmed cases of COVID-19 were found to have anti-COVID IgG. COVID-19 IgG antibody reactive cases may not show any symptoms. Police force is at high risk of exposure. Serosurveys can help to find the spread of infection in the community and aid in planning healthcare strategies. Key Words: COVID-19, SARS CoV-2, Seroprevalence, Pandemic, Asymptomatic cases.


Trifunctional Dibromomaleimide Reagents Built Around A Lysine Scaffold Deliver Site-selective Dual-modality Antibody Conjugation.
We describe the synthesis and application of a selection of trifunctional reagents for the dual-modality modification of native, solvent accessible disulfide bonds in trastuzumab. The reagents were developed from the dibromomaleimide (DBM) platform with two orthogonal clickable functional groups built around a lysine core. We also describe the development of an aryl diselenide additive which enables antibody disulfide reduction in 4 minutes and a rapid overall reduction-bridging-double click sequence.


AUTO-SMASH: a self-calibrating technique for SMASH imaging. SiMultaneous Acquisition of Spatial Harmonics.
Recently a new fast magnetic resonance imaging strategy, SMASH, has been described, which is based on partially parallel imaging with radiofrequency coil arrays. In this paper, an internal sensitivity calibration technique for the SMASH imaging method using self-calibration signals is described. Coil sensitivity information required for SMASH imaging is obtained during the actual scan using correlations between undersampled SMASH signal data and additionally sampled calibration signals with appropriate offsets in k-space. The advantages of this sensitivity reference method are that no extra coil array sensitivity maps have to be acquired and that it provides coil sensitivity information in areas of highly non-uniform spin-density. This auto-calibrating approach can be easily implemented with only a small sacrifice of the overall time savings afforded by SMASH imaging. The results obtained from phantom imaging experiments and from cardiac studies in nine volunteers indicate that the self-calibrating approach is an effective method to increase the potential and the flexibility of rapid imaging with SMASH.


Molecular Pathogenesis and the Possible Role of Mitochondrial Heteroplasmy in Thoracic Aortic Aneurysm.
Thoracic aortic aneurysm (TAA) is a life-threatening condition associated with high mortality, in which the aortic wall is deformed due to congenital or age-associated pathological changes. The mechanisms of TAA development remain to be studied in detail, and are the subject of active research. In this review, we describe the morphological changes of the aortic wall in TAA. We outline the genetic disorders associated with aortic enlargement and discuss the potential role of mitochondrial pathology, in particular mitochondrial DNA heteroplasmy, in the disease pathogenesis.


The public health exposome and pregnancy-related mortality in the United States: a high-dimensional computational analysis.
Racial inequities in maternal mortality in the U.S. continue to be stark. The 2015-2018, 4-year total population, county-level, pregnancy-related mortality ratio (PRM; deaths per 100,000 live births; National Center for Health Statistics (NCHS), restricted use mortality file) was linked with the Public Health Exposome (PHE). Using data reduction techniques, 1591 variables were extracted from over 62,000 variables for use in this analysis, providing information on the relationships between PRM and the social, health and health care, natural, and built environments. Graph theoretical algorithms and Bayesian analysis were applied to PHE/PRM linked data to identify latent networks. PHE variables most strongly correlated with total population PRM were years of potential life lost and overall life expectancy. Population-level indicators of PRM were overall poverty, smoking, lack of exercise, heat, and lack of adequate access to food. In this high-dimensional analysis, overall life expectancy, poverty indicators, and health behaviors were found to be the strongest predictors of pregnancy-related mortality. This provides strong evidence that maternal death is part of a broader constellation of both similar and unique health behaviors, social determinants and environmental exposures as other causes of death.


The structure-activity relationships of a series of suicide inhibitors of phospholipase A2.
A series of mechanism-based inhibitors of phospholipase A2 (SIBLINKS) were synthesized. These new SIBLINKS are phospholipid analogues that contain a para-substituted phenyl 3,3-dimethylglutaryl group in the place of the sn-2 acyl chain. The effect of the phenyl leaving group on inhibitory activity was studied by varying the electron-withdrawing ability of the para-substituted group. A strong correlation was observed between the leaving group potential of the suicide inhibitor and the inhibitory activity of the derivative toward cobra venom phospholipase A2.


Signal amplification and output of CRISPR/Cas-based biosensing systems: A review.
CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR-associated) proteins are powerful gene-editing tools because of their ability to accurately recognize and manipulate nucleic acids. Besides gene-editing function, they also show great promise in biosensing applications due to the superiority of easy design and precise targeting. To improve the performance of CRISPR/Cas-based biosensing systems, various nucleic acid-based signal amplification techniques are elaborately incorporated. The incorporation of these amplification techniques not only greatly increases the detection sensitivity and specificity, but also extends the detectable target range, as well as makes the use of various signal output modes possible. Therefore, summarizing the use of signal amplification techniques in sensing systems and elucidating their roles in improving sensing performance are very necessary for the development of more superior CRISPR/Cas-based biosensors for various applications. In this review, CRISPR/Cas-based biosensors are summarized from two aspects: the incorporation of signal amplification techniques in three kinds of CRISPR/Cas-based biosensing systems (Cas9, Cas12 and Cas13-based ones) and the signal output modes used by these biosensors. The challenges and prospects for the future development of CRISPR/Cas-based biosensors are also discussed.


Condylar hyperplasia and facial asymmetry: report of five cases.
Condylar hyperplasia of mandible is overdevelopment of condyle, unilaterally or bilaterally, leading to facial asymmetry, mandibular deviation, malocclusion and articular dysfunction. This is a series of five such patients managed at our centre.


Differentiation of herbs linked to "Chinese herb nephropathy" from the liquid chromatographic determination of aristolochic acids.
A HPLC method was developed and applied to analyze aristolochic acids (AA-I and AA-II) in Chinese medicinal herbs. The herb samples were extracted by using ultrasonication with the extraction efficiency of better than 82%. Extracts were then filtered and injected onto a C18 column eluting under a gradient program using methanol and water-containing 0.5% acetic acid. The method with the detection limits of 1.33 ng for AA-I and 7.29 ng for AA-II per injection was successfully applied for the analysis of traditional Chinese medicine (TCM) and related products and differentiation of Chinese medicinal herbs that have previously been misused and caused toxicological effects. The developed protocol provided an example that analysis of selected component markers could serve for health security and quality control of TCM consumption.


Strategies for enhancing the initiation of cholesterol lowering medication among patients at high cardiovascular disease risk: a qualitative descriptive exploration of patient and general practitioners' perspectives on a facilitated relay intervention in Alberta, Canada.
The objective of our study was to explore the perspectives of patients and general practitioners (GPs) regarding interventions to increase initiation of cholesterol lowering medication (or statins), including a proposed laboratory-based facilitated relay intervention. Qualitative descriptive study using interviews and focus groups for data collection, and thematic analysis for data analysis. Primary care providers and patients in Calgary, Alberta, Canada. 17 GPs with primarily community-based, non-academic practices with at least 1 year of practice experience participated in semistructured interviews. 14 patients at high risk of cardiovascular disease participated in focus groups. Exploration of strategies that might be used to enhance the prescription of, and adherence to statin therapy for patients with statin-indicated conditions. GPs proposed a variety of interventions to improve statin prescription, including electronic record audit solutions, GP directed education, and patient-oriented campaigns. Patients expressed that they may benefit from being provided access to their laboratory test results, as well as targeted education. Both parties provided positive feedback on the proposed laboratory-based facilitated relay intervention, while pointing out areas for improvement. Notably, GPs were concerned that the patient-directed component of the intervention might jeopardise therapeutic relationships, and patients were concerned about accidental disclosure of personal health information. Important considerations for the design of facilitated relay messaging should include brevity, simplicity and the provision of contact information for inquiries. GPs and patients described several suggestions for increasing statin initiation and welcomed the proposal of a laboratory-based facilitated relay strategy. These findings support further testing of this intervention which may enhance GPs' ability to successfully engage patients in cardiovascular risk reduction through statin therapy.


Structural basis for substrate transport in the GLUT-homology family of monosaccharide transporters.
Here we present two structures of the major facilitator (MFS) xylose transporter XylE from Escherichia coli in inward open and partially occluded inward open conformations. These structures provide key information about the transport cycle of XylE and the closely related human GLUT transporters. This is, to our knowledge, the first MFS transporter structure determined in more than one conformational state, which may establish XylE as an important MFS model protein.


Emergence of herpes simplex virus-1 syncytial variants with altered virulence for mice after selection with a natural carrageenan.
Antiviral therapy against herpes simplex virus based on sulfated polysaccharides, like carrageenans, represents a new alternative for genital herpes infections treatment and arises the concern about the appearance of resistant viral populations. We characterized the F strain of herpes simplex virus-1 passaged in the presence of a natural carrageenan isolated from the red seaweed Gigartina skottbergii in view of the virulence for mice of isolated viral clones. Viral clones (syn14-1 and syn17-2) showed a syncytial phenotype and a mild resistance to carrageenan, heparin, acyclovir, and brivudine. Both clones were avirulent for BALB/c mice when inoculated intravaginally, whereas F strain produced high mortality. Attenuation correlated with low levels of TNF-[alpha], interleukin-6, and IFN-[gamma] in vaginal lavages although virus titers were similar to those obtained for F strain. On the contrary, they showed a marked virulence when inoculated intranasally leading to a generalized spreading of virus. Results confirm the hypothesis that selection of herpes simplex virus-1 with a carrageenan in vitro leads to the emergence of variants with a differential virulence when compared to the original virus. This finding should be addressed when an antiviral therapy against genital herpes infection employing a natural carrageenan is under consideration.


Net emission reductions from electric cars and heat pumps in 59 world regions over time.
Electrification of passenger road transport and household heating features prominently in current and planned policy frameworks to achieve greenhouse gas emissions reduction targets. However, since electricity generation involves using fossil fuels, it is not established where and when the replacement of fossil fuel-based technologies by electric cars and heat pumps can effectively reduce overall emissions. Could electrification policy backfire by promoting their diffusion before electricity is decarbonised? Here, we analyse current and future emissions trade-offs in 59 world regions with heterogeneous households, by combining forward-looking integrated assessment model simulations with bottom-up life-cycle assessment. We show that already under current carbon intensities of electricity generation, electric cars and heat pumps are less emission-intensive than fossil fuel-based alternatives in 53 world regions, representing 95% of global transport and heating demand. Even if future end-use electrification is not matched by rapid power sector decarbonisation, it likely avoids emissions in almost all world regions.


Delivery of the reduced form of vitamin K2(20) to NIH/3T3 cells partially protects against rotenone induced cell death.
Mitochondria generate energy through the action of the electron transport chain (ETC) and ATP synthase. Mitochondrial malfunction can lead to various disorders, including neurodegenerative diseases. Several reports have shown that menaquinone-4 (MK-4, vitamin K2(20)), a safe drug for osteoporosis, may improve mitochondrial function. Here, we hypothesized that the efficient delivery of menahydroquinone-4 (MKH), an active form of MK-4, could exert a supporting effect. We verified the effects of MKH delivery on mitochondrial dysfunction by using MK-4 and MKH ester derivatives in NIH/3T3 mouse fibroblast cells treated with mitochondrial inhibitors. MK-4 and MKH derivatives suppressed cell death, the decline in mitochondrial membrane potential (MMP), excessive reactive oxygen species (ROS) production, and a decrease in intrinsic coenzyme Q9 (CoQ9) induced by rotenone (ROT, complex I inhibitor). MK-4 and MKH derivatives delivered MKH to NIH/3T3 cells, acting as an effective MKH prodrug, proving that the delivered MKH may reflect the mitigation effects on ROT-induced mitochondrial dysfunction. MKH prodrugs are also effective against 3-nitropropionic acid (3-NP, complex II inhibitor) and carbonyl cyanide-m-chlorophenylhydrazone (CCCP, uncoupler)-induced cell death. In conclusion, MKH delivery may mitigate mitochondrial dysfunction by maintaining MMP, ROS, and CoQ9, indicating that MKH prodrugs may be good candidates for treating mitochondrial disorders.


[Participation of traumatized children and adolescents affected by provisional safeguards (removal and custody of children ace. to Para. 42 SGB VIII)_].
This study analyzes important variables of settings of children taken into state custody and records trauma exposure. 52 children and adolescents with e~periences of removal and custody were questioned online in the social network Facebook. Traumatic stressors before removal and custody were assessed as well as the reasons that lead .to removal and custody and the subsequent burdens. In more than every other case the children and adolescents reported that they were not involved in important decisions during removal and custody. After termination of the removal and custody process, 50% did not want to return to their parents. Compared to children wanting to return to their parents, children who did not want to return home display signs of severe physical and emotional neglect as well as extreme physical abuse. Even though they have no desire to return, they are often sent back to their parents against their will. Children who are removed and put in state custody should be included when deciding important questions. Whether or not they wish to return to their parents should be taken into consideration more strongly. Children who are sent back to theirparents against their will suffer from on going traumatization.


Can self-administered questionnaires supplant objective testing of erectile function? A comparison between the International Index Of Erectile Function and objective studies.
To determine whether the results of the self-reported International Index of Erectile Function (IIEF) to assess erectile function can overestimate the degree of erectile impairment. A total of 32 consecutive patients seeking treatment for erectile dysfunction (ED) at a urologist's office were evaluated by completion of the erectile function domain of the IIEF. Nocturnal penile tumescence testing using the Rigiscan (Timm Medical Technologies Inc., USA) was performed in these patients after completion of the IIEF. The median IIEF-6 score was 9 of 30 (range, 1-25; mean, 11/30). Rigiscan results were abnormal in six patients (19%), normal in 25 patients (78%), and unable to interpret in one patient (3%). IIEF-6 scores were subdivided by severity along with Rigiscan results. There was no correlation between age, IIEF score, or Rigiscan results. In conclusion, the IIEF is a useful tool and is helpful for follow-up of a patient to evaluate efficacy of treatments for ED, but should not replace objective testing to diagnose the quality of ED.


T-cell dysregulation is associated with disease severity in Parkinson's Disease.
The dysregulation of peripheral immunity in Parkinson's Disease (PD) includes changes in both the relative numbers and gene expression of T cells. The presence of peripheral T-cell abnormalities in PD is well-documented, but less is known about their association to clinical parameters, such as age, age of onset, progression rate or severity of the disease. We took a detailed look at T-cell numbers, gene expression and activation in cross-sectional cohorts of PD patients and age-matched healthy controls by means of flow cytometry and NanoString gene expression assay. We show that the well-pronounced decrease in relative T-cell numbers in PD blood is mostly driven by a decrease of CD8+ cytotoxic T cells and is primarily associated with the severity of the disease. In addition, we demonstrate that the expression of inflammatory genes in T cells from PD patients is also associated with disease severity. PD T cells presented with increased activation upon stimulation with phytohemagglutinin that also correlated with disease severity. In summary, our data suggest that the consequences of disease severity account for the changes in PD T cells, rather than age, age of onset, duration or the disease progression rate.


Selective Activation of peripheral nerve fibre groups of different diameter by triangular shaped stimulus pulses.
1. The differential block of cutaneous nerve fibres has been achieved with a simple method of electrical stimulation, employing a single pair of active electrodes. 2. The method allows the selective activation of 95% of small myelinated (delta) axons, without activation of the larger (beta) ones; and activation of unmyelinated (C) fibres, without A fibre activation. Asynchronous firing of myelinated axons was absent in the majority of the experiments. 3. The method employs triangularly shaped electrical pulses, with a steep rise front and a slow exponential decay. The outward flow of current at the cathode fires conducted impulses in both larger and smaller axons, and the inward flow inactivates differentially the conduction in the smaller ones. 4. The differential effect of anodal currents rests upon the greater internal conductance and greater conduction velocity of larger fibres. 5. The method has the advantage over the conventional polarization block of simpler surgical preparation, longer nerve survival and minimal latency distortion. However, it cannot be applied in experiments requiring physiological stimulation of peripheral receptors.


Deep reinforcement learning for treatment planning in high-dose-rate cervical brachytherapy.
High-dose-rate (HDR) brachytherapy (BT) is an effective cancer treatment method in which the radiation source is placed within the body. Treatment planning is a critical component for a successful outcome. Almost all currently proposed treatment planning methods are built on stochastic heuristic algorithms, which limits the generation of higher quality plans. This study proposed a novel treatment planning method to adjust dwell times in a human-like fashion to improve the quality of the plan. We built an intelligent treatment planner network (ITPN) based on deep reinforcement learning (DRL). The network architecture of ITPN is Dueling Double-Deep Q Network. The state is the dwell time of each dwell position and the action is which dwell time to adjust and how to adjust it. A hybrid equivalent uniform dose objective function was established and assigned corresponding rewards according to its changes. Experience replay was performed with the epsilon greedy algorithm and SumTree data structure. In the evaluation of ITPN using 20 patient cases, D90, D100 and V100 showed no significant difference compared with inverse planning simulated annealing (IPSA) optimization. However, D2cc of bladder, rectum and sigmoid, V150 and V200 were significant reduced, and homogeneity index and conformity index were significantly increased. The proposed ITPN was able to generate higher quality plans based on the learned dwell time adjustment policy than IPSA. This is the first artificial intelligence system that can directly determine the dwell times of HDR BT, which demonstrated the potential feasibility of solving optimization problems via DRL.


Increased costimulatory molecule expression of thymic and peripheral B cells and a sensitivity to IL-21 in myasthenia gravis.
B cells may contribute to the pathogenesis of myasthenia gravis with anti-acetylcholine antibodies (AChR+ MG) by co-stimulation or selection of T cells. In this study, we investigated costimulatory molecules on B cells in the blood and in the thymus as well as by TLR9 and IL-21 stimulations in AChR+ MG patients with or without immunosuppressive treatment and controls. CD80 and CD86 expression on B cells was increased in the peripheral blood and in the thymus of untreated patients. CD86 was further amplified by IL-21. A role for activated B cells, active thymic environment and IL-21 is implicated in MG.


A nomogram model based on the combination of the systemic immune-inflammation index, body mass index, and neutrophil/lymphocyte ratio to predict the risk of preoperative deep venous thrombosis in elderly patients with intertrochanteric femoral fracture: a retrospective cohort study.
Deep vein thrombosis (DVT) has been considered as a frequent and serious consequence of intertrochanteric femoral fractures in the elderly. Several negative repercussions of DVT can be considerably mitigated by its timely recognition and treatment. The current work was aimed at exploring the factors independently predicting DVT among cases suffering from intertrochanteric femoral fractures and validate their predictive usefulness in diagnosing DVT. Between April 2017 and July 2022, clinical information from 209 cases showing preoperative DVT for femoral intertrochanteric fractures were retrospectively evaluated. In patients with femoral intertrochanteric fractures, logistic regression analysis with a backward stepwise method was adopted for detecting independent predictors for the diagnosis of preoperative DVT. Using multivariate logistic regression, a nomogram prediction model was developed and verified with the testing group. According to multivariate logistic regression model, body mass index (BMI) (OR 0.79, 95% CI 0.63-0.99, P = 0.042), neutrophil/lymphocyte ratio (NLR) (OR 7.29, 95% CI 1.53, 34.64, P = 0.0012), and systemic immune-inflammation index (SII) (OR 6.61, 95% CI 2.35, 18.59, P = 0.001) were independent predictors for DVT before surgery among cases developing intertrochanteric femoral fracture. AUC values were 0.862 and 0.767 for training and testing groups, separately, while their mean errors in the calibration curve were 0.027 and 0.038 separately. Decision curve analysis (DCA) curve revealed a high value of clinical application for both groups. Upon admission, BMI, NLR, and SII are independent predictors of DVT before surgery among cases developing intertrochanteric femoral fractures. Additionally, the nomogram based on the BMI, NLR, and SII can assist clinicians in determining if preventive and symptomatic therapies are required to improve DVT prognosis and reduce its associated mortality.


Desmoplastic fibroma of the hand: case report.
Desmoplastic fibroma is a benign tumor of the soft tissue and rarely of the bone. It typically presents in the trunk and proximal limbs, but it is quite rare in the hands. We present a rare case of desmoplastic fibroma of the soft tissues of the hand that presented as a slow-growing, painless, well-encapsulated mass.


A role for EHD4 in the regulation of early endosomal transport.
All four of the C-terminal Eps15 homology domain (EHD) proteins have been implicated in the regulation of endocytic trafficking. However, the high level of amino acid sequence identity among these proteins has made it challenging to elucidate the precise function of individual EHD proteins. We demonstrate here with specific peptide antibodies that endogenous EHD4 localizes to Rab5-, early embryonic antigen 1 (EEA1)- and Arf6-containing endosomes and colocalizes with internalized transferrin in the cell periphery. Knock-down of EHD4 expression by both small interfering RNA and short hairpin RNA leads to the generation of enlarged early endosomal structures that contain Rab5 and EEA1 as well as internalized transferrin or major histocompatibility complex class I molecules. In addition, cargo destined for degradation, such as internalized low-density lipoprotein, also accumulates in the enlarged early endosomes in EHD4-depleted cells. Moreover, we have demonstrated that these enlarged early endosomes are enriched in levels of the activated GTP-bound Rab5. Finally, we show that endogenous EHD4 and EHD1 interact in cells, suggesting coordinated involvement in the regulation of receptor transport along the early endosome to endocytic recycling compartment axis. The results presented herein provide evidence that EHD4 is involved in the control of trafficking at the early endosome and regulates exit of cargo toward both the recycling compartment and the late endocytic pathway.


A method for separation of pigments from plasmodia of the true slime molds, Physarum polycephalum and Physarum nudum.
Plasmodia of the true slime molds Physarum polycephalum and Physarum nudum were grown on agar semidefined medium (J. W. Daniel and H. Baldwin (1964) in Methods in Cell Physiology (Precsott, D. M., Ed.), Vol. 1, pp. 9-44, Academic Press, New York.) and pigments were extracted from 8-day-old plasmodia with the same solvent mixture that was used later as a mobile phase in the HPLC analysis. The separation was carried out on a strong anion exchanger column in a methanol/borate buffer solution. Under these conditions eight pigments from P. polycephalum and eight from P. nudum were revealed. This method can be used for detailed studies of plasmodial pigments in these species.


Neuroprotective Effect of Sub-lethal Hyperthermia Preconditioning in a Rat Model of Repeated Closed Head Injury.
Repeated mild traumatic brain injury (rTBI), one of the most common forms of traumatic brain injury, is a worldwide severe public health concern. rTBI induces cumulative neuronal injury, neurological dysfunction, and cognitive deficits. Although there are clinical treatment methods, there is still an urgent need to develop preventive approaches for susceptible populations. Using a repeated closed head injury (rCHI) rat model, we interrogate the effect of sub-lethal hyperthermia preconditioning (SHP) on rCHI-induced neuronal injury and behavioral changes. Our study applied the repeated weight-drop model to induce the rCHI. According to the changes of heat shock protein 70 (HSP 70) in the cortex and hippocampus following a single SHP treatment in normal rats, the SHP was delivered to the rats 18 h before rCHI. We found that HSP significantly alleviated rCHI-induced anxiety-like behaviors and impairments in motor abilities and spatial memory. SHP exerts significant neuroprotection against rCHI-induced neuronal damage, apoptosis, and neuroinflammation. Our findings support the potential use of SHP as a preventative approach for alleviating rCHI-induced brain damage.


[Comparative morphological and gene systematics analysis of the Proteocephalus thymalli (Cestoda: Proteocephalidae), a parasite of graylings in lakes Hovsogol and Baikal].
Results of comparative morphological and gene analyses of the cestode Proteocephalus thymalli, an intestine parasite of the lakes Hovsogol (Thymallus arcticus nigrescens) and Lake Baikal graylings (Thymallus arcticus baicalensis) are presented for the first time. The results indicate that representatives of the P. thymalli from these fishes are really two different species.


A depth dose study between AAA and AXB algorithm against Monte Carlo simulation using AIP CT of a 4D dataset from a moving phantom.
To identifying depth dose differences between the two versions of the algorithms using AIP CT of a 4D dataset. Motion due to respiration may challenge dose prediction of dose calculation algorithms during treatment planning. The two versions of depth dose calculation algorithms, namely, Anisotropic Analytical Algorithm (AAA) version 10.0 (AAAv10.0), AAA version 13.6 (AAAv13.6) and Acuros XB dose calculation (AXB) algorithm version 10.0 (AXBv10.0), AXB version 13.6 (AXBv13.6), were compared against a full MC simulated 6X photon beam using QUASAR respiratory motion phantom with a moving chest wall. To simulate the moving chest wall, a 4 cm thick wax mould was attached to the lung insert of the phantom. Depth doses along the central axis were compared in the anterior and lateral beam direction for field sizes 2 × 2 cm2, 4 × 4 cm2 and 10 × 10 cm2. For the lateral beam direction, the moving chest wall highlighted differences of up to 105% for AAAv10.0 and 40% for AXBv10.0 from MC calculations in the surface and buildup doses. AAAv13.6 and AXBv13.6 agrees with MC predictions to within 10% at similar depth. For anterior beam doses, dose differences predicted for both versions of AAA and AXB algorithm were within 7% and results were consistent with static heterogeneous studies. The presence of the moving chest wall was capable of identifying depth dose differences between the two versions of the algorithms. These differences could not be identified in the static chest wall as shown in the anterior beam depth dose calculations.


Serum biomarkers identification by iTRAQ and verification by MRM: S100A8/S100A9 levels predict tumor-stroma involvement and prognosis in Glioblastoma.
Despite advances in biology and treatment modalities, the prognosis of glioblastoma (GBM) remains poor. Serum reflects disease macroenvironment and thus provides a less invasive means to diagnose and monitor a diseased condition. By employing 4-plex iTRAQ methodology, we identified 40 proteins with differential abundance in GBM sera. The high abundance of serum S100A8/S100A9 was verified by multiple reaction monitoring (MRM). ELISA and MRM-based quantitation showed a significant positive correlation. Further, an integrated investigation using stromal, tumor purity and cell type scores demonstrated an enrichment of myeloid cell lineage in the GBM tumor microenvironment. Transcript levels of S100A8/S100A9 were found to be independent poor prognostic indicators in GBM. Medium levels of pre-operative and three-month post-operative follow-up serum S100A8 levels predicted poor prognosis in GBM patients who lived beyond median survival. In vitro experiments showed that recombinant S100A8/S100A9 proteins promoted integrin signalling dependent glioma cell migration and invasion up to a threshold level of concentrations. Thus, we have discovered GBM serum marker by iTRAQ and verified by MRM. We also demonstrate interplay between tumor micro and macroenvironment and identified S100A8 as a potential marker with diagnostic and prognostic value in GBM.


A novel design of Cu(I) active site on the metal-organic framework for exploring the structural transformation of Fenton-like catalysts through in situ "capturing" OH.
The mutual transformation of reactive oxygen species may affect the structural transformation of catalysts during the Fenton-like processes. Its in-depth understanding is essential to achieve high catalytic activity and stability. In this study, a novel design of Cu(I) active sites based on the metal-organic framework (MOF) is proposed to "capture" OH- produced via Fenton-like processes and re-coordinate the oxidized Cu sites. The Cu(I)-MOF presents an excellent removal efficiency for sulfamethoxazole (SMX), with a high removal kinetic constant of 7.146 min-1. Combing DFT calculations with experimental observations, we have revealed that the Cu of Cu(I)-MOF exhibits a lower d-band center, enabling efficient activation of H2O2 and spontaneous "capturing" of OH- to form Cu-MOF, which can be reorganized into the Cu(I)-MOF through molecular regulation for recycle. This research demonstrates a promising Fenton-like approach for solving the trade-off between catalytic activity and stability and provides new insights into the design and synthesis of efficient MOF-based catalysts for water treatment.


Sequential vs. kissing balloon angioplasty for stenting of bifurcation coronary lesions.
Coronary angioplasty of bifurcation lesions remains a technical challenge and is believed to result in low procedural success associated with the risk of side-branch occlusion. Furthermore, long-term results are associated with a high rate of reintervention. The aim of the study was to evaluate the immediate and long-term clinical and angiographic results of sequential vs. simultaneous balloon angioplasty (kissing balloon technique) for stenting of bifurcation coronary lesions. Between December 1999 and January 2001, 59 patients underwent coronary angioplasty because of symptomatic bifurcation lesions type III (i.e., side branch originates from within the target lesion of the main vessel, and both main and side branch are angiographically narrowed more than 50%). Twenty-six patients were treated with simultaneous and 33 patients with sequential balloon angioplasty. Main-vessel stent placement was mandatory; side-branch stenting and platelet IIb/IIIa antagonists were allowed at the discretion of the operator. Kissing balloon technique offered no advantage in terms of procedural success or need for repeat target vessel revascularization due to restenosis at 6-month follow-up. Using sequential balloon angioplasty, permanent or transient side-branch compromise rate (TIMI flow < 3) was significantly higher than after kissing balloon technique (33% vs. 0%, respectively; P = 0.003). Major clinical events in-hospital or at 6-month follow-up, however, showed no significant differences. Kissing balloon angioplasty reduces the rate of transient side-branch occlusion compared to sequential PTCA but does not improve immediate or long-term outcome compared to sequential PTCA for stenting of bifurcation lesions.


Membranoproliferative glomerulonephritis in patients with cystic fibrosis: coincidence or comorbidity? A case series.
Cystic fibrosis (CF) is perceived as a childhood illness. However, with advances in medical science, patients are enjoying lives extending well into adulthood. This article reviews two cases of membranoproliferative glomerulonephritis (MPGN) in adults with CF. One patient with severe CF pulmonary disease had concomitant renal failure during hospitalization for a pulmonary exacerbation. Subsequent evaluations, including complement levels, were consistent with MPGN. The second patient had been recently diagnosed with colon cancer and was found to be suffering from acute renal failure. Diagnostic evaluation likewise confirmed the MPGN diagnosis. Immunologic associations linking CF and MPGN, including derangements in the complement system and the effects of superantigen production, are reviewed.


[To substantiation of vitamin and mineral level in fortified food products].
This review outlines the scientific rationale and commentary for the introduction of sanitary rules and norms governing the enrichment of foods of mass consumption with vitamins and minerals, which were harmonized with EU documents and Codex Alimentarius.


Contribution of primary care to health: an individual level analysis from Tibet, China.
There have been significant improvements in health outcomes in Tibet, health disparities between Tibet and the rest of China has been greatly reduced. This paper tests whether there was a positive association between good primary care and better health outcomes in Tibet. A validated Tibetan version of the Primary Care Assessment Tool (PCAT-T) was used to collect data on 1386 patients aged over 18 years old accessing primary care. Self-rated health (SRH) was employed to measure health outcomes. A multiple binary logistic regression model was used to explore the association between primary care quality and self-rated health status after controlling for socio-demographic and lifestyle variables. This study found that primary care quality had a significant positive association with self-rated health status. Among the nine domains of PCAT-T, family centeredness domain had the highest Odds Ratio (OR = 1.013) with SRH. Patients located in rural area, with higher education levels, without depression, and less frequent drinking were more likely to self-rate as "good health" compared with the reference group. In Tibet, higher quality primary care was associated with better self-rated health status. Primary care should be much strengthened in future health system reform in Tibet.


Ability of 6 grams of nitrogen from a combination of rice, wheat, and milk to meet protein requirements of young men for 4 weeks.
Young men consumed a diet that provided 6.0 g of nitrogen, of which rice, wheat, and milk supplied 33, 38, and 29%, respectively, for 28 days following adjustment. This diet contained amounts of essential amino acids that were at least twice the minimal required amounts reported for men. Mean nitrogen balances in four successive 7-day periods were 0.27 +/- 0.13, 0.25 +/- 0.08, 0.10 +/- 0.07 and 0.24 +/- 0.12 g; and the mean for 28 days was 0.22 +/- 0.05 g. Nitrogen retention did not differ significantly between periods. All men who weighed between 65 and 72 kg retained small amounts of nitrogen but one who weighed 78 kg was in slightly negative balance. The mean balances as reported do not provide an allowance for integumental and other losses. The daily protein intake from these sources, equivalent to 0.5 g/kg of body weight, was a critical level slightly lower than the amount appropriate for long-term maintenance of young men weighing 70 kg.


Biochemical genetics of Es-14 (formerly Es-Si) and a new esterase variation, Es-15, of the laboratory rat (Rattus norvegicus): biochemistry, tissue expression, and linkage to Es-1 in linkage group V.
The segregation of rat esterases controlled by loci residing in linkage group V (LGV) has been studied in two backcross series, (LEW/Han X BN/Han)F1 X LEW/Han and (LEW/Han X LE/Han)F1 X LEW/Han. Es-14 (formerly Es-Si) was shown to be closely linked to Es-1. A new esterase locus, Es-15, was described which codes for a liver isozyme. The distribution pattern of three alleles at the Es-15 locus is presented for 52 independent inbred strains. Close linkage of Es-15 to Es-14 and to Es-1 was established, proposing the following gene order: [Es-2, Es-10]-[ES-1, ES-14, ES-15]. The esterase loci on LGV are thus separated into two gene clusters, cluster 1 and cluster 2. These conclusions are supported by the strain distribution patterns of the two RI strain series, LXB and DXE.


A severe presentation of chronic non-infectious osteomyelitis associated with ulcerative colitis: a case report.
Chronic Non-Infectious Osteomyelitis (CNO) is a chronic, relapsing, self-limiting inflammation of the bone. Although it is rare, CNO has been associated with inflammatory bowel disease and frequently precedes the initial diagnosis. We present a case of CNO in a patient with known ulcerative colitis in clinical remission who presented with purulent multifocal joint effusions in the setting of elevated inflammatory markers and fever suspicious for bacterial osteomyelitis. Our patient is a 12-year-old girl with ulcerative colitis who presented with fevers and insidious onset of joint pain at multiple sites. She had multiple joint effusions on imaging and blood and joint cultures were negative. Biopsy of the left acromion demonstrated acute and chronic osteomyelitis with areas of necrosis and granulomatous inflammation suggestive of CNO. Patient was started on high dose corticosteroids as well as methotrexate injections with marked improvement in symptoms. This case highlights that while purulent effusions are often indicative of bacterial osteomyelitis, the consideration of CNO in a patient with inflammatory bowel disease (IBD) with multifocal small bone involvement and negative blood cultures should be considered.


Efficacy of a multigenic protein vaccine containing multimeric HIV gp160 against heterologous SHIV clade C challenges.
To determine whether multigenic protein immunogens including native, trimeric HIV clade C (HIV-C) gp160 could cross-protect macaques against mucosal challenge with clade C (SHIV-C) mismatched for env. Because AIDS vaccine recipients are unlikely to encounter exactly matched HIV strains and to represent the diversity of locally circulating HIV-C strains, we selected env genes to generate the gp160 immunogen and SHIV-C from different, recently infected infants of the same clinical cohort in Zambia. In a model of postnatal HIV-C transmission, infant macaques were immunized with soluble viral proteins, including trimeric HIV1084i Env, and challenged with SHIV-1157ip; protein-only vaccination was compared with a DNA prime/protein boost strategy. All vaccinated and control monkeys were exposed orally to low-dose, R5-tropic SHIV-1157ip encoding heterologous env. Animals with no or only transient infection were rechallenged intrarectally with a high dose of R5 SHIV-1157ipd3N4, a 'late', animal-evolved SHIV-1157ip variant. Animals were followed prospectively for immune parameters and viral RNA loads. Vaccination induced cross-neutralizing antibodies. Compared to controls, vaccinees had significantly lower peak viral RNA loads, and one vaccine recipient remained completely virus-free, even in lymphoid tissues. There was a trend for the protein-only vaccine to yield better protection than the combined modality approach. Protein-only immunogens induced significant protection against heterologous viruses encoding env from locally circulating viruses.


Quantification of Cross-Contamination of Campylobacter jejuni during Food Preparation in a Model Kitchen in China.
Numerous outbreak investigations and case-control studies of campylobacteriosis have provided evidence that handling Campylobacter-contaminated chicken products is a high risk factor for infection and illness. In this study, the cross-contamination and transfer rates of Campylobacter jejuni from chicken to ready-to-eat food were determined in various food handling scenarios. Skinless raw chicken breasts were artificially contaminated with C. jejuni and diced on cutting boards of three different materials. Whether cold water, cold water with detergent, or hot water was used, statistically significant differences were found between the transfer rates of C. jejuni to unwashed and washed cutting boards or hands, respectively. When both kitchen knife and cutting board were reused after dicing the artificially contaminated chicken, the transfer rates of C. jejuni to cucumber cut on bamboo, wooden, and plastic cutting boards were 16.28, 12.82, and 5.32%, respectively. The transfer rates from chicken to bread, a large lift-up water faucet handle, and a small twist faucet handle via unwashed hands were 0.49, 4.64, and 3.14%, respectively. This research provides scientific evidence that various types of contaminated kitchenware and cook's hands are vital potential vehicles for the cross-contamination of Campylobacter from raw chicken to ready-to-eat food and emphasizes the importance of timely and proper cleaning to prevent cross-contamination during food handling; therefore, high-quality consumer education to reduce the risk of foodborne infection is urgent and necessary.


Factors that predict postoperative motion in patients treated with reverse shoulder arthroplasty.
Reverse shoulder arthroplasty (RSA) has proven to be a useful yet inconsistent tool to manage a variety of pathologic conditions. Factors believed to lead to poor postoperative range of motion (ROM) may be associated with preoperative diagnosis, poor preoperative ROM, and surgical factors such as inability to lengthen the arm. The purpose of this study was to analyze multiple factors that may be predictive of motion after RSA. Our hypothesis is that intraoperative ROM is most predictive of postoperative ROM. Between February 2003 and April 2011, 540 patients (217 men and 323 women) treated with RSA were evaluated with measurements of preoperative, intraoperative, and postoperative ROM at a follow-up, where ROM was found to have plateaued at 1 year as determined by a pilot study. A regression analysis was performed to define independent predictive factors of postoperative active ROM. Intraoperative forward flexion was the strongest predictor of final postoperative ROM, followed by gender and preoperative ROM. Age and arm lengthening were not significant independent predictors. Controlling for gender and preoperative ROM, patients with an intraoperative elevation of 90° gained 29° in postoperative forward elevation (P < .001), 120° gained approximately 40° in postoperative forward elevation (P < .001), 150° gained approximately 56° in postoperative forward elevation (P < .001) and 180° gained approximately 62° in postoperative forward flexion (P < .001). Intraoperative forward flexion is the strongest predictor of postoperative ROM. Surgeons may use intraoperative motion as a powerful decision-making tool regarding soft tissue tension in RSA.


Revision of the acetabular component in dysplastic hips previously reconstructed with a shelf autograft: study of the outcome with special assessment of bone-stock changes.
In this retrospective study we evaluated the proficiency of shelf autograft in the restoration of bone stock as part of primary total hip replacement (THR) for hip dysplasia, and in the results of revision arthroplasty after failure of the primary arthroplasty. Of 146 dysplastic hips treated by THR and a shelf graft, 43 were revised at an average of 156 months, 34 of which were suitable for this study (seven hips were excluded because of insufficient bone-stock data and two hips were excluded because allograft was used in the primary THR). The acetabular bone stock of the hips was assessed during revision surgery. The mean implant-bone contact was 58% (50% to 70%) at primary THR and 78% (40% to 100%) at the time of the revision, which was a significant improvement (p < 0.001). At primary THR all hips had had a segmental acetabular defect > 30%, whereas only five (15%) had significant segmental bone defects requiring structural support at the time of revision. In 15 hips (44%) no bone graft or metal augments were used during revision. A total of 30 hips were eligible for the survival study. At a mean follow-up of 103 months (27 to 228), two aseptic and two septic failures had occurred. Kaplan-Meier survival analysis of the revision procedures demonstrated a ten-year survival rate of 93.3% (95% confidence interval (CI) 78 to 107) with clinical or radiological failure as the endpoint. The mean Oxford hip score was 38.7 (26 to 46) for non-revised cases at final follow-up. Our results indicate that the use of shelf autografts during THR for dysplastic hips restores bone stock, contributing to the favourable survival of the revision arthroplasty should the primary procedure fail.


Optic nerve response and retinal structure in rainbow trout of different sizes.
This study presents evidence of ultraviolet (UV) sensitive, ON center ganglion cells in the fish retina. We determined the spectral sensitivity of ON and OFF responses from the optic nerve mass potential in small (18.0 - 28.5 g) and large (59.5-835 g) rainbow trout, with special reference to UV sensitivity. Under a mid+long-wavelength adapting background, the ON response of small fish revealed the presence of a UV cone mechanism (lambda max 390 nm) which was absent in large specimens. Under similar background conditions, the OFF response of both small and large fish showed one sensitivity peak, dominated by inputs from an M-cone mechanism. An almost complete absence of the accessory corner cones from the retinal mosaic was correlated with the loss of UV sensitivity.


Comparison of various strategies to define the optimal target population for liver fibrosis screening: A population-based cohort study.
Liver fibrosis screening is recommended in high-risk populations, but the optimal definition of "high risk" remains to be established. We compared the performance of several risk-stratification strategies in a population-based setting. Data were obtained from the Finnish population-based health examination surveys Health 2000 and FINRISK 2002-2012. The Chronic Liver Disease Risk Score (CLivD) was compared to previously published risk-stratification strategies based on elevated liver enzymes, alcohol use, diabetes, fatty liver index, body mass index, and/or metabolic risk factors for their ability to detect either advanced liver fibrosis or incident severe liver events. Advanced fibrosis was defined as an Enhanced Liver Fibrosis (ELFTM ) score >9.8 in the Health 2000 study (n = 6084), and incident liver events were ascertained from registry linkage in the combined FINRISK 2002-2012 and Health 2000 cohort (n = 26,957). Depending on the cohort, 53%-60% of the population was considered at risk using the CLivD strategy (low-intermediate-high risk, excluding the minimal-risk category), compared to 30%-32% according to the other risk-stratification strategies. The CLivD captured 85%-91% of cases in the population with advanced liver fibrosis and 90% of incident severe liver events within 10 years from baseline. This compares to 33%-44% and 56%-67% captured by the other risk-stratification strategies, respectively. The 10-year cumulative incidence of liver events varied by risk-stratification strategy (1.0%-1.4%). Compared to previously reported traditional risk factor-based strategies, use of the CLivD captured substantially more cases with advanced liver disease in the population and may be superior for targeting further fibrosis screening.


Bacillus sphaericus LMG 22257 is physiologically suitable for self-healing concrete.
The suitability of using a spore-forming ureolytic strain, Bacillus sphaericus, was evaluated for self-healing of concrete cracks. The main focus was on alkaline tolerance, calcium tolerance, oxygen dependence, and low-temperature adaptability. Experimental results show that B. sphaericus had a good tolerance. It can grow and germinate in a broad range of alkaline pH. The optimal pH range is 7 ∼ 9. High alkaline conditions (pH 10 ∼ 11) slow down but not stop the growth and germination. Oxygen was strictly needed during bacterial growth and germination, but not an essential factor during bacterial urea decomposition. B. sphaericus also had a good Ca tolerance, especially at a high bacterial concentration of 108 cells/mL; no significant influence was observed on bacterial ureolytic activity of the presence of 0.9M Ca2+. Furthermore, at a low temperature (10 °C), bacterial spores germinated and revived ureolytic activity with some retardation. However, this retardation can be counteracted by using a higher bacterial concentration and by supplementing yeast extract. It can be concluded that B. sphaericus is a suitable bacterium for application in bacteria-based self-healing concrete.


Targeted deep sequencing of cell-free DNA in serous body cavity fluids with malignant, suspicious, and benign cytology.
Liquid biopsy using cell-free DNA (cfDNA) presents new opportunities for solid tumor genotyping. While studies have demonstrated the utility of cfDNA from plasma, cfDNA from other body fluids remains underexplored. We evaluated the molecular features and clinicopathologic correlates of cfDNA from serous body cavity fluids by performing hybrid capture-based next-generation sequencing (NGS) on cfDNA isolated from residual effusion supernatants. Twenty-one serous effusions from pleural (n = 15), peritoneal (n = 5), and pericardial (n = 1) cavity were analyzed. The supernatants provided a median cfDNA concentration of 10.3 ng/µL. Notably, all effusions were sequenced successfully to a median depth >1000×, revealing a broad range of genetic alterations including single nucleotide variants, small insertions and deletions, amplifications, and fusions. Specifically, pathogenic alterations were identified in all malignant fluids (13/13), all fluids suspicious for malignancy (2/2), and 1 benign fluid (1/6) from a patient with metastatic cancer. To validate our findings, we examined matching results from 11 patients who underwent additional testing using formalin-fixed, paraffin-embedded (FFPE) specimens. In 8 patients, the paired results between FFPE and supernatant testing were concordant, whereas in the remaining 3 patients, supernatant analysis identified additional variants likely associated with resistance to targeted therapies. Additional comparison between FFPE and supernatant testing showed no difference in DNA concentration (P = .5), depth of coverage (P = .6), or allele frequency of pathogenic mutations (P = .7). cfDNA isolated from serous body cavity fluids represents a promising source of genomic input for targeted NGS.


Soy Isoflavone Intake and Bladder Cancer Risk in Japan: From the Takayama Study.
Background: There is growing evidence suggesting that soy isoflavones play a protective role in the development of cancer. However, few epidemiological studies have investigated the association between soy isoflavone intake and bladder cancer.Methods: We evaluated the associations of soy and isoflavone intakes with bladder cancer incidence in a population-based prospective study in Japan. Subjects were 14,233 men and 16,584 women age 35 years or older in September 1992. Soy and isoflavone intakes were assessed via a validated food-frequency questionnaire, while controlling for total energy intake. Cancer incidence was mainly confirmed through regional population-based cancer registries. Bladder cancer was defined as code C67 according to the International Classification of Diseases and Health Related Problems, 10th Revision.Results: During mean follow-up of 13.6 years, 120 men and 41 women had developed bladder cancer. After adjustments for multiple confounders, compared with the lowest quartile of soy food intake, the estimated hazard ratios for the second, third, and highest quartiles of soy food intake were 0.74, 0.52, and 0.55, respectively, in men (P-trend: 0.023). The corresponding values were 0.60, 0.75, and 0.64, respectively, in women (P-trend: 0.43). Similar inverse associations were observed between isoflavone intake and bladder cancer risk.Conclusions: A significant decreased risk of bladder cancer was observed among men who had higher intakes of total soy and isoflavones.Impact: Our finding on the potential benefit of consuming soy foods against bladder cancer is promising and warrants further studies. Cancer Epidemiol Biomarkers Prev; 27(11); 1371-5. ©2018 AACR.


Automated determination of microbial peroxidase activity in fermentation samples using hydrogen peroxide as the substrate and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) as the electron donor in a flow injection system.
An automated flow injection method has been developed for the determination of microbial peroxidase activity. The substrate used was hydrogen peroxide and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate (ABTS) was used as the electron donor. In the presence of hydrogen peroxide, peroxidase catalyses the dehydrogenation of ABTS, resulting in the formation of a resonance-stabilized radical cation of ABTS. The green-blue colour formed, recorded at 418 nm, is taken as a measure of the peroxidase activity. The general technical conditions and the general enzymic kinetics have been optimized. Conditions for activation and stabilization of the enzyme were found, e.g., ammonium sulfate acts as a peroxidase activator. The resulting method has a good precision, sensitivity and speed.


Evaluation of hormonal testing in the screening for in vitro fertilization (IVF) of women with tubal factor infertility.
To evaluate the frequency of abnormal prolactin and thyroid stimulating hormone (TSH) test results in ovulatory women with tubal factor infertility who were screened for in vitro fertilization (IVF). Charts were identified from 112 ovulatory women with follicle stimulating hormone (FSH) < 20 mIU/ml who were diagnosed with tubal factor infertility and were screened for IVF with thyroid stimulating hormone (TSH) and prolactin levels. Women previously diagnosed with thyroid disease were subsequently excluded and 98 subjects remained. All subjects were determined to be ovulatory by biphasic basal body temperature (BBT) charts, luteal phase progesterone > 4 ng/ml, or endometrial biopsy revealing secretory endometrium. Results of cycle day 3 serum TSH and prolactin concentrations were recorded. The normal range for each test reflects the geometric mean +/- 2 standard deviations (i.e., 95% interval), as obtained from the reference laboratory. Under this construct, hypothesis tests were performed to determine whether or not our study population was consistent with the reference range of normal hormone levels. Under the null hypothesis (normal levels), we expected 5% of the TSH tests to be abnormal (i.e., high or low levels), and 2.5% of the prolactin tests to be abnormal (i.e., high levels). Exact bionomial confidence intervals and P-values were calculated. We also tested for age trend in the proportion of abnormal results. Study subjects had an age range of 25-43. In the study group, 4 (0.041) out of the 98 women screened had abnormal TSH levels. Of these four abnormal TSH results, three were elevated (i.e., TSH > 4.6 microIU/ml) and one was low (i.e., TSH < 0.6 microIU/ml). The frequency of an abnormal TSH value was not significantly different from that expected from the reference laboratory normal values (95% CI 0.011, 0.101). Of the 98 subjects, 7 (0.071) had abnormal prolactin levels, which was significantly different from that expected from the reference laboratory normal values (95% CI 0.029, 0.142; P = 0.023). When stratified by age, there was no observed trend of abnormalities for TSH or prolactin levels with increasing age. In ovulatory women presenting for IVF with tubal factor infertility, our results show that routine screening with a TSH test does not yield a significantly higher proportion of abnormal results than that expected from the reference laboratory normal values. However, prolactin level screening was found to yield a higher incidence of abnormal tests than expected from the reference laboratory normal values.


Alerts in electronic medical records to promote a colorectal cancer screening programme: a cluster randomised controlled trial in primary care.
Participation rates in colorectal cancer screening are below recommended European targets. To evaluate the effectiveness of an alert in primary care electronic medical records (EMRs) to increase individuals' participation in an organised, population-based colorectal cancer screening programme when compared with usual care. Cluster randomised controlled trial in primary care centres of Barcelona, Spain. Participants were males and females aged 50-69 years, who were invited to the first round of a screening programme based on the faecal immunochemical test (FIT) (n = 41 042), and their primary care professional. The randomisation unit was the physician cluster (n = 130) and patients were blinded to the study group. The control group followed usual care as per the colorectal cancer screening programme. In the intervention group, as well as usual care, an alert to health professionals (cluster level) to promote screening was introduced in the individual's primary care EMR for 1 year. The main outcome was colorectal cancer screening participation at individual participant level. In total, 67 physicians and 21 619 patients (intervention group) and 63 physicians and 19 423 patients (control group) were randomised. In the intention-to-treat analysis screening participation was 44.1% and 42.2% respectively (odds ratio 1.08, 95% confidence interval [CI] = 0.97 to 1.20, P = 0.146). However, in the per-protocol analysis screening uptake in the intervention group showed a statistically significant increase, after adjusting for potential confounders (OR, 1.11; 95% CI = 1.02 to 1.22; P = 0.018). The use of an alert in an individual's primary care EMR is associated with a statistically significant increased uptake of an organised, FIT-based colorectal cancer screening programme in patients attending primary care centres.


Are You Prepared for End-of-Life Care? A Content Review of Canadian End-of-Life Care Standards and Competencies for Saskatchewan.
The provision of end-of-life care is receiving attention locally, provincially, and nationally in Canada. It is important to ensure that interprofessional standards and competencies are in place to provide quality end-of-life care that meets the needs of patients and their families. The purpose of this content review was to identify core standards and competencies essential to an interprofessional team providing end-of-life care. The researchers conducted a review of health professional associations and registration bodies that support professionals providing end-of-life care to identify existing standards and competencies. Key concepts were reviewed and organized using thematic analysis; relationships were developed; and core themes for interprofessional end-of-life care were identified. Four themes essential to the provision of end-of-life care were common across all health professions: (1) access to care, (2) professional practice, (3) person-centered care, and (4) the process and delivery of care. Health professional associations need to ensure end-of-life care standards and competencies are in place for the provision of appropriate and holistic care. Aligning standards and competencies across professions improves the preparedness of health professionals to provide interprofessional end-of-life care.


High gasoline prices and mortality from motor vehicle crashes and air pollution.
To estimate the effects of increasing gas prices on mortality. We developed a simulation-based partial equilibrium model that estimated the public health effects of a 20% rise in gas prices. Estimates on price elasticity for gasoline, price elasticity of motor vehicle crashes, relations among gasoline use, air pollution, and mortality were drawn from literature in economics, epidemiology, and medicine. For sustained 20% increases in gasoline prices over 1 year, and assuming other prices and factors were constant, we estimated: 1994 (range, 997 to 4984) fewer deaths from vehicle crashes and 600 (range, 300 to 1500) fewer deaths from air pollution. Combining both, we estimated 2594 fewer deaths. A Monte Carlo simulation involving varying assumptions on elasticities and relations indicated that 95% of the combined reduction in deaths was between 1747 and 3714. Results suggest that high gas prices have public health implications.


Metabolic reservoir cycles in cancer.
Cancer cells possess various biological processes to ensure survival and proliferation even under unfavorable conditions such as hypoxia, nutrient deprivation, and oxidative stress. One of the defining hallmarks of cancer cells is their ability to reprogram their metabolism to suit their needs. Building on over a decade of research in the field of cancer metabolism, numerous unique metabolic capabilities are still being discovered in the present day. One recent discovery in the field of cancer metabolism that was hitherto unexpected is the ability of cancer cells to store vital metabolites in forms that can be readily converted to glucose and glutamine for later use. We called these forms "metabolic reservoirs." While many studies have been conducted on storage molecules such as glycogen, triglyceride, and phosphocreatine (PCr), few have explored the concept of "metabolic reservoirs" for cancer as a whole. In this review, we will provide an overview of this concept, the previously known reservoirs including glycogen, triglyceride, and PCr, and the new discoveries made including the newly discovered reservoirs such as N-acetyl-aspartyl-glutamate (NAAG), lactate, and γ- aminobutyric acid (GABA). We will also discuss whether disrupting these reservoir cycles may be a new avenue for cancer treatment.


Designing suitable shoes to prevent foot frostbite through optimization of the geometric dimensions of the shoe and sock model.
To prevent frostbite in cold environments, proper dimensions and materials for different parts of shoes along with the optimal design of shoe geometry were investigated. Furthermore, the optimal geometry of shoes was computed using an optimization algorithm to provide maximum thermal protection for the foot while having the lowest weight. The results showed that the length of the shoe sole and the thickness of the sock are the most effective parameters in foot protection against frostbite. Using thicker socks, which only increased the weight by roughly 11%, enhanced the minimum foot temperature by more than 2.3 times. HIGHLIGHTSOptimal design of shoe geometry is used to prevent frostbite in cold environments.A model of a biothermal nonlinear model is developed for the barefoot.Length of the shoe sole and the thickness of the sock are the most effective parameters in protecting the foot against frostbite.For the selected weather conditions, the toes are most likely to have frostbite.The best shoe for the selected weather conditions is the shoe that has the highest amount of thermal insulation in the toe area.


Association between Macronutrients Intake, Visceral Obesity and Blood Pressure in a Sample of Obese Egyptian Women.
Study the association between the total caloric intake, protein, lipid, and some classes of fatty acids of the diet, and their effects on blood pressure in a sample of Egyptian obese women with and without visceral obesity. Five hundred forty-nine obese women were included in the study with mean age of 38.1 ± 11.56 years and mean Body mass index [BMI] of 36.17 ± 7.23. They enrolled in a program for losing weight. Visceral fat was determined using ultrasound. Blood pressure was measured 3 times and the mean was recorded. Twenty four hours dietary recall was reported. Thirty point four percentages of samples has visceral obesity ≥ 7cm; they were the older, showed higher values of BMI, visceral obesity and blood pressure. Significant difference was found between groups regarding mean value of BMI, visceral obesity, both systolic blood pressure SBP and diastolic blood pressure DBP and most of the daily macronutrients intake. In groups (2&3) positive significant correlation was recorded between (SBP) & (DBP) and total daily intake of total calories, carbohydrate, total fat, saturated fatty acids and cholesterol, and negative significant correlation with total daily intake of total protein, animal and vegetable protein, linolenic and linoleic fatty acids, while oleic fatty acid showed negative correlation with SBP&DBP in all groups. This study emphasizes the hypothesis that the macronutrients composition of diet influences blood pressure in different ways, in obese patients with visceral obesity.


Investigating the association of Lamotrigine and Phenytoin-induced Stevens-Johnson syndrome/Toxic Epidermal Necrolysis with HLA-B*1502 in Iranian population.
Previous studies have found an association between HLA-B*1502 allele and lamotrigine-induced Stevens-Johnson syndrome (SJS)/ toxic epidermal necrosis (TEN) spectrum in Han Chinese populations. This study aims to investigate the association between HLA-B*1502 and lamotrigine- or phenytoin- induced SJS/TEN in an Iranian population. The medical records of twenty-eight lamotrigine-induced SJS/TEN patients and twenty-five lamotrigine-tolerant controls as well as eight phenytoin-induced SJS/TEN and twelve phenytoin-tolerant controls were extracted between March 2013 and March 2019 from the university hospitals in Mashhad, Iran. The presence of HLA-B*1502 allele was determined using real-time polymerase chain reaction (PCR). Among lamotrigine-induced patients with SJS/TEN, 11 (39.3%) patients tested positive for the HLA-B*1502 while only 3 (12.0%) of the lamotrigine-tolerant controls tested positive for this allele. The risk of lamotrigine-induced SJS/TEN was significantly higher in patients with HLA-B*1502, with an odds ratio (OR) of 4.74 [95% confidence interval (CI) 1.14-19.73, p = 0.032]. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HLA-B*1502 for lamotrigine-induced SJS/TEN was 39.29%, 88.00%, 78.57% and 56.41%, respectively. The HLA-B*1502 allele was present in 2 (25.0%) of phenytoin-induced SJS/TEN cases and 5 (41.7%) of the phenytoin-tolerant controls tested positive for HLA-B*1502 allele. The risk of phenytoin-induced SJS/TEN was not higher in the patients with HLA-B*1502 (OR = 0.467 [95% confidence interval (CI) 0.065-3.34, p = 0.642]). Lamotrigine-induced SJS/TEN is associated with HLA-B*1502 allele in an Iranian population but this is not the case for phenytoin-induced SJS/TEN.


Hospitals' future depends upon long-range planning.
In order for hospitals to shape their own future, it is necessary for them to take the initiative in establishing a solid and continual planning process. Strategic planning should take into consideration the external environment and the internal responses to that environment. The New Jersey Hospital Association, which has developed such a plan, offers information to other associations and their members who are considering a similar undertaking.


Inhibition of mitosis by an antibody to the mitotic calcium transport system.
Calcium ions are important in the regulation of mitotic apparatus assembly and in the control of chromosome movement. Changes in intracellular free calcium concentration, [Ca2+]i are achieved by an intracellular calcium-transport system which is highly conserved in different cell types. A membrane-bound protein of relative molecular mass (Mr) 46,000 (46K) is part of this transport system and has been implicated in the regulation of the [Ca2+]i changes associated with the course of mitosis. A monoclonal antibody against this 46K protein inhibits Ca2+-uptake into isolated Ca2+-sequestering membranes and specifically labels membranes associated with the mitotic apparatus of sea urchin embryos. Here we investigate the relationship between the intracellular calcium transport system and mitosis by injection of this monoclonal antibody into living mitotic sea urchin embryos. We find that after injection the intracellular free calcium increases up to 10(-6) M, the mitotic apparatus is rapidly destroyed and the cell is irreversibly blocked in its development.


Safety and efficacy of directly-acting antiviral therapy for chronic hepatitis C virus in elderly people.
In Italy, the prevalence of hepatitis C virus (HCV) infection is higher in the elderly, although the efficacy and safety of treatment in this population has not been extensively studied. Moreover, little is known about how much pharmacological interaction affects eligibility to treatment and to what extent the treatment affects subsequent outcomes. We retrospectively analyzed the efficacy and safety of directly acting antivirals (DAAs), drug-to-drug interactions, and post-treatment outcomes in 138 patients with HCV aged 70 years or older, who were consecutively treated in our center between 2015 and 2020. The mean age was 77 years old (range = 70-95 years old). The Cumulative Illness Rating Scale of pretherapy severity was classified as moderate to severe in 65% of patients. Fifty-five patients (40%) presented compensated cirrhosis, eight of which were complicated by hepatocellular carcinoma (HCC) and all were cured before treatment. One hundred two patients (74%) were taking two or more drugs (range = 0-5 concomitant drugs registered) and in 29 patients (21%) we found potential drug-to-drug interaction. In 11 of those 29 patients (38%), we were forced to change the chronic therapy, when all therapeutic regimens were equal in terms of efficacy and interactions, to avoid potentially serious drug interactions. One serious adverse event occurred in our sample population (i.e., diverticular bleeding due to interaction with direct oral anticoagulants [DOACs]), whereas mild side effects occurred in 37% of patients. The undetectability of HCV RNA at the end of treatment was achieved in 97% of patients, whereas a sustained virological response (SVR) 12 and SVR 24 were obtained in 98% of patients. When comparing pretherapy with post-therapy data, after a medium follow-up of 15 months (median = 1 year, minimum = 2 months, and maximum = 4 years), we observed a reduction in the incidence of episodes of liver decompensation in patients with cirrhosis and a slight increase in the incidence of HCC (with 6 recurrent and 5 de novo HCC), diagnosed within 13 months from the end of therapy. In all patients, we found a significant improvement in all ultrasound variables and a significant reduction in the elastographic measurements. No significant differences in outcomes were observed dividing the population into patients aged ≥ 80 and < 80 years old. Directly acting antiviral therapy was found to be safe and effective in elderly people, and, despite the large number of concomitant drugs, pharmacological interactions appeared to not affect the adherence to therapy or the incidence of adverse events. Side effects were mostly independent from the type of DAA used and from the burden of comorbidity. In long-term follow-up, the benefit of DAA therapy mainly concerned liver pathology and should be strongly advised in patients with cirrhosis. The therapy was found to not affect extrahepatic comorbidities but allowed to end follow-up in noncirrhotic patients with savings in terms of resources. Finally, patients should not be excluded based on age if they have a good performance status.


Enrichment and Transcriptional Characterization of Stem Cells Isolated from Human Glioblastoma Cell Lines.
Glioblastomas (GBM) are the most frequent and aggressive brain tumors due to their recurrence and resistance to current therapies. These characteristics are associated with the presence of glioma stem cells (GSCs), mainly identified by the detection of the membrane antigens CD133 and CD15. The main source of GSCs has been biopsies of tumors. However, alternatives are sought from cell lines because more homogeneous populations can be obtained with high yields. This chapter describes a method for the enrichment and characterization of GSCs from cell lines derived from human GBM by selective culture with serum-free neural stem cell medium and growth factors. The technique offers alternatives for the enrichment and characterization of GSCs, that could contribute to a better understanding of the biology of GBMs.