Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.
Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.


Microfabricating high-aspect-ratio structures in polyurethane-methacrylate (PUMA) disposable microfluidic devices.
We recently reported a new UV-curable polyurethane-methacrylate (PUMA) resin that has excellent qualities as a disposable microfluidic substrate for clinical diagnostic applications. This article discusses strategies to improve the production yield of PUMA chips that contain dense and high-aspect-ratio features, which presents unique challenges in demolding and bonding steps. These fabrication improvements were deployed to produce a microfiltration device that contained closely spaced and high-aspect-ratio columns, suitable for retaining and concentrating cells or beads from a highly diluted suspension.


Surgical treatment of large corneal dermoid.
Corneal and limbal dermoids are uncommon choristomatous corneal tumors. They clinically present as round or oval, whitish or yellowish cones protruding on the anterior surface of the eyeball. They are composed of ectodermal (keratinized epithelium, hairs, sebaceous and sudoriferous glands, nerves, smooth muscles and, less frequently, teeth) and mesodermal elements (fibrous tissue, fat, blood vessels and cartilage) combined in different proportion. If fat dominates in histology of the tumor, it is called a lipodermoid. A case of a two-year old boy with a large corneal dermoid on the right eye is presented. Dermoid covered almost the whole cornea and was associated with adherence of the atrophic iris to the posterior corneal surface and partial congenital cataract. Surgical therapy included excision of dermoid together with the superficial lamellae of the corneal stroma and penetrating keratoplasty. Satisfactory tectonic and esthetic outcome was achieved and has been maintained for four postoperative years now.


Orally Active Epoxyeicosatrienoic Acid Analogs.
Biologically active epoxyeicosatrienoic acid (EET) regioisomers are synthesized from arachidonic acid by cytochrome P450 epoxygenases of endothelial, myocardial, and renal tubular cells. EETs relax vascular smooth muscle and decrease inflammatory cell adhesion and cytokine release. Renal EETs promote sodium excretion and vasodilation to decrease hypertension. Cardiac EETs reduce infarct size after ischemia-reperfusion injury and decrease fibrosis and inflammation in heart failure. In diabetes, EETs improve insulin sensitivity, increase glucose tolerance, and reduce the renal injury. These actions of EETs emphasize their therapeutic potential. To minimize metabolic inactivation, 14,15-EET agonist analogs with stable epoxide bioisosteres and carboxyl surrogates were developed. In preclinical rat models, a subset of agonist analogs, termed EET-A, EET-B, and EET-C22, are orally active with good pharmacokinetic properties. These orally active EET agonists lower blood pressure and reduce cardiac and renal injury in spontaneous and angiotensin hypertension. Other beneficial cardiovascular actions include improved endothelial function and cardiac antiremodeling actions. In rats, EET analogs effectively combat acute and chronic kidney disease including drug- and radiation-induced kidney damage, hypertension and cardiorenal syndrome kidney damage, and metabolic syndrome and diabetes nephropathy. The compelling preclinical efficacy supports the prospect of advancing EET analogs to human clinical trials for kidney and cardiovascular diseases.


Predictors of smoking reduction without formal intervention.
The Reduction of Smoking in Cardiac Patients (ROSCAP) Study is a randomized controlled trial to test the effectiveness of a smoking reduction strategy to decrease tobacco-related harm, promote cessation, and improve biochemical and clinical indicators of toxin exposure among patients with heart disease. We analyzed baseline characteristics of patients enrolled for participation to investigate predictors of spontaneous smoking reduction prior to study enrollment. Past reducers were more likely to be males (p=.009) and had higher past peak smoking level (p<.0001) than nonreducers. Gender and number of heart disease diagnoses predicted the occurrence of spontaneous reduction and its extent. Age and a history of chronic obstructive pulmonary disease also predicted the extent of reduction. Cotinine and nicotine levels per cigarette per day were significantly higher among past spontaneous reducers than nonreducers. Spontaneous reduction is common among medically ill smokers. Past history of heart disease is a strong predictor of prior reduction. There is evidence of compensation among past spontaneous reducers.


Infection dynamics in coexisting sexual and asexual host populations: support for the Red Queen hypothesis.
The persistence of sexual reproduction is a classic problem in evolutionary biology. The problem stems from the fact that, all else equal, asexual lineages should rapidly replace coexisting sexual individuals due to the cost of producing males in sexual populations. One possible countervailing advantage to sexual reproduction is that, on average, outcrossed offspring are more resistant than common clones to coevolving parasites, as predicted under the Red Queen hypothesis. In this study, we evaluated the prevalence of infection by a sterilizing trematode (Microphallus sp.) in a natural population of freshwater snails that was composed of both sexual and asexual individuals (Potamopyrgus antipodarum). More specifically, we compared the frequency of infection in sexual and asexual individuals over a 5-year period at four sites at a natural glacial lake (Lake Alexandrina, South Island, New Zealand). We found that at most sites and over most years, the sexual population was less infected than the coexisting asexual population. Moreover, the frequency of uninfected sexual females was periodically greater than two times the frequency of uninfected asexual females. These results give clear support for a fluctuating parasite-mediated advantage to sexual reproduction in a natural population.


Symptom Clusters and Quality of Life in Hospice Patients with Cancer
Background: Symptom control is an important part of palliative care and important to achieve optimal quality of life (QOL). Studies have shown that patients with advanced cancer suffer from diverse and often severe physical and psychological symptoms. The aim is to explore the influence of symptom clusters on QOL among patients with advanced cancer. Materials and Methods: 709 patients with advanced cancer were recruited to participate in a clinical trial focusing on symptom management and QOL. Patients were adults newly admitted to hospice home care in one of two hospices in southwest Florida, who could pass mental status screening. The instruments used for data collection were the Demographic Data Form, Memorial Symptom Assessment Scale (MSAS), and the Hospice Quality of Life Index-14. Results: Exploratory factor analysis and multiple regression were used to identify symptom clusters and their influence on QOL. The results revealed that the participants experienced multiple concurrent symptoms. There were four symptom clusters found among these cancer patients. Individual symptom distress scores that were the strongest predictors of QOL were: feeling pain; dry mouth; feeling drowsy; nausea; difficulty swallowing; worrying and feeling nervous. Conclusions: Patients with advanced cancer reported various concurrent symptoms, and these form symptom clusters of four main categories. The four symptoms clusters have a negative influence on patients' QOL and required specific care from different members of the hospice healthcare team. The results of this study should be used to guide health care providers' symptom management. Proper attention to symptom clusters should be the basis for accurate planning of effective interventions to manage the symptom clusters experienced by advanced cancer patients. The health care provider needs to plan ahead for these symptoms and manage any concurrent symptoms for successful promotion of their patient's QOL.


Faculty and organizational characteristics associated with informatics/health information technology adoption in DNP programs.
Nursing informatics/health information technology are key components of graduate nursing education and an accreditation requirement, yet little is known about the extent to which doctor of nursing practice (DNP) curricula include these content domains. The purpose of this descriptive study was to elicit perceptions of DNP program directors relative to (a) whether and how the American Association of Colleges of Nursing's (AACN's) Essential IV standard has been met in their DNP programs; (b) whether the Technology Informatics Guiding Educational Reform Initiative Foundation's Phase II competencies have been integrated in their programs; and (c) the faculty and organizational characteristics associated with the adoption of the AACN's Essential IV. In 2011, an electronic survey was sent to all 138 DNP program directors identified on the AACN Web site with an 81.2% response rate. Findings include variation in whether and how programs have integrated informatics/health information technology content, a lack of informatics-certified and/or master's-prepared faculty, and a perceived lack of faculty awareness of informatics curricular guidelines. DNP program director and dean awareness and support of faculty informatics education, use of informatics competency guidelines, and national policy and stimulus funding support are recommended to promote curricular inclusion and the engagement of nurses in strong informatics practices.


Relationship of glutamate and aspartate to the periaqueductal gray-raphe magnus projection: analysis using immunocytochemistry and microdialysis.
This study tested the hypothesis that the excitatory amino acid transmitters glutamate and/or aspartate are associated with the periaqueductal gray (PAG)-raphe magnus (NRM) projection. Retrograde neuroanatomical tracing procedures utilizing the tracers WGA-HRP or D-[3H]-aspartate were combined with immunocytochemical localization of glutamate or aspartate to determine if glutamate and/or aspartate immunostained neurons projected to the NRM. Both glutamate- and aspartate-immunoreactive cells in the PAG were found to project to the NRM. Double labeling immunocytochemichemical procedures indicated that glutamate and aspartate are co-localized in many PAG neurons, suggesting the following possibilities: (a) one of these two amino acids may serve as a precursor to the other; (b) both amino acids may be co-released from the same PAG neuron; or (c) both amino acids are present in high levels in the perikarya for metabolic purposes. At the EM level, both glutamate- and aspartate-immunoreactive terminals were identified in the NRM, strengthening the concept that both amino acids participate in synaptic transmission in this medullary nucleus. To determine if glutamate and aspartate are in fact released from PAG-NRM axons, the PAG was stimulated chemically with homocysteic acid (HCA) and amino acids were collected from the NRM using a microdialysis probe. Microinjection of HCA, but not vehicle, into the PAG resulted in the release of both glutamate and aspartate in the nucleus raphe magnus. These data suggest that both glutamate and aspartate are released from PAG fibers terminating in the NRM and provide strong support for the hypothesis that excitatory amino acids play a neurotransmitter role in the PAG-NRM pathway.


International business travel: impact on families and travellers.
Spouses and staff of the World Bank Group (WBG) were questioned about the impact of international business travel on families and travellers. Dependent variables were self reported stress, concern about the health of the traveller, and negative impact on the family. We hypothesised that several travel factors (independent variables) would be associated with these impacts. These travel factors had to do with the frequency, duration, and predictability of travel and its interference with family activities. Survey forms were developed and distributed to all spouses of travelling staff as well as a small sample of operational staff. Kendall's tau b correlation coefficients of response frequencies were computed with the data from scaled items. Written responses to open ended questions were categorised. Response rates for spouses and staff were 24% and 36%, respectively. Half the spouse sample (n=533) and almost 75% of the staff sample (n=102) reported high or very high stress due to business travel. Self reported spouse stress was associated with six out of eight travel factors. Female spouses, those with children, and younger spouses reported greater stress. Self reported staff stress was significantly associated with four out of nine travel factors. Further insight into how business travel affects families and staff (including children's behavioural changes) and how families cope was gained through responses to written questions. The findings support the notion that lengthy and frequent travel and frequent changes in travel dates which affect family plans, all characteristic of WBG missions, negatively affects many spouses and children (particularly young children) and that the strain on families contributes significantly to the stress staff feel about their travel. Policies or management practices that take into consideration family activities and give staff greater leeway in controlling and refusing travel may help relieve stress.


Quantitative justification for target concentration intervention--parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides.
[1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration. Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (> or =20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance. A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h(-1) 70 kg(-1); intercompartmental clearance (CLic), 1 l h(-1) 70 kg(-1); volume of central compartment (V1), 19.5 l 70 kg(-1); volume of peripheral compartment (V2) 11.2 l 70 kg(-1). Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80-125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.


Evaluation of the risk of PRRSV transmission via ingestion of muscle from persistently infected pigs.
The objectives of this experiment were to determine how long porcine reproductive and respiratory syndrome virus (PRRSV) could be detected in muscle tissues of experimentally infected pigs and to evaluate the transmissibility of PRRSV to pigs via ingestion of quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR)-positive muscle tissues. Serum, lymphoid tissues, and muscle (M. longissimus dorsi) samples were collected from 135 pigs (89 PRRSV-inoculated pigs and 46 negative control). Between 28 and 202 days post-inoculation, 13 of 89 (14.6%) muscle samples were positive by qRT-PCR. Among these 13, PRRSV was isolated from four of the 13 corresponding serum samples and three of 13 lymphoid tissue samples. In addition, infectious virus was detected in lymphoid tissue homogenates of six of 13 pigs by intramuscular bioassay. Swine transmissibility studies were performed by feeding thirteen 3-week-old PRRSV-naive pigs (recipient pigs) qRT-PCR-positive muscle and then monitoring recipients for evidence of PRRSV viremia by qRT-PCR. No transmission of PRRSV to recipient pigs via consumption of muscle samples was observed. These data suggested that qRT-PCR detected non-infectious PRRSV in pig meat and/or PRRSV is not highly transmissible to susceptible pigs via consumption of PRRSV-contaminated meat.


VIP interview: Paul M. Ellwood, Jr., M.D.
Paul Ellwood, Jr., M.D., is president of Health Outcomes Institute, a nonprofit health policy research organization, and President of the Jackson Hole Group in Teton Village, Wyoming, a health care reform policy think tank. He has been called one of the most important figures in American health care in the last half century. Dr. Ellwood has been a leader in introducing competition into the marketplace through health maintenance organizations (HMOs) and preferred provider organizations (PPOs); encouraging the business coalition movement; developing medical staff-hospital joint venture approaches to integrating health delivery, and installing the Outcomes Management System for payors, patients, and providers. He is now concentrating on working with health care leaders of the Jackson Hole Group to devise and implement The 21st Century American Health System, a comprehensive proposal for health care policy reform in the private and public sectors. Their objective is to ensure universal insurance coverage, managed competition, and health outcomes accountability.


In Vivo Molecular Responses of Fast and Slow Muscle Fibers to Lipopolysaccharide in a Teleost Fish, the Rainbow Trout (Oncorhynchus mykiss).
The physiological consequences of the activation of the immune system in skeletal muscle in fish are not completely understood. To study the consequences of the activation of the immune system by bacterial pathogens on skeletal muscle function, we administered lipopolysaccharide (LPS), an active component of Gram-negative bacteria, in rainbow trout and performed transcriptomic and proteomic analyses in skeletal muscle. We examined changes in gene expression in fast and slow skeletal muscle in rainbow trout at 24 and 72 h after LPS treatment (8 mg/kg) by microarray analysis. At the transcriptional level, we observed important changes in metabolic, mitochondrial and structural genes in fast and slow skeletal muscle. In slow skeletal muscle, LPS caused marked changes in the expression of genes related to oxidative phosphorylation, while in fast skeletal muscle LPS administration caused major changes in the expression of genes coding for glycolytic enzymes. We also evaluated the effects of LPS administration on the fast skeletal muscle proteome and identified 14 proteins that were differentially induced in LPS-treated trout, primarily corresponding to glycolytic enzymes. Our results evidence a robust and tissue-specific response of skeletal muscle to an acute inflammatory challenge, affecting energy utilization and possibly growth in rainbow trout.


Data-driven nonlinear aeroelastic models of morphing wings for control.
Accurate and efficient aeroelastic models are critically important for enabling the optimization and control of highly flexible aerospace structures, which are expected to become pervasive in future transportation and energy systems. Advanced materials and morphing wing technologies are resulting in next-generation aeroelastic systems that are characterized by highly coupled and nonlinear interactions between the aerodynamic and structural dynamics. In this work, we leverage emerging data-driven modelling techniques to develop highly accurate and tractable reduced-order aeroelastic models that are valid over a wide range of operating conditions and are suitable for control. In particular, we develop two extensions to the recent dynamic mode decomposition with control (DMDc) algorithm to make it suitable for flexible aeroelastic systems: (1) we introduce a formulation to handle algebraic equations, and (2) we develop an interpolation scheme to smoothly connect several linear DMDc models developed in different operating regimes. Thus, the innovation lies in accurately modelling the nonlinearities of the coupled aerostructural dynamics over multiple operating regimes, not restricting the validity of the model to a narrow region around a linearization point. We demonstrate this approach on a high-fidelity, three-dimensional numerical model of an airborne wind energy system, although the methods are generally applicable to any highly coupled aeroelastic system or dynamical system operating over multiple operating regimes. Our proposed modelling framework results in real-time prediction of nonlinear unsteady aeroelastic responses of flexible aerospace structures, and we demonstrate the enhanced model performance for model predictive control. Thus, the proposed architecture may help enable the widespread adoption of next-generation morphing wing technologies.


Evaluation of EEG Headset Mounting for Brain-Computer Interface-Based Stroke Rehabilitation by Patients, Therapists, and Relatives.
Brain-computer interfaces (BCIs) have successfully been used for motor recovery training in stroke patients. However, the setup of BCI systems is complex and may be divided into (1) mounting the headset and (2) calibration of the BCI. One of the major problems is mounting the headset for recording brain activity in a stroke rehabilitation context, and usability testing of this is limited. In this study, the aim was to compare the translational aspects of mounting five different commercially available headsets from a user perspective and investigate the design considerations associated with technology transfer to rehabilitation clinics and home use. No EEG signals were recorded, so the effectiveness of the systems have not been evaluated. Three out of five headsets covered the motor cortex which is needed to pick up movement intentions of attempted movements. The other two were as control and reference for potential design considerations. As primary stakeholders, nine stroke patients, eight therapists and two relatives participated; the stroke patients mounted the headsets themselves. The setup time was recorded, and participants filled in questionnaires related to comfort, aesthetics, setup complexity, overall satisfaction, and general design considerations. The patients had difficulties in mounting all headsets except for a headband with a dry electrode located on the forehead (control). The therapists and relatives were able to mount all headsets. The fastest headset to mount was the headband, and the most preferred headsets were the headband and a behind-ear headset (control). The most preferred headset that covered the motor cortex used water-based electrodes. The patients reported that it was important that they could mount the headset themselves for them to use it every day at home. These results have implications for design considerations for the development of BCI systems to be used in rehabilitation clinics and in the patient's home.


Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series.
OBJECT In patients with large or symptomatic brain lesions from metastatic melanoma, the value of resection of metastases to facilitate administration of systemic ipilimumab therapy has not yet been described. The authors undertook this study to investigate whether craniotomy creates the opportunity for patients to receive and benefit from ipilimumab who would otherwise succumb to brain metastasis prior to the onset of regression. METHODS All patients with metastatic melanoma who received ipilimumab and underwent craniotomy for metastasis resection between 2008 and 2014 at the Massachusetts General Hospital were identified through retrospective chart review. The final analysis included cases involving patients who underwent craniotomy within 3 months prior to initiation of therapy or up to 6 months after cessation of ipilimumab administration. RESULTS Twelve patients met the inclusion criteria based on timing of therapy (median age 59.2). The median number of metastases at the time of craniotomy was 2. The median number of ipilimumab doses received was 4. Eleven of 12 courses of ipilimumab were stopped for disease progression, and 1 was stopped for treatment-induced colitis. Eight of 12 patients had improvement in their performance status following craniotomy. Of the 6 patients requiring corticosteroids prior to craniotomy, 3 tolerated corticosteroid dose reduction after surgery. Ten of 12 patients had died by the time of data collection, with 1 patient lost to follow-up. The median survival after the start of ipilimumab treatment was 7 months. CONCLUSIONS In this series, patients who underwent resection of brain metastases in temporal proximity to receiving ipilimumab had qualitatively improved performance status following surgery in most cases. Surgery facilitated corticosteroid reduction in select patients. Larger analyses are required to better understand possible synergies between craniotomy for melanoma metastases and ipilimumab treatment.


Effects of Lactobacillus GG on genes expression pattern in small bowel mucosa.
Probiotics have been used for cure and prevention of several clinical conditions. However, further insights into the mechanism of action are needed to understand the rationale of their use. The aim of this study was to investigate the influence of Lactobacillus GG on the genetic expression patterns in the small bowel mucosa. Six male patients (38+/-5 years) with endoscopically proven oesophagitis were enrolled. All patients were treated for 1 month with esomeprazole and randomised to receive Lactobacillus GG or placebo. After 1 month of treatment, upper endoscopy was repeated. Biopsies of the duodenal mucosa were taken prior to and after the treatment, and the genes expression patterns were assessed using GeneChip Human U133A array. Genes with significant expression changes were selected and analysed to identify specific cellular pathways modified by Lactobacillus GG. To support the array data, 10 target genes were studied using Syber-Green PCR. Microarray analysis showed that Lactobacillus GG administration determined the up- and down-regulation of 334 and 92 genes, respectively. Real-time PCR confirmed the reliability of the analysis. Lactobacillus GG mainly affected the expression of genes involved in immune response and inflammation (TGF-beta and TNF family members, cytokines, nitric oxide synthase 1, defensin alpha 1), apoptosis, cell growth and cell differentiation (cyclins and caspases, oncogenes), cell-cell signalling (ICAMs and integrins), cell adhesion (cadherins), signal transcription and transduction. These data indicate that administration of Lactobacillus GG is associated with a complex genetic response of the duodenal mucosa, reflected by the up- and down-regulation of several genes involved in specific cellular pathways.


Enantioselective determination of methylphenidate and ritalinic acid in whole blood from forensic cases using automated solid-phase extraction and liquid chromatography-tandem mass spectrometry.
A chiral liquid chromatography tandem mass spectrometry (LC-MS-MS) method was developed and validated for quantifying methylphenidate and its major metabolite ritalinic acid in blood from forensic cases. Blood samples were prepared in a fully automated system by protein precipitation followed by solid-phase extraction. The LC-MS-MS method was linear in the range of 0.5 to 500 ng/g for the enantiomers of both analytes. For concentrations above the limit of quantification, coefficients of variation were 15% or less, and the accuracy was 89 to 94%. For 12 postmortem samples in which methylphenidate was not determined to be related to the cause of death, the femoral blood concentration of d-methylphenidate ranged from 5 to 58 ng/g, and from undetected to 48 ng/g for l-methylphenidate (median d/l-ratio 5.9). Ritalinic acid was present at concentrations 10-20 times higher with roughly equal amounts of the d- and l-forms. In blood from 10 living subjects that were not suspected of being intoxicated by methylphenidate, the concentration ranges and patterns were similar to those of the postmortem cases. Thus, methylphenidate does not appear to undergo significant postmortem redistribution.


Evaluation of the number of laser-Doppler measurements in assessing regional diaphragmatic microcirculation.
As regional diaphragmatic microvascular blood flow varies widely, the aim in this study was to estimate the number of repeated measurements, obtained by Laser-Doppler flowmetry (LDF), required to achieve a standard level of precision. In 40 urethane-anesthetized Sprague-Dawley rats, computer-aided LDF scanning coupled with a microscope generated diaphragmatic blood flow (Qdi) ranging between 94 and 944 mV with the frequency histogram displaying non-Gaussian distributions. A sampling technique was used to assess the number of measuring sites required for valid estimates of the regional diaphragmatic microvascular flow. From a total of 1,000 Qdi values, random samples of sizes between 5 and 100 were repeatedly drawn to estimate the variability of median flow. Our data shows that the 95th percentile decreased gradually, from a +30% error at n = 5 down to +20% at n = 15-20, remained between +20 and +15% up to n = 35, and reached +10% at n = 50. Moreover, by expressing the precision level of measurements as the length of a 95% confidence interval (beta), a linear relationship between beta values obtained either by the sampling method or repeated measures analysis of variance can be shown (r = 0.902, p < 0.001); beta values by either method were within +/-20% error of the mean values at sample sizes above n = 15. It is therefore recommended that for microscope-guided LDF scanning in the assessment of the distribution of diaphragmatic microvascular blood flow, at least 15 repeated measurements should be done to reach an acceptable standard level of precision. However, facing with clinical situations where 'blind' LDF scanning inevitably includes measurements over large vessels, the minimal sample sizes required to represent tissue perfusion demand further exploration.


Interprofessional collaborative reasoning by residents and nurses in internal medicine: Evidence from a simulation study.
Clinical reasoning has been studied in residents or nurses, using interviews or patient-provider encounters. Despite a growing interest in interprofessional collaboration, the notion of collaborative reasoning has not been well studied in clinical settings. Our study aims at exploring resident-nurse collaborative reasoning in a simulation setting. We enrolled 14 resident-nurse teams from a general internal medicine division in a mixed methods study. Teams each managed one of four acute case scenarios, followed by a stimulated-recall session. A qualitative, inductive analysis of the transcripts identified five dimensions of collaborative reasoning: diagnostic reasoning, patient management, patient monitoring, communication with the patient, and team communication. Three investigators (two senior physicians, one nurse) assessed individual and team performances using a five-point Likert scale, and further extracted elements supporting the collaborative reasoning process. Global assessment of the resident-nurse team was not simply an average of individual performances. Qualitative results underlined the need to improve situational awareness, particularly for task overload. Team communication helped team members stay abreast of each other's thoughts and improve their efficiency. Residents and nurses differed in their reasoning processes, and awareness of this difference may contribute to improving interprofessional collaboration. Understanding collaborative reasoning can provide an additional dimension to interprofessional education.


n-Alkylboronic acid inhibitors reveal determinants of ligand specificity in the quorum-quenching and siderophore biosynthetic enzyme PvdQ.
The enzyme PvdQ (E.C. 220.127.116.11) from Pseudomonas aeruginosa is an N-terminal nucleophile hydrolase that catalyzes the removal of an N-myristyl substituent from a biosynthetic precursor of the iron-chelating siderophore pyoverdine. Inhibitors of pyoverdine biosynthesis are potential antibiotics since iron is essential for growth and scarce in most infections. PvdQ also catalyzes hydrolytic amide bond cleavage of selected N-acyl-l-homoserine lactone quorum-sensing signals used by some Gram-negative pathogens to coordinate the transcription of virulence factors. The resulting quorum-quenching activity of PvdQ has potential applications in antivirulence therapies. To inform both inhibitor design and enzyme engineering efforts, a series of n-alkylboronic acid inhibitors of PvdQ was characterized to reveal determinants of ligand selectivity. A simple homologation series results in compounds with Ki values that span from 4.7 mM to 190 pM, with a dependence of ΔGbind values on chain length of -1.0 kcal/mol/CH2. X-ray crystal structures are determined for the PvdQ complexes with 1-ethyl-, 1-butyl-, 1-hexyl-, and 1-octylboronic acids at 1.6, 1.8, 2.0, and 2.1 Å resolution, respectively. The 1-hexyl- and 1-octylboronic acids form tetrahedral adducts with the active-site N-terminal Ser217 in the β-subunit of PvdQ, and the n-alkyl substituents are bound in the acyl-group binding site. The 1-ethyl- and 1-butylboronic acids also form adducts with Ser217 but instead form trigonal planar adducts and extend their n-alkyl substituents into an alternative binding site. These results are interpreted to propose a ligand discrimination model for PvdQ that informs the development of PvdQ-related tools and therapeutics.


Intelligent identification of fragmented non-magnetic materials for end-of-life refrigerator recycling.
E-waste is a valuable secondary resource containing numerous toxic substances and high-value components. If improperly handled, it will cause severe environmental pollution. Therefore, efficient recycling of this material can reduce environmental pollution. However, after crushing, fine crushing, and magnetic separation, a substantial quantity of fragmented non-magnetic materials with high value, such as copper andg aluminum, remain. Refrigerators, as typical e-waste, have a similar composition to fragmented non-magnetic materials. Consequently, this paper focuses on the issues of low efficiency, environmental pollution, and resource waste in sorting fragmented non-magnetic materials from waste refrigerators. This paper constructs a data set of fragmented non-magnetic materials of refrigerators, augments the data set, and identifies fragmented non-magnetic materials of refrigerators using a computer vision-based deep learning method. In this study, YOLOv5s is used as the benchmark model. The CBAM module is added to the backbone to enable intelligent identification and sorting of fragmented non-magnetic materials in refrigerators. The final identification efficiency of waste refrigerators meets the requirements of industrial applications, with an accuracy rate of 98.3%, a recall rate of 96.8%, and an average accuracy of 98%. Based on the similarity of the composition of e-waste fragmented materials, this model sorting method can be applied to sorting additional e-waste fragmented materials. Furthermore, it provides the theoretical foundation for promoting e-waste resourcefulness.Implications: This paper proposes a recognition model based on YOLOv5s to solve the problems of low sorting efficiency, environmental pollution, harm to health, and resource waste of non-magnetic crushed material from refrigerators. The recognition model principally addresses the following issues: a deep learning model is developed for recognition and sorting to improve e-waste recognition and sorting efficiency. Concerning the issue of environmental benefits in an ecological environment, a vision-based automatic identification method is proposed to sort harmful waste, such as foam, to preserve the ecological environment. In response to the problem of resource waste, this project improves the purity of precious metals, resulting in a recovery rate of 99.1% for copper and 96.44% for aluminum. In other words, the cost of recovering metals has increased. The identification model of non-magnetic crushed material in refrigerators satisfies production identification and sorting requirements. In addition, the method has application and promotion value, sorting a theoretical foundation and method for identifying and classifying e-waste.


Effects of islet hormones on nerve-mediated and acetylcholine-evoked secretory responses in the isolated pancreas of normal and diabetic rats.
This study employs the pancreas of normal and diabetic rats to investigate the relationship between the endocrine and exocrine pancreas in the control of exocrine secretion employing enzyme and immunohistochemical and physiological techniques. Acetylcholine esterase (ACh-E) positive nerves were distributed in the interacinar regions of the pancreas lying close to the exocrine cells. There was no difference between the cholinergic innervation of the pancreas in normal and diabetic rat. Insulin (INS) immunopositive cells were observed in the peripheral and central portions of the Islet of Langerhans in the pancreas of normal rat. In the diabetic animals the number of INS-positive cells were decreased. In contrast, glucagon (GLU) and somatostatin (SOM)-immunopositive cells were identified mainly in the peripheral parts of the Islets of Langerhans and their numbers increased markedly in the diabetic pancreas. Insulin alone had no significant effect on amylase secretion in the normal pancreas whereas GLU and SOM evoked small increases in amylase out compared to basal. In contrast, the islet hormones have no detectable secretory effect on the diabetic pancreas compared to control. Both electrical field stimulation (EFS) of intrinsic secretomotor nerves and exogenous application of acetylcholine (ACh) resulted in marked increases in amylase secretion. In pancreatic acini and acinar cells ACh evoked dose-dependent increases in amylase release. In normal pancreatic segments a combination of either INS or GLU with EFS or ACh resulted in marked potentiation of amylase output. In contrast, SOM inhibited the EFS-evoked amylase output but enhanced the secretory response to ACh. In pancreatic acini and acinar cells from normal rat and in pancreatic segments from diabetic rats, the islet hormones had no potentiating effect on the ACh-evoked secretory response. Similarly, in the diabetic rat the islet hormone had no effect on EFS-evoked amylase output. In fura-2 loaded pancreatic acinar cells ACh-induced a marked increase in intracellular free calcium concentration [Ca2+]i compared to basal. Either INS or GLU, but not SOM, elicited a small increase in [Ca2+]i. Combining either INS or GLU with ACh resulted in a potentiation of [Ca2+]i compared with ACh alone. In contrast, SOM had no significant effect on the ACh-induced [Ca2+]i compared to the response obtained with ACh alone. In pancreatic acinar cells of diabetic rat ACh-elicited similar magnitude of [Ca2+]i compared to acinar cells of normal rat. However, when the islet hormones were combined with ACh there was no enhancement of [Ca2+]i compared to ACh alone. The results indicate that the potentiation of either EFS or ACh-evoked secretory responses by the islet hormones seem to occur only in pancreatic segments which have intact viable Islets of Langerhans and not in either acini and acinar cells or from the pancreas of diabetic rat. Moreover, it is apparent that cellular Ca2+ is involved with the interaction of ACh with either INS or GLU.


Effect of Transcranial Direct Current Stimulation Combined With Patient-Controlled Intravenous Morphine Analgesia on Analgesic Use and Post-Thoracotomy Pain. A Prospective, Randomized, Double-Blind, Sham-Controlled, Proof-of-Concept Clinical Trial.
Transcranial direct current stimulation (tDCS) is used for various chronic pain conditions, but experience with tDCS for acute postoperative pain is limited. This study investigated the effect of tDCS vs. sham stimulation on postoperative morphine consumption and pain intensity after thoracotomy. This is a single-center, prospective, randomized, double-blind, sham-controlled trial in lung cancer patients undergoing thoracotomy under general anesthesia. All patients received patient-controlled (PCA) intravenous morphine and intercostal nerve blocks at the end of surgery. The intervention group (a-tDCS, n = 31) received anodal tDCS over the left primary motor cortex (C3-Fp2) for 20 min at 1.2 mA, on five consecutive days; the control group (n = 31) received sham stimulation. Morphine consumption, number of analgesia demands, and pain intensity at rest, with movement and with cough were recorded at the following intervals: immediately before (T1), immediately after intervention (T2), then every hour for 4 h (Т3-Т6), then every 6 h (Т7-Т31) for 5 days. We recorded outcomes on postoperative days 1 and 5 and conducted a phone interview inquiring about chronic pain 1 year later (NCT03005548). A total of 62 patients enrolled, but tDCS was prematurely stopped in six patients. Fifty-five patients (27 a-tDCS, 28 sham) had three or more tDCS applications and were included in the analysis. Cumulative morphine dose in the first 120 h after surgery was significantly lower in the tDCS [77.00 (54.00-123.00) mg] compared to sham group [112.00 (79.97-173.35) mg, p = 0.043, Cohen's d = 0.42]. On postoperative day 5, maximum visual analog scale (VAS) pain score with cough was significantly lower in the tDCS group [29.00 (20.00-39.00) vs. 44.50 (30.00-61.75) mm, p = 0.018], and pain interference with cough was 80% lower [10.00 (0.00-30.00) vs. 50.00 (0.00-70.00), p = 0.013]. One year after surgery, there was no significant difference between groups with regard to chronic pain and analgesic use. In lung cancer patients undergoing thoracotomy, three to five tDCS sessions significantly reduced cumulative postoperative morphine use, maximum VAS pain scores with cough, and pain interference with cough on postoperative day 5, but there was no obvious long-term benefit from tDCS.


Prevalence of and associated factors for sarcopenia in patients with liver cirrhosis: A systematic review and meta-analysis.
Sarcopenia is associated with poor outcomes in patients with cirrhosis. However, the prevalence of and associated factors for developing sarcopenia in this population remain to be determined. This study aimed to summarize the prevalence, characteristics, and associated factors of sarcopenia in patients with cirrhosis. Electronic searches were performed from inception to June 9, 2022 to identify the eligible studies. We meta-analyzed the prevalence of sarcopenia in overall patients with cirrhosis and subgroups. Both crude and adjusted odds ratios (ORs) were pooled using the random effects model. A total of 55 studies involving 13,158 patients from 17 countries were included. The overall prevalence of sarcopenia was 40.1 % (95 % CI 35.4%-44.9 %) in patients with cirrhosis. The pooled prevalence was higher in males, Child-Pugh class C cirrhosis, decompensated stage, ascites, subjective global assessment class C cirrhosis, and when sarcopenia was defined by L3-SMI (third lumbar-skeletal muscle index) at a higher cutoff. In multivariate analysis, older age (adjusted OR 1.04, 95 % CI 1.00-1.07), male (adjusted OR 4.75, 95 % CI 2.72-8.28), lower body mass index (BMI) (adjusted OR 0.78, 95 % CI 0.73-0.83), alcoholic liver disease (ALD) (adjusted OR 1.43, 95 % CI 1.19-1.72), but not ascites and hepatic encephalopathy, were significantly associated with an increased risk of sarcopenia in patients with cirrhosis. Sarcopenia is a prevalent complication, and older age, male patients, lower BMI, and patients with ALD are associated with an increased risk of sarcopenia in patients with cirrhosis.


Maintenance medication for schizophrenia: strategies for dose reduction.
Balancing the demonstrated effectiveness of antipsychotic medication for long-term maintenance treatment of schizophrenia with the risk of developing tardive dyskinesia (TD) has led to attempts to reduce dosage. Research using two methods is reviewed in this article; continuous low dose and intermittent or targeted medication. Both methods require monitoring of patients and treating decompensations with medication. Studies reviewed in this article indicate that these strategies are feasible for many patients, but are associated with higher risk of relapse than maintaining an established moderate dose. For low dose, relapse rates are higher if treatment continues for a second year, if dosage is very low, or if patients are not stable. However, low dose administration also leads to reduce adverse effects (including TD in at least one study) and improved subjective well being. Targeted medication leads to reduction of administered dose and side effects but to no clear benefit in terms of TD or social functioning. No studies reported to date have compared these strategies directly. Ongoing and future research will do this and identify those patients for whom these strategies can be implemented without increased relapse risk.


Involvement of young Australian adults in meal preparation: cross-sectional associations with sociodemographic factors and diet quality.
Involvement in meal preparation has the potential to affect diet quality, but has not been thoroughly investigated. The study aims were to describe the involvement of young adult men and women in meal preparation and to investigate whether extent of involvement was associated with diet quality. During 2004 to 2006, a national sample of 2,814 Australian adults aged 26 to 36 years completed a self-administered questionnaire on demographics, diet, and lifestyle factors. Participants were asked to report who was usually responsible for preparing the main meal on working days. Responses were categorized as "myself," "shared," or "someone else." Diet quality was assessed by calculating the mean number of daily servings for each food group. Analysis of variance was used to test for differences in means of dietary intake data. More women (65%) than men (29%) had sole responsibility for meal preparation. Shared meal preparation was reported by 23% of women and 27% of men. Factors associated with greater involvement in meal preparation included marital status, education, occupation, and physical activity. After adjusting for sociodemographic and lifestyle factors, men who prepared the main meal themselves had a higher intake of lean meat and alternatives. Women who shared the meal preparation had higher intakes of vegetables and dairy; however, these differences in diet quality were only small. These results suggest that strategies seeking to motivate greater involvement in meal preparation might not be sufficient to markedly improve diet quality in young Australian adults.


Federated repositories of X-ray diffraction images.
There is a pressing need for the archiving and curation of raw X-ray diffraction data. This information is critical for validation, methods development and improvement of archived structures. However, the relatively large size of these data sets has presented challenges for storage in a single worldwide repository such as the Protein Data Bank archive. This problem can be avoided by using a federated approach, where each institution utilizes its institutional repository for storage, with a discovery service overlaid. Institutional repositories are relatively stable and adequately funded, ensuring persistence. Here, a simple repository solution is described, utilizing Fedora open-source database software and data-annotation and deposition tools that can be deployed at any site cheaply and easily. Data sets and associated metadata from federated repositories are given a unique and persistent handle, providing a simple mechanism for search and retrieval via web interfaces. In addition to ensuring that valuable data is not lost, the provision of raw data has several uses for the crystallographic community. Most importantly, structure determination can only be truly repeated or verified when the raw data are available. Moreover, the availability of raw data is extremely useful for the development of improved methods of image analysis and data processing.


Serum-soluble B7x is elevated in renal cell carcinoma patients and is associated with advanced stage.
B7x is the newest member of the B7-CD28 family and is thought to dampen immune responses via negative costimulation. Tumor expression of B7x was recently described in renal cell carcinoma (RCC) and was associated with poor outcome. We developed an assay to detect serum-soluble B7x (sB7x) and investigated 101 patients with clear cell RCC who underwent nephrectomy between 2003 and 2007. For controls, we obtained serum from 101 sex-matched blood donors within the same age range. Following an ELISA for sB7x, detectable levels (>0.1 ng/mL) of sB7x were observed in 53 RCC patients compared with 18 controls (P < 0.001). Median (range) concentrations of sB7x for RCC patients and controls were 14.4 ng/mL (0.1-56.9) and 2.7 ng/mL (0.2-37.1), respectively. For RCC patients with detectable sB7x, median levels were significantly higher for patients with a tumor thrombus (19.2 versus 6.6 ng/mL; P = 0.007), positive lymph nodes (41.3 versus 10.3 ng/mL; P = 0.018), and distant metastases at nephrectomy (43.3 versus 8.5 ng/mL; P = 0.002) and tended to be higher in patients with high-grade tumors (18.8 versus 8.5; P = 0.090). Additionally, median sB7x levels for tumor-node-metastasis stage I to IV RCC were 6.6, 10.3, 14.5, and 43.3 ng/mL, respectively (P = 0.012). In this first evaluation of sB7x in RCC, we show that RCC patients are more likely to have detectable sB7x compared with controls and higher sB7x levels correlate with advanced tumor stage. These early results merit further investigation of this serum marker for potential diagnostic and prognostic purposes.


Electrolyzed Water as a Novel Sanitizer in the Food Industry: Current Trends and Future Perspectives.
Electrolyzed water (EW) has gained immense popularity over the last few decades as a novel broad-spectrum sanitizer. EW can be produced using tap water with table salt as the singular chemical additive. The application of EW is a sustainable and green concept and has several advantages over traditional cleaning systems including cost effectiveness, ease of application, effective disinfection, on-the-spot production, and safety for human beings and the environment. These features make it an appropriate sanitizing and cleaning system for use in high-risk settings such as in hospitals and other healthcare facilities as well as in food processing environments. EW also has the potential for use in educational building, offices, and entertainment venues. However, there have been a number of issues related to the use of EW in various sectors including limited knowledge on the sanitizing mechanism. AEW, in particular, has shown limited efficacy on utensils, food products, and surfaces owing to various factors, the most important of which include the type of surface, presence of organic matter, and type of tape water used. The present review article highlights recent developments and offers new perspectives related to the use of EW in various areas, with particular focus on the food industry.


Georgette Kidess, the First Female Neurosurgeon in Palestine.
The aim of this study is to detail the background, training, and career of Dr. Georgette Kidess, the first and still the only female neurosurgeon in Palestine. In addition, we mention the obstacles that women face during their neurosurgical career and how to overcome them. Also, we discuss different methods to attract female medical students to neurosurgery. Information was gathered only from direct face-to-face interviews with Dr. Kidess. Georgette Kidess was born on May 2, 1952, in Nablus, Palestine. She received the degree of Doctor of Medicine (M.D.) at Eberhard Karls Universität, Tübingen, Germany in 1979. She worked as a neurosurgeon at the Hadassah EinKarem Hospital in Jerusalem and subsequently established the first neurosurgical department at the Ramallah Governmental Hospital in Ramallah in 1986. Thereafter, she has continued a career in private practice, currently at Saint Luke's Hospital, Nablus. Dr. Kidess played a major part in establishing neurosurgery in Palestine. She was among the founders of the Palestinian Neurosurgical Society in 2014. In this article, we recount Dr. Kidess's contributions and achievements to neurosurgery in Palestine. Her commitment, persistence, and diligence enabled her to overcome great odds and become the first female neurosurgeon in Palestine. We hope that her story will inspire and open the doors for subsequent women to enter and enhance neurosurgery, especially in the Middle East.


BEST-Blockchain-Enabled Secure and Trusted Public Emergency Services for Smart Cities Environment.
In the last few years, the Internet of things (IoT) has recently gained attention in developing various smart city applications such as smart healthcare, smart supply chain, smart home, smart grid, etc. The existing literature focuses on the smart healthcare system as a public emergency service (PES) to provide timely treatment to the patient. However, little attention is given to a distributed smart fire brigade system as a PES to protect human life and properties from severe fire damage. The traditional PES are developed on a centralised system, which requires high computation and does not ensure timely service fulfilment. Furthermore, these traditional PESs suffer from a lack of trust, transparency, data integrity, and a single point of failure issue. In this context, this paper proposes a Blockchain-Enabled Secure and Trusted (BEST) framework for PES in the smart city environment. The BEST framework focuses on providing a fire brigade service as a PES to the smart home based on IoT device information to protect it from serious fire damage. Further, we used two edge computing servers, an IoT controller and a service controller. The IoT and service controller are used for local storage and to enhance the data processing speed of PES requests and PES fulfilments, respectively. The IoT controller manages an access control list to keep track of registered IoT gateways and their IoT devices, avoiding misguiding the PES department. The service controller utilised the queue model to handle the PES requests based on the minimum service queue length. Further, various smart contracts are designed on the Hyperledger Fabric platform to automatically call a PES either in the presence or absence of the smart-home owner under uncertain environmental conditions. The performance evaluation of the proposed BEST framework indicates the benefits of utilising the distributed environment and the smart contract logic. The various simulation results are evaluated in terms of service queue length, utilisation, actual arrival time, expected arrival time, number of PES departments, number of PES providers, and end-to-end delay. These simulation results show the effectiveness and feasibility of the BEST framework.


Human psychopharmacology of hoasca, a plant hallucinogen used in ritual context in Brazil.
A multinational, collaborative, biomedical investigation of the effects of hoasca (ayahuasca), a potent concoction of plant hallucinogens, was conducted in the Brazilian Amazon during the summer of 1993. This report describes the psychological assessment of 15 long-term members of a syncretic church that utilizes hoasca as a legal, psychoactive sacrament as well as 15 matched controls with no prior history of hoasca ingestion. Measures administered to both groups included structured psychiatric diagnostic interviews, personality testing, and neuropsychological evaluation. Phenomenological assessment of the altered state experience as well as semistructured and open-ended life story interviews were conducted with the long-term use hoasca group, but not the hoasca-naive control group. Salient findings included the remission of psychopathology following the initiation of hoasca use along with no evidence of personality or cognitive deterioration. Overall assessment revealed high functional status. Implications of this unusual phenomenon and need for further investigation are discussed.


Exonic sequencing and MLH3 gene expression analysis of breast cancer patients.
Breast cancer is the most common cancer in women worldwide. Detection of breast cancer susceptibility genes is an important issue. Also, MLH3 is a DNA mismatch repair gene and mutation in this gene is harmful in different cancers. This study aimed to use exome sequencing to uncover previously undetected breast cancer-predisposing variants. Also, we investigated the MLH3 gene expression of breast cancer patients which can be a breast cancer susceptibility gene. A total of 80 samples including 40 paired normal and cancer tissue samples were collected at Zheen International Hospital, Erbil, Iraq. Exome sequencing was used to identify mutations. Different in silico tools were used to predict the effect of mutation on the structural features or protein function. Real-time PCR was used for assessing the expression of MLH3 in breast cancer patients. We identified 26 variants in breast cancer patients, 22 inherited variants were found in MLH3, CHECK2, BRCA1, BRCA2, BLM, TP53, MSH6, NBN and PTEN genes and 4 somatic variants were found in PALB2, RAD50 and RBM10 genes. It was found that the expression of the MLH3 gene in tumor samples was significantly down-regulated compared with normal tissues. Statistically, high significance was found. The decreased expression of MLH3 was significant in all ranges of ages and all breast cancer types. Also, the expression of MLH3 decreased significantly in patients with breast cancer grades of II and III. In conclusion, MLH3 can be used as a susceptibility gene especially in grades II and III of breast cancer.


Herbicide resistance and cross-resistance: changes at three distinct sites in the herbicide-binding protein.
Plants and algae resistant to the commonly used s-triazine herbicides display a wide spectrum of cross-resistance to other herbicides that act in a similar manner. Analysis of uniparental mutants of the green alga Chlamydomonas reinhardi showed that three different amino acid residues in the 32-kilodalton thylakoid membrane protein can be independently altered to produce three different patterns of resistance to s-triazine and urea-type herbicides. These results clarify the molecular basis for herbicide resistance and cross-resistance. Two of the mutations do not alter normal electron transport and thus may have applications of agronomic interest.


Porphyromonas gingivalis-derived lysine gingipain enhances osteoclast differentiation induced by tumor necrosis factor-α and interleukin-1β but suppresses that by interleukin-17A: importance of proteolytic degradation of osteoprotegerin by lysine gingipain.
Periodontitis is a chronic inflammatory disease accompanied by alveolar bone resorption by osteoclasts. Porphyromonas gingivalis, an etiological agent for periodontitis, produces cysteine proteases called gingipains, which are classified based on their cleavage site specificity (i.e. arginine (Rgps) and lysine (Kgps) gingipains). We previously reported that Kgp degraded osteoprotegerin (OPG), an osteoclastogenesis inhibitory factor secreted by osteoblasts, and enhanced osteoclastogenesis induced by various Toll-like receptor (TLR) ligands (Yasuhara, R., Miyamoto, Y., Takami, M., Imamura, T., Potempa, J., Yoshimura, K., and Kamijo, R. (2009) Lysine-specific gingipain promotes lipopolysaccharide- and active-vitamin D3-induced osteoclast differentiation by degrading osteoprotegerin. Biochem. J. 419, 159-166). Osteoclastogenesis is induced not only by TLR ligands but also by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-17A, in inflammatory conditions, such as periodontitis. Although Kgp augmented osteoclastogenesis induced by TNF-α and IL-1β in co-cultures of mouse osteoblasts and bone marrow cells, it suppressed that induced by IL-17A. In a comparison of proteolytic degradation of these cytokines by Kgp in a cell-free system with that of OPG, TNF-α and IL-1β were less susceptible, whereas IL-17A and OPG were equally susceptible to degradation by Kgp. These results indicate that the enhancing effect of Kgp on cytokine-induced osteoclastogenesis is dependent on the difference in degradation efficiency between each cytokine and OPG. In addition, elucidation of the N-terminal amino acid sequences of OPG fragments revealed that Kgp primarily cleaved OPG in its death domain homologous region, which might prevent dimer formation of OPG required for inhibition of receptor activator of nuclear factor κB ligand. Collectively, our results suggest that degradation of OPG by Kgp is a crucial event in the development of osteoclastogenesis and bone loss in periodontitis.


Structure of the Borrelia burgdorferi ATP-dependent metalloprotease FtsH in its functionally relevant hexameric form.
ATP-dependent proteases FtsH are conserved in bacteria, mitochondria, and chloroplasts, where they play an essential role in degradation of misfolded/unneeded membrane and cytosolic proteins. It has also been demonstrated that the FtsH homologous protein BB0789 is crucial for mouse and tick infectivity and in vitro growth of the Lyme disease-causing agent Borrelia burgdorferi. This is not surprising, considering B. burgdorferi complex life cycle, residing in both in mammals and ticks, which requires a wide range of membrane proteins and short-lived cytosolic regulatory proteins to invade and persist in the host organism. In the current study, we have solved the crystal structure of the cytosolic BB0789166-614, lacking both N-terminal transmembrane α-helices and the small periplasmic domain. The structure revealed the arrangement of the AAA+ ATPase and the zinc-dependent metalloprotease domains in a hexamer ring, which is essential for ATPase and proteolytic activity. The AAA+ domain was found in an ADP-bound state, while the protease domain showed coordination of a zinc ion by two histidine residues and one aspartic acid residue. The loop region that forms the central pore in the oligomer was poorly defined in the crystal structure and therefore predicted by AlphaFold to complement the missing structural details, providing a complete picture of the functionally relevant hexameric form of BB0789. We confirmed that BB0789 is functionally active, possessing both protease and ATPase activities, thus providing novel structural-functional insights into the protein, which is known to be absolutely necessary for B. burgdorferi to survive and cause Lyme disease.


Multiplex loop-mediated isothermal amplification-based lateral flow dipstick for simultaneous detection of 3 food-borne pathogens in powdered infant formula.
In this study, we established a rapid, simple, and sensitive method for visual and point-of-care detection of Salmonella spp., Cronobacter spp., and Staphylococcus aureus in powdered infant formula (PIF) based on multiplex loop-mediated isothermal amplification (mLAMP) combined with lateral flow dipstick (LFD). Three different species-specific target genes, siiA of Salmonella spp., internal transcribed space (ITS) of Cronobacter spp., and nuc of Staph. aureus, were applied in the mLAMP with biotin-, digoxin-, and Texas Red-modified forward inner primers and fluorescein isothiocyanate (FITC)-modified backward inner primers. After mLAMP, a large number of modified amplicons were detected with LFD; one end of the amplicon was conjugated to the anti-FITC antibody on gold nanoparticles and the other end to streptavidin (anti-digoxin or anti-Texas Red antibody) on test lines. Visual inspection of the device relies on the presence of a red band formed by accumulation of sandwich composites. The detection limits of this mLAMP-LFD assay for Salmonella spp., Cronobacter spp., and Staph. aureus in PIF without enrichment were 4.2, 2.6, and 3.4 cfu/g, respectively. The whole method can be completed in less than 1 h. Thus, mLAMP-LFD is a rapid and efficient method for simultaneously detecting Salmonella spp., Cronobacter spp., and Staph. aureus in PIF.


Effect of dietary level of protein or methionine and threonine on the amino acids and catecholamines in brain of rats fed a high tyrosine diet.
When rats were fed a high tyrosine diet (5% in diet), plasma tyrosine, brain tyrosine, norepinephrine (NE), and 3-methoxy-4-hydroxyphenylethyleneglycol-sulfate (MHPG-SO4) were increased. The concentrations of brain tyrosine were directly correlated with those of plasma tyrosine and tyrosine ratios (tyrosine/large neutral amino acid (LNAA)) in plasma and brain. When rats were fed a high tyrosine diet with increasing amounts of the dietary protein, the contents of brain tyrosine and MHPG-SO4 decreased stepwise. By the supplementation of both methionine and threonine to the high tyrosine diet, the enhancement of brain tyrosine and MHPG-SO4 caused by tyrosine was significantly reduced. These results suggest that effects of tyrosine toxicity such as growth retardation or external pathological lesions may be due to the accelerated NE-turnover in the brain accompanied by the enhancement of brain tyrosine concentration. The supplemented methionine and threonine may cause an increase of tyrosine utilization, because methionine and threonine are the most limiting amino acids in casein, and also may inhibit the uptake of tyrosine into the brain via the blood-brain barrier.


Development of a single-meal fish consumption advisory for methyl mercury.
Methyl mercury (meHg) contamination of fish is the leading cause of fish consumption advisories in the United States. These advisories have focused upon repeated or chronic exposure, whereas risks during pregnancy may also exist from a single-meal exposure if the fish tissue concentration is high enough. In this study, acute exposure to meHg from a single fish meal was analyzed by using the one-compartment meHg biokinetic model to predict maternal hair concentrations. These concentrations were evaluated against the mercury hair concentration corresponding to the U.S. Environmental Protection Agency's reference dose (RfD), which is intended to protect against neurodevelopmental effects. The one-compartment model was validated against blood concentrations from three datasets in which human subjects ingested meHg in fish, either as a single meal or multiple meals. Model simulations of the single-meal scenario at different fish meHg concentrations found that concentrations of 2.0 ppm or higher can be associated with maternal hair concentrations elevated above the RfD level for days to weeks during gestation. A single-meal fish concentration cutoff of > or = 2.0 ppm is an important consideration, especially because this single high exposure event might be in addition to a baseline meHg body burden from other types of fish consumption. This type of single-meal advisory requires that fish sampling programs provide data for individual rather than composited fish, and take into account seasonal differences that may exist in fish concentrations.


[Growth of small for gestational age preterm infants].
To describe the linear growth and growth velocity of preterm infants born small for gestational age according to variables such as weight, length and head circumference, from birth to three months of corrected age. Prospective study of one hundred preterm infants born small for gestational age from 28 to 36 weeks after birth and classified as small according to the weight for their gestational age. The anthropometric data was obtained at birth, and continued to be measured weekly until the probable delivery date and monthly until three months of corrected age. Growth curves were calculated according to the mean values adjusted by the polynomial function of Count model. The infants' growth curves for the three variables were much below the ones of the preterm infants with adequate size for gestational age until the fortieth week. However, the head circumference growth reached the 10th percentile curve of the NCHS at the fortieth week, and the 25th percentile at three months of corrected age. The weight growth curve reached the 10th percentile curve around one month and a half for males and two months and a half for females. The length growth curve reached the 10th percentile for males at three months of corrected age and it almost reached that percentile for females after the same period of time. A tendency of recovering weight and length related to preterm infants with adequate size and term newborns was observed. The head circumference showed an obvious and early recovery.


Standardizing and Evaluating Transitions of Care in the Era of Duty Hour Reform: One Institution's Resident-Led Effort.
Compliance with the Accreditation Council for Graduate Medical Education duty hour standards may necessitate more frequent transitions of patient responsibility. We created a multidisciplinary Patient Safety and Quality Council with a Task Force on Handoffs (TFH), engaging residents at a large, university-based institution. The TFH identified core content of effective handoffs and patterned institutional content on the SIGNOUTT mnemonic. A web-based module highlighting core content was developed for institutional orientation of all trainees beginning summer 2011 to standardize handoff education. The TFH distributed handoff material and catalogued additional program initiatives in teaching and evaluating handoffs. A standard handoff evaluation tool, assessing content, culture, and communication, was developed and "preloaded" into the institution-wide electronic evaluation system to standardize evaluation. The TFH developed questions pertaining to handoffs for an annual institutional survey in 2011 and 2012. Acceptability of efforts was measured by program participation, and feasibility was measured by estimating time and financial costs. Programs found the TFH's efforts to improve handoffs acceptable; to date, 13 program-specific teaching initiatives have been implemented, and the evaluation tool is being used by 5 programs. Time requirements for TFH participants average 2 to 3 h/mo, and financial costs are minimal. More residents reported having education on handoffs (58% [388 of 668] versus 42% [263 of 625], P < .001) and receiving adequate signouts (69% [469 of 680] versus 61% [384 of 625], P = .004) in the 2012 survey, compared with 2011. Use of a multispecialty resident leadership group to address content, education, and evaluation of handoffs was feasible and acceptable to most programs at a large, university-based institution.


Conarubins A-D: Four Monoterpene-Chalcone Conjugates from Conamomum rubidum and Their Anti-inflammatory and Cytotoxic Activities.
Four novel compounds, conarubins A-D (1-4), were isolated from the whole plants of Conamomum rubidum collected in Vietnam. Their structures were elucidated by extensive spectroscopic analyses and by quantum chemical calculations of NMR and ECD. Compounds 1 and 2 were the first examples of monoterpene-monoterpene-chalcone conjugates in nature, whereas compound 4 was an unprecedented monoterpene-substituted chalcone containing a 3,4,5-trioxygenated cyclohexa-2,5-diene-1-one ring. The anti-inflammatory and cytotoxic activities of all isolates were investigated.


A premature infant with Costello syndrome due to a rare G13C HRAS mutation.
Costello syndrome is caused by mutations in the HRAS proto-oncogene whose clinical features in the first year of life include fetal and neonatal macrosomia with subsequent growth impairment due to severe feeding difficulties. We report on a premature male with Costello syndrome due to a rare G13C HRAS mutation and describe his clinical features and evolution during the first year of life. The diagnosis of Costello syndrome may be difficult at birth, especially in very preterm infants in whom feeding difficulties, reduced subcutaneous adipose tissue and failure to thrive are also part of their typical presentation.


A controlled study of postpartum depression in adult women.
The main purpose of the study was to examine the hypothesis that the postpartum period represents a time of increased risk for depression. The other psychosocial variables on stress, social support and self-esteem were also measured. Adult women, ranging in age from 22 to 45 years, comprised two samples: 148 postnatal women (22 to 44 years) and 148 controls (22 to 45 years). Five sets of instruments were used to collect data: the Demographic Data Form, the Perceived Stress Scale, the Interpersonal Support Evaluation List, the Coopersmith's Self-Esteem Inventory, and the Beck Depression Inventory. Although the postnatal group tended to have a higher rate of depression, the difference was not statistically significant. No significant differences in stress, social support, self-esteem or depression were found between these two groups. However, postnatal women reported significantly higher somatic symptoms of depression than controls. Results of the stepwise multiple regression indicated that the best subset to predict postpartum depression was self-esteem, stress, postnatal complication and work status. The best subset to predict depression of controls included self-esteem, social support, socioeconomic status and stress. Our data indicate that the psychosocial health status of postnatal women is not significantly different from the controls, although the postnatal women complain more about the loss of bodily functions. The possible explanations deserve further research.


Temporal Association Between Respiratory Events and Reflux in Patients With Obstructive Sleep Apnea and Laryngopharyngeal Reflux.
The aim of the current study was to test the hypothesis that there is a temporal correlation between reflux episodes and respiratory events in patients with laryngopharyngeal reflux and obstructive sleep apnea. Adults with clinically diagnosed laryngopharyngeal reflux confirmed by two validated instruments (reflux symptom index ≥ 13 and reflux finding score ≥ 7) and obstructive sleep apnea (OSA) underwent full polysomnography with concomitant and synchronized multichannel intraluminal impedance-pH esophageal monitoring. The apnea-hypopnea and arousal indexes that occurred 15, 30, and 45 minutes before and after each reflux episode were recorded and compared to full-night apnea and hypopnea and arousal index. We studied 27 patients (14 males, age 51.7 ± 9.1 years, body mass index 32.4 ± 4.2 kg/m²) with laryngopharyngeal reflux (reflux symptom index 16 ± 2 and reflux finding score 12 ± 3) and OSA (apnea-hypopnea index = 32.3 ± 28.4 events/h). We evaluated 102 reflux episodes. Almost half of the reflux episodes occurred while awake (43.1%) and only five reflux episodes (4.9%) occurred during an obstructive respiratory event. The apnea and hypopnea and arousal indexes 15, 30, and 45 minutes before and after reflux episodes were lower than full-night apnea and hypopnea and arousal indexes, respectively. Among patients with well-established laryngopharyngeal reflux and OSA, there is no temporal association between reflux and obstructive respiratory events. Even though the data comprised a small sample size, it seems that a more complex mechanism is involved with these two highly prevalent diseases.


Comparing daily physiological and psychological benefits of gratitude and optimism using a digital platform.
Gratitude and optimism are positive psychological dispositions associated with beneficial outcomes. To examine their associations with physiological and psychological experiences in daily life, we examined data from an Ecological Momentary Assessment study (N = 4,825), including blood pressure, heart rate, and reports of stress, health behaviors, and thoughts. Trait gratitude and trait optimism both predicted lower heart rate and blood pressure, better sleep quality, more exercise, less stress, more positive expectations and reflections, and greater feelings of appreciation toward others. However, gratitude and optimism were not completely overlapping constructs: Gratitude was a stronger predictor of felt appreciation toward others and pleasantness when reflecting on the best part of the day, whereas optimism was a stronger predictor of sleep quality, lower stress, and lower unpleasantness when reflecting on the worst part of the day. These associations reveal both similar and differential influences of positive dispositions on psychological and physiological outcomes that provide insight into health consequences. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Reverse STAR for retrograde recanalisation in a chronic total coronary artery occlusion present for 21 years.
Reopening chronic total occlusions (CTOs) has been shown to alleviate anginal symptoms as well improve left ventricular ejection fraction. In patients with previous coronary artery bypass grafts, management of CTOs may avoid the need for repeat surgery. A variety of techniques have been described including subintimal tracking and re-entry (STAR) and CART approaches. The anatomy and the length of time that a CTO is present can determine whether it can be reopened. The present report describes a variation on the STAR technique used to open a CTO present for 21 years.


Impact resistance of ophthalmic lenses of various strengths and the influence of frame design.
Protection of the eyes by safety type spectacle, sunglass and goggle lenses has received considerable attention in recent years. Such protection can be enhanced by design of the frame. We report from 476 lenses mounted in 238 frames and subjected to 9,397 impacts. Maximum blows were delivered by a one inch diameter steel ball falling from a height of 122 inches. Results indicated that the force required to fracture lenses in plastic frame mountings was more than twice that required for fracture of identical strength lenses in wire rims. Minus cylindrical lenses were the most frangible. The lowest fracture and posterior dislocation rates were found in industrial plastic frames with a retaining lip. Greater energy attenuation can be induced in a heat tempered glass lens by even edge compression. Good lens and frame design, when properly correlated, should provide impact attenuation distinctly exceeding conventional standards.


Competitive survival in a devastated industry: Evidence from hotels during COVID-19.
In the face of COVID-19, the federal government scrambled to provide emergency funding to businesses, but did not always take into account the heterogeneous nature of firms, especially within industries. Using the lodging industry as the application, this article shows that businesses' failure risk in a pandemic depends on a business' native ability to adapt to changing safety needs, in particular its ability to provide a socially distanced environment. Hotels not well suited to social distancing-for example, destination-type hotels with large gathering spaces and many personalized services-offered deeper price discounts or closed down altogether during the pandemic. Simpler hotels with fewer ancillary services were more likely to remain open, with a substantial proportion actually increasing prices. Area infection rates mattered little. Effects are identified by comparing prepandemic expectations of outcomes to updated within-pandemic expectations of outcomes, all while holding the place and the time of consumption fixed.


Antituberculosis drug resistance in immigrants to Alberta, Canada, with tuberculosis, 1982-1994.
Provincial Tuberculosis Service, Alberta, Canada. To estimate resistance rates of Mycobacterium tuberculosis to antituberculosis drugs in relation to previous treatment, country of origin, age and duration of residence in Canada. Retrospective chart review of all culture-positive tuberculosis diagnosed between 1982 and 1994 in immigrants to Alberta. A total of 753 immigrants with culture-positive tuberculosis were studied; 131 patients (17.4%, 95% Confidence Interval [CI] 14.7, 20.1) had strains resistant to one or more of the first-line medications (isoniazid [INH], rifampin [RIF], ethambutol [EMB], pyrazinamide [PZA], and streptomycin [SM]). Initial and secondary resistance rates were 16.4% and 30.3%, respectively (P = 0.003, Odds ratio [OR] 2.2, 95% CI 1.3, 3.8). Resistance occurred in 22.2% of patients 40 years of age and under, and in 13.8% of those over 40 years of age (P = 0.005, OR 1.8, 95% CI 1.2, 2.6). Resistant M. tuberculosis was isolated from 20.4% of those who had lived in Canada for less than 15 years, and in 9.0% of those who had immigrated to Canada more than 15 years before diagnosis (P < 0.001; OR 2.4, 95% CI 1.3, 4.2). Resistance rates to individual medications in all immigrants were as follows: INH 9.9% (95% CI 7.8, 12.0), RIF 0.8% (95% CI 0.2, 1.4), EMB 1.9% (95% CI 1.0, 2.8), PZA 1.9% (95% CI 0.3, 3.5), and SM 12.9% (95% CI 10.4, 15.4). Immigrants from Vietnam, China, and the Philippines had tuberculosis strains that were resistant to one or more of the first line medications in 30.2%, 21.8%, and 15.5% of cases, respectively (P = 0.04). In industrialized countries such as Canada where most cases of tuberculosis are diagnosed among the foreign-born, drug resistance surveys continue to be an important part of an effective tuberculosis control program.


State-of-the-Art lecture. Statins and blockers of the renin-angiotensin system: vascular protection beyond their primary mode of action.
In addition to their primary mode of action, statins and blockers of the renin-angiotensin system possess common additional properties that are under active investigation. The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of shared effects that target the arterial wall. These and other properties may eventually become exploited for the improved treatment of cardiovascular diseases and of other diseases apparently unrelated to the cardiovascular field, including inflammation and cancer. This review analyzes the current knowledge on the pleiotropic properties of these classes of drugs. Direct comparison indicates that study of the associations among these drugs may eventually disclose additive or synergistic effects that, perhaps even at lower dosages, may provide improved vascular protection and a strong alliance against several atherogenic mechanisms.


Implementation and microbiological stability of dose-banded ganciclovir infusion bags prepared in series by a robotic system.
The implementation of dose-banding (DB) in centralised, pharmacy-based cytotoxic drug preparation units allows the preparation of standardised doses in series. The aim of this study was to evaluate the feasibility of DB for the prescribing of ganciclovir (GV) infusion solutions and to investigate the microbiological stability of dose-banded, automatically prepared ready-to-administer GV infusion bags by media-fill simulation tests and sterility tests. The frequency of prescription of GV doses was retrospectively analysed before and after implementing the DB scheme. Four dose-ranges or 'bands' and the corresponding standard doses (250, 300, 350, 400 mg) were identified. The maximum variance was set at ±10% of the individually prescribed dose. The aseptic preparation of a series of GV infusion bags was simulated with double strength tryptic soy broth as growth medium and prefilled 0.9% NaCl polyolefin infusion bags as primary packaging materials. The simulation process was performed with the APOTECAchemo robot on five consecutive days. In total, 50 infusion bags were filled, incubated and stored for 12 weeks at room temperature. The media-filled bags were visually inspected for turbidity after 2, 4, 8, 10 and 12 weeks. Following incubation, growth promotion tests were performed. During the simulation tests, airborne contamination was monitored with settle plates and microbial surface contamination with contact plates. Pooled sterility tests were performed for a series of 10 standard GV infusion bags after a 12-week storage period under refrigeration (2 °C-8 °C). After implementation of the DB scheme, about 60% of the prescribed GV doses were prepared as standard preparations by the robotic system. The number of different GV doses was reduced by 61.8% (76 vs 29). None of the 50 media-filled bags showed turbidity after a storage period of 12 weeks, indicating the absence of microorganisms. The environmental monitoring with settle/contact plates matched the recommended limits set for cleanroom Grade A zones, except in the loading area of the robot. Media fills used for the sterility tests remained clear during the incubation period, thereby revealing sterility. Positive growth promotion tests proved the process's reliability. A DB scheme for prescribing and preparation of standard GV infusion bags was successfully implemented. Microbiological tests of aseptic preparation of infusion bags in series by the APOTECAchemo robot revealed an adequate level of sterility and a well-controlled aseptic procedure. The sterility was maintained over extended storage periods, thereby encouraging extended beyond-use dating.


Identifying the turning point: using the transtheoretical model of change to map intimate partner violence disclosure in emergency department settings.
Background. The transtheoretical model of change (TTM) was used as a framework to examine the steps that women took to disclose intimate partner violence (IPV) in urban emergency departments. Methods. Mapping methods portrayed the evolving nature of decisions that facilitated or inhibited disclosure. This paper is a secondary analysis of qualitative data from a mixed methods study that explored abused women's decision making process about IPV disclosure. Findings. Change maps were created for 19 participants with movement from the precontemplation to the maintenance stages of the model. Disclosure often occurred after a significant "turning point event" combined with a series of smaller events over a period of time. The significant life event often involved a weighing of options where participants considered the perceived risks against the potential benefits of disclosure. Conclusions. Abused women experienced intrusion from the chaotic nature of the emergency department. IPV disclosure was perceived as a positive experience when participants trusted the health care provider and felt control over their decisions to disclose IPV. Practice Implications. Nurses can use these findings to gauge the readiness of women to disclose IPV in the emergency department setting.


Induction of CD4+ T-cell anergy and apoptosis by activated human B cells.
B cells are well-known mediators of humoral immunity and serve as costimulators in the generation of T cell-mediated responses. In several mouse models, however, it was observed that B cells can also down-regulate immune reactions, suggesting a dual role for B cells. Due to this discrepancy and so far limited data, we directly tested the effects of primary human B cells on activated CD4(+) T helper cells in vitro. We found that under optimal costimulation large, activated CD25(+) B cells but not small CD25(-) B cells induced temporary T-cell anergy, determined by cell division arrest and down-regulation of cytokine production. In addition, large CD25(+) B cells directly induced CD95-independent apoptosis in a subpopulation of activated T cells. Suppression required direct B-T-cell contact and was not transferable from T to T cell, excluding potential involvement of regulatory T cells. Moreover, inhibitory effects involved an IL-2-dependent mechanism, since decreasing concentrations of IL-2 led to a shift from inhibitory toward costimulatory effects triggered by B cells. We conclude that activated CD25(+) B cells are able to costimulate or down-regulate T-cell responses, depending on activation status and environmental conditions that might also influence their pathophysiological impact.


The Ripple Effect: A Train-the-Trainer Model to Exponentially Increase Organizational Faculty Development.
This article was migrated. The article was marked as recommended. Faculty development is a key component of undergraduate and graduate medical education and is required for accreditation. Many institutions face the challenges of training large numbers of faculty at multiple locations on a recurring basis. In order to meet the faculty development demands of our organization, we implemented a train-the trainer model of faculty development. A train-the-trainer program was created using deliberate practice as the theoretical framework. The primary goals of the program were to enhance content knowledge and develop facilitation skills of the participants (called faculty trainers). Two separate cohorts received 40 hours of in-person training consisting of attending the faculty development workshops as a learner, providing feedback to course faculty, facilitating and participating in journal club sessions on relevant content, and practicing facilitation and receiving feedback on the workshops. Cohorts 1 and 2 were trained on how to deliver 6 and 7 workshops, respectively. An additional 16 hours of training and further feedback occurred when faculty trainers delivered the workshops at outside institutions. Twenty-nine faculty trainers from 15 specialties and subspecialties were trained, including 18 in the first cohort (January 2018) and 14 in the second cohort (February 2019) with 3 who participated in both cohorts. From January 2018 to January 2020, faculty trainers delivered 298 workshops to 3742 attendees at 25 locations. For the faculty trainers, 1477 evaluations were completed with 1031 (88.1%) rated as excellent, 141 (9.5%) rated as good, and 8 (0.5%) as average. There were no fair or poor ratings. Our train-the-trainer program effectively developed a community of national faculty developers. Faculty trainer output was substantial and early evaluations of performance were positive. The model outlined in this paper serves as a potential sustainable model for other institutions desiring to train a cadre of faculty developers for their organization.


Pushed to the Fringe - The Impact of Vaccine Hesitancy on Children and Families.
Vaccine hesitancy has been described as any delay or refusal of vaccines despite their availability and is increasing in Australia and other middle to high-income countries. The aim of this study is to gain a deep understanding of the experiences and influences on vaccine hesitant children and their families. A qualitative interview approach was undertaken with vaccine hesitant parents and pregnant women (n = 12). Semi-structured interviews were conducted by telephone. Inductive thematic analysis was undertaken on data obtained using the guidelines of Braun and Clarke. Three main themes were identified in this study, including Pushed to the fringe; A culture of Distrust; and Coerced choices. The study revealed that vaccine hesitant parents felt isolated and pushed to the fringe of society. They also expressed dissatisfaction with the Australian "No Jab - No Pay" and "No Jab - No Play" legislation. This contributed to feelings of marginalization. Participants also cited a breakdown in the therapeutic relationships, which impacted their child's health. Additionally, a lack of sufficient information was received to achieve informed consent. These results suggest that there is a need for enhanced education for some health-care professionals, many of whom have reported being confronted by conversations with vaccine hesitant parents.


Designing of the Cooling Vest from Paraffin Compounds and Evaluation of its Impact Under Laboratory Hot Conditions.
The phase change materials (PCMs) have the appropriate properties for controlling heat strain. One of the well-known PCMs is paraffin. This study aimed to design the cooling vest from the cheap commercial paraffin compound and evaluation of its effectiveness under laboratory hot conditions. the cooling vest was made of the polyester fabric and it had 17 aluminum packs. The each of aluminum packs was filled by 135 g of prepared paraffin with a proper melting point in the range of 15-35°C. an experimental study was conducted on ten male students under warm conditions (air temperature = 40°C, relative humidity = 40%) in a climatic chamber. Each participant was tested without cooling vest and with cooling in two activities rate on treadmill to include: light (2.8 km/h) and moderate (4.8 km/h). The time of this test was 30 min in each stage. During the test, the heart rate, the oral temperature, the skin temperature were measured every 4 min. Finally, data were analyzed using the Kolmogrov-Smirnov and repeated measurement ANOVA test in SPSS 16. The latent heat of the prepared paraffin compound and the peak of the melting point were 108 kJ/kg and 30°C, respectively. The mean and standard deviation of heart rate, oral temperature, and skin temperature with cooling vest in light activity were 103.9 (12.12) beat/min, 36.77 (0.32)°C, and 31.01 (1.96)°C and in moderate activity were 109.5 (12.57) beat/min, 36.79 (0.20)°C, and 29.69 (2.23)°C, respectively. There is a significant difference between parameters with a cooling vest and without cooling (P < 0.05). The designed cooling vest with low cost can be used to prevent thermal strain and to increase the physiological stability against the heat. However, the latent heat of this cooling vest was low.