Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes.
We employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH). Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH. This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.


Two-photon imaging of glutathione levels in intact brain indicates enhanced redox buffering in developing neurons and cells at the cerebrospinal fluid and blood-brain interface.
Glutathione is the major cellular thiol present in mammalian cells and is critical for maintenance of redox homeostasis. However, current assay systems for glutathione lack application to intact animal tissues. To map the levels of glutathione in intact brain with cellular resolution (acute tissue slices and live animals), we have used two-photon imaging of monochlorobimane fluorescence, a selective enzyme-mediated marker for reduced glutathione. Previously, in vitro experiments using purified components and cultured glial cells attributed cellular monochlorobimane fluorescence to a glutathione S-transferase-dependent reaction with GSH. Our results indicate that cells at the cerebrospinal fluid or blood-brain interface, such as lateral ventricle ependymal cells (2.73 +/- 0.56 mm; glutathione), meningeal cells (1.45 +/- 0.09 mm), and astroglia (0.91 +/- 0.08 mm), contain high levels of glutathione. In comparison, layer II cortical neurons contained 20% (0.21 +/- 0.02 mm) the glutathione content of nearby astrocytes. Neuronal glutathione labeling increased 250% by the addition of the cell-permeable glutathione precursor N-acetylcysteine indicating that the monochlorobimane level or glutathione S-transferase activity within neurons was not limiting. Regional mapping showed that glutathione was highest in cells lining the lateral ventricles, specifically ependymal cells and the subventricular zone, suggesting a possible function for glutathione in oxidant homeostasis of developing neuronal progenitors. Consistently, developing neurons in the subgranular zone of dentate gyrus contained 3-fold more glutathione than older neurons found in the neighboring granular layer. In conclusion, mapping of glutathione levels in intact brain demonstrates a unique role for enhanced redox potential in developing neurons and cells at the cerebrospinal fluid and blood-brain interface.


Multi-Staged Regulation of Lipid Signaling Mediators during Myogenesis by COX-1/2 Pathways.
Cyclooxygenases (COXs), including COX-1 and -2, are enzymes essential for lipid mediator (LMs) syntheses from arachidonic acid (AA), such as prostaglandins (PGs). Furthermore, COXs could interplay with other enzymes such as lipoxygenases (LOXs) and cytochrome P450s (CYPs) to regulate the signaling of LMs. In this study, to comprehensively analyze the function of COX-1 and -2 in regulating the signaling of bioactive LMs in skeletal muscle, mouse primary myoblasts and C2C12 cells were transfected with specific COX-1 and -2 siRNAs, followed by targeted lipidomic analysis and customized quantitative PCR gene array analysis. Knocking down COXs, particularly COX-1, significantly reduced the release of PGs from muscle cells, especially PGE2 and PGF2α, as well as oleoylethanolamide (OEA) and arachidonoylethanolamine (AEA). Moreover, COXs could interplay with LOXs to regulate the signaling of hydroxyeicosatetraenoic acids (HETEs). The changes in LMs are associated with the expression of genes, such as Itrp1 (calcium signaling) and Myh7 (myogenic differentiation), in skeletal muscle. In conclusion, both COX-1 and -2 contribute to LMs production during myogenesis in vitro, and COXs could interact with LOXs during this process. These interactions and the fine-tuning of the levels of these LMs are most likely important for skeletal muscle myogenesis, and potentially, muscle repair and regeneration.


Metformin Corrects Abnormal Circadian Rhythm and Kir4.1 Channels in Diabetes.
Diabetic retinopathy (DR) is a leading cause of visual impairment. Müller cells in DR are dysfunctional due to downregulation of the inwardly rectifying potassium channel Kir4.1. Metformin, a commonly used oral antidiabetic drug, is known to elicit its action through 5' adenosine monophosphate-activated protein kinase (AMPK), a cellular metabolic regulator; however, its effect on Kir4.1 channels is unknown. For this study, we hypothesized that metformin treatment would correct circadian rhythm disruption and Kir4.1 channel dysfunction in db/db mice. Metformin was given orally to db/db mice. Wheel-running activity, retinal levels of Kir4.1, and AMPK phosphorylation were determined at study termination. In parallel, rat retinal Müller cell line (rMC-1) cells were treated using metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to assess the effect of AMPK activation on the Kir4.1 channel. The wheel-running activity of the db/db mice was improved following the metformin treatment. The Kir4.1 level in Müller cells was corrected after metformin treatment. Metformin treatment led to an upregulation of clock regulatory genes such as melanopsin (Opn4) and aralkylamine N-acetyltransferase (Aanat). In rMC-1 cells, AMPK activation via AICAR and metformin resulted in increased Kir4.1 and intermediate core clock component Bmal-1 protein expression. The silencing of Prkaa1 (gene for AMPKα1) led to decreased Kir4.1 and Bmal-1 protein expression. Our findings demonstrate that metformin corrects abnormal circadian rhythm and Kir4.1 channels in db/db mouse a model of type 2 diabetes. Metformin could represent a critical pharmacological agent for preventing Müller cell dysfunction observed in human DR.


A cemented cup with acetabular impaction bone grafting is more cost-effective than an uncemented cup in patients under 50 years.
Acetabular deficiencies in young patients can be restored in several ways during total hip arthroplasty. Currently, cementless cups are most frequently used. Impaction bone grafting of acetabular defects is a more biological approach, but is it cost-effective in young patients on the long term? We designed a decision model for a cost-utility analysis of a cemented cup with acetabular impaction bone grafting versus an uncemented cup, in terms of cost per quality-adjusted life year (QALY) for the young adult with acetabular bone deficiency, in need for a primary total hip arthroplasty. Outcome probabilities and effectiveness were derived from the Radboud University Nijmegen Medical Centre and the Norwegian Hip Register. Multiple sensitivity analyses were used to assess the contribution of the included variables in the model's outcome. Cemented cups with impaction bone grafting were more cost-effective compared to the uncemented option in terms of costs per QALY. A scenario suggesting equal primary survival rates of both cemented and uncemented cups still showed an effect gain of the cemented cup with impaction bone grafting, but at higher costs. Based on this model, the first choice of treatment of the acetabular bone deficient osteoarthritic hip in a young patient is reconstruction with impaction bone grafting and a cemented cup.


A review of influenza immunisation in Lothian.
To assess the influence of the Chief Medical Officer's annual guidelines on influenza immunisation and to estimate vaccine uptake particularly of those resident in long-stay residential facilities and of other recommended at-risk groups. Postal questionnaires. Lothian, Scotland (population 750,000). All consultants caring for patients in long stay National Health Service facilities; a random sample of all general practitioners (GP's) in Lothian; managers/charge nurses of all local authority, private and voluntary long stay facilities in Lothian and continuing care facilities in the National Health Service including adults and children. Number (%) of general practitioners offering influenza vaccine to at-risk groups as defined in the Chief Medical Officer's guidelines; number (%) of hospital consultants caring for long-stay patients in hospital in Lothian who offer influenza vaccine to the same at-risk groups; percentage of long-stay residents/patients who received influenza vaccine in 1992-3. Seventy nine (75%) GPs said they offered influenza vaccine to all at-risk groups; 15 (14%) GPs said they did not care for patients in long-stay facilities but offered vaccine to the other at-risk groups; 12 (11%) GPs who did have long-stay residents on their list, offered vaccine to some of them only and to all other at-risk groups; 14 (56%) hospital consultants did not offer influenza vaccine to long-stay patients; 10 (40%) immunised only those at risk from chronic medical conditions if their quality of life was good; 1 (4%) consultant offered vaccine to all long-stay patients. In the winter of 1992-3, the mean proportion of residents immunised in private nursing homes was 65%, in residential homes 68.5%, and in long-stay National Health Service wards 4.5%. GPs commented that annual publicity was confusing for the public, vaccine was not available at the right time and there was uncertainty on the efficacy of the vaccine. Hospital consultants were reluctant to immunise patients with a poor quality of life or who were demented and unable to give consent. A large majority of GPs followed official advice and offered influenza vaccine to long-stay patients and other at risk groups. Hospital consultants offered influenza vaccine only to a small proportion of their long-stay patients, primarily those with a good quality of life.


Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial.
The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio. We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78-1.14] vs. 0.75 [IQR 0.57-0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75-245] vs. 135 [IQR 94-222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160-210] vs. 280 [IQR 250-300] mg; p < 0.001). Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C). Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients. ClinicalTrials.gov Unique identifier NCT03532594.


Death in sports and recreation.
In a 10 year survey of deaths during sports and recreation, 110 deaths occurred and 80% of these were due to unnatural causes, the majority being drowning. Twenty-two cases were due to natural causes mainly due to failure of the circulatory system. The mechanism of death was briefly discussed and it was deemed advisable for those who are going to undertake a training programme in running or athletics to have a medical examination. This is especially important if one is over 30 years of age and have family history of heart disease and high blood pressure and those who led a sedentary life.


Focusing and energy deposition inside random media.
The degree of control over waves transmitted through random media is determined by characteristics of the singular values of the transmission matrix. This Letter explores focusing and energy deposition in the interior of disordered samples and shows that these are determined by the singular values of the matrix relating the field channels inside a medium to the incident channels. Through calculations and simulations, we discovered that the variation with depth of the maximal energy density and the contrast in optimal focusing are determined by the participation number M(z) of the energy density eigenvalues, while its inverse gives the variance of the energy density at z in a single configuration.


An empirical examination of the social bond theory of drug use.
The purpose of the present study was to investigate the relationship between control theory, measured through a created social bond scale, and the respondents' self-admitted drug use (alcohol, marijuana, tobacco, amphetamines, and barbiturates). An analysis was conducted of self-reported drug use data from a general Texas adult population. This analysis included a series of bivariate cross-comparison correlations between the independent variable (social bond) and the dependent drug variables. The relationship between the independent and dependent variables was further examined by calculating the correlation and level of significance within selected categories of several demographic (age, race, sex, education, income, and marital status) variables. The results showed a significant positive correlation between reduced social bonding and greater drug use. However, while these relationships were significant, they were relatively weak and of little explanatory value. It was concluded that Hirschi's social bond theory fails to provide an adequate explanation for the use of drugs within the framework of this analysis.


Development and Validation of Prediction Models of Adverse Kidney Outcomes in the Population With and Without Diabetes.
To predict adverse kidney outcomes for use in optimizing medical management and clinical trial design. In this meta-analysis of individual participant data, 43 cohorts (N = 1,621,817) from research studies, electronic medical records, and clinical trials with global representation were separated into development and validation cohorts. Models were developed and validated within strata of diabetes mellitus (presence or absence) and estimated glomerular filtration rate (eGFR; ≥60 or <60 mL/min/1.73 m2) to predict a composite of ≥40% decline in eGFR or kidney failure (i.e., receipt of kidney replacement therapy) over 2-3 years. There were 17,399 and 24,591 events in development and validation cohorts, respectively. Models predicting ≥40% eGFR decline or kidney failure incorporated age, sex, eGFR, albuminuria, systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, and BMI, and, in those with diabetes, hemoglobin A1c, insulin use, and oral diabetes medication use. The median C-statistic was 0.774 (interquartile range [IQR] = 0.753, 0.782) in the diabetes and higher-eGFR validation cohorts; 0.769 (IQR = 0.758, 0.808) in the diabetes and lower-eGFR validation cohorts; 0.740 (IQR = 0.717, 0.763) in the no diabetes and higher-eGFR validation cohorts; and 0.750 (IQR = 0.731, 0.785) in the no diabetes and lower-eGFR validation cohorts. Incorporating the previous 2-year eGFR slope minimally improved model performance, and then only in the higher-eGFR cohorts. Novel prediction equations for a decline of ≥40% in eGFR can be applied successfully for use in the general population in persons with and without diabetes with higher or lower eGFR.


Risk factors for excess weight loss and hypernatremia in exclusively breast-fed infants.
Data were prospectively obtained from exclusively breast-fed healthy term neonates at birth and from healthy mothers with no obstetric complication to determine risk factors for excess weight loss and hypernatremia in exclusively breast-fed infants. Thirty-four neonates with a weight loss > or = 10% were diagnosed between April 2001 and January 2005. Six of 18 infants who were eligible for the study had hypernatremia. Breast conditions associated with breast-feeding difficulties (P < 0.05), primiparity (P < 0.005), less than four stools (P < 0.001), pink diaper (P < 0.001), delay at initiation of first breast giving (P < 0.01), birth by cesarean section (P < 0.05), extra heater usage (P < 0.005), extra heater usage among mothers who had appropriate conditions associated with breast-feeding (P < 0.001), mean weight loss in neonates with pink diaper (P < 0.05), mean uric acid concentration in neonates with pink diaper (P < 0.0001), fever in hypernatremic neonates (P < 0.02), and the correlation of weight loss with both serum sodium and uric acid concentrations (P < 0.02) were determined. Excessive weight loss occurs in exclusively breast-fed infants and can be complicated by hypernatremia and other morbidities. Prompt initiation of breast-feeding after delivery and prompt intervention if problems occur with breast-feeding, in particular poor breast attachment, breast engorgement, delayed breast milk "coming in", and nipple problems will help promote successful breast-feeding. Careful follow-up of breast-feeding dyads after discharge from hospital, especially regarding infant weight, is important to help detect inadequate breast-feeding. Environmental factors such as heaters may exacerbate infant dehydration.


Updated aluminum pharmacokinetics following infant exposures through diet and vaccination.
Aluminum is a ubiquitous element that is released naturally into the environment via volcanic activity and the breakdown of rocks on the earth's surface. Exposure of the general population to aluminum occurs primarily through the consumption of food, antacids, and buffered analgesics. Exposure to aluminum in the general population can also occur through vaccination, since vaccines often contain aluminum salts (frequently aluminum hydroxide or aluminum phosphate) as adjuvants. Because concerns have been expressed by the public that aluminum in vaccines may pose a risk to infants, we developed an up-to-date analysis of the safety of aluminum adjuvants. Keith et al. [1] previously analyzed the pharmacokinetics of aluminum for infant dietary and vaccine exposures and compared the resulting body burdens to those based on the minimal risk levels (MRLs) established by the Agency for Toxic Substances and Disease Registry. We updated the analysis of Keith et al. [1] with a current pediatric vaccination schedule [2]; baseline aluminum levels at birth; an aluminum retention function that reflects changing glomerular filtration rates in infants; an adjustment for the kinetics of aluminum efflux at the site of injection; contemporaneous MRLs; and the most recent infant body weight data for children 0-60 months of age [3]. Using these updated parameters we found that the body burden of aluminum from vaccines and diet throughout an infant's first year of life is significantly less than the corresponding safe body burden of aluminum modeled using the regulatory MRL. We conclude that episodic exposures to vaccines that contain aluminum adjuvant continue to be extremely low risk to infants and that the benefits of using vaccines containing aluminum adjuvant outweigh any theoretical concerns.


Calpain and cell death.
Neither the early nor the late steps in apoptosis have been defined biochemically. Several different signalling pathways have been implicated, and these are familiar from other signalling paradigms. In what way could they lead to cell death, when under the usual conditions they are involved in reversible activation events? A possible role for proteolysis is suggested, because the cleavage of a peptide bond is one of the few irreversible processes in cellular metabolism, and death, after all, is an irreversible outcome. In this review we discuss the calcium-dependent neutral protease calpain, a member of the papain family of cysteine proteases quite distinct from the ICE family. Calpain has been shown to play an essential role in several important examples of physiologic apoptosis. It seems to play its part after the various 'private' pathways have been invoked, but before the final common pathway.


Be SMART: examining the experience of implementing the NHS Health Check in UK primary care.
The NHS Health Check was designed by UK Department of Health to address increased prevalence of cardiovascular disease by identifying risk levels and facilitating behaviour change. It constituted biomedical testing, personalised advice and lifestyle support. The objective of the study was to explore Health Care Professionals' (HCPs) and patients' experiences of delivering and receiving the NHS Health Check in an inner-city region of England. Patients and HCPs in primary care were interviewed using semi-structured schedules. Data were analysed using Thematic Analysis. Four themes were identified. Firstly, Health Check as a test of 'roadworthiness' for people. The roadworthiness metaphor resonated with some patients but it signified a passive stance toward illness. Some patients described the check as useful in the theme, Health check as revelatory. HCPs found visual aids demonstrating levels of salt/fat/sugar in everyday foods and a 'traffic light' tape measure helpful in communicating such 'revelations' with patients. Being SMART and following the protocolrevealed that few HCPs used SMART goals and few patients spoke of them. HCPs require training to understand their rationale compared with traditional advice-giving. The need for further follow-up revealed disparity in follow-ups and patients were not systematically monitored over time. HCPs' training needs to include the use and evidence of the effectiveness of SMART goals in changing health behaviours. The significance of fidelity to protocol needs to be communicated to HCPs and commissioners to ensure consistency. Monitoring and measurement of follow-up, e.g., tracking of referrals, need to be resourced to provide evidence of the success of the NHS Health Check in terms of healthier lifestyles and reduced CVD risk.


Purification and characterization of an anabolic fumarate reductase from Methanobacterium thermoautotrophicum.
An oxygen-sensitive fumarate reductase has been purified from the cytosol fraction of the cells of the archaebacterium Methanobacterium thermoautotrophicum. A major portion of the purification was performed inside an anaerobic chamber, employing reducing agents to maintain low redox potentials. The apparent molecular weight of the native enzyme is 78,000. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated a minimal subunit molecular weight of about 20,000. Iodoacetamide (1 mM) and copper chloride (5 mM) caused significant loss in the enzyme activity. The optimum temperature for the enzymatic activity was 75 degrees C. The pH optimum was found to be 7.0. The fumarate reductase had an apparent Km of 0.20 mM for fumarate. Purified enzyme was colorless; spectroscopic studies indicated the absence of flavins as a cofactor. The spectral data, however, suggested the presence of an unknown cofactor tightly bound to the enzyme. Fumarate reductase is involved in the anabolic rather than the catabolic metabolism of M. thermoautotrophicum.


SO2 -catalyzed steam explosion: the effects of different severity on digestibility, accessibility, and crystallinity of lignocellulosic biomass.
Lignocellulosic biomass is the most promising feedstock for biofuels production. To enhance the efficiency of enzymatic hydrolysis, lignocellulosics needs to be pretreated to lower their recalcitrance. SO(2) -catalyzed steam explosion is an efficient and relatively cost-efficient pretreatment method for softwood. This work investigates the effects of steam explosion severity on the digestibility, accessibility, and crystallinity of Loblolly pine. Higher severity was found to increase the accessibility of the feedstock while also promoting nonselective degradation of carbohydrates. The adsorption behavior of Celluclast® enzymes on steam-exploded Loblolly pine (SELP) can be described by a Langmuir isotherm. Cellulose crystallinity was found to first increase and then decrease with increasing pretreatment severity. A linear relationship between initial hydrolysis rates and crystallinity index (CrI) of pretreated Loblolly pine was found; moreover, a strong correlation between X-ray diffraction intensities and initial rates was confirmed. The findings demonstrate the significance of CrI in enzymatic hydrolysis of pretreated lignocellulosic biomass.


Chimpanzee facial symmetry: a biometric measure of chimpanzee health.
This paper reports a study of fitness indicator theory in chimpanzees. First, it establishes a theoretical perspective for the study of fitness indicator theory and the relationships among indicators of fitness in humans and other animals. Second, it describes a methodology for assessing facial fluctuating asymmetry (FA) in a sample (N = 21) of zoo chimpanzees (Pan troglodytes). Third, associations among chimpanzee facial FA and health are described. FA was positively associated with negative health symptoms, and negatively associated with general health. Results are discussed under the framework of good genes theory.


Inter-day test-retest reliability and feasibility of isokinetic, isometric, and isotonic measurements to assess quadriceps endurance in people with chronic obstructive pulmonary disease: A multicenter study.
The aims were to determine reliability and feasibility of measurements to assess quadriceps endurance in people with chronic obstructive pulmonary disease. Sixty participants (forced expiratory volume in one second (mean ± standard deviation) 55 ± 18% of predicted, age 67 ± 8 years) were tested in an inter-day, test-retest design. Isokinetic, isometric, and isotonic protocols were performed using a computerized dynamometer. Test-retest relative and absolute reliability was determined via intraclass correlation coefficient (ICC), coefficient of variation (CV%), and limits of agreement (LoA%). Isokinetic total work demonstrated very high relative reliability (ICC: [95% confidence interval] = 0.98 [0.94-0.99]) and the best absolute reliability (CV% (LoA%) = 6.5% (18.0%)). Isokinetic fatigue index, isometric, and isotonic measures demonstrated low-to-high relative reliability (ICC = 0.64 [0.46-0.77], 0.88 [0.76-0.94], 0.91 [0.85-0.94]), and measures of absolute reliability (CV% (LoA%)) were 20.3% (56.4%), 14.9% (40.8%), and 15.8% (43.1%). For isokinetic total work and isometric measurements, participants performed better on retest (4.8% and 10.0%, respectively). The feasibility was similar across protocols with an average time consumption of less than 7.5 minutes. In conclusion, isokinetic, isometric, and isotonic measurements of quadriceps endurance were feasible to a similar extent and presented low-to-very high relative reliability. Absolute reliability seems to favor isokinetic total work measurements.


A coefficient of determination (R2 ) for generalized linear mixed models.
Extensions of linear models are very commonly used in the analysis of biological data. Whereas goodness of fit measures such as the coefficient of determination (R2 ) or the adjusted R2 are well established for linear models, it is not obvious how such measures should be defined for generalized linear and mixed models. There are by now several proposals but no consensus has yet emerged as to the best unified approach in these settings. In particular, it is an open question how to best account for heteroscedasticity and for covariance among observations present in residual error or induced by random effects. This paper proposes a new approach that addresses this issue and is universally applicable for arbitrary variance-covariance structures including spatial models and repeated measures. It is exemplified using three biological examples.


First Report of Sweet Cherry Virescence Disease in China and Its Association with Infection by a 'Candidatus Phytoplasma ziziphi'-Related Strain.
Sweet cherry (Prunus avium L.) is a deciduous tree originating in the Black Sea/Caspian Sea region where Asia and Europe converge. Being highly valued for its timber and fruit, sweet cherry has been cultivated and naturalized on all continents. Over the past decade, the area of sweet cherry cultivation increased rapidly in China and has reached 140,000 ha. In April 2013, sweet cherry trees (cv. Summit) exhibiting floral virescence symptoms were observed in two orchards located in suburban Taian, Shandong Province, China. The diseased trees developed flowers having white petals with green veins or abnormal floral structures having cupped, green petals. The affected flowers failed to set fruit. A month following the first appearance of the virescence symptoms, the diseased trees became wilted and eventually died. Leaf and stem samples were collected from nine symptomatic and two nearby symptomless trees. Total DNA was extracted from each sample using the Plant Quick DNA Extract Kit (TianGen, Beijing, China). Nested-PCR was carried out using phytoplasma-universal primer pairs P1/P7 and R16F2n/R16R2 (1). All PCR assays with DNA templates from symptomatic samples yielded an amplicon of 1.25 kb, corresponding to the full-length F2nR2 region of phytoplasmal 16S rDNA. No amplicon was generated in PCRs containing DNA templates from symptomless plants. The amplicons were cloned into plasmid vector pMD18-T (TaKaRa, Dalian, China) and sequenced. The obtained sequences were nearly identical, and a representative sequence was deposited into GenBank (Accession No. KF268424). An analysis of the sequence through the iPhyClassifier (4) revealed that the sweet cherry virescence (SCV) disease was associated with infection by a phytoplasma closely related to the reference strain of 'Candidatus Phytoplasma ziziphi.' The 16S rDNA F2nR2 region of the SCV phytoplasma shared 99.8% nucleotide sequence identity with that of 'Candidatus Phytoplasma ziziphi' reference strain (Accession No. AB052876). A computer-simulated restriction fragment length polymorphism (RFLP) analysis of the SCV phytoplasma 16S rDNA F2nR2 sequence with a set 17 restriction enzymes (3) resulted in a collective RFLP profile identical to the reference pattern of the elm yellows phytoplasma group, subgroup B (16SrV-B). Phytoplasmal diseases of sweet cherry were reported previously in Europe and the etiological agents were phytoplasmas of other groups, including the aster yellows group (16SrI), the X-disease group (16SrIII), and the apple proliferation group (16SrX) (2). To our knowledge, this is the first report of a phytoplasmal disease of sweet cherry in China, and the SCV phytoplasma is a new member of the subgroup 16SrV-B. Presence of 16SrV-B phytoplasmas and their etiological association with various plant diseases in China have been reported previously; affected host plants included jujube, hemp fiber, paper mulberry, Chinese cherry, plum, apricot, red barberry, clover, dianthus, elm, and sunshine tree. Our identification of the SCV phytoplasma expands the known plant host range of the 16SrV-B phytoplasma lineage. The impact of the SCV phytoplasma in the regional ecosystem and in sweet cherry production is being assessed. References: (1) I. M. Lee et al. Int. J. Syst. Bacteriol. 48:1153, 1998. (2) S. Paltrinieri et al. Acta Hort. 550:365, 2001. (3) W. Wei et al. Int. J. Syst. Evol. Microbiol. 57:1855, 2007. (4) Y. Zhao et al. Int. J. Syst. Evol. Microbiol. 59:2582, 2009.


Biomass accumulation patterns for removing volatile organic compounds in rotating drum biofilters.
A rotating drum biofilter (RDB) with multi-layered foam media was developed for the improvement of current biofiltration technology. The biofilter was used to investigate the effects of organic loadings and influent volatile organic compound (VOC) concentrations on VOC removal efficiency and biomass accumulation. These effects were evaluated using diethyl ether and toluene separately as model VOCs at an empty bed contact time (EBCT) of 30 s. When the toluene loading increased from 2.0 to 4.0 and 8.0 kgCOD m(-3) day(-1), toluene removal efficiency of the biofilter decreased from over 99% to 78% and 74%, respectively. The biomass distribution was found to be more even within the medium when removing toluene than when removing diethyl ether. Higher organic loading also resulted in the more even distribution of the biomass. The ratios of biomass accumulation rates in the medium of the outermost, middle and innermost layers ranged from 1:0.11:0.02 when removing diethyl ether at 2.0 kgCOD m(-3) day(-1) to 1:0.69:0.51 when removing toluene at 8.0 kgCOD m(-3) day(-1). Review of these ratios revealed three biomass accumulation patterns: surface pattern, in-depth pattern and shallow pattern. Different patterns represent different removal mechanisms in the biofiltration process. Improved biofilter design and operation should be based on the biomass accumulation pattern.


[Saliva and plasma levels of carbamazepine have a poor correlation: a pilot study].
Carbamazepine is one of the most commonly used anticonvulsants for the treatment of epilepsy and its plasma concentrations must be monitored periodically to obtain a useful and safe clinical effect. There is not a good relationship between the dose of the carbamazepine and their effects in humans, but the effects of this drug have been well correlated with its plasma levels. To measure the correlation between plasma and saliva levels of carbamazepine in children with epilepsy. Saliva and plasma levels of carbamazepine were measured by using instrumental planar chromatography in 11 epileptic children aged 8 to 15 years treated with the drug for at least six months. The mean saliva/plasma ratio was 0.18+/-0.05 and the mean of carbamazepine concentration in saliva, expressed as a percentage of concentrations in plasma, was 17.97+/-5.40. There was a poor linear correlation (r=0.37) between the concentrations of carbamazepine in both fluids. In this group of epileptic children the correlation between saliva and plasma carbamazepine levels was weak.


The patient, the drug and the kidney.
Recent policy changes have focused attention on the prevalence of chronic kidney disease (CKD) in the UK. In particular, automatic reporting of estimated glomerular filtration rate (e-GFR) is a requirement of the National Service Framework (NSF) for Renal Services in England. Also, the Quality and Outcomes Framework (QOF) of the UK General Medical Services (GMS) Contract (revised in April 2006) requires GPs to keep a renal register of patients with CKD with e-GFRs below 60 mL/min/1.73 m2. Prescribers managing such patients are faced with difficult decisions about starting or continuing treatment with drugs that are handled by, or potentially toxic to, the kidney. Here we review methods of identifying and classifying CKD in adults and the implications of CKD for patients' health. We also offer advice on prescribing for these patients while minimising the risks of drug-related renal toxicity. We do not aim to give detailed guidance on every drug, but rather to highlight general principles of drug therapy and key sources of information and advice.


A Case of Arachnoid Cyst Presenting with Cognitive Impairment and Hypomania Symptoms.
Arachnoid cysts are benign congenital malformations of the arachnoid which account for approximately 1.4% of the intracranial lesions. Although it is usually asymptomatic, it may be accompanied by headache, hydrocephalus and seizure. Psychiatric disorders associated with arachnoid cysts are rare. In this article, we present a giant arachnoid cyst with hypomania symptoms and marked cognitive impairment. A 44-year-old female patient was admitted to our outpatient clinic with a 4-year history of headache, nervousness and attention problems. Magnetic resonance imaging revealed a giant arachnoid cyst with a size of 5.5x10.5x12.5 cm was found in the left hemisphere of the patient. Considering the patient's irritability, increase in the amount of speech, flight of ideas, sleep disturbance and attention disorders, the diagnosis of hypomania was made. The neuropsychological tests showed that the speed of information processing, mental flexibility and attention functions decreased, and executive functions were impaired. The patient was consulted to the neurosurgery department. But no surgical treatment was offered. Drug therapy for hypomanic symptoms and cognitive impairment was planned, but could not be started since the patient did not attend to the follow-up exams. Albeit the lack of followup constitutes a limitation for our report, we believe that the size of the cyst, significant impairment of cognitive functions and the presence of hypomania symptoms might contribute significantly to the literature. Other cases with arachnoid cyst displaying cognitive impairment were summarized in our article.


Talking through the tough: Identifying facilitating factors to preparation for bias and racial-ethnic discrimination conversations among families from minoritized ethnic-racial groups.
Parent-child conversations about race-related issues serve a protective function for minoritized families and are needed to help children of color thrive in the United States (Hughes et al., Advances in Child Development and Behavior, 51, 2016 and 1). Despite the difficulties that parents experience in having such conversations to prepare youth to cope with discrimination (Priest et al., International Journal of Intercultural Relations, 43, 2014 and 139), parents are actively engaging in these courageous conversations with the aim of protecting their youth. In order to fully understand and support parents having these conversations, our study sought to identify conversation facilitators (i.e., strategies currently being implemented and viewed as successful and/or viewed as potentially helpful) to engage in preparation for bias and racial-ethnic discrimination conversations from the perspective of parents and youth. The current qualitative study draws upon focus group data collected from parents and youth from African American, Chinese American, Mexican American, and Indian American (South Asian) families (N = 138 individuals; 30 focus groups). Reflections were transcribed and coded by a racially and ethnically diverse research team using an inductive thematic analysis approach (Braun & Clarke, Qualitative Research in Psychology, 3, 2006 and 77). Shared and unique facilitators to engaging in preparation for bias and racial-ethnic discrimination conversations were identified across the four racial-ethnic groups. Shared facilitators broadly centered on parent-youth relationship quality, conversation characteristics, and quality, and conversation content and relevance. Unique facilitators broadly centered on communication style and needs and conversation content. Shared and unique facilitators warrant more attention to best support minoritized families. The use of findings in developing interventions to support marginalized parents, youth, and families is addressed.


Quantitative description and modeling of real networks.
We present data analysis and modeling of two particular cases of study in the field of growing networks. We analyze World Wide Web data set and authorship collaboration networks in order to check the presence of correlation in the data. The results are reproduced with good agreement through a suitable modification of the standard Albert-Barabási model of network growth. In particular, intrinsic relevance of sites plays a role in determining the future degree of the vertex.


The double-density sign: a radiographic finding suggestive of an os acromiale.
An os acromiale results from the failure of fusion of the acromial secondary centers of ossification. It is most easily seen radiographically on an axillary lateral view. The purpose of the present study was to describe two simple radiographic findings, the double-density sign on a standard anteroposterior view of the shoulder and a cortical irregularity found on a supraspinatus outlet view, that are highly suggestive of an os acromiale. Anteroposterior, axillary lateral, and supraspinatus outlet radiographs of thirty-four shoulders in thirty adult patients with an os acromiale were reviewed by two independent observers and were compared with those of a control group of thirty-one shoulders in twenty-nine patients without an os acromiale. Statistical analysis was performed with use of a generalized logistic regression model to determine if an os acromiale could be detected on all three radiographic views. A kappa analysis was performed to determine interobserver reliability. In the group with an os acromiale, twenty-eight shoulders had a meso-acromion and six had a pre-acromion. A double-density sign was noted on the anteroposterior radiograph of 82.4% of the shoulders, an os acromiale was noted on the axillary lateral radiograph of 95.6% of the shoulders, and a cortical irregularity was noted on the supraspinatus outlet radiograph of 75.8% of the shoulders. In the control group, a double-density sign was noted on the anteroposterior radiograph of 4.8% of the shoulders, no os acromiale was seen on the axillary lateral radiograph of any of the shoulders, and a cortical irregularity was noted on the supraspinatus outlet radiograph of one shoulder. These differences between the os acromiale and control groups were significant (p < 0.0001). The overall sensitivities of the anteroposterior, axillary, and supraspinatus outlet views for the detection of an os acromiale were 82.4%, 94.1%, and 73.5%, respectively. The overall specificities of the three views were 95.2%, 100%, and 98.4%, respectively. The interobserver reliabilities of the three views were 0.66, 0.88, and 0.7, respectively (p < 0.0001). The double-density sign on a standard anteroposterior radiograph of the shoulder and a cortical irregularity on the supraspinatus outlet view are highly suggestive of an os acromiale. An os acromiale should be suspected in a patient with these radiographic findings. Diagnostic study, Level IV-1 (case-control study). See Instructions to Authors for a complete description of levels of evidence.


Speedballing with needle embolization: case study and review of the literature.
Foreign-body embolization is not an uncommon occurrence. However, to our knowledge, there are only ten reported cases of needle embolization associated with intravenous drug use. We report the sudden death of a 49-year-old white male with a known history of crack cocaine abuse. At autopsy, suspicious needle marks were noted on the right lower extremity. The lungs were of increased weight at 1000 and 1090 g and appeared edematous. The heart weighed 520 g and had a normal red-brown myocardium. Upon sectioning, a broken hypodermic needle of very small caliber was identified in the right ventricular myocardium protruding into the right ventricular chamber. This needle apparently traveled from the injection site to the right ventricle. The right ventricle was dilated and hypertrophied, and microscopic examination showed hyperemic myocardium surrounding the needle. Sections of lung showed numerous foreign-body type giant cells containing polarizable foreign material consistent with intravenous drug use. Toxicological analysis revealed the presence of ethanol (36 mg/dL), cocaine (0.098 mg/L), benzoylecgonine (2.16 mg/L), and morphine (0.841 mg/L). Urine and blood were positive for the presence of 6-monoacetylmorphine. Based on the toxicological analysis, the cause of death was determined to be cocaine and heroin toxicity, and the manner accidental. The needle embolus was considered an incidental finding.


Echo Chambers: Emotional Contagion and Group Polarization on Facebook.
Recent findings showed that users on Facebook tend to select information that adhere to their system of beliefs and to form polarized groups - i.e., echo chambers. Such a tendency dominates information cascades and might affect public debates on social relevant issues. In this work we explore the structural evolution of communities of interest by accounting for users emotions and engagement. Focusing on the Facebook pages reporting on scientific and conspiracy content, we characterize the evolution of the size of the two communities by fitting daily resolution data with three growth models - i.e. the Gompertz model, the Logistic model, and the Log-logistic model. Although all the models appropriately describe the data structure, the Logistic one shows the best fit. Then, we explore the interplay between emotional state and engagement of users in the group dynamics. Our findings show that communities' emotional behavior is affected by the users' involvement inside the echo chamber. Indeed, to an higher involvement corresponds a more negative approach. Moreover, we observe that, on average, more active users show a faster shift towards the negativity than less active ones.


Catalytically active geometry in the reversible circularization of 'mini-monomer' RNAs derived from the complementary strand of tobacco ringspot virus satellite RNA.
The less abundant polarity of the satellite RNA of tobacco ringspot virus, designated sTobRV(-)RNA, contains a ribozyme and its substrate. We demonstrate that the ribozyme can catalyze the ligation of substrate cleavage products and that oligoribonucleotides, termed 'mini-monomers' and containing little more than covalently attached ribozyme and substrate cleavage products, circularized spontaneously, efficiently and reversibly. The kinetics of ligation and cleavage of one such mini-monomer was consistent with a simple unimolecular reaction at some temperatures. Evidence suggests that the circular ligation product includes a 5 bp stem that is connected to a 4 bp stem by a bulge loop. Reduction of the bulge loop to one nt is expected to place the 4 and 5 bp helices in a nearly coaxial, rather than an angled or parallel, orientation. Such molecules did not circularize in a unimolecular reaction but did when incubated with second, trans-acting oligoribonucleotides that had either the original or a substituted 4 bp helix. These results suggest that a bulge loop that is too small prevents formation of geometry essential for unimolecular ligation. We suggest the term 'paperclip' to represent the arrangement of RNA strands in the region of sTobRV(-)RNA that participates in the cleavage and ligation reactions.


The Role of Endoplasmic Reticulum Stress Response in Liver Regeneration.
Exposure to hepatotoxic chemicals is involved in liver disease-related morbidity and mortality worldwide. The liver responds to damage by triggering compensatory hepatic regeneration. Physical agent or chemical-induced liver damage disrupts hepatocyte proteostasis, including endoplasmic reticulum (ER) homeostasis. Post-liver injury ER experiences a homeostatic imbalance, followed by active ER stress response signaling. Activated ER stress response causes selective upregulation of stress response genes and downregulation of many hepatocyte genes. Acetaminophen overdose, carbon tetrachloride, acute and chronic alcohol exposure, and physical injury activate the ER stress response, but details about the cellular consequences of the ER stress response on liver regeneration remain unclear. The current data indicate that inhibiting the ER stress response after partial hepatectomy-induced liver damage promotes liver regeneration, whereas inhibiting the ER stress response after chemical-induced hepatotoxicity impairs liver regeneration. This review summarizes key findings and emphasizes the knowledge gaps in the role of ER stress in injury and regeneration.


Revisiting the question of nucleated versus enucleated erythrocytes in birds and mammals.
Erythrocyte enucleation is thought to have evolved in mammals to support their energetic cost of high metabolic activities. However, birds face similar selection pressure yet possess nucleated erythrocytes. Current hypotheses on the mammalian erythrocyte enucleation claim that the absence of cell organelles allows erythrocytes to 1) pack more hemoglobin into the cells to increase oxygen carrying capacity and 2) decrease erythrocyte size for increased surface area-to-volume ratio, and improved ability to traverse small capillaries. In this article, we first empirically tested current hypotheses using both conventional and phylogenetically informed analysis comparing literature values of mean cell hemoglobin concentration (MCHC) and mean cell volume (MCV) between 181 avian and 194 mammalian species. We found no difference in MCHC levels between birds and mammals using both conventional and phylogenetically corrected analysis. MCV was higher in birds than mammals according to conventional analysis, but the difference was lost when we controlled for phylogeny. These results suggested that avian and mammalian erythrocytes may employ different strategies to solve a common problem. To further investigate existing hypotheses or develop new hypothesis, we need to understand the functions of various organelles in avian erythrocytes. Consequently, we covered potential physiological functions of various cell organelles in avian erythrocytes based on current knowledge, while making explicit comparisons with their mammalian counterparts. Finally, we proposed by taking an integrative and comparative approach, using tools from molecular biology to evolutionary biology, would allow us to better understand the fundamental physiological functions of various components of avian and mammalian erythrocytes.


Induction of thymomas by N-methyl-N-nitrosourea in AKR mice: interaction between the chemical carcinogen and endogenous murine leukaemia viruses.
AKR mice develop thymomas spontaneously when greater than 6 months old but when young AKR mice are treated with N-methyl-N-nitrosourea (MNU) they develop thymomas at 3-6 months of age. In this study the potential role of oncogene activation in the development of both the spontaneous and MNU-induced thymomas in AKR mice has been examined by DNA transfection into NIH3T3 mouse fibroblasts and by Southern analysis of tumour DNA. The results show that a high proportion of MNU-induced thymomas contain activated cellular rasK while no activated cellular ras genes were detected in spontaneous thymomas. Southern analysis of tumour DNA revealed that 2/30 spontaneous tumours and 2/52 MNU-induced tumours contained alterations in the c-myc gene while 5/29 spontaneous tumours and 6/56 MNU-induced tumours contained alterations in the Pim-1 gene. A more detailed analysis of the Pim-1 gene demonstrated that the alterations observed in most MNU-induced and spontaneous tumours resulted from proviral integration at the 3' end of this gene. Our analyses also demonstrated that the majority of MNU-induced tumours, including those containing rearrangements in the Pim-1 gene, lacked the somatically acquired recombinant MCF proviruses that are present in most spontaneous AKR lymphomas. These results provide evidence that the mechanisms of development of MNU-induced and spontaneous tumours in AKR mice are distinct and the development of thymomas that contain proviral integrations at the Pim-1 locus in the MNU-treated AKR mice involve cooperation between the chemical carcinogen and endogenous murine leukaemia viruses.


Optical pH measurements with water dispersion of polyaniline nanoparticles and their redox sensitivity.
A new method for optical pH and redox measurements with a commercially available water dispersion of polyaniline (PANI) nanoparticles (mean particle size, 46 nm) is presented. The pH measurements are based on the acid-base equilibrium of PANI and were carried out either by combining both the automated sequential injection analysis (SIA) and UV-visible spectrophotometric techniques or with a fiber-optic light guide. In the former case, the detection was done in continuous mode at lambda = 800 nm by using the SIA technique for transporting the sample to a flow-through cell, which was placed in the light path of the photometer. With the fiber-optic light guide, the detection was done in batch mode at lambda = 400 and 580 nm. In both methods, fresh pH reagent (PANI) solution was used in each measurement, thus overcoming the problem with hysteresis (memory effect), which is usually observed with PANI films. The PANI nanoparticles were characterized with UV-visible spectroscopy in pH buffer solutions between pH 2-12 and a protonation constant of logK(0.5H,L)(H(0.5)L) = 4.4 was calculated from these data. Fast pH measurements can be done between pH 6 and 10.5 depending on the measuring technique. It is possible to determine pH with an accuracy of 0.1 pH unit between pH 8 and 10.5 (RSD, 0.5-2%). Redox transitions typical for PANI films were also observed for water solutions of PANI nanoparticles in the presence of the hexacyanoferrate(II/III) and the iron(II/III) oxalate redox couples. The absorbance at lambda = 875 nm is linearly dependent on the logarithm of the concentration ratio (0.1-10) of the iron oxalate redox couple.


St. John's Wort for depressive disorders: results of an outpatient study with the Hypericum preparation HYP 811.
The efficacy and tolerability of a high-dose formulation of St. John's Wort extract, HYP 811, was tested in 607 patients in a 6-week, prospective, multicenter, postmarketing surveillance study. Severity of depression was assessed by physicians using the Hamilton Depression Scale; patient self-evaluation was performed using the von Zerssen Depression Scale. After 6 weeks of treatment, both scores improved by approximately 60%, on average. Disturbances in well-being, such as dejection, loss of interest, and generalized physical complaints, diminished during therapy. The tolerability of HYP 811 was rated "very good" and "good" in 89.4% of cases. After 3 weeks of treatment, dosage in 128 patients (21.1%) was successfully reduced to one capsule daily.


Importance of health assessments for conservation in noncaptive wildlife.
Wildlife health assessments help identify populations at risk of starvation, disease, and decline from anthropogenic impacts on natural habitats. We conducted an overview of available health assessment studies in noncaptive vertebrates and devised a framework to strategically integrate health assessments in population monitoring. Using a systematic approach, we performed a thorough assessment of studies examining multiple health parameters of noncaptive vertebrate species from 1982 to 2020 (n = 261 studies). We quantified trends in study design and diagnostic methods across taxa with generalized linear models, bibliometric analyses, and visual representations of study location versus biodiversity hotspots. Only 35% of studies involved international or cross-border collaboration. Countries with both high and threatened biodiversity were greatly underrepresented. Species that were not listed as threatened on the International Union for Conservation of Nature Red List represented 49% of assessed species, a trend likely associated with the regional focus of most studies. We strongly suggest following wildlife health assessment protocols when planning a study and using statistically adequate sample sizes for studies establishing reference ranges. Across all taxa blood analysis (89%), body composition assessments (81%), physical examination (72%), and fecal analyses (24% of studies) were the most common methods. A conceptual framework to improve design and standardize wildlife health assessments includes guidelines on the experimental design, data acquisition and analysis, and species conservation planning and management implications. Integrating a physiological and ecological understanding of species resilience toward threatening processes will enable informed decision making regarding the conservation of threatened species.


Engineered RNA biosensors enable ultrasensitive SARS-CoV-2 detection in a simple color and luminescence assay.
The continued resurgence of the COVID-19 pandemic with multiple variants underlines the need for diagnostics that are adaptable to the virus. We have developed toehold RNA-based sensors across the SARS-CoV-2 genome for direct and ultrasensitive detection of the virus and its prominent variants. Here, isothermal amplification of a fragment of SARS-CoV-2 RNA coupled with activation of our biosensors leads to a conformational switch in the sensor. This leads to translation of a reporter protein, for example, LacZ or nano-lantern that is easily detected using color/luminescence. By optimizing RNA amplification and biosensor design, we have generated a highly sensitive diagnostic assay that is capable of detecting as low as 100 copies of viral RNA with development of bright color. This is easily visualized by the human eye and quantifiable using spectrophotometry. Finally, this PHAsed NASBA-Translation Optical Method (PHANTOM) using our engineered RNA biosensors efficiently detects viral RNA in patient samples. This work presents a powerful and universally accessible strategy for detecting COVID-19 and variants. This strategy is adaptable to further viral evolution and brings RNA bioengineering center-stage.


Arterial auscultation in peripheral vascular disease.
Bruits between epigastrium and popliteal fossae were found in 63% of 309 patients with arterial obstruction and in 7% of 149 patients without obstruction. In the former group, ankle systolic pressure at rest was abnormal in 85% of limbs with bruits, indicating a hemodynamic abnormality. In the majority of limbs with bruits and normal pressures at rest, an abnormal pressure response to exercise suggests that auscultation is useful in detection of even milder arterial lesions. Auscultation, after exercise and during compression of arterial branches distal to the bruits, may unmark stenotic lesions that do not produce audible bruits at rest and may localize bruit-producing lesions. This study indicates that peripheral auscultation is a valuable technique for assessing the arterial system in individual patients and for screening population groups.


Spontaneous and medically induced cerebrospinal fluid leakage in the setting of pituitary adenomas: review of the literature.
Spontaneous and medically induced CSF leaks are uncommonly associated with pituitary adenomas. The aim of this study was to further characterize the clinical scenarios most closely associated with this phenomenon. A review of the literature was conducted to identify all cases of nonsurgical CSF leaks associated with pituitary adenomas. The authors aimed to identify associated risk factors and management strategies used to treat these tumors and repair the CSF leak site. Fifty-two patients with spontaneous or medically induced CSF leaks in the setting of a pituitary adenoma were identified from 29 articles published from 1980 through 2011. In 38 patients (73%), CSF rhinorrhea developed following initiation of medical therapy, whereas spontaneous CSF leakage developed as the presenting symptom in 14 patients (27%). The patients' mean age was 42.8 years (range 23-68 years). There were 35 males and 17 females. Forty-two patients (81%) had a prolactinoma, with the remaining patients having the following tumors: nonfunctioning pituitary adenoma (6 patients), growth hormone-secreting adenoma (2 patients), mammosomatotroph cell adenoma (1 patient), and ACTH-secreting adenoma (1 patient). Infrasellar tumor invasion into the paranasal sinuses was specifically reported in 56% of patients. The medical agents associated with CSF leakage were dopamine agonists (97%) and somatostatin analogs (3%). The average time from initialization of medical treatment to onset of rhinorrhea was 3.3 months (range 3 days-17 months). Nonsurgical management was successful in 4 patients, including 1 who had successful resolution with a temporary lumbar drain. Forty-six patients (88%) underwent surgical intervention to treat the CSF leak and/or resect the tumor. In 2 patients, surgery was not performed due to medical contraindications or patient preference. Nonsurgical development of CSF rhinorrhea may occur in the setting of pituitary adenomas, especially following favorable response of invasive prolactinomas to initiation of dopamine agonist therapy. Additional cases have been reported as the presenting symptom of a pituitary adenoma and are likely to be related to decreased tumor volume due to intrinsic infarction or hemorrhage, ongoing invasion, and/or increases in intracranial pressure. Surgical repair, preferentially via a transsphenoidal approach, is the recommended initial treatment for definitive repair of the CSF leak and achievement of maximal tumor resection.


Implications of 2020 Skilled Home Healthcare Payment Reform for Persons with Dementia.
The Medicare home health benefit provides episodic skilled home-based clinical care to the growing population of community-dwelling persons with dementia. As of January 1, 2020, home health payment changed: episodes shortened from 60 to 30 days, and episodes initiated in the community are now reimbursed at lower rates than episodes following institutional stays. We aim to assess the potential impact of these policy changes on this population. Cross-sectional study using the Medicare claims-linked National Health and Aging Trends Study (NHATS). A total of 1,867 NHATS respondents who received home health between 2011 and 2017. Dementia was defined through both self-report and a validated cognitive assessment through NHATS. We described the demographic, socioeconomic, and health characteristics of older adults with dementia receiving home health compared with those without dementia. We then assessed the association of dementia with both receiving community-initiated home health (vs postinstitutional) and visit timing during the home health episode. Over a follow-up period of just over 4 years, 50.2% of persons with dementia used home health compared with 15.3% of persons without dementia. Most home health provided to persons with dementia was initiated in the community (61%), compared with 37% of episodes provided to persons without dementia. Persons with dementia were more likely to receive care in days 31 to 60 of the episode compared with those without dementia. Shortening episodes and reimbursing community-initiated episodes at lower rates may disproportionately impact the highly vulnerable population of older adults with dementia, who receive more community-initiated care over longer time periods. Our work highlights the need to better understand the unique role of home health in meeting gaps in both acute- and long-term care systems for older adults with dementia. J Am Geriatr Soc 68:2303-2309, 2020.


Effects of Meditation and Music-Listening on Blood Biomarkers of Cellular Aging and Alzheimer's Disease in Adults with Subjective Cognitive Decline: An Exploratory Randomized Clinical Trial.
Telomere length (TL), telomerase activity (TA), and plasma amyloid-β (Aβ) levels have emerged as possible predictors of cognitive decline and dementia. To assess the: 1) effects of two 12-week relaxation programs on TL, TA, and Aβ levels in adults with subjective cognitive decline; and 2) relationship of biomarker changes to those in cognitive function, psychosocial status, and quality of life (QOL). Participants were randomized to a 12-week Kirtan Kriya meditation (KK) or music listening (ML) program and asked to practice 12 minutes/day. Plasma Aβ(38/40/42) and peripheral blood mononuclear cell TL and TA were measured at baseline and 3 months. Cognition, stress, sleep, mood, and QOL were assessed at baseline, 3 months, and 6 months. Baseline blood samples were available for 53 participants (25 KK, 28 ML). The KK group showed significantly greater increases in Aβ40 than the ML group. TA rose in both groups, although increases were significant only among those with higher practice adherence and lower baseline TA. Changes in both TL and TA varied by their baseline values, with greater increases among participants with values ≤50th percentile (ps-interaction <0.006). Both groups improved in cognitive and psychosocial status (ps ≤0.05), with improvements in stress, mood, and QOL greater in the KK group. Rising Aβ levels were correlated with gains in cognitive function, mood, sleep, and QOL at both 3 and 6 months, associations that were particularly pronounced in the KK group. Increases in TL and TA were also correlated with improvements in certain cognitive and psychosocial measures. Practice of simple mind-body therapies may alter plasma Aβ levels, TL, and TA. Biomarker increases were associated with improvements in cognitive function, sleep, mood, and QOL, suggesting potential functional relationships.


Virtual Training of the Myosignal.
To investigate which of three virtual training methods produces the largest learning effects on discrete and continuous myocontrol. The secondary objective was to examine the relation between myocontrol and manual motor control tests. A cohort analytic study. University laboratory. 3 groups of 12 able-bodied participants (N = 36). Participants trained the control over their myosignals on 3 consecutive days. Training was done with either myosignal feedback on a computer screen, a virtual myoelectric prosthetic hand or a computer game. Participants performed 2 myocontrol tests and 2 manual motor control tests before the first and after the last training session. They were asked to open and close a virtual prosthetic hand on 3 different velocities as a discrete myocontrol test and followed a line with their myosignals for 30 seconds as a continuous myocontrol test. The motor control tests were a pegboard and grip-force test. Discrete myocontrol test: mean velocities. Continuous myocontrol test: error and error SD. Pegboard test: time to complete. Grip-force test: produced forces. No differences in learning effects on myocontrol were found for the different virtual training methods. Discrete myocontrol ability did not significantly improve as a result of training. Continuous myocontrol ability improved significantly as a result of training, both on average control and variability. All correlations between the motor control and myocontrol test outcome measures were below .50. Three different virtual training methods showed comparable results when learning myocontrol. Continuous myocontrol was improved by training while discrete myocontrol was not. Myocontrol ability could not be predicted by the manual motor control tests.


Method for Biomonitoring DNA Adducts in Exfoliated Urinary Cells by Mass Spectrometry.
Tobacco smoking contributes to about 50% of the bladder-cancer (BC) cases in the United States. Some aromatic amines in tobacco smoke are bladder carcinogens; however, other causal agents of BC are uncertain. Exfoliated urinary cells (EUCs) are a promising noninvasive biospecimen to screen for DNA adducts of chemicals that damage the bladder genome, although the analysis of DNA adducts in EUCs is technically challenging because of the low number of EUCs and limiting quantity of cellular DNA. Moreover, EUCs and their DNA adducts must remain viable during the time of collection and storage of urine to develop robust screening methods. We employed RT4 cells, a well-differentiated transitional epithelial bladder cell line, as a cell-model system in urine to investigate cell viability and the chemical stability of DNA adducts of two prototypical bladder carcinogens: 4-aminobiphenyl (4-ABP), an aromatic amine found in tobacco smoke, and aristolochic acid I (AA-I), a nitrophenanthrene found in Aristolochia herbaceous plants used for medicinal purposes worldwide. The cell viability of RT4 cells pretreated with 4-ABP or AA-I in urine exceeded 80%, and the major DNA adducts of 4-ABP and AA-I, quantified by liquid chromatography-mass spectrometry, were stable for 24 h. Thereafter, we successfully screened EUCs of mice treated with AA-I to measure DNA adducts of AA-I, which were still detected 25 days following treatment with the carcinogen. EUCs are promising biospecimens that can be employed for the screening of DNA adducts of environmental and dietary genotoxicants that may contribute to the development of BC.


P2Y12-ADP Receptor Blockade in Chronic Kidney Disease Patients With Acute Coronary Syndromes.
Because of its high prevalence, chronic kidney disease (CKD) remains a major health hazard throughout the world. Patients with CKD have a high prevalence and incidence of acute coronary syndromes (ACS). Despite decades of improved care, their higher risk profile persists and cardiovascular diseases remain their leading cause of death. Along with the reduction of glomerular filtration rate, several physiological processes are impacted and participate in the pathophysiology of ischemic and bleeding events. CKD is associated with an accelerated and severe course of atherothrombotic disease, and this relates to a modified vascular milieu with alterations on the level of the coagulation cascade and platelet aggregation. In addition, pharmacokinetics of several drugs, in particular antithrombotics, are altered and differ from that of non-CKD patients. Patients with CKD therefore represent a challenging population for both physicians and researchers. In addition to these perturbations of physiological processes, CKD patients face 2 major issues. First, there is a clear gap in scientific research as they are commonly underrepresented or excluded from major clinical trials. This is particularly true regarding antithrombotic treatment during ACS. Second, there is a gap in offering evidence-based treatment for these patients including state-of-the art options for revascularization and modern antiplatelet treatment, both of which are commonly underused. During the last decade, new potent oral P2Y12-ADP receptor antagonists, prasugrel and ticagrelor, which are more potent antiplatelet agents compared with clopidogrel, were introduced for ACS treatment. However, despite the fact that CKD patients represent a large proportion of those experiencing an ACS and are considered at high risk, there is a lack of dedicated trials and we are left with subgroup analysis of large randomized clinical trials were stage 4 and dialysis patients were rare. In the present review we summarize the mechanisms involved in the high ischemic and bleeding risk of CKD patients and the risk-benefit ratio of potent antiplatelet drugs during ACS.


Host Range of, and Plant Reaction to, Subanguina picridis.
The host range of the knapweed nematode, Subanguina picridis (Kirjanova) Brzeski, under controlled environmental conditions was extended to include, in addition to Russian knapweed, Acroptilon repens (L.) DC., plant species within the Centaureinae, and Carduinae subtribes of the Cynareae tribe of the Asteraceae family. Examination of host response to nematode infection revealed that Russian knapweed was the only highly susceptible host plant. Diffuse knapweed (Centaurea diffusa Lam.) was moderately susceptible, and other plants which formed galls were resistant to S. picridis.


ELT-1, a GATA-like transcription factor, is required for epidermal cell fates in Caenorhabditis elegans embryos.
Epidermal cells are generated during Caenorhabditis elegans embryogenesis by several distinct lineage patterns. These patterns are controlled by maternal genes that determine the identities of early embryonic blastomeres. We show that the embryonically expressed gene elt-1, which was shown previously to encode a GATA-like transcription factor, is required for the production of epidermal cells by each of these lineages. Depending on their lineage history, cells that become epidermal in wild-type embryos become either neurons or muscle cells in elt-1 mutant embryos. The ELT-1 protein is expressed in epidermal cells and in their precursors. We propose that elt-1 functions at an early step in the specification of epidermal cell fates.


Real-Time Diagnosis System of COVID-19 Using X-Ray Images and Deep Learning.
The novel coronavirus named COVID-19 has quickly spread among humans worldwide, and the situation remains hazardous to the health system. The existence of this virus in the human body is identified through sputum or blood samples. Furthermore, computed tomography (CT) or X-ray has become a significant tool for quick diagnoses. Thus, it is essential to develop an online and real-time computer-aided diagnosis (CAD) approach to support physicians and avoid further spreading of the disease. In this research, a convolutional neural network (CNN) -based Residual neural network (ResNet50) has been employed to detect COVID-19 through chest X-ray images and achieved 98% accuracy. The proposed CAD system will receive the X-ray images from the remote hospitals/healthcare centers and perform diagnostic processes. Furthermore, the proposed CAD system uses advanced load balancer and resilience features to achieve fault tolerance with zero delays and perceives more infected cases during this pandemic.


The Sorin stentless pericardial valve: implant technique and hemodynamic profile.
Stentless porcine xenografts have had significant impact on the hemodynamics, left ventricular remodeling, and survival after aortic valve replacement. We sought to establish a similar trend for the stentless pericardial valve. In a consecutive unselected series of 54 patients over 65 years of age, we refined the implant method for the stentless aortic pericardial valve and defined the pitfalls. We used a detailed echocardiographic study designed by the Food and Drug Administration to define the early valve hemodynamics and changes in left ventricular function. The valve is user friendly. With an easily reproducible implant technique, very low mean (7.1+/-3.4 mm Hg) and peak (13.6+/-6.3 mm Hg) transvalvular gradients were obtained, which did not decline significantly with time. Left ventricular mass index declined accordingly over 6 months (147+/-49 g/m2 to 125+/-39 g/m2). Mild aortic regurgitation, which did not influence left ventricular mass regression, occurred (26%) predominantly in the first half of the series because of size discrepancy between the annulus and a dilated sinotubular junction. Aortic regurgitation was virtually eliminated by tailoring of the sinotubular junction in the noncoronary sinus. The stentless pericardial valve provides excellent early hemodynamics and is a realistic alternative to the stentless porcine xenograft or aortic homograft for subcoronary aortic valve replacement in elderly patients. Valve durability is yet to be defined.


A Bioreactor to Identify the Driving Mechanical Stimuli of Tissue Growth and Remodeling.
Tissue growth and remodeling are essential processes that should ensure long-term functionality of tissue-engineered (TE) constructs. Even though it is widely recognized that these processes strongly depend on mechanical stimuli, the underlying mechanisms of mechanically induced growth and remodeling are only partially understood. It is generally accepted that cells sense mechanical changes and respond by altering their surroundings, by means of extracellular matrix growth and remodeling, in an attempt to return to a certain preferred mechanical homeostatic state. However, the exact mechanical cues that trigger cells to synthesize and remodel their environment remain unclear. To identify the driving mechanical stimuli of these processes, it is critical to be able to temporarily follow the mechanical state of developing tissues under physiological loading conditions. Therefore, a novel "versatile tissue growth and remodeling" (Vertigro) bioreactor was developed that is capable of tissue culture and mechanical stimulation for a prolonged time period, while simultaneously performing mechanical testing. The Vertigro's unique two-chamber design allows easy, sterile handling of circular 3D TE constructs in a dedicated culture chamber, while a separate pressure chamber facilitates a pressure-driven dynamic loading regime during culture. As a proof-of-concept, temporal changes in the mechanical state of cultured tissues were quantified using nondestructive mechanical testing by means of a classical bulge test, in which the tissue displacement was tracked using ultrasound imaging. To demonstrate the successful development of the bioreactor system, compositional, structural, and geometrical changes were qualitatively and quantitatively assessed using a series of standard analysis techniques. With this bioreactor and associated mechanical analysis technique, a powerful toolbox has been developed to quantitatively study and identify the driving mechanical stimuli of engineered tissue growth and remodeling.


[Temperature quenching of cytochrome P-450 fluorescence in proteoliposomes with different physical states of the lipid bilayer].
Studies were carried out of temperature quenching of self-fluorescence of cytochrome P-450 in solution and liposomes from natural phosphatidylcholine, dimiristoylphosphatidylcholine, dipalmitoylphosphatidylcholine. The fluorescence spectrum of cytochrome P-450 is a superposition of triptophane and tyrosine components. During protein incorporation into liposomes a significant short-wave shift of the emission spectrum takes place. Temperature dependence of the intensity of cytochrome P-450 self-fluorescence in solution has bends at 30, 45 and 50 degrees C. When protein is incorporated into liposomes the location of bends depends on individual properties of lipids forming the bilayer. Effect of lipid surrounding on temperature conformational rearrangements of cytochrome P-450 molecule is discussed.


Healing process of skin after CO2 laser ablation at low irradiance: a comparison of continuous-wave and pulsed mode.
The purpose of the present study was to compare the healing process of rabbit's skin after the ablation of continuous wave CO(2) laser and pulsed CO(2) laser at low irradiances. Because of its advantages, the CO(2) laser has been viewed as an alternative to the traditional scalpel. Simple thermal models suggest that suitably short pulses of laser irradiation can leave a smaller thermal damaged zone to ablated tissue, which may lead to faster healing. One continuous-wave (cw, 2 watt) and two pulsed CO(2) lasers (sp(1), 100 Hz, 2 watt; and sp(2), 25 Hz, 2 watt) were used to ablate twelve rabbits' ear skin for 2 min, respectively. After sacrifice at 0, 3, 7, 14, 28, and 56 days postsurgery, gross observation and histological examination were performed. sp(1) and sp(2) resulted in similar ablation rates to cw laser. At 3, 7, 14, and 28 days postsurgery, the scores of the group cw were significantly lower than both the sp(1) and sp(2) scores (p < 0.01). From 7 to 28 days, wounds of sp1 showed the best histological outcomes. At a relatively low irradiance, pulsed CO(2) laser is capable of bloodless skin ablation with improved wound healing. Increasing repetition rate of the CO(2) laser may help to achieve a better surgical outcome. Pulsed CO(2) laser may be a valuable instrument for ablation skin and skin lesions.


Has the rate of CD4 cell count decline before initiation of antiretroviral therapy changed over the course of the Dutch HIV epidemic among MSM?
Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline. Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART, <100 CD4 cells/mm³, or AIDS) among therapy-naïve MSM HIV-1 seroconverters in the Netherlands. These models make different assumptions about the censoring process. All 3 models estimated lower median CD4 cell counts 9 months after seroconversion in later calendar years (623, 582, and 541 cells/mm³ for 1984-1995 [n = 111], 1996-2002 [n = 139], and 2003-2007 seroconverters [n = 356], respectively, shared-parameter model). Only the 2 joint-models found a trend for a steeper decline of CD4 cell counts with seroconversion in later calendar years (overall p-values 0.002 and 0.06 for the pattern-mixture and the shared-parameter model, respectively). In the shared-parameter model the median decline from 9 to 48 months was 276 cellsmm³ for 1984-1995 seroconverters and 308 cells/mm³ for 2003-2007 seroconverters (difference in slope, p = 0.045). Mixed-effects models underestimate the CD4 cell decline prior to starting ART. Joint-models suggest that CD4 cell count declines more rapidly in patients infected between 2003 and 2007 compared to patients infected before 1996.


Molecular Interaction Mechanism of a 14-3-3 Protein with a Phosphorylated Peptide Elucidated by Enhanced Conformational Sampling.
Enhanced conformational sampling, a genetic-algorithm-guided multidimensional virtual-system coupled molecular dynamics, can provide equilibrated conformational distributions of a receptor protein and a flexible ligand at room temperature. The distributions provide not only the most stable but also semistable complex structures and propose a ligand-receptor binding process. This method was applied to a system consisting of a receptor protein, 14-3-3ε, and a flexible peptide, phosphorylated myeloid leukemia factor 1 (pMLF1). The results present comprehensive binding pathways of pMLF1 to 14-3-3ε. We identified four thermodynamically stable clusters of MLF1 on the 14-3-3ε surface and free-energy barriers among some clusters. The most stable cluster includes two high-density spots connected by a narrow corridor. When pMLF1 passes the corridor, a salt-bridge relay (switching) related to the phosphorylated residue of pMLF1 occurs. Conformations in one high-density spot are similar to the experimentally determined complex structure. Three-dimensional distributions of residues in the intermolecular interface rationally explain the binding constant changes resulting from the alanine mutation experiment for the residues. We also performed a simulation of nonphosphorylated peptide and 14-3-3ε, which demonstrated that the complex structure was unstable, suggesting that phosphorylation of the peptide is crucially important for binding to 14-3-3ε.


Significance, epidemiology, and prevention of peritoneal dialysis catheter infections.
Catheter infections are a major cause of morbidity, catheter loss, and transfer to hemodialysis. These infections are mainly due to S. aureus. To date, treatment is less than optimal. Therefore, the primary goal should be prevention of catheter infections. Prevention is based on improving catheter design and implantation technique while using careful exit-site care. Prophylaxis with antimicrobials such as intranasal mupirocin or the use of silver-impregnated catheters appears promising as a way to reduce the risk of developing S. aureus infections. To optimize patient outcome, one must focus on these preventive measures.


Does pinealectomy affect the recovery rate after spinal cord injury?
Previous reports documented demonstrated that melatonin, a free radical scavenger, is important in protecting against oxidative stress-induced tissue damage after spinal cord injury (SCI). This study was undertaken to investigate the effects of pinealectomy (PX) and administration of exogenous melatonin after SCI in rats. These animals were randomized into six groups, each having 12 rats. Group 1 underwent laminectomy alone. Group 2 underwent laminectomy followed by SCI and received no medication. Group 3 underwent laminectomy followed by SCI and received melatonin. Group 4 underwent PX and laminectomy alone. Group 5 underwent PX and laminectomy followed by SCI and received no medication. Group 6 underwent PX and laminectomy followed by SCI and received melatonin. Melatonin (100 mg/kg) was given intraperitoneally immediately after trauma to the rats in the groups 3 and 6. PX caused a significant increase in the malondialdehyde (MDA), nitrite oxide (NO), glutathione (GSH), xanthine oxidase (XO) levels and decrease in GSH levels as compared with the control group. Trauma to the spinal cord results in significantly higher oxidative stress. Melatonin administration significantly reduced MDA, XO and NO levels, and increased GSH levels in the spinal cord after trauma. Exogenous melatonin treatment after trauma attenuated tissue lesion area and accelerated motor recovery rate. These findings suggest that reduction in endogenous melatonin after PX makes the rats more vulnerable to trauma and exogenous melatonin administration has an important neuroprotective effect on the level of the spinal cord.


Comparison of self-reported week-day and weekend-day sitting time and weekly time-use: results from the Australian Longitudinal Study on Women's Health.
The study of sedentary behavior is a relatively new area in population health research, and little is known about patterns of sitting time on week-days and weekend-days. To compare self-reported week-day and weekend-day sitting time with reported weekly time spent in other activities. Data were from 8,717 women born between 1973 and 1978 ('younger'), and 10,490 women born between 1946 and 1951 ('mid-age') who completed surveys for the Australian Longitudinal Study on Women's Health in 2003 and 2001, respectively. They were asked about time spent sitting on week-days and weekend-days. The women were also asked to report time spent in employment, active leisure, passive leisure, home duties, and studying. Mean week-day and weekend-day sitting times were compared with time-use using analysis of variance. Younger women sat more than mid-aged women, and sitting time was higher on week-days than on weekend-days in both cohorts. There were marked positive associations between week-day and weekend-day sitting times and time spent in passive leisure in both cohorts, and with time spent studying on week-days for the younger women. Week-day sitting time was markedly higher in women who reported >35 h in employment, compared with those who worked <35 h. In contrast, there were inverse associations between sitting time and time spent in home duties. Associations between sitting and active leisure were less consistent. Although week-day sitting time was higher than weekend-day sitting time, the patterns of the relationships between week-day and weekend-day sitting and time-use were largely similar, except for time spent in employment.


Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics.
The structure-based design, chemical synthesis, and biological evaluation of various ketomethylene-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The ketomethylene-containing inhibitors typically display slightly reduced 3CP inhibition activity relative to the corresponding peptide-derived molecules, but they also exhibit significantly improved antiviral properties. Optimization of the ketomethylene-containing compounds is shown to provide several highly active 3C protease inhibitors which function as potent antirhinoviral agents (EC90 = <1 microM) against multiple virus serotypes in cell culture.


A pitfall of using 2-[(2E)-3-(4-tert-butylphenyl)-2-methylprop-2-enylidene]malononitrile as a matrix in MALDI TOF MS: chemical adduction of matrix to analyte amino groups.
2-[(2E)-3-(4-tert-Butylphenyl)-2-methylprop-2-enylidene]malononitrile (DCTB) has been considered as an excellent matrix for matrix-assisted laser desorption/ionization (MALDI) of many types of synthetic compounds. However, it might provide troublesome results for compounds containing aliphatic primary or secondary amino groups. For these compounds, strong extra ion peaks with a mass difference of 184.1 Da were usually observed, which might falsely indicate the presence of some unknown impurities that were not detected by other matrices. On the basis of the possible mechanisms proposed, these extra ions are the products of nucleophilic reactions between analyte amino groups and DCTB molecules or radical cations. In these reactions, an amino group replaces the dicyanomethylene group of DCTB forming a matrix adduct via a -C=N-bond. An aliphatic primary amine could react easily with DCTB and the reaction could start once they are mixed in a MALDI solution. For an aliphatic secondary amine, on the other hand, the reaction most likely occurs in the gas phase. Protonation of amino groups by adding acid seems to be a useful way to stop DCTB adduction for compounds with one single amino group, but not for compounds with multiple amino groups. Unlike aliphatic primary or secondary amines, aliphatic tertiary amines and aromatic amines do not yield DCTB adducts. This is because tertiary amines do not have the required transferrable H-(N) atom to form an extra -C=N-bond, while aromatic amines are not sufficiently nucleophilic to attack DCTB. In view of the possible matrix adduction, care should be taken in MALDI time-of-flight mass spectrometry (TOF MS) when DCTB is used as the matrix for compounds containing amino group(s).


Determination of quantitative trait loci (QTL) for early maturation in rainbow trout (Oncorhynchus mykiss).
To identify quantitative trait loci (QTL) influencing early maturation (EM) in rainbow trout (Oncorhynchus mykiss), a genome scan was performed using 100 microsatellite loci across 29 linkage groups. Six inter-strain paternal half-sib families using three inter-strain F(1) brothers (approximately 50 progeny in each family) derived from two strains that differ in the propensity for EM were used in the study. Alleles derived from both parental sources were observed to contribute to the expression of EM in the progeny of the brothers. Four genome-wide significant QTL regions (i.e., RT-8, -17, -24, and -30) were observed. EM QTL detected on RT-8 and -24 demonstrated significant and suggestive QTL effects in both male and female progeny. Furthermore, within both male and female full-sib groupings, QTL on RT-8 and -24 were detected in two or more of the five parents used. Significant genome-wide and several strong chromosome-wide QTL for EM localized to different regions in males and females, suggesting some sex-specific control. Namely, QTL detected on RT-13, -15, -21, and -30 were associated with EM only in females, and those on RT-3, -17, and -19 were associated with EM only in males. Within the QTL regions identified, a comparison of syntenic EST markers from the rainbow trout linkage map with the zebrafish (Danio rerio) genome identified several putative candidate genes that may influence EM.


Effect of Technology-Enhanced Screening in Addition to Standard Targeted Clinician Education on the Duration of Untreated Psychosis: A Cluster Randomized Clinical Trial.
Reducing the duration of untreated psychosis (DUP) is essential to improving outcomes for people with first-episode psychosis (FEP). Current US approaches are insufficient to reduce DUP to international standards of less than 90 days. To determine whether population-based electronic screening in addition to standard targeted clinician education increases early detection of psychosis and decreases DUP, compared with clinician education alone. This cluster randomized clinical trial included individuals aged 12 to 30 years presenting for services between March 2015 and September 2017 at participating sites that included community mental health clinics and school support and special education services. Eligible participants were referred to the Early Diagnosis and Preventative Treatment (EDAPT) Clinic. Data analyses were performed in September and October 2019 for the primary and secondary analyses, with the exploratory subgroup analyses completed in May 2021. All sites in both groups received targeted education about early psychosis for health care professionals. In the active screening group, clients also completed the Prodromal Questionnaire-Brief using tablets at intake; referrals were based on those scores and clinical judgment. In the group receiving treatment as usual (TAU), referrals were based on clinical judgment alone. Primary outcomes included DUP, defined as the period from full psychosis onset to the date of the EDAPT diagnostic telephone interview, and the number of individuals identified with FEP or a psychosis spectrum disorder. Exploratory analyses examined differences by site type, completion rates between conditions, and days from service entry to telephone interview. Twenty-four sites agreed to participate, and 12 sites were randomized to either the active screening or TAU group. However, only 10 community clinics and 4 school sites were able to fully implement population screening and were included in the final analysis. The total potentially eligible population size within each study group was similar, with 2432 individuals entering at active screening group sites and 2455 at TAU group sites. A total of 303 diagnostic telephone interviews were completed (178 [58.7%] female individuals; mean [SD] age, 17.09 years [4.57]). Active screening sites reported a significantly higher detection rate of psychosis spectrum disorders (136 cases [5.6%], relative to 65 [2.6%]; P < .001) and referred a higher proportion of individuals with FEP and DUP less than 90 days (13 cases, relative to 4; odds ratio, 0.30; 95% CI, 0.10-0.93; P = .03). There was no difference in mean (SD) DUP between groups (active screening group, 239.0 days [207.4]; TAU group 262.3 days [170.2]). In this cluster trial, population-based technology-enhanced screening across community settings detected more than twice as many individuals with psychosis spectrum disorders compared with clinical judgment alone but did not reduce DUP. Screening could identify people undetected in US mental health services. Significant DUP reduction may require interventions to reduce time to the first mental health contact. ClinicalTrials.gov Identifier: NCT02841956.


National health and optometry: a follow-up study.
A stratified probability sample of the Houston, Texas population was interviewed with a previously described questionnaire (Allen, D., and D. Levi, National Health and Optometry--a survey of public attitudes. Am. J. Optom., 52 (4): 291-300, (1975) to assess present opinion of national health care and public awareness of vision care and its role in a national health care system. Of the population surveyed, 72% favored a national health care bill, some 10% lower than reported 1 year previously. A large percentage of the population sampled favored inclusion of vision care. The results are described in terms of demographic trends for those who have received optometric and ophthalmological care.