Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform.
Early descriptions of patients admitted to hospital during the COVID-19 pandemic showed a lower prevalence of asthma and chronic obstructive pulmonary disease (COPD) than would be expected for an acute respiratory disease like COVID-19, leading to speculation that inhaled corticosteroids (ICSs) might protect against infection with severe acute respiratory syndrome coronavirus 2 or the development of serious sequelae. We assessed the association between ICS and COVID-19-related death among people with COPD or asthma using linked electronic health records (EHRs) in England, UK. In this observational study, we analysed patient-level data for people with COPD or asthma from primary care EHRs linked with death data from the Office of National Statistics using the OpenSAFELY platform. The index date (start of follow-up) for both cohorts was March 1, 2020; follow-up lasted until May 6, 2020. For the COPD cohort, individuals were eligible if they were aged 35 years or older, had COPD, were a current or former smoker, and were prescribed an ICS or long-acting β agonist plus long-acting muscarinic antagonist (LABA-LAMA) as combination therapy within the 4 months before the index date. For the asthma cohort, individuals were eligible if they were aged 18 years or older, had been diagnosed with asthma within 3 years of the index date, and were prescribed an ICS or short-acting β agonist (SABA) only within the 4 months before the index date. We compared the outcome of COVID-19-related death between people prescribed an ICS and those prescribed alternative respiratory medications: ICSs versus LABA-LAMA for the COPD cohort, and low-dose or medium-dose and high-dose ICSs versus SABAs only in the asthma cohort. We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs for the association between exposure categories and the outcome in each population, adjusted for age, sex, and all other prespecified covariates. We calculated e-values to quantify the effect of unmeasured confounding on our results. We identified 148 557 people with COPD and 818 490 people with asthma who were given relevant respiratory medications in the 4 months before the index date. People with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA-LAMA combinations (adjusted HR 1·39 [95% CI 1·10-1·76]). Compared with those prescribed SABAs only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1·55 [1·10-2·18]), whereas those given a low or medium dose were not (1·14 [0·85-1·54]). Sensitivity analyses showed that the apparent harmful association we observed could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS that were not recorded in the database (e value lower 95% CI 1·43). Our results do not support a major role for regular ICS use in protecting against COVID-19-related death among people with asthma or COPD. Observed increased risks of COVID-19-related death can be plausibly explained by unmeasured confounding due to disease severity. UK Medical Research Council.


The COFU3 Study. Improvement in cognitive function, attention, mental performance with Pycnogenol® in healthy subjects (55-70) with high oxidative stress.
This 12-month product registry study evaluated the effects of supplementation with French pine bark extract (Pycnogenol(®)) on cognitive function, attention, and mental performance in healthy subjects with high oxidative stress. Healthy subjects (age range 55-70) were screened - within a cardiovascular screening program - for oxidative stress. Out of 150 subjects, high oxidative stress was present in 44; the use of the supplement Pycnogenol(®) was suggested (100 mg/day). These subjects decided to use Pycnogenol(®) and accepted to be evaluated by assessing cognitive functions. A group of subjects with comparable oxidative stress was followed as a reference. IQ Code (Informant Questionnaire on Cognitive Decline in the Elderly), daily tasks, cognitive function, oxidative stress and the short Blessed tests (SBT) were used (in defined scales) to evaluate cognitive functions (COFU). As for the IQ Code, at 12 months there was a significantlty total lower score in Pycnogenol(®) patients and also a lower value (P<0.05) for 14 out of 16 items in the questionnaire. Daily tasks: all items were improved (P<0.05) with supplementation in comparison with controls. The improvement was seen for all 12 items (P<0.05) with the supplement. Cognitive function values (visual scale line) indicated a significant improvement (P<0.05) in all elements present in the questionnaire with the 12-month supplementation (no significant variations in controls). Oxidative stress was comparable in both groups at inclusion. It was significantly decreased with Pycnogenol(®) (-28.07%; P<0.05) at 12 months; there was no decrease in controls. The short blessed test (SBT) value was significantly increased in controls (P<0.05); but significantly decreased in the Pycnogenol(®) group (P<0.05). Values for supplemented patients at 12 months were almost within the normal range (21 out or 38 were below the normal value of 4). Tolerability and compliance for Pycnogenol(®) were optimal with >97% of the doses of the supplement correctly used. No side effects were observed, recorded or described. Pycnogenol(®) supplementation for 12 months appears to improve cognitive function and oxidative stress in normal subjects between 55 and 70 years of age.


Stability of radiomic features in CT perfusion maps.
This study aimed to identify a set of stable radiomic parameters in CT perfusion (CTP) maps with respect to CTP calculation factors and image discretization, as an input for future prognostic models for local tumor response to chemo-radiotherapy. Pre-treatment CTP images of eleven patients with oropharyngeal carcinoma and eleven patients with non-small cell lung cancer (NSCLC) were analyzed. 315 radiomic parameters were studied per perfusion map (blood volume, blood flow and mean transit time). Radiomics robustness was investigated regarding the potentially standardizable (image discretization method, Hounsfield unit (HU) threshold, voxel size and temporal resolution) and non-standardizable (artery contouring and noise threshold) perfusion calculation factors using the intraclass correlation (ICC). To gain added value for our model radiomic parameters correlated with tumor volume, a well-known predictive factor for local tumor response to chemo-radiotherapy, were excluded from the analysis. The remaining stable radiomic parameters were grouped according to inter-parameter Spearman correlations and for each group the parameter with the highest ICC was included in the final set. The acceptance level was 0.9 and 0.7 for the ICC and correlation, respectively. The image discretization method using fixed number of bins or fixed intervals gave a similar number of stable radiomic parameters (around 40%). The potentially standardizable factors introduced more variability into radiomic parameters than the non-standardizable ones with 56-98% and 43-58% instability rates, respectively. The highest variability was observed for voxel size (instability rate >97% for both patient cohorts). Without standardization of CTP calculation factors none of the studied radiomic parameters were stable. After standardization with respect to non-standardizable factors ten radiomic parameters were stable for both patient cohorts after correction for inter-parameter correlations. Voxel size, image discretization, HU threshold and temporal resolution have to be standardized to build a reliable predictive model based on CTP radiomics analysis.


An anti-inflammatory and antioxidant nutritional supplement for hypoalbuminemic hemodialysis patients: a pilot/feasibility study.
A low serum albumin concentration < 3.8 g/dL, a marker of malnutrition-inflammation complex syndrome, is observed in approximately half of all maintenance hemodialysis (MHD) patients in the United States and is strongly associated with increased mortality. We hypothesized that a novel oral nutritional intervention with anti-inflammatory and antioxidant properties taken during routine dialysis sessions is well tolerated and corrects hypoalbuminemia in MHD patients. Controlled clinical study. An outpatient dialysis facility affiliated with a tertiary care community medical center with six equally distributed hemodialysis shifts and 163 MHD patients. Among all MHD outpatients of three selected HD shifts (n = 81 patients), 21 subjects had a serum albumin level < 3.8 g/dL. One patient who was hospitalized before the intervention was excluded. The other three dialysis shifts, with 82 MHD outpatients including 20 hypoalbuminemic subjects, were observed as concurrent controls. The nutritional intervention included one can of Oxepa and one can of Nepro to be taken together orally during each routine hemodialysis session for 4 weeks. Each can contains 237 mL fluid. Oxepa provides 355 calories and 14.8 g protein per can, includes maltodextrin, medium-chain triglycerides, borage oil, and refined and deodorized fish oil, and is designed for critically ill patients with inflammation and oxidative stress. Each can of Oxepa includes 1,020 mg gamma-linolenic acid, 3,100 mg caprylic acid, 1,080 mg eicosapentaenoic acid, 75 mg taurine, 2,840 IU vitamin A activity, 75 IU vitamin E, and 200 mg vitamin C. Nepro provides 475 calories and 16.7 g protein per can; includes high-oleic safflower oil, corn syrup solids, and fructo-oligosaccharides; and is tailored for the nutritional needs of MHD patients. Oxepa and Nepro also contain L-carnitine, 43 mg and 62 mg, respectively. Serum albumin pretrial and posttrial. Studied outpatients (12 men and 8 women) were aged 60.4 +/- 13.0 (SD) years. Three patients had started MHD treatment between 1.5 and 3 months before the intervention. Nine patients were diabetic. Preintervention serum albumin, 3.44 +/- 0.34 g/dL (mean +/- SD) increased to 3.68 +/- 0.34 g/dL (P = .001) 4 weeks after the start of the intervention. In 16 patients, serum albumin level increased by 0.2 to 1.3 g/dL, whereas in 4 patients the serum albumin level decreased by 0.2 to 0.6 g/dL. Three patients reported diarrhea, and one diabetic patient had increased serum glucose values. No other side effects were noted. In 20 control outpatients not receiving nutritional intervention, serum albumin did not change from 3.46 +/- 0.20 to 3.47 +/- 10.44 g/dL (P = .47). In hypoalbuminemic MHD patients, a short-term in-center nutritional intervention with one can of Nepro and one can of Oxepa during HD is practical, convenient, well-tolerated, and associated with a significant increase in serum albumin level. Well-designed randomized placebo-controlled clinical trials are needed to verify the safety and effectiveness of this nutritional intervention and its impact on clinical outcome in hypoalbuminemic MHD patients.


Quantitative changes in Gimap3 and Gimap5 expression modify mitochondrial DNA segregation in mice.
Mammalian mitochondrial DNA (mtDNA) is a high-copy maternally inherited genome essential for aerobic energy metabolism. Mutations in mtDNA can lead to heteroplasmy, the co-occurence of two different mtDNA variants in the same cell, which can segregate in a tissue-specific manner affecting the onset and severity of mitochondrial dysfunction. To investigate mechanisms regulating mtDNA segregation we use a heteroplasmic mouse model with two polymorphic neutral mtDNA haplotypes (NZB and BALB) that displays tissue-specific and age-dependent selection for mtDNA haplotypes. In the hematopoietic compartment there is selection for the BALB mtDNA haplotype, a phenotype that can be modified by allelic variants of Gimap3. Gimap3 is a tail-anchored member of the GTPase of the immunity-associated protein (Gimap) family of protein scaffolds important for leukocyte development and survival. Here we show how the expression of two murine Gimap3 alleles from Mus musculus domesticus and M. m. castaneus differentially affect mtDNA segregation. The castaneus allele has incorporated a uORF (upstream open reading frame) in-frame with the Gimap3 mRNA that impairs translation and imparts a negative effect on the steady-state protein abundance. We found that quantitative changes in the expression of Gimap3 and the paralogue Gimap5, which encodes a lysosomal protein, affect mtDNA segregation in the mouse hematopoietic tissues. We also show that Gimap3 localizes to the endoplasmic reticulum and not mitochondria as previously reported. Collectively these data show that the abundance of protein scaffolds on the endoplasmic reticulum and lysosomes are important to the segregation of the mitochondrial genome in the mouse hematopoietic compartment.


A matched cohort study investigating premature, accentuated, and accelerated aging in people living with HIV.
The impact of HIV infection on the aging process is disputed and largely unknown. We aimed to identify whether people living with HIV experience premature, accelerated, and/or accentuated aging by investigating the development of four age-related non-communicable diseases in people living with versus without HIV. This population-based matched cohort study design used UK-based primary care electronic health records from the IQVIA Medical Research Database. Between January 2000 and January 2020, all people living with and without HIV aged ≥18 years were eligible. Outcomes included cardiovascular disease (CVD), hypertension, type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), which were identified by Read codes. We used age at diagnosis to investigate premature aging and age at exit date to investigate accentuation and acceleration. For each outcome, people with and without HIV were excluded if they had the outcome of interest at baseline. Participants were matched based on propensity scores (1:1 ratio). Linear regression was used to report any difference in age at diagnosis between the two groups and to report the prevalence trends for age at exit date. In total, 8880 people living with HIV were matched with 8880 people without HIV and were found to have an earlier onset of CVD (54.5 vs. 56.8; p = 0.002). Similarly, people living with HIV had an earlier onset of hypertension (49.7 vs. 51.4; p = 0.002). No difference was found for T2DM or CKD (53.4 vs. 52.6; p = 0.368 and 57.6 vs. 58.1; p = 0.483, respectively). The burden of CKD increased over time, whereas no difference in the burden was found for the other conditions. The earlier development of CVD and hypertension in people living with HIV than in those without HIV indicates premature aging, whereas the increased burden of CKD indicates accelerated aging.


Photovoice in the workplace: A participatory method to give voice to workers to identify health and safety hazards and promote workplace change-a study of university custodians.
Photovoice, a photographic participatory action research methodology was used in a workplace setting to assess hazards that were creating extremely high injury and incidents rates for university custodians and to promote the conditions to eliminate or reduce those hazards. University custodians participated in a Photovoice project to identify, categorize, and prioritize occupational hazards and to discuss and propose solutions to these problems. Results were presented to management and to all custodians for further discussion. The effort was led by a worker-based union-sponsored participatory evaluation team in partnership with a university researcher. Visual depiction of hazardous tasks and exposures among custodians and management focused primarily on improper or unsafe equipment, awkward postures, lifting hazards, and electrical hazards. The process of taking pictures and presenting them created an ongoing discussion among workers and management regarding the need for change and for process improvements, and resulted in greater interest and activity regarding occupational health among the workers. In a follow-up evaluation 1-year later, a number of hazards identified through Photovoice had been corrected. Injury rates for custodians had decreased from 39% to 26%. Photovoice can be an important tool, not just for identifying occupational hazards, but also empowering workers to be more active around health and safety and may facilitate important changes in the workplace.


Crescentic glomerulonephritis: a clinical and histomorphological analysis of 46 cases.
Crescentic glomerulonephritis (CrGN), defined as crescents involving more than 50% of the glomeruli, includes pauci-immune, immune complex-mediated and anti-glomerular basement membrane disease. The present study was aimed at evaluating the various clinical, biochemical and histological parameters in CrGN with respect to these categories and clinical outcome. Renal biopsies diagnosed as CrGN between Jan 2008 and Feb 2010 were included. Clinical and laboratory parameters were retrieved along with the therapeutic approach and clinical outcome, wherever available. Renal biopsy slides were evaluated for various glomerular, tubulo-interstitial and arteriolar features. Appropriate statistical tests were applied for significance. A total of 46 cases of CrGN were included; majority (71.7%) of cases were pauci-immune (PI) while 28.3% were immune complex-mediated (IC). Among clinical features, gender ratio was significantly different between PI and IC groups (P = 0.006). The various histological parameters, including proportion of cellular crescents, tuft necrosis and Bowman's capsule rupture, were similar in both the groups. Four unusual associations, including idiopathic membranoproliferative glomerulonephritis (MPGN), multibacillary leprosy, acute lymphoblastic leukemia and C1q nephropathy were detected. Adequate follow-up information was available in 21 (46%) of the patients. Of these, 11 (52.4%) were dialysis-dependent at the last follow-up. Adult patients required renal replacement therapy more frequently than pediatric cases (P = 0.05). Presence of arteriolar fibrinoid necrosis also showed association with poor clinical outcome (P = 0.05). Crescentic glomerulonephritis remains one of the main causes of acute renal failure with histological diagnosis. Immunohistologic examination is essential for accurate classification into one of the three categories. This condition should be considered in rare causal associations like leprosy or MPGN with renal failure, to allow for timely performed renal biopsy and appropriate aggressive therapy.


Dose-response curve of a microfluidic magnetic bead-based surface coverage sandwich assay.
Magnetic micro- and nanoparticles ('magnetic beads') have been used to advantage in many microfluidic devices for sensitive antigen (Ag) detection. Today, assays that use as read-out of the signal the number count of immobilized beads on a surface for quantification of a sample's analyte concentration have been among the most sensitive and have allowed protein detection lower than the fgmL(-1) concentration range. Recently, we have proposed in this category a magnetic bead surface coverage assay (Tekin et al., 2013 [1]), in which 'large' (2.8μm) antibody (Ab)-functionalized magnetic beads captured their Ag from a serum and these Ag-carrying beads were subsequently exposed to a surface pattern of fixed 'small' (1.0μm) Ab-coated magnetic beads. When the system was exposed to a magnetic induction field, the magnet dipole attractive interactions between the two bead types were used as a handle to approach both bead surfaces and assist with Ag-Ab immunocomplex formation, while unspecific binding (in absence of an Ag) of a large bead was reduced by exploiting viscous drag flow. The dose-response curve of this type of assay had two remarkable features: (i) its ability to detect an output signal (i.e. bead number count) for very low Ag concentrations, and (ii) an output signal of the assay that was non-linear with respect to Ag concentration. We explain here the observed dose-response curves and show that the type of interactions and the concept of our assay are in favour of detecting the lowest analyte concentrations (where typically either zero or one Ag is carried per large bead), while higher concentrations are less efficiently detected. We propose a random walk process for the Ag-carrying bead over the magnetic landscape of small beads and this model description explains the enhanced overall capture probability of this assay and its particular non-linear dose response curves.


A randomized study comparing different doses of superparamagnetic iron oxide tracer for sentinel lymph node biopsy in breast cancer: The SUNRISE study.
The non-radioactive method that uses the magnetic tracer (SPIO/Sienna) has shown to be a feasible technique for the SLN detection in breast cancer patients. The aim of this study is to assess the efficacy of different doses of a new magnetic tracer Sienna XP (Magtrace) compared to Tc-99 m and to evaluate its non-inferiority. Patients diagnosed with early-stage breast cancer cT1-3 N0, from October 2016 to August 2018 were eligible and consecutively randomized to three different doses of new SPIO used: group 1 (1 mL), group 2 (1.5 mL) and group 3 (2 mL). A total of 135 patients were included in the study, 45 in each group. Detection of SLNs with the three doses of Sienna XP (1 mL, 1.5 mL and 2 mL) showed non-inferior rates compared to the conventional technique with radiotracer (p = 0.654). Concordance by patients with SLN positive was 100% for all groups. 83 (70.3%) patients reported skin staining at one month postoperatively, significantly lower in group 1 (p = 0.042). At 6 months follow up, group 1 remains with significantly lower skin discoloration (p = 0,01). In multivariate analysis, dose of 2 mL showed statistically significant for the skin staining. The majority of patients (70%) felt that skin discoloration does not represent a problem. The use of the Sienna XP magnetic tracer at 1 mL is not inferior to higher doses of magnetic tracer neither is inferior to radiotracer. 1 mL of magnetic tracer resulted in significantly less skin discoloration compared to higher doses.


Water quality and quantity assessment of pervious pavements performance in experimental car park areas.
Pervious pavements have become one of the most used sustainable urban drainage system (SUDS) techniques in car parks. This research paper presents the results of monitoring water quality from several experimental car park areas designed and constructed in Spain with bays made of interlocking concrete block pavement, porous asphalt, polymer-modified porous concrete and reinforced grass with plastic and concrete cells. Moreover, two different sub-base materials were used (limestone aggregates and basic oxygen furnace slag). This study therefore encompasses the majority of the materials used as permeable surfaces and sub-base layers all over the world. Effluent from the test bays was monitored for dissolved oxygen, pH, electric conductivity, total suspended solids, turbidity and total petroleum hydrocarbons in order to analyze the behaviour shown by each combination of surface and sub-base materials. In addition, permeability tests were undertaken in all car parks using the 'Laboratorio Caminos Santander' permeameter and the Cantabrian Portable Infiltrometer. All results are presented together with the influence of surface and sub-base materials on water quality indicators using bivariate correlation statistical analysis at a confidence level of 95%. The polymer-modified porous concrete surface course in combination with limestone aggregate sub-base presented the best performance.


Exploratory Economic Evaluation of Buprenorphine Treatment in Opioid Use Disorder.
Burden of opioid use disorder (OUD) is expressed in economic values or health metrics like Disability Adjusted Life Years (DALYs). Disability Weight (DW), a component of DALYs is estimated using economic methods or psychometric tools. Estimating DW at patient level using psychometric tools is an alternative to non-population specific DW overestimated by economic methods. Providing Medication Assisted Treatment (MAT) using buprenorphine/naloxone film (BUP/NX-F) for OUD is limited by financial constraints. To estimate the burden of OUD at patient level and explore the cost-benefit of two buprenorphine treatment interventions. The present study was conducted alongside a randomized controlled trial of 141 adults with OUD stabilized on BUP/NX-F and randomized to BUP/NX-F with Incentivized Abstinence and Adherence Monitoring (experimental, n=70) and BUP/NX-F in usual care (control, n=71). The cost of illness was estimated applying a societal perspective. The Impairment Weight (IW) was estimated over a '0' to '1' scale, where '0' represents no impairment and '1' full impairment using the Work and Social Adjustment Scale (WSAS). Median (interquartile range) annual cost of OUD per participant was AED 498,171.1 (413,499.0 -635,725.3) and AED 538,694.4 (4,211,398.0 - 659,949.0) in the experimental and control groups, respectively (p=0.33). Illicit drug purchase represented 60 % of the annual cost of illness. At baseline, the mean Impairment Weight (IW) was 0.55 (SD 0.26) and 0.62 (SD 0.24) in the experimental and control groups, respectively. At end of the study, the IW was 0.26 (SD 0.28) representing 51% reduction in the experimental group compared to 0.42 (SD 0.33) in the control group representing a 27% reduction. Excluding imprisonment, the cost-benefit of treatment was not realized. In contrast, accounting for imprisonment, cost benefit expressed as a return-on-investment was established at 1.55 and 1.29 in the experimental and control groups, respectively. Cost benefit analysis can serve as a simple and practical tool to evaluate the cost benefit of treatment interventions. Demonstrating the cost benefit of buprenorphine treatment has the potential to facilitate public funding and accessibility to opioid assisted treatment.


Interactions between apo-(D-beta-hydroxybutyrate dehydrogenase) and phospholipids studied by intrinsic and extrinsic fluorescence.
Interactions of D-beta-hydroxybutyrate dehydrogenase with phospholipids were investigated by both intrinsic- and extrinsic-fluorescence approaches. The intrinsic fluorescence, mainly caused by tryptophan residues, increased upon re-activation in the presence of phospholipids bearing a positive charge, i.e. phosphatidylcholine, but decreased in the presence of non-re-activating phospholipids with a negative charge. This indicates either that the environment of tryptophan residues is affected by charges rather than by hydrophobic chains of phospholipids, or that the enzyme undergoes different conformational changes depending on the nature of the phospholipids. On the other hand, the graph of the temperature-dependence of the fluorescence intensities of the enzyme embedded in dimyristoylphosphatidylcholine liposomes exhibits a break around 21 degrees C. This indicates either that at least one tryptophan residue is closely in contact with the hydrophobic chains of phospholipids or that there is a change in the environment of tryptophan residues owing to the physical state of the phospholipids. The addition of D-beta-hydroxybutyrate apo-dehydrogenase to phospholipid liposomes containing diphenylhexatriene (a fluorescent probe) increased the diphenylhexatriene fluorescence polarization. Moreover, there was a partial fluorescence energy transfer from tryptophan to diphenylhexatriene. These results strongly favour the possibility that there is a portion of the enzyme polypeptide chain inserted into the phospholipid hydrophobic region. All these results demonstrate that D-beta-hydroxybutyrate apo-dehydrogenase interacts with both polar and hydrophobic parts of phospholipids and leads to small, but essential, conformational changes of the enzyme.


Multidimensional Apathy in Behavioral Variant Frontotemporal Dementia, Primary Progressive Aphasia, and Alzheimer Disease.
Apathy is prevalent in dementia, such as behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and Alzheimer disease (AD). As a multidimensional construct, it can be assessed and subsumed under a Dimensional Apathy Framework. A consistent apathy profile in bvFTD and PPA has yet to be established. The aim was to explore apathy profiles and awareness in bvFTD, PPA, and AD. A total of 12 patients with bvFTD, 12 patients with PPA, 28 patients with AD, and 20 matched controls, as well as their informants/carers, were recruited. All participants completed the Dimensional Apathy Scale (DAS), assessing executive, emotional, and initiation apathy subtypes, a 1-dimensional apathy measure, depression measure, and functional and cognitive screens. Apathy subtype awareness was determined through DAS informant/carer and self-rating discrepancy. Apathy profile comparison showed patients with bvFTD had significantly higher emotional apathy than patients with AD (P < .01) and significantly higher apathy over all subtypes than patients with PPA (Ps < .05). Additionally, patients with bvFTD had significantly lower awareness for emotional apathy (P < .01) when compared to patients with AD and PPA. All patient groups had significant global apathy over all subtypes compared to controls. The emergent apathy profile for bvFTD seems to be emotional apathy (indifference or emotional/affective neutrality), with lower self-awareness in this subtype. Further, lower self-awareness for executive apathy (lack of motivation for planning, organization, or attention) differentiates bvFTD from PPA. Future research should investigate the cognitive and neural correlates as well as the practical impact of apathy subtypes.


Depression, substance abuse and stigma among men who have sex with men in coastal Kenya.
Mental health conditions can erode quality of life and interfere with health-related behaviours such as medication adherence. We aimed to determine the prevalence and correlates of depression and other psychosocial factors among self-identified men who have sex with men (MSM) in coastal Kenya. A cross-sectional survey. Psychosocial and mental health characteristics were assessed in an audio computer-assisted self-interview (ACASI) survey among 112 MSM participating in two ongoing HIV-positive and HIV-negative cohorts in Mtwapa, Kenya. One-third of participants met criteria for major depressive disorder [16.1%, 95% confidence interval (95% CI) 9.8-24.2] or other depressive disorder (15.2%, 95% CI 9.1-23.2). Alcohol abuse was reported by 45% of respondents (95% CI 35.2-54.3) and other substance abuse by 59.8% (95% CI 50.1-69.0). Sexual and HIV stigma were moderate, with median scores of 11 [interquartile range (IQR) 6-17, potential range 0-33] and 25 (IQR 23-29, potential range 11-44), respectively. There were significant bivariate correlations between alcohol abuse, other substance abuse, sexual stigma and childhood and recent abuse. In a multivariable linear regression model, sexual stigma (beta = 0.17, 95% CI 0.03-0.32) and marriage to a woman (beta = -2.41 95% CI -4.74 to -0.09) were each associated with depression score. We found moderate to high levels of depression and substance abuse, and moderate levels of sexual stigma. These variables were highly inter-correlated and associated with an experience of trauma or abuse. Comprehensive mental health services are needed in this population to address these issues.


Brachial plexus contouring with CT and MR imaging in radiation therapy planning for head and neck cancer.
With the increasing use of intensity-modulated radiation therapy (IMRT) for the treatment of head and neck cancer, radiation oncologists are expected to have an in-depth knowledge of the computed tomographic (CT) and magnetic resonance (MR) imaging anatomy of this region to be able to accurately characterize tumor extent and define organs at risk for potential radiation injury. The brachial plexus is a complex anatomic structure in the head and neck adjacent to diseased nodes and elective nodal volumes (ie, nodal areas that are prophylactically treated because they are at high risk for micrometastatic disease) and should, therefore, be carefully identified and contoured at CT prior to IMRT planning. A number of multi-institutional protocols mandate contouring the brachial plexus as an "avoidance structure" (ie, a structure or volume that is at risk for complications of radiation therapy) in the planning of head and neck radiation therapy, and, although little information exists on the best method of doing so consistently, contouring may be facilitated with fusion CT-MR imaging software. With three-dimensional conformal radiation therapy, the brachial plexus is not routinely contoured; therefore, its dose limits are not evaluated in treatment planning. In contrast, with IMRT, tolerance doses can be set to limit the maximum dose to the brachial plexus to 60 Gy in most radiation protocols, although the true radiation tolerance dose in patients with head and neck cancer has been mentioned only sporadically in the literature. Additional studies will be required to determine if identification of the brachial plexus as an avoidance structure prior to radiation therapy planning improves treatment outcome in patients with head and neck cancer and reduces long-term toxicity in this structure.


Chemometrics and hyperspectral imaging applied to assessment of chemical, textural and structural characteristics of meat.
Spectroscopy in the visible near-infrared spectral (Vis-NIRS) range combined with imaging techniques (hyperspectral imaging, HSI) allows assessment of chemical composition, texture, and meat structure. The use of HSI in the meat and food industry has observed a significant growth in the last decade, yet its use for assessment of meat it is not optimal yet. The application of HSI for assessment of meat is reviewed with focus on its ability to capture meat unique chemical and structural characteristics. While HSI is widely used for assessment of chemical composition, a limited number of evidences on its ability to handle the effect of different sources of variation on the assessment is found. The use of spatially resolved spectroscopy has been able to detect structural information related to animal background, muscle type, rigor process and ageing. Similarly the use of texture features seem to capture unique characteristics of meat.


Nucleolin regulates c-Jun/Sp1-dependent transcriptional activation of cPLA2alpha in phorbol ester-treated non-small cell lung cancer A549 cells.
The expression of cPLA2 is critical for transformed growth of non-small cell lung cancer (NSCLC). It is known that phorbol 12-myristate 13-acetate (PMA)-activated signal transduction pathway is thought to be involved in the oncogene action in NSCLC and enzymatic activation of cPLA2. However, the transcriptional regulation of cPLA2alpha in PMA-activated NSCLC is not clear. In this study, we found that PMA induced the mRNA level and protein expression of cPLA2alpha. In addition, two Sp1-binding sites of cPLA2alpha promoter were required for response to PMA and c-Jun overexpression. Small interfering RNA (siRNA) of c-Jun and nucleolin inhibited PMA induced the promoter activity and protein expression of cPLA2alpha. Furthermore, PMA stimulated the formation of c-Jun/Sp1 and c-Jun/nucleolin complexes as well as the binding of these transcription factor complexes to the cPLA2alpha promoter. Although Sp1-binding sites were required for the bindings of Sp1 and nucleolin to the promoter, the binding of nucleolin or Sp1 to the promoter was independent of each other. Our results revealed that c-Jun/nucleolin and c-Jun/Sp1 complexes play an important role in PMA-regulated cPLA2alpha gene expression. It is likely that nucleolin binding at place of Sp1 on gene promoter could also mediate the regulation of c-Jun/Sp1-activated genes.


How well can morphology assess cell death modality? A proteomics study.
While the focus of attempts to classify cell death programs has finally shifted in 2010s from microscopy-based morphological characteristics to biochemical assays, more recent discoveries have put the underlying assumptions of many such assays under severe stress, mostly because of the limited specificity of the assays. On the other hand, proteomics can quantitatively measure the abundances of thousands of proteins in a single experiment. Thus proteomics could develop a modern alternative to both semiquantitative morphology assessment as well as single-molecule biochemical assays. Here we tested this hypothesis by analyzing the proteomes of cells dying after been treated with various chemical agents. The most striking finding is that, for a multivariate model based on the proteome changes in three cells lines, the regulation patterns of the 200-500 most abundant proteins typically attributed to household type more accurately reflect that of the proteins directly interacting with the drug than any other protein subset grouped by common function or biological process, including cell death. This is in broad agreement with the 'rigid cell death mechanics' model where drug action mechanism and morphological changes caused by it are bijectively linked. This finding, if confirmed, will open way for a broad use of proteomics in death modality assessment.


Health informatics 3.0.
Web 3.0 promises us smart computer services that will interact with each other and leverage knowledge about us and our immediate context to deliver prioritised and relevant information to support decisions and actions. Healthcare must take advantage of such new knowledge-integrating services, in particular to support better co-operation between professionals of different disciplines working in different locations, and to enable well-informed co-operation between clinicians and patients. To grasp the potential of Web 3.0 we will need well-harmonised semantic resources that can richly connect virtual teams and link their strategies to real-time and tailored evidence. Facts, decision logic, care pathway steps, alerts, education need to be embedded within components that can interact with multiple EHR systems and services consistently. Using Health Informatics 3.0 a patient's current situation could be compared with the outcomes of very similar patients (from across millions) to deliver personalised care recommendations. The integration of EHRs with biomedical sciences ('omics) research results and predictive models such as the Virtual Physiological Human could help speed up the translation of new knowledge into clinical practice. The mission, and challenge, for Health Informatics 3.0 is to enable healthy citizens, patients and professionals to collaborate within a knowledge-empowered social network in which patient specific information and personalised real-time evidence are seamlessly interwoven.


RAC/ROP GTPases and auxin signaling.
Auxin functions as a key morphogen in regulating plant growth and development. Studies on auxin-regulated gene expression and on the mechanism of polar auxin transport and its asymmetric distribution within tissues have provided the basis for realizing the molecular mechanisms underlying auxin function. In eukaryotes, members of the Ras and Rho subfamilies of the Ras superfamily of small GTPases function as molecular switches in many signaling cascades that regulate growth and development. Plants do not have Ras proteins, but they contain Rho-like small G proteins called RACs or ROPs that, like fungal and metazoan Rhos, are regulators of cell polarity and may also undertake some Ras functions. Here, we discuss the advances made over the last decade that implicate RAC/ROPs as mediators for auxin-regulated gene expression, rapid cell surface-located auxin signaling, and directional auxin transport. We also describe experimental data indicating that auxin-RAC/ROP crosstalk may form regulatory feedback loops and theoretical modeling that attempts to connect local auxin gradients with RAC/ROP regulation of cell polarity. We hope that by discussing these experimental and modeling studies, this perspective will stimulate efforts to further refine our understanding of auxin signaling via the RAC/ROP molecular switch.


Novel design of osmotic chitosan capsules characterized by asymmetric membrane structure for in situ formation of delivery orifice.
In this study, chitosan capsules with asymmetric membrane to induce osmotic effects and in situ formation of the delivery orifice were optimally prepared and characterized. Chitosan capsules were formed on stainless steel mold pins by dipping the pins into a chitosan solution followed by forming asymmetric structure by dipping into a quenching solution containing tripolyphosphate (TPP) to cause an ionic cross-linking reaction between the outer layer of chitosan and TPP. Factors influencing the properties of the capsule membrane, such as the molecular weight of chitosan, the dipping solution and dipping time, and the quenching solution and time, were optimized to successfully produce osmotic chitosan capsules with asymmetric membrane using chitosans that possessed different viscosities. In situ formation of a delivery orifice on the asymmetric membrane of the chitosan capsule was proven by the observation of a jet stream of chlorophyll being released from the capsule. Drugs with different solubility were selected, and a linear correlation between drug solubility and the initial drug release rate calculated from the slope of the drug release profile was used to verify that the delivery orifices that were in situ formed on the asymmetric membrane of the chitosan capsules induced by osmotic effect was responsible for the drug release. Water permeability across the optimally produced asymmetric membrane of the capsule from chitosan of 500 cps (300-700 cps) quenched with TPP for 30 min (C500/TPP30) was determined to be 1.40 x 10(-6)cm(2)h(-1)atm(-1) at 37.0+/-0.5 degrees C. The encapsulation of poorly water-soluble drugs, felodipine (FE) and nifedipine (NF), in such an asymmetric chitosan capsule was capable of creating a sufficient osmotic effect to activate the release of the drug with the addition of SLS and HPMC. The multiple regression equations of maximal release percent at 24h for FE and NF confirmed that both sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) positively influenced this response factor, and the effect of SLS was greater than that of HPMC.


Metabolic perturbations associated with the consumption of a ketogenic medium-chain TAG diet in dogs with idiopathic epilepsy.
Consumption of diets containing medium-chain TAG (MCT) has been shown to confer neuroprotective effects. We aim to identify the global metabolic perturbations associated with consumption of a ketogenic diet (medium-chain TAG diet (MCTD)) in dogs with idiopathic epilepsy. We used ultra-performance liquid chromatography-MS (UPLC-MS) to generate metabolic and lipidomic profiles of fasted canine serum and made comparisons between the MCTD and standardised placebo diet phases. We identified metabolites that differed significantly between diet phases using metabolite fragmentation profiles generated by tandem MS (UPLC-MS/MS). Consumption of the MCTD resulted in significant differences in serum metabolic profiles when compared with the placebo diet, where sixteen altered lipid metabolites were identified. Consumption of the MCTD resulted in reduced abundances of palmitoylcarnitine, octadecenoylcarnitine, stearoylcarnitine and significant changes, both reduced and increased abundances, of phosphatidylcholine (PC) metabolites. There was a significant increase in abundance of the saturated C17 : 0 fatty acyl moieties during the MCTD phase. Lysophosphatidylcholine (17 : 0) (P=0·01) and PC (17:0/20:4) (P=0·03) were both significantly higher in abundance during the MCTD. The data presented in this study highlight global changes in lipid metabolism, and, of particular interest, in the C17 : 0 moieties, as a result of MCT consumption. Elucidating the global metabolic response of MCT consumption will not only improve the administration of current ketogenic diets for neurological disease models but also provides new avenues for research to develop better diet therapies with improved neuroprotective efficacies. Future studies should clarify the involvement and importance of C17 : 0 moieties in endogenous MCT metabolic pathways.


Neurophysiological evidence of motor preparation in inner speech and the effect of content predictability.
Self-generated overt actions are preceded by a slow negativity as measured by electroencephalogram, which has been associated with motor preparation. Recent studies have shown that this neural activity is modulated by the predictability of action outcomes. It is unclear whether inner speech is also preceded by a motor-related negativity and influenced by the same factor. In three experiments, we compared the contingent negative variation elicited in a cue paradigm in an active vs. passive condition. In Experiment 1, participants produced an inner phoneme, at which an audible phoneme whose identity was unpredictable was concurrently presented. We found that while passive listening elicited a late contingent negative variation, inner speech production generated a more negative late contingent negative variation. In Experiment 2, the same pattern of results was found when participants were instead asked to overtly vocalize the phoneme. In Experiment 3, the identity of the audible phoneme was made predictable by establishing probabilistic expectations. We observed a smaller late contingent negative variation in the inner speech condition when the identity of the audible phoneme was predictable, but not in the passive condition. These findings suggest that inner speech is associated with motor preparatory activity that may also represent the predicted action-effects of covert actions.


Familial colorectal cancer: eleven years of data from a registry program in Switzerland.
Deleterious germ-line variants involving the DNA mismatch repair (MMR) genes have been identified as the cause of the hereditary nonpolyposis colorectal cancer syndrome known as the Lynch syndrome, but in numerous familial clusters of colon cancer, the cause remains obscure. We analyzed data for 235 German-speaking Swiss families with nonpolyposis forms of colorectal cancer (one of the largest and most ethnically homogeneous cohorts of its kind) to identify the phenotypic features of forms that cannot be explained by MMR deficiency. Based on the results of microsatellite instability analysis and immunostaining of proband tumor samples, the kindreds were classified as MMR-proficient (n = 134, 57%) or MMR-deficient (n = 101, 43%). In 81 of the latter kindreds, deleterious germ-line MMR-gene variants have already been found (62 different variants, including 13 that have not been previously reported), confirming the diagnosis of Lynch syndrome. Compared with MMR-deficient kindreds, the 134 who were MMR proficient were less likely to meet the Amsterdam Criteria II regarding autosomal dominant transmission. They also had primary cancers with later onset and colon-segment distribution patterns resembling those of sporadic colorectal cancers, and they had lower frequencies of metachronous colorectal cancers and extracolonic cancers in general. Although the predisposition to colorectal cancer in these kindreds is probably etiologically heterogeneous, we were unable to identify distinct phenotypic subgroups solely on the basis of the clinical data collected in this study. Further insight, however, is expected to emerge from the molecular characterization of their tumors.


Genital ulcer disease treatment for reducing sexual acquisition of HIV.
Genital ulcer disease by virtue of disruption of the mucosal surfaces may enhance HIV acquisition. Genital ulcer disease treatment with resolution of the ulcers may therefore contribute in reducing the sexual acquisition of HIV. To determine the effects of treatment of genital ulcer disease on sexual acquisition of HIV. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, LILACS, NLM Gateway, Web of Science, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and reference lists of relevant publications for eligible studies published between 1980 and August 2011. Randomized controlled trials of any treatment intervention aimed at curing genital ulcer disease compared with an alternative treatment, placebo, or no treatment. We included only trials whose unit of randomization was the individual with confirmed genital ulcer. We independently selected studies and extracted data in duplicate; resolving discrepancies by discussion, consensus, and arbitration by third review author. We expressed study results as risk ratios (RR) with 95% confidence intervals (CI). There were three randomized controlled trials that met our inclusion criteria recruited HIV-negative participants with chancroid (two trials with 143 participants) and primary syphilis (one trial with 30 participants). The syphilis study, carried out in the US between 1995 and 1997, randomized participants to receive a single 2.0 g oral dose of azithromycin (11 participants); two 2.0 g oral doses of azithromycin administered six to eight days apart (eight participants); or benzathine penicillin G administered as either 2.4 million units intramuscular injection once or twice seven days apart (11 participants). No participant in the trial seroconverted during 12 months of follow-up. The chancroid trials, conducted in Kenya by 1990, found no significant differences in HIV seroconversion rates during four to 12 weeks of follow-up between 400 and 200 mg single oral doses of fleroxacin (one trial, 45 participants; RR 3.00; 95% CI 0.29 to 30.69), or between 400 mg fleroxacin and 800 mg sulfamethoxazole plus 160 mg trimethoprim (one trial, 98 participants; RR 0.33; 95% CI 0.04 to 3.09). Adverse events reported were mild to moderate in severity, and included Jarisch-Herxheimer reactions and gastrointestinal symptoms. The differences between the treatment arms in the incidence of adverse events were not significant. The quality of this evidence on the effectiveness of genital ulcer disease treatment in reducing sexual acquisition of HIV, according to GRADE methodology, is of very low quality. At present, there is insufficient evidence to determine whether curative treatment of genital ulcer disease would reduce the risk of HIV acquisition. The very low quality of the evidence implies that the true effect of genital ulcer disease treatment on sexual acquisition of HIV may be substantially different from the effect estimated from currently available data. However, genital ulcer diseases are public health problems in their own right and patients with these conditions should be treated appropriately; whether the treatment reduces the risk of HIV infection or not.


Degradation of glycated bovine serum albumin in microglial cells.
Glycated protein products are formed upon binding of sugars to lysine and arginine residues and have been shown to accumulate during aging and in pathologies such as Alzheimer disease and diabetes. Often these glycated proteins are transformed into advanced glycation end products (AGEs) by a series of intramolecular rearrangements. In the study presented here we tested the ability of microglial cells to degrade BSA-AGE formed by glycation reactions of bovine serum albumin (BSA) with glucose and fructose. Microglial cells are able to degrade BSA-AGEs to a certain degree by proteasomal and lysosomal pathways. However, the proteasome and lysosomal proteases are severely inhibited by cross-linked BSA-AGEs. BSA-AGEs are furthermore able to activate microglial cells. This activation is accompanied by an enhanced degradation of BSA-AGE. Therefore, we conclude that microglial cells are able to degrade glycated proteins, although cross-linked protein-AGEs have an inhibitory effect on proteolytic systems in microglial cells.


Comparing the impact of an acute exercise bout on plasma amino acid composition, intraerythrocytic Ca(2+) handling, and red cell function in athletes and untrained subjects.
The N-methyl d-aspartate receptors (NMDARs) mediating Ca(2+) uptake upon stimulation with glutamate and glycine were recently discovered in red blood cells (RBC) of healthy humans. Activation of these receptors with agonists triggered transient Ca(2+)-dependent decrease in hemoglobin oxygen affinity in RBC suspension. The aim of this study was to assess the potential physiological relevance of this phenomenon. Two groups formed by either healthy untrained volunteers or endurance athletes were subjected to a stepwise incremental cycling test to exhaustion. Plasma glutamate levels, activity of the NMDARs, and hemoglobin O2 affinity were measured in blood samples obtained before and after the exercise in both groups. Increase in plasma glutamate levels following exercise was observed in both groups. Transient Ca(2+) accumulation in response to the NMDAR stimulation with NMDA and glycine was followed by facilitated Ca(2+) extrusion from the RBC and compensatory decrease in cytosolic Ca(2+) levels. Short-term activation of the receptors triggered a transient decrease in O2 affinity of hemoglobin in both groups. These exercise-induced responses were more pronounced in athletes compared to the untrained subjects. Athletes were initially presented with lower basal intracellular Ca(2+) levels and hemoglobin oxygen affinity compared to non-trained controls. High basal plasma glutamate levels were associated with induction of hemolysis and formation of echinocytes upon stimulation with the receptor agonists. These findings suggest that glutamate release occurring during exhaustive exercise bouts may acutely facilitate O2 liberation from hemoglobin and improve oxygen delivery to the exercising muscle.


Volumes from which calcium and phosphorus X-rays arise in electron probe emission microanalysis of bone: Monte Carlo simulation.
Monte Carlo simulations of trajectories for electrons with initial energy of 10 keV through 30 keV were used to map the 3D location of characteristic x-ray photon production for the elements C, P, and Ca until the electrons either escaped as backscattered electrons (BSE) or had insignificant energy. The x-ray production volumes for phosphorus slightly exceed those for calcium, but both greatly exceed the volume through which BSE travel prior to leaving the sample. The x-ray volumes are roughly hemispherical in shape, and the oblate spheroid from which BSE derive occupies only the upper third to half the volume of x-ray generation. Energy-dispersive x-ray emission microanalysis (EDX) may not be secure as a method for the quantitation of BSE images of bone in the scanning electron microscope (SEM). Ca:P elemental ratios from EDX analyses may also be imperfect.


Predicting Positive Youth Development from Self-Regulation and Purpose in Early Adolescence.
A Positive Youth Development (PYD) perspective emphasizes adolescents' potential for healthy, successful development. Researchers have introduced a variety of constructs that may promote PYD. For example, Intentional Self-Regulation (ISR) enables youth to seek out and use resources in the environment; purpose can help youth navigate and overcome obstacles. We examine connections between ISR, purpose and two PYD outcomes: confidence and connection. Data come from 763 Scottish youth (ages 12-14). We estimated fixed-effects regression models predicting confidence and connection from both ISR and purpose, confirming outcomes were independently associated with one or both predictors. Our findings are especially salient to the field of youth purpose, linking purpose with specific PYD outcomes.


Insight into the beneficial immunomodulatory mechanism of the sevoflurane metabolite hexafluoro-2-propanol in a rat model of endotoxaemia.
Volatile anaesthetics such as sevoflurane attenuate inflammatory processes, thereby impacting patient outcome significantly. Their inhalative administration is, however, strictly limited to controlled environments such as operating theatres, and thus an intravenously injectable immunomodulatory drug would offer distinct advantages. As protective effects of volatile anaesthetics have been associated with the presence of trifluorinated carbon groups in their basic structure, in this study we investigated the water-soluble sevoflurane metabolite hexafluoro-2-propanol (HFIP) as a potential immunomodulatory drug in a rat model of endotoxic shock. Male Wistar rats were subjected to intravenous lipopolysaccharide (LPS) and thereafter were treated with HFIP. Plasma and tissue inflammatory mediators, neutrophil invasion, tissue damage and haemodynamic stability were the dedicated end-points. In an endotoxin-induced endothelial cell injury model, underlying mechanisms were elucidated using gene expression and gene reporter analyses. HFIP reduced the systemic inflammatory response significantly and decreased endotoxin-induced tissue damage. Additionally, the LPS-provoked drop in blood pressure of animals was resolved by HFIP treatment. Pathway analysis revealed that the observed attenuation of the inflammatory process was associated with reduced nuclear factor kappa B (NF-κΒ) activation and suppression of its dependent transcripts. Taken together, intravenous administration of HFIP exerts promising immunomodulatory effects in endotoxaemic rats. The possibility of intravenous administration would overcome limitations of volatile anaesthetics, and thus HFIP might therefore represent an interesting future drug candidate for states of severe inflammation.


Cisplatin Nephrotoxicity and Longitudinal Growth in Children With Solid Tumors: A Retrospective Cohort Study.
Cisplatin, a major antineoplastic drug used in the treatment of solid tumors, is a known nephrotoxin. This retrospective cohort study evaluated the prevalence and severity of cisplatin nephrotoxicity in 54 children and its impact on height and weight.We recorded the weight, height, serum creatinine, and electrolytes in each cisplatin cycle and after 12 months of treatment. Nephrotoxicity was graded as follows: normal renal function (Grade 0); asymptomatic electrolyte disorders, including an increase in serum creatinine, up to 1.5 times baseline value (Grade 1); need for electrolyte supplementation <3 months and/or increase in serum creatinine 1.5 to 1.9 times from baseline (Grade 2); increase in serum creatinine 2 to 2.9 times from baseline or need for electrolyte supplementation for more than 3 months after treatment completion (Grade 3); and increase in serum creatinine ≥3 times from baseline or renal replacement therapy (Grade 4).Nephrotoxicity was observed in 41 subjects (75.9%). Grade 1 nephrotoxicity was observed in 18 patients (33.3%), Grade 2 in 5 patients (9.2%), and Grade 3 in 18 patients (33.3%). None had Grade 4 nephrotoxicity. Nephrotoxicity patients were younger and received higher cisplatin dose, they also had impairment in longitudinal growth manifested as statistically significant worsening on the height Z Score at 12 months after treatment. We used a multiple logistic regression model using the delta of height Z Score (baseline-12 months) as dependent variable in order to adjust for the main confounder variables such as: germ cell tumor, cisplatin total dose, serum magnesium levels at 12 months, gender, and nephrotoxicity grade. Patients with nephrotoxicity Grade 1 where at higher risk of not growing (OR 5.1, 95% CI 1.07-24.3, P=0.04). The cisplatin total dose had a significant negative relationship with magnesium levels at 12 months (Spearman r=-0.527, P=<0.001).


Advanced drug delivery devices via self-assembly of amphiphilic block copolymers.
Amphiphilic block copolymers are well established as building blocks for the preparation of micellar drug carriers. Over the past decade, the effectiveness of such self-assembled drug delivery devices has been demonstrated numerous times. This review will discuss two approaches that can be used to further improve the effectiveness of amphiphilic block copolymer-based drug delivery systems. The first approach involves the chemical modification of the block copolymer building blocks. Several examples will be discussed of amphiphilic block copolymers modified with crosslinkable groups in order to increase the stability of the micellar drug carriers, or of block copolymers containing specific ligands that could ultimately allow targeted drug delivery. The second approach to improve the performance of micellar drug carriers is the addition of auxiliary agents. To illustrate this approach, the feasibility of channel proteins and metal (nano)particles to improve temporal control over the drug release process is discussed.


Genetics in the 21st Century: Implications for patients, consumers and citizens.
The first human genome project, completed in 2003, uncovered the genetic building blocks of humankind. Painstakingly cataloguing the basic constituents of our DNA ('genome sequencing') took ten years, over three billion dollars and was a multinational collaboration. Since then, our ability to sequence genomes has been finessed so much that by 2018 it is possible to explore the 20,000 or so human genes for under £1000, in a matter of days. Such testing offers clues to our past, present and future health, as well as information about how we respond to medications so that truly 'personalised medicine' is now moving closer to a reality. The impact of such a 'genomic era' is likely to have some level of impact on an increasingly large number of us, even if we are not directly using healthcare services ourselves. We explore how advancements in genetics are likely to be experienced by people, as patients, consumers and citizens; and urge policy makers to take stock of the pervasive nature of the technology as well as the human response to it.


Anti-inflammatory treatment increases angiogenesis during early fracture healing.
Both inflammation and angiogenesis are crucial for normal fracture healing. The goal of this work was to determine how anti-inflammatory treatment affects angiogenesis during early stages of fracture repair. Tibia fractures were created in adult mice and animals were treated with indomethacin (2 mg/kg/day), a non-steroidal anti-inflammatory drug, or PBS once a day beginning from 1 day before fracture and continuing to 6 days after fracture. Animals were killed at 7, 14, and 28 days after injury for histomorphometric analysis of fracture healing. A second group of animals were killed at 3 and 7 days after injury to measure tissue levels of VEGF and interleukin-1 beta (IL-1β). A third group of animals were killed at 3 and 7 days after injury for stereology analysis of macrophage and neutrophil infiltration and tissue vascularization. Indomethacin significantly decreased bone and cartilage formation at 7 days after fracture compared to controls. Indomethacin decreased the tissue levels of IL-1β at 3 days after fracture but did not affect the recruitment of macrophages or neutrophils to injured limbs. Indomethacin-treated fractures had similar length density and surface density of vasculature as the controls at 3 days after injury. At 7 days after fracture, vasculature in indomethacin-treated fractures exhibited higher length density and surface density than that in controls. By 28 days after injury, indomethacin-treated fractures still exhibited defects in fracture repair. Anti-inflammatory treatments using indomethacin impair bone and cartilage formation and increase tissue vascularization in the callus during early fracture healing.


Influence of dietary sodium on waterborne copper toxicity in rainbow trout, Oncorhynchus mykiss.
Juvenile rainbow trout were fed diets containing control (0.26 mmol/g) or elevated (1.3 mmol/g) dietary Na+ in combination with either background (19 nmol/L) or moderately elevated levels (55 or 118 nmol/L) of waterborne Cu for 21 d. Unidirectional waterborne Na+ uptake rates (measured with 22Na) were up to four orders of magnitude higher than those of Cu (measured with 64Cu). Chronic exposure to elevated dietary Na+ alone or in combination with elevated waterborne Cu decreased whole-body uptake rates of waterborne Na+ and Cu. Accumulation of new Cu and Na+ at the gills was positively and highly significantly correlated and responded to the experimental treatments in a similar fashion, suggesting that Na+ and Cu have common branchial uptake pathways and that dietary Na+ preexposure modifies these pathways. Chronic exposure to elevated waterborne Cu significantly increased Cu concentrations in the liver but caused only modest increases in total Cu concentrations in the whole body and gill. Chronic exposure to elevated dietary Na+ slightly decreased whole-body Cu concentration on day 14 and greatly reduced liver Cu concentration on days 14 and 21; new Cu accumulation in whole-body, gill, and internal organs was reduced on all days. Chronic exposure to elevated waterborne Cu or dietary Na+ alone reduced short-term gill Cu binding at low waterborne Cu concentrations. At high waterborne Cu concentrations, chronic exposure to elevated waterborne Cu had no effect, while elevated dietary Na+ increased Cu binding to the gills. Combined chronic exposure to elevated dietary Na+ and waterborne Cu decreased gill Cu binding over the entire range of Cu concentrations tested. Clearly, chronic exposure to elevated dietary Na+ and waterborne Cu appears to modify gill Cu-binding characteristics and may be important considerations in future development of a chronic biotic ligand model for Cu.


Live attenuated VZV vaccination induces antitumor immunity in ATLL patients.
Adult T cell leukemia/lymphoma (ATLL) is a CD4-positive peripheral T cell lymphoma caused by human T cell lymphotropic virus type 1 (HTLV-1). Although ATLL is quite difficult to be cured, up-regulation of cellular immunity such as HTLV-1 Tax-specific cytotoxic T lymphocytes (CTLs) has been proved to be important to obtain long-term survival. At present, no efficacious method to activate ATLL-specific cellular immunity is available. This study aimed to investigate whether live attenuated varicella-zoster virus (VZV) vaccination to ATLL can activate HTLV-1 Tax-specific cellular immune response. A total of 3 indolent- and 3 aggressive-type ATLL patients were enrolled. All aggressive-type patients had the VZV vaccination after completing anti-ATLL treatment including mogamulizumab, which is a monoclonal antibody for C-C chemokine receptor 4 antigen, plus combination chemotherapy, whereas all indolent-type patients had the VZV vaccination without any antitumor treatment. Cellular immune responses including Tax-specific CTLs were analyzed at several time points of pre- and post-VZV vaccination. After the VZV vaccination, a moderate increase in 1 of 3 indolent-type patients and obvious increase in all 3 aggressive-type patients in Tax-specific CTLs percentage were observed. The increase in the cell-mediated immunity against VZV was observed in all indolent- and aggressive-type patients after VZV vaccination. To conclude, VZV vaccination to aggressive-type ATLL patients after mogamulizumab plus chemotherapy led to the up-regulation of HTLV-1 Tax-specific CTLs without any adverse event. Suppression of regulatory T lymphocytes by mogamulizumab may have contributed to increase tumor immunity in aggressive-type ATLL patients. Japan Registry of Clinical Trials number, jRCTs051180107.


Q-switched ruby laser treatment of oculodermal melanosis (nevus of Ota).
The Q-switched ruby laser at 694 nm, a wavelength well absorbed by melanin relative to other optically absorbing structures in skin, causes highly selective destruction of pigment-laden cells. In addition, the 20- to 40-ns pulse duration produced by this laser approximates the thermal relaxation time for the melanosomes, thereby confining the energy to the target. The Q-switched ruby laser was used to treat 47 patients (11 males and 36 females) with nevus of Ota during the period December 1991 to 1994. The involved facial area ranged from 3 x 3 cm2 to 20 x 20 cm2. The energy fluence used varied from 8 to 10 J/cm2, and the number of treatments ranged from 1 to 8 (mean 3.4). The results were graded on the basis of cleaning and fading as follows: poor (0 to 25 percent), fair (26 to 50 percent), good (51 to 75 percent), and excellent (76 to 100 percent). The mean follow-up period was 15 months. Poor and/or fair results were found in 8 patients who received one treatment and 7 patients who had two treatments. Good results were seen in 1 patient who had two treatments, 7 patients who received three treatments, and 3 patients who had four treatments. Twenty-one patients had excellent results after three or more treatments of the whole lesion. In conclusion, this laser system produces clinically significant fading of nevus of Ota in patients without complications such as hypertrophic scarring or permanent changes in the normal skin pigmentation.


Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis.
Fused in sarcoma (FUS) is mutated in both sporadic amyotrophic lateral sclerosis (ALS) and familial ALS patients. The mechanisms underlying neurodegeneration are not fully understood, but FUS redistributes from the nucleus to the cytoplasm in affected motor neurons, where it triggers endoplasmic reticulum (ER) stress. Ataxin-2 is a polyglutamine protein which normally contains 22 repeats, but expanded repeats (>34) are found in Spinocerebellar Ataxia type 2. Recently ataxin-2 with intermediate length repeats (27-33) was found to increase the risk of ALS. Here we show that ataxin-2 with an ALS-linked intermediate length repeat (Q31) is a potent modifier of FUS pathology in cellular disease models. Translocation of FUS to the cytoplasm and ER stress were significantly enhanced by co-expression of mutant FUS with ataxin-2 Q31. Ataxin-2 also co-localized with FUS in sporadic and FUS-linked familial ALS patient motor neurons, co-precipitated with FUS in ALS spinal cord lysates, and co-localized with FUS in the ER-Golgi compartments in neuronal cell lines. Fragmentation of the Golgi apparatus is linked to neurodegeneration in ALS and here we show that Golgi fragmentation is induced in cells expressing mutant FUS. Moreover, Golgi fragmentation was enhanced, and the early stages of apoptosis were triggered, when ataxin-2 Q31 was co-expressed with mutant FUS. These findings describe new cellular mechanisms linking ALS with ataxin-2 intermediate length polyQ expansions and provide further evidence linking disruption to ER-Golgi compartments and FUS pathology in ALS.


Prevalence of False-Negative Results of Intraoperative Consultation on Surgical Margins During Resection of Gastric and Gastroesophageal Adenocarcinoma.
Intraoperative consultation (IOC) on surgical margins during curative intent resection of gastric and gastroesophageal adenocarcinoma presents sampling and interpretive challenges. A false-negative (FN) IOC result can affect clinical care. Many factors may be associated with higher risk for an FN result of IOC on surgical margins. To assess the prevalence and clinical implications of FN results of IOC on surgical margins during resection of gastric and gastroesophageal adenocarcinoma. This retrospective study assessed the results of IOC on surgical margins to determine the prevalence of FN results and the accuracy and clinical implications of the results for patients undergoing curative intent resection for gastric or gastroesophageal adenocarcinoma. The study examined patients with gastric or gastroesophageal adenocarcinoma who underwent resection with curative intent at a single-institution referral center from January 1, 1992, to December 31, 2015. Curative intent gastric and/or esophageal resection. False-negative results of IOC on surgical margins, accuracy of the results, factors associated with decreased accuracy of the results, and clinical implications of FN results. This study included 2002 patients (median age, 65 years; 1343 [67.1%] male; 1638 [81.8%] white) who received 3171 IOCs on surgical margins. Of the 3171 IOCs, the prevalence of FN results was 1.7%, with an accuracy of 98.1%. The prevalence of an FN IOC result was 1.2% for esophageal margins, 2.0% for gastric margins, and 2.5% for duodenal margins (P = .04). The prevalence of an FN IOC result was higher for patients with diffuse or signet ring disease compared with those without (2.6% vs 1.2%, P = .002) and for those not receiving neoadjuvant radiotherapy compared with those receiving neoadjuvant radiotherapy (1.4% vs 0.7%, P < .001). The prevalence of FN results of IOCs performed by nongastrointestinal pathologists was similar to that of IOCs performed by gastrointestinal pathologists (2.3% vs 1.9%, P = .60). The disease-specific survival was 34 months (95% CI, 20.7-47.2 months) for those with an FN result and 26.9 months (95% CI, 18.3-35.4; P = .72) for those with a true-positive result. Half of the patients with FN IOC results received further margin-directed therapy, including subsequent resection or radiotherapy. This study found that IOC on surgical margins was accurate at a specialty center. Signet ring or diffuse disease, duodenal margins, and not receiving neoadjuvant radiotherapy were challenging scenarios for IOC on surgical margins. The use of IOC on surgical margins may be optimal when it will affect intraoperative decision making framed by the stage of disease, tumor location, and surgical fitness of the patient.


Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies.
Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in the NZM2410 strain of mice. Our previous work has shown that B6.NZMc1 mice, congenic for Sle1, exhibit loss of tolerance to chromatin but do not develop any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle3, exhibit low-grade polyclonal B- and T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monocongenics, the present study reveals that B6.NZMc1|c7 mice, bicongenic for Sle1 and Sle3, exhibit splenomegaly, significantly expanded populations of activated B and CD4(+) T cells, and a robust, variegated IgG autoantibody response targeting multiple components of chromatin (including double-stranded DNA), intact glomeruli, and basement membrane matrix antigens. As one might predict, these mice, particularly the females, exhibit highly penetrant glomerulonephritis. These findings lend strong support to a two-step epistatic model for the formation of pathogenic, nephrophilic autoantibodies in lupus. Whereas loci such as Sle1 may serve to breach tolerance to chromatin, full-blown pathogenic maturation of the autoantibody response appears to require additional input from other loci (such as Sle3) and gender-based factors.


Variation in timely surgery for severe open tibial fractures by time and place of presentation in England from 2012 to 2019 : a cohort study using data collected nationally by the Trauma Audit and Research Network.
Several studies have reported that patients presenting during the evening or weekend have poorer quality healthcare. Our objective was to examine how timely surgery for patients with severe open tibial fracture varies by day and time of presentation and by type of hospital. This cohort study included patients with severe open tibial fractures from the Trauma Audit and Research Network (TARN). Provision of prompt surgery (debridement within 12 hours and soft-tissue coverage in 72 hours) was examined, using multivariate logistic regression to derive adjusted risk ratios (RRs). Time was categorized into three eight-hour intervals for each day of the week. The models were adjusted for treatment in a major trauma centre (MTC), sex, age, year of presentation, injury severity score, injury mechanism, and number of operations each patient received. We studied 8,258 patients from 175 hospitals. Patients presenting during the day (08:00 to 15:59; risk ratio (RR) 1.11, 95% confidence interval (CI) 1.02 to 1.20) were more likely to receive debridement within 12 hours, and patients presenting at night (16:00 to 23:59; RR 0.56, 95% CI 0.51 to 0.62) were less likely to achieve the target; triage to a MTC had no effect. Day of presentation was associated with soft-tissue coverage within 72 hours; patients presenting on a Thursday or Friday being less likely to receive this surgery within 72 hours (Thursday RR 0.88, 95% CI 0.81 to 0.97; Friday RR 0.89, 95% CI 0.81 to 0.98), and the standard less likely to be achieved for those treated in 'non-MTC' hospitals (RR 0.76, 95% CI 0.70 to 0.82). Variations in care were observed for timely surgery for severe open tibial fractures with debridement surgery affected by time of presentation and soft-tissue coverage affected by day of presentation and type of hospital. The variation is unwarranted and highlights that there are opportunities to substantially improve the delivery and quality of care for patients with severe open tibial fracture.Cite this article: Bone Jt Open 2022;3(12):941-952.


The Effects of Romantic Love on Mentalizing Abilities.
The effects of the human pair-bonded state of "romantic love" on cognitive function remain relatively unexplored. Theories on cognitive priming suggest that a state of love may activate love-relevant schemas, such as mentalizing about the beliefs of another individual, and may thus improve mentalizing abilities. On the other hand, recent functional MRI (fMRI) research on individuals who are in love suggests that several brain regions associated with mentalizing may be "deactivated" during the presentation of a love prime, potentially affecting mentalizing cognitions and behaviors. The current study aimed to investigate experimentally the effect of a love prime on a constituent aspect of mentalizing-the attribution of emotional states to others. Ninety-one participants who stated they were "deeply in love" with their romantic partner completed a cognitive task involving the assessment of emotional content of facial stimuli (the Reading the Mind in the Eyes task) immediately after the presentation of either a love prime or a neutral prime. Individuals were significantly better at interpreting the emotional states of others after a love prime than after a neutral prime, particularly males assessing negative emotional stimuli. These results suggest that presentation of a love stimulus can prime love-relevant networks and enhance subsequent performance on conceptually related mentalizing tasks.


Heritability of Caries Scores, Trajectories, and Disease Subtypes.
Previous studies report that dental caries is partially heritable, but there is uncertainty in the magnitude of genetic effects and little understanding of how genetic factors might influence caries progression or caries subtypes. This study aimed to estimate the relative importance of genetic and environmental factors in the etiology of different caries outcomes using a twin-based design. Analysis included up to 41,678 twins in the Swedish Twin Register aged 7 to 97 y, and dental data were obtained from preexisting dental records. The outcome measures were 1) summary indices of caries experience, 2) parameters representing trajectory in caries progression derived from longitudinal modeling, and 3) caries scores in groups of biologically similar tooth surfaces derived from hierarchical clustering of tooth surfaces (termed caries clusters). Additive genetic factors explained between 49.1% and 62.7% of variation in caries scores and between 50.0% and 60.5% of variation in caries trajectories. Seven caries clusters were identified, which had estimates of heritability lying between 41.9% and 54.3%. Shared environmental factors were important for only some of these clusters and explained 16% of variation in fissure caries in molar teeth but little variation in other clusters of caries presentation. The genetic factors influencing these clusters were only partially overlapping, suggesting that different biological processes are important in different groups of tooth surfaces and that innate liability to some patterns of caries presentation may partially explain why groups of tooth surfaces form clusters within the mouth. These results provide 1) improved quantification of genetic factors in the etiology of caries and 2) new data about the role of genetics in terms of longitudinal changes in caries status and specific patterns of disease presentation, and they may help lay the foundations for personalized interventions in the future.


Mixed-source reintroductions lead to outbreeding depression in second-generation descendents of a native North American fish.
Reintroductions are commonly employed to preserve intraspecific biodiversity in fragmented landscapes. However, reintroduced populations are frequently smaller and more geographically isolated than native populations. Mixing genetically, divergent sources are often proposed to attenuate potentially low genetic diversity in reintroduced populations that may result from small effective population sizes. However, a possible negative tradeoff for mixing sources is outbreeding depression in hybrid offspring. We examined the consequences of mixed-source reintroductions on several fitness surrogates at nine slimy sculpin (Cottus cognatus) reintroduction sites in south-east Minnesota. We inferred the relative fitness of each crosstype in the reintroduced populations by comparing their growth rate, length, weight, body condition and persistence in reintroduced populations. Pure strain descendents from a single source population persisted in a greater proportion than expected in the reintroduced populations, whereas all other crosstypes occurred in a lesser proportion. Length, weight and growth rate were lower for second-generation intra-population hybrid descendents than for pure strain and first-generation hybrids. In the predominant pure strain, young-of the-year size was significantly greater than any other crosstype. Our results suggested that differences in fitness surrogates among crosstypes were consistent with disrupted co-adapted gene complexes associated with beneficial adaptations in these reintroduced populations. Future reintroductions may be improved by evaluating the potential for local adaptation in source populations or by avoiding the use of mixed sources by default when information on local adaptations or other genetic characteristics is lacking.


Steroid-based anion receptors and transporters.
Anion binding and transport are important goals of supramolecular chemistry, especially in light of the potential for biological activity. Success depends on scaffolds which can preorganise polar functionality for anion recognition, and can maintain the right physical properties (e.g. solubility) to operate in the desired medium (e.g. a cell membrane). In this tutorial review we show how steroids, and in particular the bile acids, can provide good solutions to the problem. Not only do they provide rigid frameworks for mounting H-bond donor functionality, but their lipophilic nature ensures that they remain compatible with non-polar environments. Podands derived from cholic acid (cholapods) have proved especially useful, being tuneable, readily accessible and exceptionally powerful. For example, affinities up to 10(11) M(-1) have been measured for neutral cholapods binding chloride salts in chloroform. Steroid-based anion receptors can also display interesting selectivities, demonstrating the principle that discrimination improves with binding strength, and showing good enantioselectivities with chiral anions. The binding strength of cholapods and related systems allows them to act as transmembrane anion carriers. Again activity is exceptionally high, with measurable chloride transport at cholapod:lipid ratios of just 1:250,000 in vesicle membranes. These steroidal systems may present a real opportunity for the development of useful biological activity based on anion transport.


Comparison of endometrial prostanoid profiles in three infertile subgroups: the missing part of receptivity?
To study the prostanoid profile of the endometria of patients with recurrent implantation failure (RIF), unexplained infertility (UIF), and recurrent miscarriages (RM), and to compare them with the endometria of healthy fertile controls. Prospective cohort study. University hospital. Fifteen patients with RIF, 18 patients with UIF, 16 patients with RM, and 23 fertile controls were recruited. Endometrial samples were taken during the window of implantation. After tissue homogenization and extraction, analysis with ultra-performance liquid chromatography diode array detector electrospray ionisation tandem mass spectrometry was performed. Concentrations of prostaglandin (PG) D1, PGE1, PGF1α, 6-ketoPGF1α, PGD2, PGE2, PGF2α, 15-deoxy-Δ12,14-PGJ2, PGD3, PGE3, PGF3α, thromboxane B2, 13,14-dihydro-PGE1, 13,14-dihydro-PGF1α, 13,14-dihydro-PGF2α, 13,14-dihydro-15-keto-PGE1, 13,14-dihydro-15-keto-PGE2, and 13,14-dihydro-15-keto-PGF2α were assessed. Comparison of the endometria of patients with UIF and the controls showed no statistically significant differences. When the endometria of patients with RIF were compared with the controls, thromboxane B2 (TXB2) was found significantly higher (843.1 pg/mg vs. 133.5 pg/mg). When the endometria of patients with RM were compared with controls, 13,14-dihydro-15-keto PGF2α and TXB2 were found significantly higher (3907.30 pg/mg vs. 17.80 pg/mg and 858.7 pg/mg vs. 133.5 pg/mg respectively). We identified increased endometrial presence of TXB2 in patients with RM and RIF, and 13,14-dihydro-15-keto PGF2α in patients with RM. Although common ground is observed for RM and RIF, prostanoids, on the other hand, might make their own contribution to endometrial receptivity as important as genes and proteins. Attempts to normalize the prostaglandin profile of the endometrium via enzymatic activity can open new therapeutic options.


Discovery of COVID-19 Inhibitors Targeting the SARS-CoV-2 Nsp13 Helicase.
The raging COVID-19 pandemic caused by SARS-CoV-2 has infected tens of millions of people and killed several hundred thousand patients worldwide. Currently, there are no effective drugs or vaccines available for treating coronavirus infections. In this study, we have focused on the SARS-CoV-2 helicase (Nsp13), which is critical for viral replication and the most conserved nonstructural protein within the coronavirus family. Using homology modeling that couples published electron-density with molecular dynamics (MD)-based structural refinements, we generated structural models of the SARS-CoV-2 helicase in its apo- and ATP/RNA-bound conformations. We performed virtual screening of ∼970 000 chemical compounds against the ATP-binding site to identify potential inhibitors. Herein, we report docking hits of approved human drugs targeting the ATP-binding site. Importantly, two of our top drug hits have significant activity in inhibiting purified recombinant SARS-CoV-2 helicase, providing hope that these drugs can be potentially repurposed for the treatment of COVID-19.


Studies on antidyslipidemic effects of Morinda citrifolia (Noni) fruit, leaves and root extracts.
The objective of present study was to provide the pharmacological basis for the medicinal use of Morinda citrifolia Linn in dyslipidemia using the aqueous-ethanolic extracts of its fruits (Mc.Cr.F), leaves (Mc.Cr.L) and roots (Mc.Cr.R). Mc.Cr.F, Mc.Cr.L and Mc.Cr.R showed antidyslipidemic effects in both triton (WR-1339) and high fat diet-induced dyslipidemic rat models to variable extents. All three extracts caused reduction in total cholesterol and triglyceride levels in triton-induced dyslipidemia. In high fat diet-induced dyslipidemia all these extracts caused significant reduction in total cholesterol, triglyceride, low density lipoprotein-cholesterol (LDL-C), atherogenic index and TC/HDL ratio. Mc.Cr.R extract also caused increase in high density lipoprotein-cholesterol (HDL-C). The Mc.Cr.L and Mc.Cr.R reduced gain in body weight with a reduction in daily diet consumption but Mc.Cr.F had no effect on body weight and daily diet consumption. These data indicate that the antidyslipidemic effect of the plant extracts was meditated through the inhibition of biosynthesis, absorption and secretion of lipids. This may be possibly due partly to the presence of antioxidant constituents in this plant. Therefore, this study rationalizes the medicinal use of Morinda citrifolia in dyslipidemia.


Effects of combined administration of vitamins C and E on reactive hyperemia and inflammatory process in chronic smokers.
Purpose of this study was to investigate the effect of combined administration of antioxidant vitamins C and E on endothelial function and serum levels of inflammatory markers such as tumor necrosis factor alpha (TNF-alpha), interleukines 1b (IL-1b) and 6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin in chronic smokers. Forty-three smokers were randomly divided into four groups receiving vitamin C 2 g/day (group A), vitamin C 2 g/day plus vitamin E 400 IU/day (group B), vitamin C 2 g/day plus vitamin E 800 IU/day (group C) or no antioxidant treatment (group D), for 4 weeks. Forearm blood flow (FBF) was measured using venous occlusion strain gauge plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) was expressed as the percentage change from baseline to post reactive hyperemia blood flow. RH% was significantly increased in groups B (P<0.05) and C (P<0.01), but remained unaffected in groups A and D. Serum levels of IL-1b, IL-6, sVCAM-1 and sICAM-1 were significantly reduced in group C (P<0.05, respectively), but remained unaffected in groups A, B and D. Thus, short term administration of vitamins C (2 g/day) and E (800 IU/day) reduces serum levels of IL-1b, IL-6, sVCAM-1 and sICAM-1, and improves forearm vasodilatory response to reactive hyperemia in healthy young smokers, while monotherapy with vitamin C alone is ineffective.


Large-Scale Discovery and Validation Studies Demonstrate Significant Reductions in Circulating Levels of IL8, IL-1Ra, MCP-1, and MIP-1β in Patients With Type 1 Diabetes.
Previous studies have attempted to elucidate the potential role of various cytokines and chemokines in human type 1 diabetes (T1D); however, the precise role of these serum proteins in T1D is still controversial and undetermined primarily due to the small sample sizes of the previous studies. We profiled a panel of serum cytokines and chemokines using a large-scale, two-stage study design for the discovery and validation of the serum proteins associated with T1D. The participants were patients with T1D and islet autoantibody-negative control subjects from the Phenome and Genome of Diabetes Autoimmunity study. Thirteen cytokines and chemokines were measured in serum of 4424 subjects using multiplex immunoassays. Using 1378 samples in Stage 1, we found that four of the 13 proteins are significantly lower in patients with T1D than controls (IL8: odds ratio [OR] = 0.40; P = 5.7 × 10(-19); IL-1Ra: OR = 0.42; P = 1.1 × 10(-13); MCP-1: OR = 0.60; P = 6.7 × 10(-9); and MIP-1β: OR = 0.63; P = 4.2 × 10(-7)). Our confirmation data with 3046 samples in Stage 2 further confirmed the significant negative associations of these four proteins with T1D (IL8: OR = 0.43; P = 8.9 × 10(-32); IL-1Ra: OR = 0.56, P = 3.7 × 10(-27); MCP-1: OR = 0.61, P = 4.3 × 10(-17); and MIP-1β: OR = 0.69, P = 2.4 × 10(-13)). Quartile analyses also suggested that significantly more T1D cases have protein levels in the bottom quartile than in the top quartile for all four proteins: IL8 (OR = 0.09), IL-1Ra (OR = 0.18), MCP-1 (OR = 0.38), and MIP-1β (OR = 0.44). Furthermore, the negative associations between T1D and serum levels of all four proteins are stronger in genetically high-risk groups compared with the moderate and low-risk groups. IL8, IL-1Ra, MCP-1, and MIP-1β are significantly lower in patients with T1D than controls.


Clinical and tree hollow populations of human pathogenic yeast in Hamilton, Ontario, Canada are different.
Yeast are among the most frequent pathogens in humans. The dominant yeast causing human infections belong to the genus Candida and Candida albicans is the most frequently isolated species. However, several non-C. albicans species are becoming increasingly common in patients worldwide. The relationships between yeast in humans and the natural environments remain poorly understood. Furthermore, it is often difficult to identify or exclude the origins of disease-causing yeast from specific environmental reservoirs. In this study, we compared the yeast isolates from tree hollows and from clinics in Hamilton, Ontario, Canada. Our surveys and analyses showed significant differences in yeast species composition, in their temporal dynamics, and in yeast genotypes between isolates from tree hollows and hospitals. Our results are inconsistent with the hypothesis that yeast from trees constitute a significant source of pathogenic yeast in humans in this region. Similarly, the yeast in humans and clinics do not appear to contribute to yeast in tree hollows.


Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.
Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.


Development and validation of a clinical score for predicting risk of adenoma at screening colonoscopy.
Currently, no clinical tools use demographic and risk factor information to predict the risk of finding an adenoma in individuals undergoing colon cancer screening. Such a tool would be valuable for identifying those who would most benefit from screening colonoscopy. We used baseline data from men and women who underwent screening colonoscopy from the randomized, multicenter National Colonoscopy Study (NCS) to develop and validate an adenoma risk model. The study, conducted at three sites in the United States (Minneapolis, MN; Seattle, WA; and Shreveport, LA) asked all participants to complete baseline questionnaires on clinical risk factors and family history. Model parameters estimated from logistic regression yielded an area under the receiver operating characteristic curve (AUROCC) used to assess prediction. Five hundred forty-one subjects were included in the development model, and 1,334 in the validation of the risk score. Variables in the prediction of adenoma risk for colonoscopy screening were age (likelihood ratio test for overall contribution to model, P < 0.001), male sex (P < 0.001), body mass index (P < 0.001), family history of at least one first-degree relative with colorectal cancer (P = 0.036), and smoking history (P < 0.001). The adjusted AUROCC of 0.67 [95% confidence interval (CI), 0.61-0.74] for the derivation cohort was not statistically significantly different from that in the validation cohort. The adjusted AUROCC for the entire cohort was 0.64 (95% CI, 0.60-0.67). We developed and validated a simple well-calibrated risk score. This tool may be useful for estimating risk of adenomas in screening eligible men and women.


DeepC: predicting 3D genome folding using megabase-scale transfer learning.
Predicting the impact of noncoding genetic variation requires interpreting it in the context of three-dimensional genome architecture. We have developed deepC, a transfer-learning-based deep neural network that accurately predicts genome folding from megabase-scale DNA sequence. DeepC predicts domain boundaries at high resolution, learns the sequence determinants of genome folding and predicts the impact of both large-scale structural and single base-pair variations.


Synchronized reinjection and coalescence of droplets in microfluidics.
Coalescence of two kinds of pre-processed droplets is necessary to perform chemical and biological assays in droplet-based microfluidics. However, a robust technique to accomplish this does not exist. Here we present a microfluidic device to synchronize the reinjection of two different kinds of droplets and coalesce them, using hydrostatic pressure in conjunction with a conventional syringe pump. We use a device consisting of two opposing T-junctions for reinjecting two kinds of droplets and control the flows of the droplets by applying gravity-driven hydrostatic pressure. The hydrostatic-pressure operation facilitates balancing the droplet reinjection rates and allows us to synchronize the reinjection. Furthermore, we present a simple but robust module to coalesce two droplets that sequentially come into the module, regardless of their arrival times. These re-injection and coalescence techniques might be used in lab-on-chip applications requiring droplets with controlled numbers of solid materials, which can be made by coalescing two pre-processed droplets that are formed and sorted in devices.