Computer simulations of hard pear-shaped particles

We report results obtained from Monte Carlo simulations investi- gating mesophase formation in two model systems of hard pear-shaped particles. The first model considered is a hard variant of the trun- cated Stone-Expansion model previously shown to form nematic and smectic mesophases when embedded within a 12-6 Gay-Berne-like po- tential [1]. When stripped of its attractive interactions, however, this system is found to lose its liquid crystalline phases. For particles of length to breadth ratio k = 3, glassy behaviour is seen at high pressures, whereas for k = 5 several bi-layer-like domains are seen, with high intradomain order but little interdomain orientational correlation. For the second model, which uses a parametric shape parameter based on the generalised Gay-Berne formalism, results are presented for particles with elongation k = 3; 4 and 5. Here, the systems with k = 3 and 4 fail to display orientationally ordered phases, but that with k = 5 shows isotropic, nematic and, unusually for a hard-particle model, interdigitated smectic A2 phases.</p

Sodium glucose co-transporter 2 inhibition increases epidermal growth factor expression and improves outcomes in patients with type 2 diabetes

Underlying molecular mechanisms of the kidney protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with type 2 diabetes (T2D). The underlying molecular mechanisms of the SGLT2 inhibitor canagliflozin on EGF using single-cell RNA sequencing from kidney tissue were examined. Urinary EGF-to-creatinine ratio (uEGF/Cr) was measured in 3521 CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52. Associations of uEGF/Cr with kidney outcome were assessed using multivariable-adjusted Cox regression models. Single-cell RNA sequencing was performed using protocol kidney biopsy tissue from ten young patients with T2D on SGLT2i, six patients with T2D on standard care only, and six healthy controls (HCs). In CANVAS, each doubling in baseline uEGF/Cr was associated with a 12% (95% confidence interval 1-22) decreased risk of kidney outcome. uEGF/Cr decreased after 52 weeks with placebo and remained stable with canagliflozin (between-group difference +7.3% (2.0-12.8). In young persons with T2D, EGF mRNA was primarily expressed in the thick ascending loop of Henle. Expression in biopsies from T2D without SGLT2i was significantly lower compared to HCs, whereas treatment with SGLT2i increased EGF levels closer to the healthy state. In young persons with T2D without SGLT2i, endothelin-1 emerged as a key regulator of the EGF co-expression network. SGLT2i treatment was associated with a shift towards normal EGF expression. Thus, decreased uEGF represents increased risk of kidney disease progression in patients with T2D. Canagliflozin increased kidney tissue expression of EGF and was associated with a downstream signaling cascade linked to tubular repair and reversal of tubular injury.</p

Association between TNF Receptors and KIM-1 with Kidney Outcomes in Early-Stage Diabetic Kidney Disease

Background and objectives: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. Tumor Necrosis Factor Receptor (TNFR)-1, TNFR-2 and Kidney Injury Marker (KIM)-1 are known to be associated with kidney disease progression in patients with micro- or macroalbuminuria. We assessed the value of TNFR-1, TNFR-2 and KIM-1 as prognostic biomarkers for CKD progression in patients with type 2 diabetes and normoalbuminuria. Design, setting, participants and measurements: TNFR-1, TNFR-2, and KIM-1 were measured using immunoassays in plasma samples from patients with type 2 diabetes at high cardiovascular risk participating in the CANVAS trial. We used multivariable adjusted Cox proportional hazards analyses to estimate hazard ratios per doubling of each biomarker for the kidney outcome and stratified the population by the 4th quartile of each biomarker distribution and assessed the number of events and event rates. Results: In patients with normoalbuminuria (N=2,553), 51 kidney outcomes were recorded during a median follow-up of 6.1 (IQR 5.8 to 6.4) years (event rate 3.5 [95%CI 2.6-4.6] per 1,000-patient-years). Each doubling of baseline TNFR-1 (HR 4.16; 95%CI 1.80-9.61) and TNFR-2 (HR 2.35; 95%CI 1.51-3.63) was associated with a higher risk for the kidney outcome. Baseline KIM-1, UACR and eGFR were not associated with kidney outcomes. The event rates in the highest quartile of the TNFR-1 (≥2,992 ng/ml) or TNFR-2 (≥11,394 ng/ml) were 5.6 and 7.0 events per 1000-patient-years compared to 2.4 and 2.8 in the lower three quartiles. Conclusion: TNFR-1 and TNFR-2 are associated with kidney outcomes in patients with type 2 diabetes and normoalbuminuria

Utilization of case presentations in medical microbiology to enhance relevance of basic science for medical students

Background : Small-group case presentation exercises (CPs) were created to increase course relevance for medical students taking Medical Microbiology (MM) and Infectious Diseases (ID) Methods : Each student received a unique paper case and had 10 minutes to review patient history, physical exam data, and laboratory data. Students then had three minutes to orally present their case and defend why they ruled in or out each of the answer choices provided, followed by an additional three minutes to answer questions. Results : Exam scores differed significantly between students who received the traditional lecture-laboratory curriculum (Group I) and students who participated in the CPs (Group II). In MM, median unit exam and final exam scores for Group I students were 84.4% and 77.8%, compared to 86.0% and 82.2% for Group II students (P&#x200A;&#60;&#x200A;0.018; P&#x200A;&#60;&#x200A;0.001; Mann-Whitney Rank Sum Test). Median unit and final ID exam scores for Group I students were 84.0% and 80.0%, compared to 88.0% and 86.7% for Group II students (P&#x200A;&#60;&#x200A;0.001; P&#x200A;&#60;&#x200A;0.001). Conclusion : Students felt that the CPs improved their critical thinking and presentation skills and helped to prepare them as future physicians

The impact of canagliflozin on the risk of neuropathy events:A post-hoc exploratory analysis of the CREDENCE trial

Aim: Canagliflozin reduces the risk, and progression, of diabetic kidney disease. We hypothesized that it may improve the microvascular complication of neuropathy. Methods: The CREDENCE trial randomized participants with type 2 diabetes and kidney disease to canagliflozin 100 mg daily or placebo. Neuropathy events were defined post-hoc as any reported adverse event consistent with a peripheral or autonomic neuropathy event. The effect of canagliflozin and predictors of neuropathy events were estimated using Cox regression analysis. In sensitivity analyses the endpoint was restricted to sensorimotor polyneuropathy, diabetic neuropathy, and non-autonomic neuropathy events. Results: Almost half (48.8%) of the 4401 participants had a diagnosis of neuropathy at baseline. Over a median of 2.45 years of follow up, 657 people experienced a neuropathy event (63.2 per 1000 patient-years). Independent factors associated with higher risk of experiencing neuropathy events were non-white race, younger age, higher glycated haemoglobin and lower estimated glomerular filtration rate. The incidence of neuropathy events was similar in people randomized to canagliflozin and placebo (334/2202 vs. 323/2199; HR 1.04, 95% CI 0.89 to 1.21, P = 0.66). Canagliflozin had no impact on sensorimotor polyneuropathy (HR 0.93, 95% CI 0.69 to 1.25, P = 0.63), diabetic neuropathy (HR 0.91, 95% CI 0.68 to 1.22, P = 0.52), or non-autonomic neuropathy (HR 1.03, 95% CI 0.87 to 1.21, P = 0.77). The lack of effect on neuropathy events was consistent in subgroup analyses. Conclusion: Canagliflozin did not affect the risk of neuropathy events in the CREDENCE trial. Future large randomized studies with prespecified neuropathy endpoints are required to determine the impact of sodium glucose cotransporter 2 inhibitors on diabetic neuropathy

Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.

Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms

Establishing nurse-led active surveillance for men with localised prostate cancer: development and formative evaluation of a model of care in the ProtecT trial.

Objectives To develop a nurse-led, urologist-supported model of care for men managed by active surveillance or active monitoring (AS/AM) for localised prostate cancer and provide a formative evaluation of its acceptability to patients, clinicians and nurses. Nurse-led care, comprising an explicit nurse-led protocol with support from urologists, was developed as part of the AM arm of the Prostate testing for cancer and Treatment (ProtecT) trial. Design Interviews and questionnaire surveys of clinicians, nurses and patients assessed acceptability. Setting Nurse-led clinics were established in 9 centres in the ProtecT trial and compared with 3 non-ProtecT urology centres elsewhere in UK. Participants Within ProtecT, 22 men receiving AM nurse-led care were interviewed about experiences of care; 11 urologists and 23 research nurses delivering ProtecT trial care completed a questionnaire about its acceptability; 20 men managed in urology clinics elsewhere in the UK were interviewed about models of AS/AM care; 12 urologists and three specialist nurses working in these clinics were also interviewed about management of AS/AM. Results Nurse-led care was commended by ProtecT trial participants, who valued the flexibility, accessibility and continuity of the service and felt confident about the quality of care. ProtecT consultant urologists and nurses also rated it highly, identifying continuity of care and resource savings as key attributes. Clinicians and patients outside the ProtecT trial believed that nurse-led care could relieve pressure on urology clinics without compromising patient care. Conclusions The ProtecT AM nurse-led model of care was acceptable to men with localised prostate cancer and clinical specialists in urology. The protocol is available for implementation; we aim to evaluate its impact on routine clinical practice

Measurement of the Charged Multiplicities in b, c and Light Quark Events from Z0 Decays

Average charged multiplicities have been measured separately in $b$, $c$ and light quark ($u,d,s$) events from $Z^0$ decays measured in the SLD experiment. Impact parameters of charged tracks were used to select enriched samples of $b$ and light quark events, and reconstructed charmed mesons were used to select $c$ quark events. We measured the charged multiplicities: $\bar{n}_{uds} = 20.21 \pm 0.10 (\rm{stat.})\pm 0.22(\rm{syst.})$, $\bar{n}_{c} = 21.28 \pm 0.46(\rm{stat.}) ^{+0.41}_{-0.36}(\rm{syst.})$ $\bar{n}_{b} = 23.14 \pm 0.10(\rm{stat.}) ^{+0.38}_{-0.37}(\rm{syst.})$, from which we derived the differences between the total average charged multiplicities of $c$ or $b$ quark events and light quark events: $\Delta \bar{n}_c = 1.07 \pm 0.47(\rm{stat.})^{+0.36}_{-0.30}(\rm{syst.})$ and $\Delta \bar{n}_b = 2.93 \pm 0.14(\rm{stat.})^{+0.30}_{-0.29}(\rm{syst.})$. We compared these measurements with those at lower center-of-mass energies and with perturbative QCD predictions. These combined results are in agreement with the QCD expectations and disfavor the hypothesis of flavor-independent fragmentation.Comment: 19 pages LaTex, 4 EPS figures, to appear in Physics Letters

Assessment of the MACC reanalysis and its influence as chemical boundary conditions for regional air quality modeling in AQMEII-2

The Air Quality Model Evaluation International Initiative (AQMEII) has now reached its second phase which is dedicated to the evaluation of online coupled chemistry-meteorology models. Sixteen modeling groups from Europe and five from North America have run regional air quality models to simulate the year 2010 over one European and one North American domain. The MACC re-analysis has been used as chemical initial (IC) and boundary conditions (BC) by all participating regional models in AQMEII-2. The aim of the present work is to evaluate the MACC re-analysis along with the participating regional models against a set of ground-based measurements (O3, CO, NO, NO2, SO2, SO42−) and vertical profiles (O3 and CO). Results indicate different degrees of agreement between the measurements and the MACC re-analysis, with an overall better performance over the North American domain. The influence of BC on regional air quality simulations is analyzed in a qualitative way by contrasting model performance for the MACC re-analysis with that for the regional models. This approach complements more quantitative approaches documented in the literature that often have involved sensitivity simulations but typically were limited to only one or only a few regional scale models. Results suggest an important influence of the BC on ozone for which the underestimation in winter in the MACC re-analysis is mimicked by the regional models. For CO, it is found that background concentrations near the domain boundaries are rather close to observations while those over the interior of the two continents are underpredicted by both MACC and the regional models over Europe but only by MACC over North America. This indicates that emission differences between the MACC re-analysis and the regional models can have a profound impact on model performance and points to the need for harmonization of inputs in future linked global/regional modeling studies

Second Generation Leptoquark Search in p\bar{p} Collisions at s\sqrt{s} = 1.8 TeV

We report on a search for second generation leptoquarks with the D\O\ detector at the Fermilab Tevatron $p\bar{p}$ collider at $\sqrt{s}$ = 1.8 TeV. This search is based on 12.7 pb$^{-1}$ of data. Second generation leptoquarks are assumed to be produced in pairs and to decay into a muon and quark with branching ratio $\beta$ or to neutrino and quark with branching ratio $(1-\beta)$. We obtain cross section times branching ratio limits as a function of leptoquark mass and set a lower limit on the leptoquark mass of 111 GeV/c$^{2}$ for $\beta = 1$ and 89 GeV/c$^{2}$ for $\beta = 0.5$ at the 95%\ confidence level.Comment: 18 pages, FERMILAB-PUB-95/185-