Randomized controlled trial of a clinical decision support system for painful polyneuropathy

IntroductionDespite the existence of guidelines, painful neuropathy is often inappropriately treated. We sought to determine the effectiveness of a clinical decision support system on guideline‐recommended medication use.MethodsWe randomized neurology providers, stratified by subspecialty, to a best practice alert (BPA) linked to a Smartset or a BPA alone when seeing patients with neuropathy. The primary outcome was the proportion of patients with uncontrolled nerve pain prescribed a guideline‐recommended medication. Generalized estimating equations were used to assess effectiveness.ResultsSeventy‐five neurology providers (intervention 38, control 37) treated 2697 patients with neuropathy (intervention 1026, control 671). Providers did not acknowledge the BPA in 1928 (71.5%) visits. Only four of eight intervention arm neurologists who treated patients with uncontrolled nerve pain opened the Smartset. The intervention was not associated with guideline‐recommended medication use (odds ratio 0.52, 0.18‐1.48; intervention 52%, control 54.8%).DiscussionOur intervention did not improve prescribing practices for painful neuropathy. Physicians typically ignored the BPAs/Smartset; therefore, future studies should mandate their use or employ alternate strategies.See editorial on pages 552–553 in this issue.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154934/1/mus26774.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154934/2/mus26774_am.pd

Bilateral nerve conduction studies in the evaluation of distal symmetric polyneuropathy

IntroductionNerve conduction studies are used to aid in the diagnosis of distal symmetric polyneuropathy (DSP). It is unclear whether bilateral lower extremity nerve conduction studies (NCS) are needed when evaluating for suspected DSP.MethodsWe retrospectively analyzed NCS from patients who presented to the University of Michigan electromyography laboratory between July 1, 2016 and December 31, 2017 with symptoms of DSP to assess agreement and correlation between left and right lower extremity NCS parameters.ResultsWe found significant agreement between abnormalities in individual nerve parameters of the left and right lower extremities of 105 patients, most notably in the sural nerve. In the 53 patients with bilateral sural, peroneal, and tibial studies, there was also significant agreement between whether the left and right met electrodiagnostic criteria for DSP (κ = 0.77).DiscussionBilateral lower extremity NCS may have limited utility in the evaluation of suspected DSP. Muscle Nerve, 2019Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151276/1/mus26616.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151276/2/mus26616_am.pd

Debris-covered glacier systems and associated glacial lake outburst flood hazards:Challenges and prospects

Glaciers respond sensitively to climate variability and change, with associated impacts on meltwater production, sea-level rise and geomorphological hazards. There is a strong societal interest in understanding the current response of all types of glacier systems to climate change and how they will continue to evolve in the context of the whole glacierized landscape. In particular, understanding the current and future behaviour of debris-covered glaciers is a 'hot topic' in glaciological research because of concerns for water resources and glacier-related hazards. The state of these glaciers is closely related to various hazardous geomorphological processes which are relatively poorly understood. Understanding the implications of debris-covered glacier evolution requires a systems approach. This includes the interplay of various factors such as local geomorphology, ice ablation patterns, debris characteristics and glacier lake growth and development. Such a broader, contextualized understanding is prerequisite to identifying and monitoring the geohazards and hydrologic implications associated with changes in the debris-covered glacier system under future climate scenarios. This paper presents a comprehensive review of current knowledge of the debris-covered glacier landsystem. Specifically, we review state-of-the-art field-based and the remote sensing-based methods for monitoring debris-covered glacier characteristics and lakes and their evolution under future climate change. We advocate a holistic process-based framework for assessing hazards associated with moraine-dammed glacio-terminal lakes that are a projected end-member state for many debris-covered glaciers under a warming climat

Diabetes and obesity are the main metabolic drivers of peripheral neuropathy

ObjectiveTo determine the associations between individual metabolic syndrome (MetS) components and peripheral neuropathy in a large populationâ based cohort from Pinggu, China.MethodsA crossâ sectional, randomly selected, populationâ based survey of participants from Pinggu, China was performed. Metabolic phenotyping and neuropathy outcomes were performed by trained personnel. Glycemic status was defined according to the American Diabetes Association criteria, and the MetS using modified consensus criteria (body mass index instead of waist circumference). The primary peripheral neuropathy outcome was the Michigan Neuropathy Screening Instrument (MNSI) examination. Secondary outcomes were the MNSI questionnaire and monofilament testing. Multivariable models were used to assess for associations between individual MetS components and peripheral neuropathy. Treeâ based methods were used to construct a classifier for peripheral neuropathy using demographics and MetS components.ResultsThe mean (SD) age of the 4002 participants was 51.6 (11.8) and 51.0% were male; 37.2% of the population had normoglycemia, 44.0% prediabetes, and 18.9% diabetes. The prevalence of peripheral neuropathy increased with worsening glycemic status (3.25% in normoglycemia, 6.29% in prediabetes, and 15.12% in diabetes, P < 0.0001). Diabetes (odds ratio [OR] 2.60, 95% CI 1.77â 3.80) and weight (OR 1.09, 95% CI 1.02â 1.18) were significantly associated with peripheral neuropathy. Age, diabetes, and weight were the primary splitters in the classification tree for peripheral neuropathy.InterpretationSimilar to previous studies, diabetes and obesity are the main metabolic drivers of peripheral neuropathy. The consistency of these results reinforces the urgent need for effective interventions that target these metabolic factors to prevent and/or treat peripheral neuropathy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143679/1/acn3531_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143679/2/acn3531.pd

Seasonal forecasts of North Atlantic tropical cyclone activity in the North American Multi-Model Ensemble

The North American Multi-Model Ensemble (NMME)-Phase II models are evaluated in terms of their retrospective seasonal forecast skill of the North Atlantic (NA) tropical cyclone (TC) activity, with a focus on TC frequency. The TC identification and tracking algorithm is modified to accommodate model data at daily resolution. It is also applied to three reanalysis products at the spatial and temporal resolution of the NMME-Phase II ensemble to allow for a more objective estimation of forecast skill. When used with the reanalysis data, the TC tracking generates realistic climatological distributions of the NA TC formation and tracks, and represents the interannual variability of the NA TC frequency quite well. Forecasts with the multi-model ensemble (MME) when initialized in April and later tend to have skill in predicting the NA seasonal TC counts (and TC days). At longer leads, the skill is low or marginal, although one of the models produces skillful forecasts when initialized as early as January and February. At short lead times, while demonstrating the highest skill levels the MME also tends to significantly outperform the individual models and attain skill comparable to the reanalysis. In addition, the short-lead MME forecasts are quite reliable. At regional scales, the skill is rather limited and mostly present in the western tropical NA and the Caribbean Sea. It is found that the overall MME forecast skill is limited by poor representation of the low-frequency variability in the predicted TC frequency, and large fluctuations in skill on decadal time scales. Addressing these deficiencies is thought to increase the value of the NMME ensemble in providing operational guidance

Anti-apoptotic effect of HCV core gene of genotype 3a in Huh-7 cell line

<p>Abstract</p> <p>Background</p> <p>Hepatitis C virus (HCV) Core protein regulates multiple signaling pathways and alters cellular genes expression responsible for HCV induced pathogenesis leading to hepatocellular carcinoma (HCC). Prevalence of HCV genotype 3a associated HCC is higher in Pakistan as compare to the rest of world; however the molecular mechanism behind this is still unclear. This study has been designed to evaluate the effect of HCV core 3a on apoptosis and cell proliferation which are involved in HCC</p> <p>Methodology</p> <p>We examined the in vitro effect of HCV Core protein of genotype 3a and 1a on cellular genes involved in apoptosis by Real time PCR in liver cell line (Huh-7). We analyzed the effect of HCV core of genotype 1a and 3a on cell proliferation by MTT assay and on phosphrylation of Akt by western blotting in Huh-7 cells.</p> <p>Results</p> <p>The HCV 3a Core down regulates the gene expression of Caspases (3, 8, 9 and 10), Cyto C and p53 which are involved in apoptosis. Moreover, HCV 3a Core gene showed stronger effect in regulating protein level of p-Akt as compared to HCV 1a Core accompanied by enhanced cell proliferation in Huh-7 cell line.</p> <p>Conclusion</p> <p>From the current study it has been concluded that reduced expression of cellular genes involved in apoptosis, increased p-Akt (cell survival gene) and enhanced cell proliferation in response to HCV 3a core confirms anti apoptotic effect of HCV 3a Core gene in Huh-7 that may lead to HCC.</p

Hymyc1 Downregulation Promotes Stem Cell Proliferation in Hydra vulgaris

Hydra is a unique model for studying the mechanisms underlying stem cell biology. The activity of the three stem cell lineages structuring its body constantly replenishes mature cells lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. In vertebrates, one of many genes that participate in regulating stem cell homeostasis is the protooncogene c-myc, which has been recently identified also in Hydra, and found expressed in the interstitial stem cell lineage. In the present paper, by developing a novel strategy of RNA interference-mediated gene silencing (RNAi) based on an enhanced uptake of small interfering RNAi (siRNA), we provide molecular and biological evidence for an unexpected function of the Hydra myc gene (Hymyc1) in the homeostasis of the interstitial stem cell lineage. We found that Hymyc1 inhibition impairs the balance between stem cell self renewal/differentiation, as shown by the accumulation of stem cell intermediate and terminal differentiation products in genetically interfered animals. The identical phenotype induced by the 10058-F4 inhibitor, a disruptor of c-Myc/Max dimerization, demonstrates the specificity of the RNAi approach. We show the kinetic and the reversible feature of Hymyc1 RNAi, together with the effects displayed on regenerating animals. Our results show the involvement of Hymyc1 in the control of interstitial stem cell dynamics, provide new clues to decipher the molecular control of the cell and tissue plasticity in Hydra, and also provide further insights into the complex myc network in higher organisms. The ability of Hydra cells to uptake double stranded RNA and to trigger a RNAi response lays the foundations of a comprehensive analysis of the RNAi response in Hydra allowing us to track back in the evolution and the origin of this process

Tailor-Made Zinc-Finger Transcription Factors Activate FLO11 Gene Expression with Phenotypic Consequences in the Yeast Saccharomyces cerevisiae

Cys2His2 zinc fingers are eukaryotic DNA-binding motifs, capable of distinguishing different DNA sequences, and are suitable for engineering artificial transcription factors. In this work, we used the budding yeast Saccharomyces cerevisiae to study the ability of tailor-made zinc finger proteins to activate the expression of the FLO11 gene, with phenotypic consequences. Two three-finger peptides were identified, recognizing sites from the 5′ UTR of the FLO11 gene with nanomolar DNA-binding affinity. The three-finger domains and their combined six-finger motif, recognizing an 18-bp site, were fused to the activation domain of VP16 or VP64. These transcription factor constructs retained their DNA-binding ability, with the six-finger ones being the highest in affinity. However, when expressed in haploid yeast cells, only one three-finger recombinant transcription factor was able to activate the expression of FLO11 efficiently. Unlike in the wild-type, cells with such transcriptional activation displayed invasive growth and biofilm formation, without any requirement for glucose depletion. The VP16 and VP64 domains appeared to act equally well in the activation of FLO11 expression, with comparable effects in phenotypic alteration. We conclude that the functional activity of tailor-made transcription factors in cells is not easily predicted by the in vitro DNA-binding activity

The chronostratigraphy of the Haua Fteah cave (Cyrenaica, northeast Libya)

The 1950s excavations by Charles McBurney in the Haua Fteah, a large karstic cave on the coast of northeast Libya, revealed a deep sequence of human occupation. Most subsequent research on North African prehistory refers to his discoveries and interpretations, but the chronology of its archaeological and geological sequences has been based on very early age determinations. This paper reports on the initial results of a comprehensive multi-method dating program undertaken as part of new work at the site, involving radiocarbon dating of charcoal, land snails and marine shell, cryptotephra investigations, optically stimulated luminescence (OSL) dating of sediments, and electron spin resonance (ESR) dating of tooth enamel. The dating samples were collected from the newly exposed and cleaned faces of the upper 7.5 m of the w14.0 m-deep McBurney trench, which contain six of the seven major cultural phases that he identified. Despite problems of sediment transport and reworking, using a Bayesian statistical model the new dating program establishes a robust framework for the five major lithostratigraphic units identified in the stratigraphic succession, and for the major cultural units. The age of two anatomically modern human mandibles found by McBurney in Layer XXXIII near the base of his Levalloiso-Mousterian phase can now be estimated to between 73 and 65 ka (thousands of years ago) at the 95.4% confidence level, within Marine Isotope Stage (MIS) 4. McBurney’s Layer XXV, associated with Upper Palaeolithic Dabban blade industries, has a clear stratigraphic relationship with Campanian Ignimbrite tephra. Microlithic Oranian technologies developed following the climax of the Last Glacial Maximum and the more microlithic Capsian in the Younger Dryas. Neolithic pottery and perhaps domestic livestock were used in the cave from the mid Holocene but there is no certain evidence for plant cultivation until the Graeco-Roman period