Short-time weight-bearing capacity assessment for non-ambulatory patients with subacute stroke: reliabiltiy and discriminative power

BACKGROUND: Weight-bearing capacity (WBC) on the hemiparetic leg is crucial for independent walking, and is thus an important outcome to monitor after a stroke. A specific and practical assessment in non-ambulatory patients is not available. This is of importance considering the increasing administration of high intensive gait training for the severely impaired stroke population. The aim was to develop a fast and easy-to-perform assessment for WBC on a foot pressure plate to be used in clinical routine. METHODS: WBC was assessed in the frontal plane in 30 non-ambulatory patients with subacute stroke and 10 healthy controls under 3 conditions: static, dynamic, and rhythmic. Force–time curves for the hemiparetic leg (patients with stroke) and the non-dominant leg (healthy controls) were normalised as a percentage of body weight (%BW), and the means analysed over 60, 30, and 15 s (static) and the mean of the peak values for 15, 10, 5, 4, and 3 repetition trials (dynamic, rhythmic). The data were tested for discriminative power and reliability. Dynamic and rhythmic tests could discriminate between patients with stroke and healthy controls over all periods (15, 10, 5, 4, and 3 repetitions) (p < 0.001), but not the static test (60 s, p = 0.639; 30 s, p = 0.708; 15 s, p = 0.685). Excellent relative intra-session [intra-class correlation (ICC) >0.829] and inter-session reliability (ICC = 0.740) were found for 3 repetitions in the dynamic test with acceptable absolute reliability [standard error of measurement (SEM) <5 %BW, minimal detectable difference (MDD) <12.4 %BW] and no within- or between-test differences (trial 1, p = 0.792; trial 2, p = 0.067; between trials, p = 0.102). CONCLUSIONS: Three dynamic repetitions of loading the hemiparetic leg are sufficient to assess WBC in non-ambulatory patients with subacute stroke. This is an important finding regarding the implementation of a fast and easy-to-perform assessment for routine clinical usage in patients with limited standing ability

Control of mitogenic and motogenic pathways by miR-198, diminishing hepatoma cell growth and migration

Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths, worldwide. MicroRNAs, inhibiting gene expression by targeting various transcripts, are involved in genomic dysregulation during hepatocellular tumorigenesis. In previous studies, microRNA-198 (miR-198) was shown to be significantly downregulated in HCV-positive hepatocellular carcinoma (HCC). Herein, the function of miR-198 in hepatocellular carcinoma cell growth and gene expression was studied. In hepatoma cell-types with low levels of liver-specific transcription factor HNF1α indicating a low differentiation grade, miR-198 expression was most downregulated. However, miR-198 treatment did not restore the expression of the liver-specific transcription factors HNF1α or HNF4α. Importantly, overexpression of miR-198 in Pop10 hepatoma cells markedly reduced cell growth. In agreement, comprehensive gene expression profiling by microarray hybridisation and real-time quantification revealed that central signal transducers of proliferation pathways were downregulated by miR-198. In contrast, genes mediating cellular adherence were highly upregulated by miR-198. Thus, the low expression of E-cadherin and claudin-1, involved in cell adhesion and cell-cell contacts, was abolished in hepatoma cells after miR-198 overexpression. This definite induction of both proteins by miR-198 was shown to be accompanied by a significantly impaired migration activity of hepatoma Pop10 cells. In conclusion, miR-198 acts as a tumor suppressor by repression of mitogenic and motogenic pathways diminishing cell growth and migration

Geminal Diol of Dihydrolevoglucosenone as a Switchable Hydrotrope : A Continuum of Green Nanostructured Solvents

The addition of water to dihydrolevoglucosenone (Cyrene) creates a solvent mixture with highly unusual properties and the ability to specifically and efficiently solubilize a wide range of organic compounds, notably, aspirin, ibuprofen, salicylic acid, ferulic acid, caffeine, and mandelic acid. The observed solubility enhancement (up to 100-fold) can be explained only by the existence of microenvironments mainly centered on Cyrene's geminal diol. Surprisingly, the latter acts as a reversible hydrotrope and regulates the polarity of the created complex mixture. The possibility to tune the polarity of the solvent mixture through the addition of water, and the subsequent generation of variable amounts of Cyrene's geminal diol, creates a continuum of green solvents with controllable solubilization properties. The effective presence of microheterogenieties in the Cyrene/water mixture was adequately proven by (1) Fourier transform infrared/density functional theory showing Cyrene dimerization, (2) electrospray mass-spectrometry demonstrating the existence of dimers of Cyrene's geminal diol, and (3) the variable presence of single or multiple tetramethylsilane peaks in the 1 H NMR spectra of a range of Cyrene/water mixtures. The Cyrene-water solvent mixture is importantly not mutagenic, barely ecotoxic, bioderived, and endowed with tunable hydrophilic/hydrophobic properties

Effective cardiac resynchronization therapy for an adolescent patient with dilated cardiomyopathy seven years after mitral valve replacement and septal anterior ventricular exclusion

Cardiac resynchronization therapy (CRT) is a new treatment for refractory heart failure. However, most heart failure patients treated with CRT are middle-aged or old patients with idiopathic or ischemic dilated cardiomyopathy. We treated a 17 year 11 month old girl with dilated cardiomyopathy after mitral valve replacement (MVR) and septal anterior ventricular exclusion (SAVE). Seven years after the SAVE procedure, she presented complaining of palpitations and general fatigue with normal activity. Her echocardiogram showed reduced left ventricular function. Despite of optimal medical therapy, her left ventricular function continued to decline and she experienced regular arrhythmias such as premature ventricular contractions. We thus elected to perform cardiac resynchronization therapy with defibrillator (CRT-D). After CRT-D, her clinical symptoms improved dramatically and left ventricular ejection fraction (LVEF) improved from 31.2% to 51.3% as assessed by echocardiogram. Serum BNP levels decreased from 448.2 to 213.6 pg/ml. On ECG, arrhythmias were remarkably reduced and QRS duration was shortened from 174 to 152 msec. In conclusion, CRT-D is an effective therapeutic option for adolescent patients with refractory heart failure after left ventricular volume reduction surgery

The Genetic Signature of Sex-Biased Migration in Patrilocal Chimpanzees and Humans

A large body of theoretical work suggests that analyses of variation at the maternally inherited mitochondrial (mt)DNA and the paternally inherited non-recombining portion of the Y chromosome (NRY) are a potentially powerful way to reveal the differing migratory histories of men and women across human societies. However, the few empirical studies comparing mtDNA and NRY variation and known patterns of sex-biased migration have produced conflicting results. Here we review some methodological reasons for these inconsistencies, and take them into account to provide an unbiased characterization of mtDNA and NRY variation in chimpanzees, one of the few mammalian taxa where males routinely remain in and females typically disperse from their natal groups. We show that patterns of mtDNA and NRY variation are more strongly contrasting in patrilocal chimpanzees compared with patrilocal human societies. The chimpanzee data we present here thus provide a valuable comparative benchmark of the patterns of mtDNA and NRY variation to be expected in a society with extremely female-biased dispersal

Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far

Palatal development of preterm and low birthweight infants compared to term infants – What do we know? Part 1: The palate of the term newborn

BACKGROUND: The evidence on prematurity as 'a priori' a risk for palatal disturbances that increase the need for orthodontic or orthognathic treatment is still weak. Further well-designed clinical studies are needed. The objective of this review is to provide a fundamental analysis of methodologies, confounding factors, and outcomes of studies on palatal development. One focus of this review is the analysis of studies on the palate of the term newborn, since knowing what is 'normal' is a precondition of being able to assess abnormalities. METHODS: A search profile based on Cochrane search strategies applied to 10 medical databases was used to identify existing studies. Articles, mainly those published before 1960, were identified from hand searches in textbooks, encyclopedias, reference lists and bibliographies. Sources in English, German, and French of more than a century were included. Data for term infants were recalculated if particular information about weight, length, or maturity was given. The extracted values, especially those from non-English paper sources, were provided unfiltered for comparison. RESULTS: The search strategy yielded 182 articles, of which 155 articles remained for final analysis. Morphology of the term newborn's palate was of great interest in the first half of the last century. Two general methodologies were used to assess palatal morphology: visual and metrical descriptions. Most of the studies on term infants suffer from lack of reliability tests. The groove system was recognized as the distinctive feature of the infant palate. The shape of the palate of the term infant may vary considerably, both visually and metrically. Gender, race, mode of delivery, and nasal deformities were identified as causes contributing to altered palatal morphology. Until today, anatomical features of the newborn's palate are subject to a non-uniform nomenclature. CONCLUSION: Today's knowledge of a newborn's 'normal' palatal morphology is based on non-standardized and limited methodologies for measuring a three-dimensional shape. This shortcoming increases bias and is the reason for contradictory research results, especially if pathologic conditions like syndromes or prematurity are involved. Adequate measurement techniques are needed and the 'normal palatal morphology' should be defined prior to new clinical studies on palatal development

Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far

A living WHO guideline on drugs for covid-19

CITATION: Agarwal, A. et al. 2022. A living WHO guideline on drugs for covid-19. British Medical Journal, 370. doi:10.1136/bmj.m3379The original publication is available at https://jcp.bmj.com/This living guideline by Arnav Agarwal and colleagues (BMJ 2020;370:m3379, doi:10.1136/bmj.m3379) was last updated on 22 April 2022, but the infographic contained two dosing errors: the dose of ritonavir with renal failure should have read 100 mg, not 50 mg; and the suggested regimen for remdesivir should have been 3 days, not 5-10 days. The infographic has now been corrected.Publishers versio