Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST)

<p><b>Background and Purpose:</b> The Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) unadjusted results demonstrated that intravenous alteplase is well tolerated and that the effects were comparable with those seen in randomized, controlled trials (RCTs) when used in routine clinical practice within 3 hours of ischemic stroke onset. We aimed to identify outcome predictors and adjust the outcomes of the SITS-MOST to the baseline characteristics of RCTs.</p> <p><b>Methods:</b> The study population was SITS-MOST (n=6483) and pooled RCTs (n=464) patients treated with intravenous alteplase within 3 hours of stroke onset. Multivariable, backward stepwise regression analyses (until P≤0.10) were performed to identify the outcome predictors for SITS-MOST. Variables appearing either in the final multivariable model or differing (P<0.10) between SITS-MOST and RCTs were included in the prediction model for the adjustment of outcomes. Main outcome measures were symptomatic intracerebral hemorrhage, defined as National Institutes of Health Stroke Scale deterioration ≥1 within 7 days with any hemorrhage (RCT definition), mortality, and independency as defined by modified Rankin Score of 0 to 2 at 3 months.</p> <p><b>Results:</b> The adjusted proportion of symptomatic intracerebral hemorrhage for SITS-MOST was 8.5% (95% CI, 7.9 to 9.0) versus 8.6% (6.3 to 11.6) for pooled RCTs; mortality was 15.5% (14.7 to 16.2) versus 17.3% (14.1 to 21.1); and independency was 50.4% (49.6 to 51.2) versus 50.1% (44.5 to 54.7), respectively. In the multivariable analysis, older age, high blood glucose, high National Institutes of Health Stroke Scale score, and current infarction on imaging scans were related to poor outcome in all parameters. Systolic blood pressure, atrial fibrillation, and weight were additional predictors of symptomatic intracerebral hemorrhage. Current smokers had a lower rate of symptomatic intracerebral hemorrhage. Disability before current stroke (modified Rankin Score 2 to 5), diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers, and male sex were related to high mortality at 3 months.</p> <p><b>Conclusions:</b> The adjusted outcomes from SITS-MOST were almost identical to those in relevant RCTs and reinforce the conclusion drawn previously in the unadjusted analysis. We identified several important outcome predictors to better identify patients suitable for thrombolysis.</p&gt

Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism.

OBJECTIVE: Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. METHODS: Whole exome sequencing was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. RESULTS: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. INTERPRETATION: Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function. ANN NEUROL 2021

Climate change and the rise of the central Asian Silk Roads

The final centuries BCE (Before Common Era) saw the main focus of trade between the Far East and Europe switch from the so called Northern Route across the Asian steppes to the classical silk roads. The cities across central Asia flourished and grew in size and importance. While clearly there were political, economic and cultural drivers for these changes, there may also have been a role for changes in climate in this relatively arid region of Asia. Analysis of a new ensemble of snapshot global climate model simulations, run every 250 years over the last 6000 years, allows us to assess the long term climatological changes seen across the central Asian arid region through which the classical Silk Roads run. While the climate is comparatively stable through the Holocene, the fluctuations seen in these simulations match significant cultural developments in the region. From 1500 BCE the deterioration of climate from a transient precipitation peak, along with technological development and the immigration of Aryan nomads, drove a shift towards urbanization and probably irrigation, culminating in the founding of the major cities of Bukhara and Samarkand around 700–500 BCE. Between 1000 and 250 BCE the modelled precipitation in the central Asian arid region undergoes a transition towards wetter climates. The changes in the Western Disturbances, which is the key weather system for central Asian precipitation, provides 10% more precipitation and the increased hydrological resources may provide the climatological foundation for the golden era of Silk Road trade

In search of tools for the use of Country-Image (CI) in the brand

Existing country image (CI) literature tends to focus on consumer behaviour. In contrast, this paper approaches CI from the point of view of the firm. In doing so, it seeks to identify the means by which international companies associate a brand with a specific country of origin in order to build brand values. In particular, it looks at the use of CI cues in brand strategies. The paper is based on exploratory research comprising a case study of two contrasting companies from the cosmetics industry, Natura, a domestic company, and the French-owned L’Occitane, both of which draw on images of Brazil to build their brands. Specific elements of CI used in branding are identified, and the extent to which the use of these differs depending on the origin of the owning company is explored. The cases suggest that CI can be exploited in different contexts. Through analysis of the elements used by both companies to build strong brands associated with the Brazilian CI—Natura Cosméticos and L’Occitane au Brésil—six tools are identified that can be combined by firms to deliver brand values, derived from any country, through the use of CI

A synthesis of hydrogen isotope variability and its hydrological significance at the Qinghai-Tibetan Plateau

Hydrogen isotope ratios of sedimentary biomarkers are known to record the climatic variability in terrestrial and marine environments. However, there is still a lack of calibration studies that can quantitatively retrace the driving forces, especially at the Tibetan Plateau. Here, we elaborate the actual influence of environmental parameters such as temperature, evapotranspiration, salinity and biosynthetic fractionation on dD values of n-alkanes. We measured hydrogen isotope values (dD) of n-alkanes in recent sediment and plant samples as well as dD values of different water sources (lake and inflow water, precipitation as well as leaf, root and soil water) from six Tibetan lakes along a 10-spanning longitudinal transect covering an aridity gradient. As expected, the deuterium record can be used to distinguish two water pools at the Plateau: (I) precipitation water, which supplies water for the lake inflow and terrestrial plants, and (II) enriched lake water having a clear evaporative signal. Based on significant correlations of the source water and dD values of nalkanes, dD of alkane n-C23 record the lake water isotope composition and track the evaporative enrichment of the lake system. In contrast, dD of alkane n-C29 can be used to retrace the isotope composition of the inflow displaying the integrated rainfall signal in the vegetation period modified by soil and leaf water evaporation. While temperature changes are less pronounced across the Tibetan transect, the isotopic difference between C23 and C29 could potentially be used as a proxy to reconstruct effective moisture (precipitation minus evaporation). Areas with lower precipitation amounts and higher evaporation rates are characterized by higher DdDC23eC29 values. This relationship is more pronounced in regions with mean annual precipitation below 350 mm. Even in contrasting environments, the application of the dD proxies is very promising. Combining other Tibetan studies, it is possible to present a comprehensive picture of the usage of compound-specific hydrogen isotopes of n-alkanes on the Tibetan Platea