86 research outputs found
4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy
Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment
Regulation of microRNA biogenesis and turnover by animals and their viruses
Item does not contain fulltextMicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes
Global mortality from dementia : Application of a new method and results from the Global Burden of Disease Study 2019
Introduction Dementia is currently one of the leading causes of mortality globally, and mortality due to dementia will likely increase in the future along with corresponding increases in population growth and population aging. However, large inconsistencies in coding practices in vital registration systems over time and between countries complicate the estimation of global dementia mortality. Methods We meta-analyzed the excess risk of death in those with dementia and multiplied these estimates by the proportion of dementia deaths occurring in those with severe, end-stage disease to calculate the total number of deaths that could be attributed to dementia. Results We estimated that there were 1.62 million (95% uncertainty interval [UI]: 0.41-4.21) deaths globally due to dementia in 2019. More dementia deaths occurred in women (1.06 million [0.27-2.71]) than men (0.56 million [0.14-1.51]), largely but not entirely due to the higher life expectancy in women (age-standardized female-to-male ratio 1.19 [1.10-1.26]). Due to population aging, there was a large increase in all-age mortality rates from dementia between 1990 and 2019 (100.1% [89.1-117.5]). In 2019, deaths due to dementia ranked seventh globally in all ages and fourth among individuals 70 and older compared to deaths from other diseases estimated in the Global Burden of Disease (GBD) study. Discussion Mortality due to dementia represents a substantial global burden, and is expected to continue to grow into the future as an older, aging population expands globally.Peer reviewe
The global burden of cancer attributable to risk factors, 2010-19: a systematic analysis for the Global Burden of Disease Study 2019
Drought stress tolerance strategies revealed by RNA-Seq in two sorghum genotypes with contrasting WUE
Global variation in anastomosis and end colostomy formation following left-sided colorectal resection
Background
End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection.
Methods
This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model.
Results
In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001).
Conclusion
Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone
Trends in extreme daily rainfall and temperature indices over South Asia
Over the last few decades, weather and climate extremes have become a major focus of researchers, the media and general public due to their damaging effects on human society and infrastructure. Trends in indices of climate extremes are studied for the South Asian region using high-quality records of daily temperature and precipitation observations. Data records from 210 (265) temperature (precipitation) observation stations are analysed over the period 1971-2000 (1961-2000). Spatial maps of station trends, time series of regional averages and frequency distribution analysis form the basis of this study. Due to the highly diverse geography of the South Asian region, the results are also described for some specific regions, such as the island of Sri Lanka; the tropical region (excluding Sri Lanka); the Greater Himalayas above 35°N, the Eastern Himalayas (Nepal) and the Thar Desert. Generally, changes in the frequency of temperature extremes over South Asia are what one would expect in a warming world; warm extremes have become more common and cold extremes less common. The warming influence is greater in the Eastern Himalayas compared with that in the Greater Himalayas. The Thar Desert also shows enhanced warming, but increases are mostly less than in the Eastern Himalayas. Changes in the indices of extreme precipitation are more mixed than those of temperature, with spatially coherent changes evident only at relatively small scales. Nevertheless, most extreme precipitation indices show increases in the South Asia average, consistent with globally averaged results. The indices trends are further studied in the context of Atmospheric Brown Clouds (ABCs) over the region. Countries falling within the ABC hotspot namely Indo-Gangetic Plain (IGP) have shown a different behaviour on the trends of extreme indices compared with the parts outside this hotspot. IGP has increased temperature and decreased rainfall and tally closely with the actual trends
Risk and time preferences: linking experimental and household survey data from Vietnam
We conducted experiments in Vietnamese villages to determine the predictors of risk and time preferences. In villages with higher mean income, people are less loss-averse and more patient. Household income is correlated with patience but not with risk. We expand measurements of risk and time preferences beyond expected utility and exponential discounting, replacing those models with prospect theory and a three-parameter hyperbolic discounting model. Comparable risk parameter estimates have been found for Chinese farmers, using our method
Neonatal Diabetes: How Research Unravelling the Genetic Puzzle Has both Widened Our Understanding of Pancreatic Development whilst Improving Children’s Quality of Life
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