Miracle-dz/UniFAR-FTUs huggingface dataset:
Hypertension Management in Older and Frail Older Patients

The prevalence of arterial hypertension, particularly systolic hypertension, is constantly rising worldwide. This is mainly the clinical expression of arterial stiffening as a result of the population’s aging. Chronic elevation in blood pressure represents a major risk factor not only for cardiovascular morbidity and mortality but also for cognitive decline and loss of autonomy later in life. Clinical evidence obtained in community-dwelling older people with few comorbidities and preserved autonomy supports the beneficial effects of lowering blood pressure in older hypertensive subjects even after the age of 80 years. However, observational studies in frail older individuals treated for hypertension have shown higher morbidity and mortality rates compared with those with lower blood pressure levels. Clearly, in very old subjects, the therapeutic strategy of one size fits all cannot be applied because of the enormous functional heterogeneity in these individuals. Geriatric medicine proposes taking into account the function/frailty/autonomy status of older people. In the present review, we propose to adapt the antihypertensive treatment using an easy-to-apply visual numeric scale allowing the identification of 3 different patient profiles according to the functional status and autonomy for activities of daily living. For the preserved function profile, strategies should be those proposed for younger old adults. For the loss of function/preserved activities of daily living’ profile, a more detailed geriatric assessment is needed to define the benefit/risk balance as well as requirements for the tailoring of the various therapeutic strategies. Lastly, for the loss of function and altered activities of daily living’ profile, therapeutic strategies should be thoroughly reassessed, including deprescribing (when considered appropriate). In the near future, controlled trials are necessary for the most frail older subjects (ie, in those systematically excluded from previous clinical trials) to gain stronger evidence regarding the benefits of the various therapeutic strategies.
THE ROLE OF DURATION IN JAPANESE SPEAKERS’ PRODUCTIONS OF ENGLISH VOWELS

Japanese uses length as a primary acoustic cue to distinguish some pairs of vowels, whereas North American English varieties rely mainly on spectral differences. While many studies investigating Japanese learners’ acquisition of English vowels have examined acoustic features, only a handful have focused in detail on durational patterns. This study adds to the latter body of research by investigating the carry-over of Japanese durational features into English. To this end, native Japanese and Canadian English speakers’ productions of CVC words were elicited using a picture-naming task. A comparison of duration data for /i/, /ɪ/, /u/, /ʊ/ in three pre-consonantal contexts (/k/, /t/, /d/) revealed that the Japanese speakers’ tense vowels were significantly longer than their lax counterparts regardless of the following consonant, while the native English speakers generally did not show such a pattern. The Japanese speakers furthermore displayed native-like lengthening of vowels before a voiced stop. Nonetheless, contrary to hypothesis, an assessment by native English listeners yielded no evidence that the exaggeration of durational differences for tense/lax contrasts adversely affected vowel intelligibility.
A systems pharmacology workflow with experimental validation to assess the potential of anakinra for treatment of focal and segmental glomerulosclerosis

Focal and Segmental Glomerulosclerosis (FSGS) is a severe glomerulopathy that frequently leads to end stage renal disease. Only a subset of patients responds to current therapies, making it important to identify alternative therapeutic options. The interleukin (IL)-1 receptor antagonist anakinra is beneficial in several diseases with renal involvement. Here, we evaluated the potential of anakinra for FSGS treatment. Molecular process models obtained from scientific literature data were used to build FSGS pathology and anakinra mechanism of action models by exploiting information on protein interactions. These molecular models were compared by statistical interference analysis and expert based molecular signature matching. Experimental validation was performed in Adriamycin- and lipopolysaccharide (LPS)-induced nephropathy mouse models. Interference analysis (containing 225 protein coding genes and 8 molecular process segments) of the FSGS molecular pathophysiology model with the drug mechanism of action of anakinra identified a statistically significant overlap with 43 shared molecular features that were enriched in pathways relevant in FSGS, such as plasminogen activating cascade, inflammation and apoptosis. Expert adjudication of molecular signature matching, focusing on molecular process segments did not suggest a high therapeutic potential of anakinra in FSGS. In line with this, experimental validation did not result in altered proteinuria or significant changes in expression of the FSGS-relevant genes COL1A1 and NPHS1. In summary, an integrated bioinformatic and experimental workflow showed that FSGS relevant molecular processes can be significantly affected by anakinra beyond the direct drug target IL-1 receptor type 1 (IL1R1) context but might not counteract central pathophysiology processes in FSGS. Anakinra is therefore not suggested for extended preclinical trials.
Baseline Serum Magnesium Level and Its Variability in Maintenance Hemodialysis Patients: Associations with Mortality

Background/Aims: The study aimed at investigating the impact of serum magnesium (Mg) baseline level and its variability on mortality in maintenance hemodialysis (MHD) patients. Methods: Eligible patients receiving regular MHD at Ningbo No. 2 Hospital between January 2009 and August 2016 were enrolled and follow-ups were conducted afterwards until death or transplantation. General information, laboratory results, and outcomes of subjects were collected. The relationship between baseline serum Mg level, its coefficient of variation (CV), and all-cause mortality and cardiovascular disease mortality were assessed, respectively. Subjects were divided into groups in 2 manners: by serum Mg level (lower Mg group: serum Mg <1.00 mmol/L, higher Mg group: serum Mg ≥1.00 mmol/L) and by serum Mg CV (high variation group: CV ≥0.149 mmol/L, middle variation group: 0.114 mmol/L ≤ CV < 0.149 mmol/L, and low variation group: CV <0.114 mmol/L). Results: 169 MHD patients were recruited in the study, with mean serum Mg 1.00 ± 0.18 mmol/L, average age 60.20 ± 15.64 years, and median dialysis duration 37.00 (18.30, 77.97) months. During the follow-up, 69 (40.83%) patients died, 24 (34.78%) of which died due to cardiovascular disease. Comparing the two groups, patients in the lower Mg group had a higher all-cause mortality (50.00 vs. 29.33%, p = 0.007). The multivariate Cox regression analysis suggested that lower Mg level was an independent factor for all-cause mortality as well as cardiovascular mortality (HR = 13.268, 95% CI 6.234–28.237, p < 0.001; HR = 12.702, 95% CI 3.737–43.174, p < 0.001, respectively). However, there were no significant statistical differences of all-cause and cardiovascular mortality among these three groups concerning Mg variation. And in the univariate and multivariate Cox regression analysis, serum magnesium CV was not the independent factor for all-cause mortality and cardiovascular mortality. Conclusions: The lower baseline serum magnesium level was associated with all-cause and cardiovascular mortality in MHD patients. However, the variability of magnesium level was not independently associated with the risk of death and further studies need to be conducted.
Hepatic Venous Pressure Gradient Measurements in Children: Correlation With Hepatic Histology and Clinical Indicators of Portal Hypertension

Objectives: In adults, elevated hepatic venous pressure gradients (HVPGs) are correlated with the degree of liver fibrosis on histopathology and predict worse outcomes including variceal bleeding and death. We aimed to examine the association between HVPG measurements, histopathologic findings, and clinical indicators of portal hypertension in children. Methods: Utilizing retrospective data from 2 pediatric centers between 2006 and 2015, we identified children who underwent simultaneous HVPG measurement and transjugular liver biopsy. Medical charts were reviewed for histopathology, imaging, endoscopic, and clinical data. Results: Forty-one children (median age 11 years) were included in the analysis with diagnoses of acute hepatitis (n = 15), chronic liver disease (n = 12), hepatic noncirrhotic portal hypertension (n = 4), acute liver failure (n = 3), and nonhepatic causes of portal hypertension (n = 7). Elevated mean HVPG measurements were found in children with acute liver failure (10 mmHg, range 4–12) and chronic liver disease (7 mmHg, range 1–12). HVPG measurements did not correlate with the histological severity of fibrosis (&rgr; = 0.23, P = 0.14) or portal inflammation (&rgr; = 0.24, P = 0.29), and no difference was found in HVPG when comparing children with and without a history of variceal bleeding (P = 0.43). Conclusions: HVPG measurements do not correlate significantly with the degree of hepatic fibrosis on biopsy. Furthermore, HVPG measurements are not associated with the presence of varices or history of variceal bleeding, suggesting the possibility of intrahepatic shunting in children with advanced liver disease. Therefore, unlike in adults, HVPG measurements may not accurately predict children who are at risk of complications from portal hypertension.
Applying the Resilience Perspective to Planning: Critical Thoughts from Theory and Practice Edited by Simin Davoudi and Libby Porter Resilience: A Bridging Concept or a Dead End?

We live in challenging times with a heightened sense of uncertainty and constant reminders of the unpredictability of what might be lurking around the corner; be it catastrophic climate events, terrorist attacks, credit crunch, youth riots, or mass redundancies. For planners in the UK, this wider sense of unease is exacerbated by a decade of constant change and perennial attacks on the value of their professional contributions to society. Among the prescribed remedies for dealing with such a state of flux, the one that is rapidly gaining currency is “resilience”. It appears that resilience is replacing sustainability in everyday discourses in much the same way as the environment has been subsumed in the hegemonic imperatives of climate change (Davoudi, 2012). Yet, it is not quite clear what resilience means, beyond the simple assumption that it is good to be resilient. Despite this lack of clarity, there is a growing number of governmental and non-governmental reports which aim to develop ready-made, off-the-shelf toolkits for resilience-building (see for example: Edwards, 2009; Young Foundation, 2010; Cabinet Office, 2011). One such report, supported by the Department of Business and Innovation and Skills (BIS) considers “crossdressing” as a way of building community resilience (RRAC, 2009, p. 10). These beg the following questions: Is resilience in danger of becoming just another buzzword? Does its malleability mean that many divergent measures, including those that might otherwise appear indefensible, can be justified in the name of resilience? Or, is it a promising concept for planning theory and practice? And if so, what are the opportunities and limitations of translating resilience from the field of ecology into planning? As the opening essay for this Interface, this paper aims to shed light on these questions in order to stimulate debate on this slippery concept and its utility. The paper will, firstly, trace the origin of resilience and unpack its three fundamentally different meanings; secondly, present a number of emerging parallels between resilience thinking and what I call the
Collaborative care intervention for patients with chronic heart failure

Introduction: Patients with chronic heart failure (HF) show many symptoms that worsen the quality of life (QoL). Collaborative care intervention (CCI) aims to improve the QoL and symptoms by integrating psychosocial and palliative strategies in chronic care. Methods: The PubMed, EMBASE, and Cochrane library databases were searched from inception to September 2018. The included studies were used to determine pooled standard mean differences (SMDs) and associated 95% confidence intervals (CIs). The data were assessed by fixed- and random effects models, respectively. Results: Twenty-one studies including 2999 patients with chronic heart failure were included. The results showed significantly improved QoL in the CCI group compared with the routine care group (SMD = 0.60, 95%CI 0.27–0.94, Pheterogeneity < .001, I2 = 94.1%). The patients who received face-to-face interventions experienced a significant improvement (SMD = 0.54, 95%CI 0.24–0.85, Pheterogeneity < .001, I2 = 88.7%) in terms of QoL compared with those administered only telephone interventions. Furthermore, significantly improved anxiety level (SMD = 0.33, 95%CI 0.12–0.55, Pheterogeneity = .612, I2 = 0%) and 6-min walk test (SMD = 0.46, 95%CI 0.29–0.64, Pheterogeneity = .458, I2 = 0%) were found in the CCI group compared with the routine care group. Conclusion: These findings confirmed that collaborative care intervention effectively improves the quality of life as well as psychological (anxiety) and physical (6-min walk test) functions in patients with chronic heart failure compared with routine care. Furthermore, face-to-face interventions show a greater improvement of QoL compared with telephone-only interventions.
Real-time optoacoustic temperature determination on cell cultures during heat exposure: a feasibility study

Abstract Objective/Purpose: In order to study the effects of hyperthermia and other temperature-related effects on cells and tissues, determining the precise time/temperature course is crucial. Here we present a non-contact optoacoustic technique, which provides temperatures during heating of cultured cells with scalable temporal and spatial resolution. Methods: A thulium laser (1.94 µm) with a maximum power of 15 W quickly and efficiently heats cells in a culture dish because of low penetration depth (1/e penetration depths of 78 µm) of the radiation in water. A repetitively Q-switched holmium laser (2.1 µm) is used simultaneously to probe temperatures at different locations in the dish by using the photoacoustic effect. Due to thermoelastic expansion of water, pressure waves are emitted and measured with an ultrasonic hydrophone at the side of the dish. The amplitudes of the waves are temperature dependent and can be used to calculate the temperature/time course at any location of probing. Results: We measured temperatures of up to 55 °C with a heating power of 6 W after 10 s, and subsequent lateral temperature profiles over time. Within this profile, temperature fluctuations were found, likely owing to thermal convection and water circulation. By using cultured retinal pigment epithelial cells, it is shown that the probe laser pulses alone cause no biological damage, while immediate cell damage occurs when heating for 10 s at temperatures exceeding 45 °C. Conclusions: This method shows great potential not only as a noninvasive, non-contact method to determine temperature/time responses of cells in culture, but also for complex tissue and other materials.
Adiabatic Control of Quantum Dot Spin in the Voigt Geometry with Optical Pulses

A basic system with important potential applications in quantum technologies is a quantum dot in the Voigt geometry. The spin states of the quantum dot in the Voigt geometry can act as a prototype qubit which can be manipulated by applied optical fields in order to produce the necessary quantum gates. The basic method for spin initialization in a quantum dot in the Voigt geometry is optical pumping. Here, we propose and analyze a new method for the coherent preparation of the quantum dot spin states based on adiabatic control methods. Specifically, we show that the application of two mutually delayed and partially overlapping optical pulses, similar to those used in stimulated Raman adiabatic passage, can lead to initialization of one of the spin states with high fidelity. We also demonstrate that the fidelity of the method may be increased by integrating the quantum dot with a micropillar cavity. Specifically, we show that a preferential Purcell-enhanced decay rate towards the target spin state, in certain cases, increases the fidelity of spin initialization of the adiabatic method. Our results are based on the numerical solution of the relevant density matrix equations for the quantum dot system, either in an isotropic photonic environment or in a micropillar cavity. The calculations presented in this paper are not limited to quantum dots in micropillar cavities. Similar effects can be obtained by other photonic structures as well, as for example, for quantum dots in photonic crystal cavities. Key–Words: Quantum dot, Optical fields, Voigt geometry, Spin initialization, Adiabatic passage, Purcell effect, Delayed optical pulses
Update on Antiepileptic Drugs 2019

PURPOSE OF REVIEW This article is an update from the article on antiepileptic drug (AED) therapy published in the last Continuum issue on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with AED monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use. RECENT FINDINGS Since the previous version of this article was published, three new AEDs, brivaracetam, cannabidiol, and stiripentol, have been approved by the US Food and Drug Administration (FDA), and ezogabine was removed from the market because of decreased use as a result of bluish skin pigmentation and concern over potential retinal toxicity. Older AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Most recently, the FDA adopted a policy that a drug’s efficacy as adjunctive therapy in adults can be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an AED has equivalent pharmacokinetics between its original approved use and its extrapolated use. In addition, the safety of the drug in pediatric patients has to be demonstrated in clinical studies that can be open label. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action. SUMMARY Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.
The mouse KLF1 Nan variant impairs nuclear condensation and erythroid maturation

Krüppel-like factor 1 (KLF1) is an essential transcription factor for erythroid development, as demonstrated by Klf1 knockout mice which die around E14 due to severe anemia. In humans, >65 KLF1 variants, causing different erythroid phenotypes, have been described. The Klf1 Nan variant, a single amino acid substitution (p.E339D) in the DNA binding domain, causes hemolytic anemia and is dominant over wildtype KLF1. Here we describe the effects of the Nan variant during fetal development. We show that Nan embryos have defects in erythroid maturation. RNA-sequencing of the Nan fetal liver cells revealed that Exportin 7 (Xpo7) was among the ~780 deregulated genes. This nuclear exportin is implicated in terminal erythroid differentiation; in particular it is involved in nuclear condensation. Indeed, KLF1 Nan fetal liver cells had larger nuclei and reduced chromatin condensation. Knockdown of XPO7 in wildtype erythroid cells caused a similar phenotype. We conclude that reduced expression of XPO7 is partially responsible for the erythroid defects observed in Nan erythroid cells.
PATHOGENICITY OF SOME IMPORTANT ROOT ROT FUNGI TO THE CHILLI CROP AND THEIR BIOLOGICAL CONTROL

A number of soil borne fungi are reported to cause diseases in chilli crop in Pakistan and induce heavy annual losses. During our survey conducted during July 2010 to August 2012 it was observed that in the chilli plants of lower areas of Sindh Province including Kunri, Kot Ghulam Muhammad, Mirpurkhas, Hyderabad, Tando Allahayar, Samaro, Umerkot and Digri show pathogenicity symptoms including wilting, stunted growth, chlorosis and blotch. Diseased plant specimens were collected and brought to laboratory. The soil borne fungi Rhizoctonia solani, Macrophomina phaseolina, Fusarium oxysporum, F. solani and Pythium sp. were isolated from specimens collected from these areas. Pathogenicity tests were carried out under greenhouse conditions using isolated fungi on chilli and colonization, and infection percentages were determined. During this study, Pythium sp. , and R. solani severely affected plants compared to other fungi tested for their pathogenicity such as F. oxysporum, F. solani and M. phaseolina. In biological control, four antagonistic fungi Aspergillus flavus, A. niger, Penicillium commune and Trichoderma harzianum were used against the above mentioned plant pathogenic fungi which successfully suppressed the activity of pathogenic fungi. In addition, it disclosed that T. harzianum was highly antagonistic towards R. solani, M. phaseolina, F. oxysporum, F. solani and Pythium spp. as it showed a strong inhibitory effect on the growth and mycelial development.
A CRISPR/Cas9-based central processing unit to program complex logic computation in human cells

Significance By enabling rational programming of mammalian cell behavior, synthetic biology is driving innovation across biomedical applications. Using Cas9-variants as core as protein-based central processing units (CPUs) that control gene expression in response to single-guide RNAs as genetic software, we have programmed scalable Boolean logic computations such as the half adder in single human cells. Combining orthogonal Cas9-variants enabled the design of multicore genetic CPUs that provide parallel arithmetic computations. The Cas9-based multicore CPU design may provide opportunities in single-cell mammalian biocomputing to provide biomedical applications. Controlling gene expression with sophisticated logic gates has been and remains one of the central aims of synthetic biology. However, conventional implementations of biocomputers use central processing units (CPUs) assembled from multiple protein-based gene switches, limiting the programming flexibility and complexity that can be achieved within single cells. Here, we introduce a CRISPR/Cas9-based core processor that enables different sets of user-defined guide RNA inputs to program a single transcriptional regulator (dCas9-KRAB) to perform a wide range of bitwise computations, from simple Boolean logic gates to arithmetic operations such as the half adder. Furthermore, we built a dual-core CPU combining two orthogonal core processors in a single cell. In principle, human cells integrating multiple orthogonal CRISPR/Cas9-based core processors could offer enormous computational capacity.