There is increasing recognition that acute kidney injury (AKI) and chronic kidney disease (CKD) are closely linked and likely promote one another. Underlying CKD now is recognized as a clear risk ...factor for AKI because both decreased glomerular filtration rate and increased proteinuria have been shown to be associated strongly with AKI. A growing body of literature also provides evidence that AKI accelerates the progression of CKD. Individuals who suffered dialysis-requiring AKI are particularly vulnerable to worse long-term renal outcomes, including end-stage renal disease. The association between AKI and subsequent renal function decline is amplified by pre-existing severity of CKD, higher stage of AKI, and the cumulative number of AKI episodes. However, residual confounding and ascertainment bias may partly explain the epidemiologic association between AKI and CKD in observational studies. As the number of AKI survivors increases, we need to better understand other clinically important outcomes after AKI, identify those at highest risk for the most adverse sequelae, and develop strategies to optimize their care.
Concentrated solar power plants (CSPs) are gaining momentum due to their potential of power generation throughout the day for base load applications in the desert regions with extremely high direct ...normal irradiance (DNI). Among various types of the CSPs, solar tower power technologies are becoming the front runners especially in the United States and around the world with the possibility to compete with traditional power generation technologies in terms of efficiency and levelized cost of electricity (LCOE). A bibliometric analysis of the publications on the CSP systems and components since 1990 shows a total of 6400+ publications and reveals an exponential growth due to reasons that CSP systems promises a lot of potential as the future large scale power source for varied applications. This review consolidates the benefits and challenges of the CSP technologies particularly in the desert regions. Thorough literature analysis as well as the meteorological data projects the trend that the CSP systems would become a reality in the Middle East and North Africa (MENA), Australia, Southwestern region of the United States, Southwestern part of China and China/Mongolia border with high direct normal irradiance. However, enormous amount of support and capital investments are needed for making these CSP systems realistic as there is not much power grid network in existence. It is evident that there are multiple challenges specifically in water consumption, materials design and development for the optimum heat transfer fluid, thermal energy storage and receiver subsystems in addition to commercial viability and environmental impacts. Each of the challenges is discussed in detail and suggestions are made to address the challenges.
Satellite-derived high-resolution precipitation products (HRPP) have been developed to address the needs of the user community and are now available with 0.25° × 0.25° (or less) subdaily resolutions. ...This paper evaluates a number of commonly available satellite-derived HRPPs covering northwest Europe over a 6-yr period. Precipitation products include the Tropical Rainfall Measuring Mission (TRMM) Multisatellite Precipitation Analysis (TMPA), the Climate Prediction Center (CPC) morphing (CMORPH) technique, the CPC merged microwave technique, the Naval Research Laboratory (NRL) blended technique, and the Precipitation Estimation from Remotely Sensed Information using Artificial Neural Networks (PERSIANN) technique. In addition, the Geosynchronous Operational Environmental Satellite (GOES) precipitation index (GPI) and the European Centre for Medium-Range Weather Forecasting (ECMWF) operational forecast model products are included for comparison. Surface reference data from the European radar network is used as ground truth, supported by the Global Precipitation Climatology Centre (GPCC) precipitation gauge analysis and gauge data over the United Kingdom. Measures of correlation, bias ratio, probability of detection, and false alarm ratio are used to evaluate the products. Results show that satellite products generally exhibit a seasonal cycle in correlation, bias ratio, probability of detection, and false alarm ratio, with poorer statistics during the winter. The ECMWF model also shows a seasonal cycle in the correlation, although the results are poorer during the summer, while the bias ratio, probability of detection, and false alarm ratio are consistent through all seasons. Importantly, all the satellite HRPPs underestimate precipitation over northwest Europe in all seasons.
Abstract Background The PHQ-9 was originally developed as a screener for depression in primary care and is commonly used in medical settings. However, surprisingly little is known about its ...psychometric properties and utility as a severity measure in psychiatric populations. We examined the full range of psychometric properties of the PHQ-9 in patients with a range of psychiatric disorders (i.e., mood, anxiety, personality, psychotic). Methods Patients ( n =1023) completed the PHQ-9 upon admission and discharge from a partial hospital, as well as other self-report measures of depression, anxiety, well-being, and a structured diagnostic interview. Results Internal consistency was good ( α =.87). The PHQ-9 demonstrated a strong correlation with a well-established measure of depression, moderate correlations with related constructs, a weak correlation with a theoretically unrelated construct (i.e., disgust sensitivity), and good sensitivity to change, with a large pre- to post-treatment effect size. Using a cut-off of ≥13, the PHQ-9 demonstrated good sensitivity (.83) and specificity (.72). A split-half exploratory factor analysis/confirmatory factor analysis suggested a two-factor solution with one factor capturing cognitive and affective symptoms and a second factor reflecting somatic symptoms. Psychometric properties did not differ between male and female participants. Limitations No clinician-rated measure of improvement, and the sample lacked ethnoracial diversity. Conclusions This first comprehensive validation of the PHQ-9 in a large, psychiatric sample supported its use as a severity measure and as a measure of treatment outcome. It also performed well as a screener for a current depressive episode using a higher cut-off than previously recommended for primary care samples.
Background
Patterns of recurrence after surgery with postoperative chemoradiotherapy (S‐CCRT) or surgery alone in patients with oesophageal squamous cell carcinoma (SCC) may differ. This might ...influence the nature and timing of subsequent management strategies.
Methods
Patients with SCC who had undergone R0 resection were included. Propensity score matching was used to select matched groups. Survival and recurrence were compared by Kaplan–Meier analysis. Univariable and multivariable Cox regression analyses were used to identify prognostic factors for overall and disease‐free survival.
Results
A total of 1390 patients were included, of whom 1000 had surgery alone and 390 underwent S‐CCRT. Propensity score matching yielded 213 well balanced pairs. The 3‐year overall survival rate and median survival time in the S‐CCRT group were 0·50 and 36·5 (95 per cent c.i. 25·1 to 52·6) months respectively, compared with 0·38 and 22·8 (18·2 to 29·0) months in the surgery‐alone group (P = 0·006). The 3‐year disease‐free survival rate and median disease‐free survival time in the S‐CCRT group were 0·46 and 30·6 (22·2 to 39·3) months respectively, compared with 0·36 and 17·6 (11·3 to 23·9) months in the surgery‐alone group (P = 0·006). The 2‐year freedom from locoregional recurrence rate was 0·87 and 0·77 in the S‐CCRT and surgery‐alone groups respectively (P = 0·003). In multivariable analysis, independent prognostic factors for disease‐free survival included age over 56 years, pT3–4 category, pN category, poor differentiation, tumour length exceeding 4·0 cm, and receiving postoperative chemoradiotherapy (hazard ratio 0·62, 95 per cent c.i. 0·47 to 0·81; P < 0·001).
Conclusion
Oesophagectomy with postoperative chemoradiotherapy was associated with longer survival and lower recurrence rates, especially at a locoregional level, compared with surgery alone.
Longer survival and less recurrence with multimodal treatment
Summary
Pityriasis rubra pilaris (PRP) represents a group of rare chronic inflammatory skin disorders in which around one in 20 affected individuals show autosomal dominant inheritance. In such cases ...there may be gain‐of‐function mutations in CARD14, encoding caspase recruitment domain‐containing protein 14 (CARD14), which activates the noncanonical nuclear factor (NF)‐κB pathway, thereby promoting cutaneous inflammation. Here we report a mother and son with PRP due to a new missense mutation in CARD14 and describe the beneficial clinical effects of ustekinumab, a monoclonal antibody against interleukins 12 and 23, in both patients. A 49‐year‐old woman and her 20‐year‐old son had lifelong, generalized, patchy erythematous scale with a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma, features consistent with generalized PRP. Topical steroids, phototherapy and oral retinoids proved ineffective. Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single‐nucleotide transversion in exon 4, c.356T>G, resulting in the missense mutation p.Met119Arg. Ustekinumab, at a dose of 45 mg every 12 weeks, brought about a significant physical and emotional improvement in both the mother and son within a few days of the initial dose, which was sustained on maintenance dosing. This report highlights the therapeutic potential of biologics that downregulate NF‐κB signalling in familial PRP with mutations in CARD14.
What's already known about this topic?
Pityriasis rubra pilaris (PRP) represents a group of rare chronic inflammatory skin disorders in which some cases show autosomal dominant inheritance.
Some cases also reveal heterozygous gain‐of‐function mutations in CARD14, encoding caspase recruitment domain‐containing protein 14 (CARD14).
Ustekinumab, an interleukin‐12/23 antagonist, is a licensed biological therapy for psoriasis, although its use has not been widely assessed in PRP, despite anecdotal reports of its potential efficacy.
What does this study add?
We report a mother and son with refractory generalized PRP. DNA sequencing revealed that both carried a new de novo missense mutation in CARD14, p.Met119Arg.
Identification of this CARD14 mutation was used as justification for a trial of ustekinumab, whereupon both patients had a beneficial clinical response, physically and emotionally, with sustained improvements over several months of follow‐up.
Ustekinumab may be considered as a targeted anti‐inflammatory therapy for familial PRP with an underlying mutation in CARD14.
Functions of S100 proteins Donato, R; Cannon, B R; Sorci, G ...
Current molecular medicine
13, Issue:
1
Journal Article
Peer reviewed
The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular ...functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.
Ophthalmic drugs are almost exclusively delivered through eye drops in spite of several deficiencies including low bioavailability and poor compliance. Contact lenses are ideally suited for delivery ...of drugs to the anterior chamber because of the placement directly on the cornea which results in a high bioavailability of at least 50 % compared to about 1–5 % for eye drops. The ten-fold increase in bioavailability reduces the amount of drug delivered, which in turn reduces the systemic loss of the drug, thereby reducing the potential for side effects. Additionally contact lenses can provide a most uniform release profile compared to the pulsatile delivery with eye drops, which can potentially result in improved therapeutic outcomes. Finally drug delivery via extended wear contact lenses can significantly improve the compliance. In spite of all these benefits, contact lenses are not yet available as drug delivery vehicles mainly because the earlier lens designs were not optimized for drug delivery. The interest in developing contact lenses for drug delivery has significantly increased in the last decade as several new techniques have been developed for designing contact lenses for extended drug delivery. The latest studies show that contact lenses can achieve extended release of a few weeks without any significant impact on critical lens properties. Also in vivo animal studies have proven safety, efficacy and increased bioavailability compared to eye drops. The future appears promising for drug eluting contact lenses but several challenges remain to be overcome regarding processing and storage issues, lack of use in the elderly population, regulatory issues, high costs of clinical studies and cost-benefit analysis.
This paper describes an all-digital PVT-variation tolerant true-random number generator (TRNG), fabricated in 45 nm high-k/metal-gate CMOS, targeted for on-die entropy generation in high-performance ...microprocessors. The TRNG harvests differential thermal-noise at the diffusion nodes of a pre-charged cross-coupled inverter pair to resolve out of metastability, generating one random bit/cycle. A self-calibrating 2-step tuning mechanism using coarse-grained configurable inverters and fine-grained programmable clock delay generators, along with an entropy-tracking feedback loop provide tolerance to 20% PVT variation-induced device mismatches, enabling lowest-reported energy-consumption of 2.9 pJ/bit with a dense layout occupying 4004 μm 2 , while achieving: (i) 2.4 Gbps random bit throughput, 7 mW total power consumption with 0.7 mW leakage power component, measured at 1.1 V, 50°C, (ii) random bitstreams that passes all NIST RNG tests with raw entropy/bit measured up to 0.9999999993, (iii) good distribution of 1's with 4-bit entropy of 3.97996 and high-entropy pattern probability of 0.066 (iv) wide operating supply voltage range with robust sub-threshold voltage performance of 14 Mbps, 5.6 μW, measured at 280 mV, 50°C, (v) 12 fine-grained high-entropy settings for the TRNG to dither in during steady-state operation, (vi) <;3% error while using an analytical ergodic Markov chain model for predicting pattern probabilities and (vii) 200x higher throughput and 9x higher energy-efficiency than previously reported implementations. Design modifications for robust operation in 22 nm high-volume manufacturing in the presence of 3σ process variations demonstrate scalability of the all-digital design to future technologies.
Background
Obesity accelerates and exacerbates the age-related changes on muscle function and exercise capacity. In addition, the middle-aged population is often overlooked when talking about the ...prevention of sarcopenia. This study investigated the effects of exercise alone or in combination with a high-protein diet on muscle function and physical fitness in middle-aged obese adults.
Materials and methods
Sixty-nine middle-aged (501–64 years old) obese adults were randomly assigned to one of the following groups: control group (C; n=23), exercise group (E; n=23) or exercise plus high-protein group (EP; n=23). Individuals within the E and EP groups received 12 weeks of exercise training; whereas, the individuals in the EP group also received a highprotein diet intervention (1.6g/kg/day). Individuals within the C group were asked to maintain their lifestyle for 12 weeks. Participants were evaluated before and after the intervention. Outcome measures included maximal exercise capacity, muscle function and functional physical performance. Analysis of covariance was used to determine the effects of the intervention.
Results
After the intervention, the E and EP groups had greater maximal work rate, peak oxygen consumption, and muscle power during muscle contractions at 180°/sec than that in the C group (P<0.05). The EP group, but not the E group, showed significant improvement in the sit-to-stand test and climbing stairs test than the C group after the intervention (P<0.05). Within group comparisons showed that the anaerobic threshold only increased in the EP group (+12% from pre-test).
Conclusions
For middle-aged obese adults, exercise with a high-protein diet not only improved muscle power and exercise capacity but also enhanced their functional physical performance.
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