Abstract Hyponatremia is a serious, but often overlooked, electrolyte imbalance that has been independently associated with a wide range of deleterious changes involving many different body systems. ...Untreated acute hyponatremia can cause substantial morbidity and mortality as a result of osmotically induced cerebral edema, and excessively rapid correction of chronic hyponatremia can cause severe neurologic impairment and death as a result of osmotic demyelination. The diverse etiologies and comorbidities associated with hyponatremia pose substantial challenges in managing this disorder. In 2007, a panel of experts in hyponatremia convened to develop the Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations that defined strategies for clinicians caring for patients with hyponatremia. In the 6 years since the publication of that document, the field has seen several notable developments, including new evidence on morbidities and complications associated with hyponatremia, the importance of treating mild to moderate hyponatremia, and the efficacy and safety of vasopressin receptor antagonist therapy for hyponatremic patients. Therefore, additional guidance was deemed necessary and a panel of hyponatremia experts (which included all of the original panel members) was convened to update the previous recommendations for optimal current management of this disorder. The updated expert panel recommendations in this document represent recommended approaches for multiple etiologies of hyponatremia that are based on both consensus opinions of experts in hyponatremia and the most recent published data in this field.
Single-cell CRISPR screens enable the exploration of mammalian gene function and genetic regulatory networks. However, use of this technology has been limited by reliance on indirect indexing of ...single-guide RNAs (sgRNAs). Here we present direct-capture Perturb-seq, a versatile screening approach in which expressed sgRNAs are sequenced alongside single-cell transcriptomes. Direct-capture Perturb-seq enables detection of multiple distinct sgRNA sequences from individual cells and thus allows pooled single-cell CRISPR screens to be easily paired with combinatorial perturbation libraries that contain dual-guide expression vectors. We demonstrate the utility of this approach for high-throughput investigations of genetic interactions and, leveraging this ability, dissect epistatic interactions between cholesterol biogenesis and DNA repair. Using direct capture Perturb-seq, we also show that targeting individual genes with multiple sgRNAs per cell improves efficacy of CRISPR interference and activation, facilitating the use of compact, highly active CRISPR libraries for single-cell screens. Last, we show that hybridization-based target enrichment permits sensitive, specific sequencing of informative transcripts from single-cell RNA-seq experiments.
Abstract Background The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatremia in clinical practice, but current management of hyponatremia and ...outcomes in patients with SIADH are not well understood. The objective of the Hyponatremia Registry was to assess the current state of management of hyponatremia due to SIADH in diverse hospital settings, specifically: which diagnostic and treatment modalities are currently employed and how rapidly and reliably they result in an increase in serum Na+ . A secondary objective was to determine whether treatment choices and outcomes differ across the United States (US) and the European Union (EU). Methods The HN Registry recorded selected diagnostic measures and utilization, efficacy, and outcomes of therapy for euvolemic HN diagnosed clinically as SIADH in 1,524 adult patients with serum sodium concentration (Na+ ) ≤130 mEq/L (1,034 from 146 US and 490 from 79 EU sites). A subgroup of patients with more rigorously defined SIADH via measurement of relevant laboratory parameters was also analyzed. Results The most common monotherapy treatments for hyponatremia in SIADH were fluid restriction (48%), isotonic (27%) or hypertonic (6%) saline, and tolvaptan (13%); 11% received no active agent. The mean rate of Na+ change (mEq/L/d) was greater for all active therapies than no active treatment. Hypertonic saline and tolvaptan produced the greatest mean rate of Na+ change (IQR both 3.0(6.0) mEq/L/d), compared to lower IQR rates of Na+ change for isotonic saline (1.5(3.0) mEq/L/d) and fluid restriction (1.0(2.3) mEq/L/d). The general pattern of responses was similar in both the US and EU cohorts. At discharge, Na+ was <135 mEq/L in 75% of patients and ≤130 mEq/L in 43%. Overly rapid correction occurred in 10.2%. Conclusions 1) Current treatment of hyponatremia in SIADH often employs therapies with limited efficacy; the most commonly chosen monotherapy treatments, fluid restriction and isotonic saline, failed to increase the serum Na+ by ≥5 mEq/L in 55% and 64% of monotherapy treatment episodes, respectively. 2) Appropriate laboratory tests to diagnose SIADH were obtained in <50% of patients; success rates in correcting hyponatremia were significantly higher when such tests were obtained. 3) Few outcome differences were found between the US and EU. A notable exception was hospital length of stay; use of tolvaptan was associated with significantly shorter length of stay in the EU but not the US. 4) Despite the availability of effective therapies, most patients with SIADH were discharged from the hospital still hyponatremic.
Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and ...the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10
, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10
, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.
Current management practices for hyponatremia (HN) are incompletely understood. The HN Registry has recorded diagnostic measures, utilization, efficacy, and outcomes of therapy for eu- or ...hypervolemic HN. To better understand current practices, we analyzed data from 3087 adjudicated adult patients in the registry with serum sodium concentration of 130 mEq/l or less from 225 sites in the United States and European Union. Common initial monotherapy treatments were fluid restriction (35%), administration of isotonic (15%) or hypertonic saline (2%), and tolvaptan (5%); 17% received no active agent. Median (interquartile range) mEq/l serum sodium increases during the first day were as follows: no treatment, 1.0 (0.0–4.0); fluid restriction, 2.0 (0.0–4.0); isotonic saline, 3.0 (0.0–5.0); hypertonic saline, 5.0 (1.0–9.0); and tolvaptan, 4.0 (2.0–9.0). Adjusting for initial serum sodium concentration with logistic regression, the relative likelihoods for correction by 5 mEq/l or more (referent, fluid restriction) were 1.60 for hypertonic saline and 2.55 for tolvaptan. At discharge, serum sodium concentration was under 135 mEq/l in 78% of patients and 130 mEq/l or less in 49%. Overly rapid correction occurred in 7.9%. Thus, initial HN treatment often uses maneuvers of limited efficacy. Despite an association with poor outcomes and availability of effective therapy, most patients with HN are discharged from hospital still hyponatremic. Studies to assess short- and long-term benefits of correction of HN with effective therapies are needed.
Abstract Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly ...in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. An expert panel assessed the potential contributions of aquaretic nonpeptide small-molecule arginine vasopressin receptor (AVPR) antagonists to hyponatremia therapies. This review presents their conclusions, including identification of appropriate treatment populations and possible future indications for aquaretic AVPR antagonists.
Abstract
The comparison of gene regulatory networks between diseased versus healthy individuals or between two different treatments is an important scientific problem. Here, we propose sc-compReg as ...a method for the comparative analysis of gene expression regulatory networks between two conditions using single cell gene expression (scRNA-seq) and single cell chromatin accessibility data (scATAC-seq). Our software, sc-compReg, can be used as a stand-alone package that provides joint clustering and embedding of the cells from both scRNA-seq and scATAC-seq, and the construction of differential regulatory networks across two conditions. We apply the method to compare the gene regulatory networks of an individual with chronic lymphocytic leukemia (CLL) versus a healthy control. The analysis reveals a tumor-specific B cell subpopulation in the CLL patient and identifies TOX2 as a potential regulator of this subpopulation.
Global energy demand, water demand, and raw materials extraction are major challenges for society as population grows. While a traditional linear economy approach leads to depletion of finite ...resources, damage to the Earth's ecosystems, and adverse impacts on human health, a paradigm shift toward implementation of circular economy principles is paramount to the reversal of world resources' exhaustion. The wastewater, or “used water,” sector can contribute to offsetting resource scarcity challenges by adopting circular economy principles to recover and reintroduce recovered resources into the economy. Transitioning to a circular economy model requires monitoring and tracking progress via metrics in the form of indicators. In this paper, a bibliometric analysis followed by a systematic literature review was conducted on available circular economy indicators in the used water treatment sector. Over 200 indicators were categorized into three impact categories: environmental, social, and economic to identify gaps in the existing literature. Results showed that less than 50% of the available circularity indicators are applied in the used water sector and environmental indicators represent the highest percentage among the potential applicable indicators. Research gaps in the circular economy literature in relation to used water treatment systems were identified and future research directions discussed.
K562 is widely used in biomedical research. It is one of three tier-one cell lines of ENCODE and also most commonly used for large-scale CRISPR/Cas9 screens. Although its functional genomic and ...epigenomic characteristics have been extensively studied, its genome sequence and genomic structural features have never been comprehensively analyzed. Such information is essential for the correct interpretation and understanding of the vast troves of existing functional genomics and epigenomics data for K562. We performed and integrated deep-coverage whole-genome (short-insert), mate-pair, and linked-read sequencing as well as karyotyping and array CGH analysis to identify a wide spectrum of genome characteristics in K562: copy numbers (CN) of aneuploid chromosome segments at high-resolution, SNVs and indels (both corrected for CN in aneuploid regions), loss of heterozygosity, megabase-scale phased haplotypes often spanning entire chromosome arms, structural variants (SVs), including small and large-scale complex SVs and nonreference retrotransposon insertions. Many SVs were phased, assembled, and experimentally validated. We identified multiple allele-specific deletions and duplications within the tumor suppressor gene
Taking aneuploidy into account, we reanalyzed K562 RNA-seq and whole-genome bisulfite sequencing data for allele-specific expression and allele-specific DNA methylation. We also show examples of how deeper insights into regulatory complexity are gained by integrating genomic variant information and structural context with functional genomics and epigenomics data. Furthermore, using K562 haplotype information, we produced an allele-specific CRISPR targeting map. This comprehensive whole-genome analysis serves as a resource for future studies that utilize K562 as well as a framework for the analysis of other cancer genomes.
In the Anthropocene, watershed chemical transport is increasingly dominated by novel combinations of elements, which are hydrologically linked together as ‘chemical cocktails.’ Chemical cocktails are ...novel because human activities greatly enhance elemental concentrations and their probability for biogeochemical interactions and shared transport along hydrologic flowpaths. A new chemical cocktail approach advances our ability to: trace contaminant mixtures in watersheds, develop chemical proxies with high-resolution sensor data, and manage multiple water quality problems. We explore the following questions: (1) Can we classify elemental transport in watersheds as chemical cocktails using a new approach? (2) What is the role of climate and land use in enhancing the formation and transport of chemical cocktails in watersheds? To address these questions, we first analyze trends in concentrations of carbon, nutrients, metals, and salts in fresh waters over 100 years. Next, we explore how climate and land use enhance the probability of formation of chemical cocktails of carbon, nutrients, metals, and salts. Ultimately, we classify transport of chemical cocktails based on solubility, mobility, reactivity, and dominant phases: (1) sieved chemical cocktails (e.g., particulate forms of nutrients, metals and organic matter); (2) filtered chemical cocktails (e.g., dissolved organic matter and associated metal complexes); (3) chromatographic chemical cocktails (e.g., ions eluted from soil exchange sites); and (4) reactive chemical cocktails (e.g., limiting nutrients and redox sensitive elements). Typically, contaminants are regulated and managed one element at a time, even though combinations of elements interact to influence many water quality problems such as toxicity to life, eutrophication, infrastructure corrosion, and water treatment. A chemical cocktail approach significantly expands evaluations of water quality signatures and impacts beyond single elements to mixtures. High-frequency sensor data (pH, specific conductance, turbidity, etc.) can serve as proxies for chemical cocktails and improve real-time analyses of water quality violations, identify regulatory needs, and track water quality recovery following storms and extreme climate events. Ultimately, a watershed chemical cocktail approach is necessary for effectively co-managing groups of contaminants and provides a more holistic approach for studying, monitoring, and managing water quality in the Anthropocene.
PDF
