bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural adaptation of vertebrate endonuclease G for 5-hydroxymethylcytosine recognition and function
Authors: Vander Zanden Crystal M , Czarny Ryan S , Ho Ethan N , Robertson Adam B , Ho P Shing 
Published: February 2020

AbstractModified DNA bases functionally distinguish the taxonomic forms of life—5-methylcytosine separates prokaryotes from eukaryotes and 5-hydroxymethylcytosine (5hmC) invertebrates from vertebrates. We demonstrate here that mouse endonuclease G (mEndoG) shows specificity for both 5hmC and Holliday junctions. The enzyme has higher affinity (&gt;50-fold) for junctions over duplex DNAs. A 5hmC-modification shifts the position of the cut site and increases the rate of DNA cleavage in modified versus unmodified junctions. The crystal structure of mEndoG shows that a cysteine (Cys69) is positioned to recognize 5hmC through a thiol-hydroxyl hydrogen bond. Although this Cys is conserved from worms to mammals, a two amino acid deletion in the vertebrate relative to the invertebrate sequence unwinds an α-helix, placing the thiol of Cys69 into the mEndoG active site. Mutations of Cys69 with alanine or serine show 5hmC-specificity that mirrors the hydrogen bonding potential of the side chain (C–H &lt; S–H &lt; O–H). A second orthogonal DNA binding site identified in the mEndoG structure accommodates a second arm of a junction. Thus, the specificity of mEndoG for 5hmC and junctions derives from structural adaptations that distinguish the vertebrate from the invertebrate enzyme, thereby thereby supporting a role for 5hmC in recombination processes.
Real-world Multicenter Analysis of Clinical Outcomes and Safety of Meropenem-Vaborbactam in Patients Treated for Serious Gram-Negative Bacterial Infections
Authors: Alosaimy Sara , Jorgensen Sarah C J , Lagnf Abdalhamid M , Melvin Sarah , Mynatt Ryan P , Carlson Travis J , Garey Kevin W , Allen David , Venugopalan Veena , Veve Michael , Athans Vasilios , Saw Stephen , Yost Christine N , Davis Susan L , Rybak Michael J 
Published: February 2020

Abstract
Fourty patients were treated with meropenem-vaborbactam (MEV) for serious Gram-negative bacterial (GNB) infections. Carbapenem-resistant Enterobacteriaceae (CRE) comprised 80.0% of all GNB infections. Clinical success occurred in 70.0% of patients. Mortality and recurrence at 30 days were 7.5% and 12.5%, respectively. One patient experienced a probable rash due to MEV.
Incidence and mortality of acute kidney injury in patients undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis
Authors: Kanduri S R , Cheungpasitporn W , Thongprayoon C , Bathini T , Kovvuru K , Garla V , Medaura J , Vaitla P , Kashani K B 
Published: February 2020

AbstractBackgroundWhile acute kidney injury (AKI) is commonly reported following hematopoietic stem cell transplant (HCT), the incidence and impact of AKI on mortality among patients undergoing HCT are not well described. We conducted this systematic review to assess the incidence and impact of AKI on mortality risk among patients undergoing HCT.MethodsOvid MEDLINE, EMBASE and the Cochrane Databases were searched from database inceptions through August 2019 to identify studies assessing the incidence of AKI and mortality risk among adult patients who developed AKI following HCT. Random-effects and generic inverse variance method of DerSimonian–Laird were used to combine the effect estimates obtained from individual studies.ResultsWe included 36 cohort studies with a total of 5144 patients undergoing HCT. Overall, the pooled estimated incidence of AKI and severe AKI (AKI Stage III) were 55.1% (95% confidence interval (CI) 46.6–63.3%) and 8.3% (95% CI 6.0–11.4%), respectively. The pooled estimated incidence of AKI using contemporary AKI definitions (RIFLE, AKIN and KDIGO criteria) was 49.8% (95% CI 41.6–58.1%). There was no significant correlation between study year and the incidence of AKI (P = 0.12) or severe AKI (P = 0.97). The pooled odds ratios of 3-month mortality and 3-year mortality among patients undergoing HCT with AKI were 3.05 (95% CI 2.07–4.49) and 2.23 (95% CI 1.06–4.73), respectively.ConclusionThe incidence of AKI among patients who undergo HCT remains high, and it has not changed over the years despite advances in medicine. AKI after HCT is associated with increased short- and long-term mortality.
Genetics of age-related clonal hematopoiesis and atherosclerotic cardiovascular disease
Authors: Jung Changhee , Evans Megan A. , Walsh Kenneth 
Published: February 2020

Purpose of review
While advanced age is the major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), we have a poor understanding of how aging promotes the progression of this disease. Recent evidence suggests that the age-dependent accumulation of somatic mutations in hematopoietic cells may represent a new causal risk factor for ASCVD.

Recent findings
A hallmark of aging is the accumulation of somatic DNA mutations in all tissues of the body. Accordingly, evidence shows that hematopoietic stem/progenitor cells accumulate somatic mutations as a function of age in nonsymptomatic individuals. When these mutations occur in driver genes that provide a selective advantage to the hematopoietic stem/progenitor cells, they undergo a clonal expansion and progressively give rise to blood leukocytes that harbor these mutations. This phenomenon, referred to as clonal hematopoiesis, has been associated with the increased risk of mortality, hematologic malignancy, ASCVD, and related diseases. Notably, many individuals exhibiting clonal hematopoiesis carry single ‘driver’ mutations in preleukemic genes including DNA methyltransferase 3a, ten-eleven translocation 2, additional sex combs like 1, and Janus kinase 2. Experimental studies show that these mutations in some of these genes can alter the inflammatory properties of the leukocyte and contribute to the pathogenesis of ASCVD.

Summary
We review recent epidemiological and experimental findings on the association between age-related clonal hematopoiesis and ASCVD by focusing on prevalent driver gene mutations.
Triglycerides and residual risk
Authors: Vallejo-Vaz Antonio J. , Corral Pablo , Schreier Laura , Ray Kausik K. 
Published: February 2020

Purpose of review
To review the recent evidence from observational/genetic/interventional studies addressing triglycerides and residual cardiovascular risk (CVRisk).

Recent findings
Large population-based and secondary prevention studies consistently show an association of higher triglycerides with increased CVRisk. This is compounded by genetic studies demonstrating an independent relationship between triglyceride raising or lowering genetic variants affecting triglyceride-rich lipoproteins (TRL) metabolism and CVRisk. Mendelian randomization analysis suggests the benefit of genetic lowering of triglycerides and LDL-cholesterol is similar per unit change in apolipoprotein-B. Among cholesterol-lowering trials, more intensive statin therapy produced greater CVRisk reductions in patients with higher TRL-cholesterol or triglycerides; proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition led to similar triglycerides reduction but greater non-HDL-C or apolipoprotein-B reductions than fibrates or fish oils. Regarding n-3 fatty acids, A Study of Cardiovascular Events in Diabetes (ASCEND) and Vitamin D and Omega-3 Trial (VITAL) primary prevention trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid failed to demonstrate cardiovascular benefits, Conversely, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) using high-dose icosapent-ethyl (purified EPA) in primary (diabetes) and secondary prevention with hypertriglyceridemia showed significant cardiovascular events reductions (greater than expected by the observed triglycerides or apolipoprotein-B reductions, suggesting potential benefits through non-lipid pathways).

Summary
Evidence suggests higher triglycerides are a marker of CVRisk and may help identify patients who benefit from intensification of therapy. Moreover, genetic studies support a causal link between TRL/triglycerides and cardiovascular disease. Treatment with high-dose EPA may be of benefit in high-risk patients with hypertriglyceridemia to reduce CVRisk.
Risk factors for myocardial infarction in very young South Asians
Authors: Gupta Mohit D. , Gupta Puneet , MP Girish , Roy Ambuj , Qamar Arman 
Published: February 2020

Purpose of review
It is only over the last few decades that the impact of coronary artery disease (CAD) in very young South Asian population has been recognized. There has been a tremendous interest in elucidating the causes behind this phenomenon and these efforts have uncovered several mechanisms that might explain the early onset of CAD in this population. The complete risk profile of very young South Asians being affected by premature CAD still remains unknown.

Recent findings
The existing data fail to completely explain the burden of premature occurrence of CAD in South Asians especially in very young individuals. Results from some studies identified nine risk factors, including low consumption of fruits and vegetables, smoking, alcohol, diabetes, psychosocial factors, sedentary lifestyle, abdominal obesity, hypertension and dyslipidemia as the cause of myocardial infarction in 90% of the patients in this population. Recent large genome-wide association studies have discovered the association of several novel genetic loci with CAD in South Asians. Nonetheless, continued scientific efforts are required to further our understanding of the causal risk factors of CAD in South Asians to address the rising burden of CVD in this vulnerable population.

Summary
In this review, we discuss established and emerging risk factors of CAD in this population.
Refractory coeliac disease: what should we be doing different?
Authors: Chetcuti Zammit Stefania , Sanders David S. , Sidhu Reena 
Published: February 2020

Purpose of review
The aim of this review is to provide insight into the diagnosis and management of patients with refractory coeliac disease (RCD) and highlight recent advances in this field.

Recent findings
The diagnosis of RCD can be more accurately confirmed with flow cytometry in addition to immunohistochemistry. Dietary input and excretion of gluten immunogenic peptides can help rule out gluten contamination, and therefore, substantiate a diagnosis of RCD type I. Small bowel capsule endoscopy (SBCE) is important at diagnosis and follow-up in addition to duodenal histology. Apart from ruling out complications, it can give information on extent of disease in the small bowel, and therefore, help assess response to therapy. Those patients with a poor response can have earlier intensification of therapy, which may result in an improved outcome. RCD also occurs in patients with serology negative coeliac disease but with an increased mortality compared with patients with serology-positive coeliac disease.

Summary
Patients with RCD can present with persistent symptoms of malnutrition but can also be completely asymptomatic. Serology is not a reliable marker to detect refractory disease. Immunostaining and flow cytometry are necessary for a diagnosis of RCD. Small bowel endoscopy enables disease extent to be assessed and allows for small bowel biopsies to be taken in case of suspicious lesions. Small bowel radiology can be complementary to small bowel endoscopy.
Basic principles of liver allocation and development over the years
Authors: Aby Elizabeth S. , Lake John R. 
Published: February 2020

Purpose of review
Prior to the enactment of the National Organ Transplant Act in 1984, there was no organized system to allocate donor organs in the United States. The process of liver allocation has come a long way since then, including the development and implementation of the Model for End-stage Liver Disease, which is an objective estimate of risk of mortality among candidates awaiting liver transplantation.

Recent findings
The Liver Transplant Community is constantly working to optimize the distribution and allocation of scare organs, which is essential to promote equitable access to a life-saving procedure in the setting of clinical advances in the treatment of liver disease. Over the past 17 years, many changes have been made. Most recently, liver distribution changed such that deceased donor livers will be distributed based on units established by geographic circles around a donor hospital rather than the current policy, which uses donor service areas as the unit of distribution. In addition, a National Liver Review Board was created to standardize the process of determining liver transplant priority for candidates with exceptional medical conditions. The aim of these changes is to allocate and distribute organs in an efficient and equitable fashion.

Summary
The current review provides a historical perspective of liver allocation and the changing landscape in the United States.
Continuous distribution as an organ allocation framework
Authors: Kasiske Bertram L. , Pyke Joshua , Snyder Jon J. 
Published: February 2020

Purpose of review
The Scientific Registry of Transplant Recipients (SRTR) supports the Organ Procurement and Transplantation Network (OPTN) efforts to better align liver allocation with the Final Rule. Here, we review recent literature related to removing place of residence or listing from organ allocation policy and describe how SRTR may help advance the OPTN policy development process.

Recent findings
In December 2018, the OPTN Board of Directors endorsed the recommendation from OPTN's ad hoc Committee on Geography to develop organ-allocation policies that do not rely on geographic boundaries, called ‘continuous distribution.’ Many objections to wider organ distribution stem from efforts to address inequities in allocation for populations within geographic regions rather than for individual patients. A continuous distribution system could equitably address the needs of individual patients, merging ethical–medical urgency with geographic feasibility.

Summary
The effort to remove geographic boundaries from organ distribution and allocation has been controversial. An integrated continuous distribution system may help focus the debate on priorities that matter most to patients.
A detailed analysis of the current status of intestinal transplantation in Latin America
Authors: Gondolesi Gabriel E. , Doeyo Mariana , Solar-Muñiz Héctor 
Published: February 2020

Purpose of reviewLatin America and the Caribbean represent a vast territory, with very different economic and healthcare realities, which result in significant disparities in the management of intestinal failure patients throughout the region. Since 1968, multiple attempts have been done to accomplish a successful intestinal transplant; but it was not until 2004, with the establishment of multidisciplinary programs, that large series with long-term results could be obtained. Currently, three countries (Colombia, Argentina, and Brazil) in the region are actively performing these procedures.Recent findingsA total number of 135 intestinal transplants have been performed; 11 attempts before 2004, and 124 after that period, 66 transplants were done in Argentina (42 in children), 40 in Colombia, 15 in Brazil (1 child), 2 in Costa Rica and 1 in México; 76% have been isolated, whereas 2 were done with living donors.SummaryPublications are still scarce, and compliance to existing registries remains limited. The challenge for the next years is to develop more ‘comprehensive units’ and extend home parenteral nutrition availability in the rest of the region. Regional cooperation and networking need to be set, in order to achieve regional self-sufficiency and improve long-term results.
Development and outcomes of the French liver allocation system
Authors: Durand François 
Published: February 2020

Purpose of review
Although most countries adopted the Model for End Stage Liver Disease (MELD) score for prioritization in liver transplantation, differences exist from country to country. The purpose of the review is to present the specificity of the French allocation policy.

Recent findings
Organ allocation in France is typically based on the MELD score and the distance between the donor and the recipient at a national level. Organs are offered to patients on a national basis, not to centers. Patients with hepatocellular carcinoma and α-fetoprotein score 2 or less receive extra points to have access to transplantation similar to that of patients with cirrhosis. A third category is represented by MELD exceptions where MELD score is inaccurate at predicting outcome. MELD exceptions include complications of cirrhosis such as refractory ascites and other conditions such as polycystic liver disease. The objective is to guarantee similar waiting list mortality and similar posttransplant outcomes for each of these categories.

Summary
The French allocation system has been created with MELD as reference for prioritization, but it also takes into account distance between the donor and the recipient. Patients with hepatocellular carcinoma and patients with MELD exceptions are prioritized to have a similar access to transplantation.
High Prevalence of Vaginal and Rectal Mycoplasma genitalium Macrolide Resistance Among Female Sexually Transmitted Disease Clinic Patients in Seattle, Washington
Authors: Khosropour Christine M. , Jensen Jørgen S. , Soge Olusegun O. , Leipertz Gina , Unutzer Anna , Pascual Rushlenne , Barbee Lindley A. , Dombrowski Julia C. , Golden Matthew R. , Manhart Lisa E. 
Published: February 2020

Background
Rectal Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are increasingly recognized as common infections among women. Little is known about the prevalence of rectal Mycoplasma genitalium (MG), rectal MG/CT/GC coinfection, or MG antimicrobial resistance patterns among women.

Methods
In 2017 to 2018, we recruited women at high risk for CT from Seattle's municipal sexually transmitted disease clinic. Participants self-collected vaginal and rectal specimens for CT/GC nucleic acid amplification testing. We retrospectively tested samples for vaginal and rectal MG using nucleic acid amplification testing and tested MG-positive specimens for macrolide resistance-mediating mutations (MRM) and ParC quinolone resistance-associated mutations (QRAMs).

Results
Of 50 enrolled women, 13 (26%) tested positive for MG, including 10 (20%) with vaginal MG and 11 (22%) with rectal MG; 8 (62%) had concurrent vaginal/rectal MG. Five (38%) were coinfected with CT, none with GC. Only 2 of 11 women with rectal MG reported anal sex in the prior year. Of MG-positive specimens, 100% of rectal and 89% of vaginal specimens had an MRM. There were no vaginal or rectal MG-positive specimens with ParC QRAMs previously associated with quinolone failure. Five MG-infected women received azithromycin for vaginal CT, 4 of whom had a MG MRM detected in their vaginal and/or rectal specimens.

Conclusions
We observed a high prevalence of macrolide-resistant vaginal and rectal MG among a population of women at high risk for CT. This study highlights how the use of antimicrobials designed to treat an identified infection—in this case, CT—could influence treatment outcomes and antimicrobial susceptibility in other unidentified infections.
Mapping the extent of heterogeneity of human CCR5+ CD4+ T cells in peripheral blood and lymph nodes
Authors: Zaunders John , Munier C. Mee Ling , McGuire Helen M. , Law Hannah , Howe Annett , Xu Yin , de St Groth Barbara Fazekas , Schofield Peter , Christ Daniel , Milner Brad , Obeid Solange , Dyer Wayne B. , Saksena Nitin K. , Kelleher Anthony D. 
Published: February 2020

Background:
CD4+ T cells that express the chemokine receptor, CCR5, are the most important target of HIV-1 infection, but their functions, phenotypes and anatomical locations are poorly understood. We aimed to use multiparameter flow cytometry to better define the full breadth of these cells.

Methods:
High-parameter fluorescence flow and mass cytometry were optimized to analyse subsets of CCR5+ memory CD4+ T cells, including CD25highCD127dim Tregs, CXCR3+CCR6− Th1-like, CCR6+CD161+CXCR3− Th17-like, integrins α4+ß7+ gut-homing, CCR4+ skin-homing, CD62L+ lymph node-homing, CD38+HLA-DR+ activated cells, and CD27−CD28− cytotoxic T lymphocytes, in a total of 22 samples of peripheral blood, ultrasound-guided fine needle biopsies of lymph nodes and excised tonsils. CCR5+ antigen-specific CD4+ T cells were studied using the OX40 flow-based assay.

Results:
10–20% of CCR5+ memory CD4+ T cells were Tregs, 10–30% were gut-homing, 10–30% were skin-homing, 20–40% were lymph node-homing, 20–50% were Th1-like and 20–40% were Th17-like cells. Up to 30% were cytotoxic T lymphocytes in CMV-seropositive donors, including cells that were either CCR5highGranzyme K+ or CCR5dimGranzyme B+. When all possible phenotypes were exhaustively analysed, more than 150 different functional and trafficking subsets of CCR5+ CD4+ T cells were seen. Moreover, a small population of resident CD69+Granzyme K+CCR5+ CD4+ T cells was found in lymphoid tissues. CMV− and Mycobacterium tuberculosis-specific CD4+ T cells were predominantly CCR5+.

Conclusion:
These results reveal for the first time the prodigious heterogeneity of function and trafficking of CCR5+ CD4+ T cells in blood and in lymphoid tissue, with significant implications for rational approaches to prophylaxis for HIV-1 infection and for purging of the HIV-1 reservoir in those participants already infected.
Productive HIV infection in astrocytes can be established via a nonclassical mechanism
Authors: Li Guan-Han , Maric Dragan , Major Eugene O. , Nath Avindra 
Published: February 2020

Objective:
Astrocytes are proposed to be a critical reservoir of HIV in the brain. However, HIV infection of astrocytes is inefficient in vitro except for cell-to-cell transmission from HIV-infected cells. Here, we explore mechanisms by which cell-free HIV bypasses entry and postentry barriers leading to a productive infection.

Methods:
HIV infection of astrocytes was investigated by a variety of techniques including transfection of CD4-expressing plasmid, treatment with lysosomotropic agents or using a transwell culture system loaded with HIV-infected lymphocytes. Infection was monitored by HIV-1 p24 in culture supernatants and integrated proviral DNA was quantified by Alu-PCR.

Results:
Persistent HIV infection could be established in astrocytes by transfection of proviral DNA, transduction with VSV-G-pseudotyped viruses, transient expression of CD4 followed by HIV infection, or simultaneous treatment with lysosomotropic chloroquine or Tat-HA2 peptide with HIV infection. In absence of these treatments, HIV entered via endocytosis as seen by electronmicroscopy and underwent lysosomal degradation without proviral integration, indicating endocytosis is a dead end for HIV in astrocytes. Nevertheless, productive infection was observed when astrocytes were in close proximity but physically separated from HIV-infected lymphocytes in the transwell cultures. This occurred with X4 or dual tropic R5X4 viruses and was blocked by an antibody or antagonist to CXCR4.

Conclusion:
A CD4-independent, CXCR4-dependent mechanism of viral entry is proposed, by which immature HIV particles from infected lymphocytes might directly bind to CXCR4 on astrocytes and trigger virus--cell fusion during or after the process of viral maturation. This mechanism may contribute to the formation of brain HIV reservoirs.