bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for an Inherited Contribution to Sepsis Susceptibility Among a Cohort of U.S. Veterans
Authors: Kempker Jordan A. , Martin Greg S. , Rondina Matthew T. , Cannon-Albright Lisa A. 
Published: January 2022

OBJECTIVES:
Analyze a unique clinical and genealogical resource for evidence of familial clustering of sepsis to test for an inherited contribution to sepsis predisposition.

DESIGN:
Observational study.

SETTING:
Veteran’s Health Affairs (VHA) Genealogy/Phenotype resource, a U.S. genealogy database with veterans individually linked to VHA electronic health records.

PATIENTS:
Sepsis was identified using International Classification of Disease, 9th Edition and 10th Edition codes. There were two comparison groups: one composed of the all veterans with linked data and deep genealogy and the other included 1,000 sets of controls, each set randomly sampled from the entire cohort after matching on sex and 10-year birth year range on a 1:1 ratio with cases.

INTERVENTIONS:
None.

MEASUREMENTS AND MAIN RESULTS:
There were 4,666 cases of sepsis from 2001 to 2018, of which 96% were male and 80% greater than or equal to 65 years old. Utilizing the Genealogical Index of Familiality, there was a significant excess of pairwise relatedness among sepsis cases over that in the control sets sampled from VHA population (p = 0.03). The relative risk (RR) of sepsis among identified relatives compared with the larger linked VHA cohort demonstrated an excess of sepsis cases in the first-degree (RR, 1.39; 95% CI, 1.03–1.92; p = 0.05) and second-degree (RR, 1.50; 95% CI, 1.07–2.17; p = 0.04) relatives that were not demonstrated in higher degree relatives. The sepsis cases clustered into 1,876 pedigrees of which 628 had a significant excess of sepsis cases among the descendants (p < 0.05).

CONCLUSIONS:
The data from this cohort of nearly all male U.S. veterans demonstrate evidence for contribution of an inherited predisposition to sepsis and the existence of pedigrees with a significant excess of diagnoses that provide a valuable resource for identification of the predisposition genes and variants responsible. This complements studies on individual genetic variants toward estimating the heritability patterns and clinical relevance of genetic sepsis predisposition.
Is the urinary kidney injury molecule an optimum biomarker for early detection of obstructive nephropathy? An experimental study
Authors: El-Hefnawy Ahmed S , El-Hussiny Mona A , Ibrahim Ahmed M. A , Ali Khadiga M , Atwa Mohammed A , Barakat Nashwa , Alhefnawy Mohamed , Shokeir Ahmed A 
Published: January 2022

Abstract

Objectives
To evaluate the urinary kidney injury molecule-1 (KIM-1) as a predictor for early detection of acute kidney injury in cases with obstructive nephropathy in an animal model and to correlate urinary KIM-1 with the progress of obstructive nephropathy on a histopathological basis.

Materials and methods
Three models of obstruction were induced in 90 male rats: unilateral partial ureteral obstruction with a normal contra-lateral kidney, with nephrectomy of a contralateral kidney (solitary kidney), and bilateral partial ureteral obstruction. Each group was further divided into 2 subgroups; the sham-group (10 rats) and the disease group (20 rats). Serum creatinine, blood urea nitrogen, and urinary KIM-1 were collected on days 0, 7, and 14. Rats were sacrificed on the 7th and 14th day for histopathological examination of the obstructed kidney.

Results
By the end of first week, there was a significant rise of all biomarker levels in all groups when compared with basal levels. Similarly, biomarker levels at the 14th day were significantly higher than those obtained at the 7th day. The urinary KIM-1 level was not detected in the baseline condition. Expression of urinary KIM-1 showed a significant rise in all models ranging from 22 to 85 fold at the 7th day and even higher levels at the 14th day. Histopathological examination confirmed the presence of different forms of tubular injury.

Conclusions
Urinary KIM-1 is significantly elevated in obstructive uropathy. Such an elevation might be advantageous in the early diagnosis and subsequent early intervention of cases with partial ureteral obstruction.
Management of cardiovascular disease in women with premature ovarian insufficiency: critical quality appraisal of clinical guidelines and algorithm development
Authors: Yang Min , Jiang Li , Yao Nan-nan 
Published: January 2022

Abstract

Objectives:
1) To assess the methodological quality of clinical practice guidelines (CPGs) associated with cardiovascular disease (CVD) in women with premature ovarian insufficiency (POI); 2) to formulate an algorithm to foster the implementation of guidelines by clinicians.

Methods:
A systematic search for CPGs in English and Chinese languages published between 2015 and 2020 was conducted. Assessment was conducted by two reviewers respectively via the Appraisal of Guidelines for Research and Evaluation II instrument. The interappraisal agreement was evaluated. Recommendations pertaining to the management of CVD in women with POI were extracted from high-score CPGs and developed into an algorithm, which was refined on the basis of expert feedback.

Results:
A total of 14 CPGs were included. Three CPGs were evaluated as “high quality,” with five “average” and six considered “low quality.” The consistency of agreement between reviewers was considered as substantial agreement to almost perfect agreement (0.72-0.90). The algorithm consisted of three categories: initial evaluation, management, and subsequent monitoring of CVD in POI. Only “management” had recommendations from all three high-quality CPGs.

Conclusions:
The overall methodological quality of most CPGs regarding CVD in women with POI is moderate to poor. A management algorithm with a clear implementation strategy was developed from high-scoring CPGs. Further research is needed to provide evidence-based health care in this field.
Cosmetic dermatology in menopause
Authors: Levin Yakir S. 
Published: January 2022

Abstract
Skin changes that accompany aging lead many to seek treatments that restore a more youthful appearance. Common issues of concern include skin tone, wrinkles, skin thinning, sagging, laxity and decreased elasticity, and hollowing of the face. This work discusses these concerns and their anatomic bases and highlights evidence for a causal role played by menopause-associated hormonal changes where such evidence exists. In addition, treatment options are discussed, with an emphasis on minimally invasive approaches. A variety of modalities are discussed, including botulinum toxins, fillers, multiple types of lasers, radiofrequency devices, focused ultrasound, chemical peels, and thread lifts. These interventions, often in combination, can achieve goals of patients seeking aesthetic rejuvenation.
Impact of coronavirus disease 2019 epidemics on prevention and care for HIV and other sexually transmitted infections
Authors: de Lazzari Elisa , Martínez-Mimbrero Alejandra , Chivite Iván , González-Cordón Ana , Mosquera Maria M. , Laguno Montserrat , Costa Josep , Bosch Jordi , Blanco Jose L. , Álvarez-Martinez Miriam , Ugarte Ainoa , Inciarte Alexy , de la Mora Lorena , Torres Berta , Martínez-Rebollar Maria , Ambrosioni Juan , Fernaández Emma , Hurtado Juan Carlos , Mallolas Josep , Miró José M. , Marcos María A. , Martínez Esteban 
Published: January 2022

Objective:
To assess the impact of coronavirus disease 2019 (COVID-19) epidemics on the prevention and care for HIV and other sexually transmitted infections at a major reference centre providing preventive and clinical services in Catalonia, Spain.

Design:
We retrospectively compared anonymized clinical and laboratory data from March to December 2020 vs. 2019.

Methods:
Monthly clinical data on HIV preexposure and postexposure prophylaxis users and on adults with HIV infection were retrieved from the administrative hospital database. Monthly tests for HIV, hepatitis B and C, Treponema pallidum, Neisseria gonorrhoeae,and Chlamydia trachomatis, and plasma lipids and glucose were recovered from the laboratory database.

Results:
There were less (↓28%, P
= 0.003) but more advanced (mean CD4+ cells/μl 305 vs. 370, P
< 0.001) HIV infections and more gonorrhoea (↑39%, P
< 0.001) and chlamydia (↑37%, P
< 0.001) infections in 2020 vs. 2019. In people with HIV, rates of HIV RNA less than 50 copies/ml remained stable (11 vs. 11%, P
= 0.147) despite less scheduled visits (↓25%, P
< 0.001). However, they had less antiretroviral prescription changes (↓10%, P
= 0.018), worse plasma lipids [mean total cholesterol 190 vs. 185 mg/dl, P
< 0.001;mean low-density lipoprotein (LDL) cholesterol 114 vs. 110 mg/dl, P
< 0.001; mean triglycerides 136 vs. 125 mg/dl, P
< 0.001; mean high-density lipoprotein (HDL) cholesterol 47 vs. 48 mg/dl, P
= 006], and an excess of mortality (↑264%, P
= 0.006) due in great part not only to COVID-19 but also to other causes.

Conclusion:
In our setting, COVID-19 epidemics was associated with an increase in some prevalent sexually transmitted infections, with less but more advanced HIV infections, and with worse nonvirologic healthcare outcomes and higher mortality in people living with HIV.
Age-Associated Gut Dysbiosis, Marked by Loss of Butyrogenic Potential, Correlates With Altered Plasma Tryptophan Metabolites in Older People Living With HIV
Authors: Ghare Smita , Singhal Richa , Bryant Vaughn , Gautam Sabina , Tirumala Chanakya Charan , Srisailam Praneet Kumar , Reyes-Vega Andrea , Ghooray Dushan , McClain Craig J. , Hoffman Kristi , Petrosino Joseph , Bryant Kendall , Govind Varan , Cohen Ronald , Cook Robert L. , Barve Shirish 
Published: January 2022

Background:
Imbalance in tryptophan (TRP) metabolism and its neuroactive metabolites, serotonin and kynurenine (KYN), is a known pathogenic mechanism underlying neurocognitive impairment. Gut microbiota plays an important role in TRP metabolism, and the production of these neuroactive molecules affects neurocognitive function. Although both HIV infection and normal aging independently induce gut dysbiosis and influence TRP metabolism, their interactive effects on compositional/functional changes in gut microbiota and consequent alterations in TRP metabolites remain largely undetermined.

Methods:
Older people living with HIV infection (PLWH, aged 50–70 years, n = 22) were enrolled in this cross-sectional pilot study. Metagenomic analysis of fecal microbiome using 16S Ribosomal ribonucleic acid gene sequencing and metabolomics analysis of plasma using mass spectrometry with a reverse-phase iquid chromatography tandem mass spectrometry were performed. Statistical analyses included the univariate linear regression and Spearman correlation analyses.

Results:
Age-associated changes in plasma levels of key neuroactive TRP metabolites, serotonin and KYN, were seen in PLWH. Specifically, we observed age-dependent decreases in serotonin and increases in KYN and KYN-to-TRP ratio, indicative of dysfunctional TRP metabolism. Furthermore, the gut dysbiosis seen in older PLWH is characterized by a reduction of Firmicutes/Bacteroidetes ratio and butyrate-producing microbial families Lachnospiraceae and Lactobacillaceae. Of importance, correspondent with gut dysbiosis, increasing age was significantly associated with decreased plasma butyrate levels, which in turn correlated positively with serotonin and negatively with KYN/TRP ratio.

Conclusions:
Age-dependent gut microbial dysbiosis distinguished by a decrease in butyrogenic potential is a key pathogenic feature associated with the shift in TRP metabolism from serotonin to KYN in older PLWH.
Novel techniques in the treatment of skin and soft tissue infection
Authors: Dryden Matthew 
Published: January 2022

Purpose of review
Global antibiotic resistance is compromising the management of soft tissue infection and Acute Bacterial Skin and Skin Structure Infection (ABSSI). This review describes a novel topical treatment Reactive Oxygen (RO) gel which could compliment and in some situations replace systemic antibiotics.

Recent findings
A novel topical treatment RO gel could have an important role in treatment, infection prevention and antimicrobial stewardship. RO is highly antimicrobial against Gram positive and negative bacteria, by slow release of oxygen radicals over a prolonged period of up to 72 h. It prevents and breaks down biofilm and may support healing by cellular signalling. Much clinical investigation remains to be delivered on RO therapy but there seem few disadvantages in its use and early clinical evaluations are extremely promising.

Summary
Managing complicated skin and soft tissue infections require more than just antibiotic treatment. Soft tissue infection healing is often compromised by underlying comorbidities and pathology and increasingly the presence of highly antimicrobial-resistant bacteria. This has been highlighted particularly in war and trauma soft tissue infection. The fundamentals of soft tissue infection repair require early surgical drainage and debridement, correction of compromised physiology and treatment of underlying conditions and appropriate antimicrobial treatment. RO therapy could be an important advance.
Cut-and-Paste DNA Insertion with Engineered Type V-K CRISPR-associated Transposases
Authors: Tou Connor J. , Orr Benno , Kleinstiver Benjamin P. 
Published: January 2022

AbstractCRISPR-associated transposases (CASTs) enable recombination-independent, multi-kilobase DNA insertions at RNA-programmed genomic locations. Type V-K CASTs offer distinct technological advantages over type I CASTs given their smaller coding size, fewer components, and unidirectional insertions. However, the utility of type V-K CASTs is hindered by a replicative transposition mechanism that results in a mixture of desired simple cargo insertions and undesired plasmid co-integrate products. Here, we overcome this limitation by engineering new CASTs with dramatically improved product purity. To do so, we compensate for the absence of the TnsA subunit in multiple type V-K CASTs by engineering a Homing Endonuclease-assisted Large-sequence Integrating CAST compleX, or HELIX system. HELIX utilizes a nicking homing endonuclease (nHE) fused to TnsB to restore the 5 “ nicking capability needed for dual-nicking of the DNA donor. By leveraging distinct features of both type V-K and type I systems, HELIX enables cut-and-paste DNA insertion with up to 99.3% simple insertion product purity, while retaining robust integration efficiencies on genomic targets. Furthermore, we demonstrate the versatility of this approach by generating HELIX systems for other CAST orthologs. We also establish the feasibility of creating a minimal, 3-component HELIX, simplifying the number of proteins that must be expressed. Together, HELIX streamlines and improves the application of CRISPR-based transposition technologies, eliminating barriers for efficient and specific RNA-guided DNA insertions.
Transcriptomic, proteomic and functional consequences of codon usage bias in human cells during heterologous gene expression
Authors: Picard Marion A.L. , Leblay Fiona , Cassan Cécile , Willemsen Anouk , Daron Josquin , Bauffe Frédérique , Decourcelle Mathilde , Demange Antonin , Bravo Ignacio G. 
Published: January 2022

ABSTRACTDifferences in codon frequency between genomes, genes, or positions along a gene, modulate transcription and translation efficiency, leading to phenotypic and functional differences. Here, we present a multiscale analysis of the effects of synonymous codon recoding during heterologous gene expression in human cells, quantifying the phenotypic consequences of codon usage bias at different molecular and cellular levels, with an emphasis on translation elongation.Six synonymous versions of an antibiotic resistance gene were generated, fused to a fluorescent reporter, and independently expressed in HEK293 cells. Multiscale phenotype was analysed by means of: quantitative transcriptome and proteome assessment, as proxies for gene expression; cellular fluorescence, as a proxy for single-cell level expression; and real-time cell proliferation in absence or presence of antibiotic, as a proxy for the cell fitness.We show that differences in codon usage bias strongly impact the molecular and cellular phenotype: (i) they result in large differences in mRNA levels and in protein levels, leading to differences of over fifteen times in translation efficiency; (ii) they introduce unpredicted splicing events; (iii) they lead to reproducible phenotypic heterogeneity; and (iv) they lead to a trade-off between the benefit of antibiotic resistance and the burden of heterologous expression.In human cells in culture, codon usage bias modulates gene expression by modifying mRNA availability and suitability for translation, leading to differences in protein levels and eventually eliciting functional phenotypic changes.IMPORTANCESynonymous codons encode for the same amino acid, but they are not neutral regarding gene expression or protein synthesis. Bias between synonymous codons have evolved naturally and are also applied in biotechnology protein production. We have studied the multilevel impact of codon usage on a human cell system. We show that differences in codon usage lead to transcriptomic, proteomic and functional changes, modulating gene expression and cellular phenotype.
PD1+ T-cells correlate with Nerve Fiber Density as a prognostic biomarker in patients with resected perihilar cholangiocarcinoma
Authors: Tan Xiuxiang , Rosin Mika , Appinger Simone , Bednarsch Jan , Liu Dong , Wiltberger Georg , Vallejo Juan Garcia , Lang Sven , Czigany Zoltan , Boroojerdi Shiva , Gaisa Nadine T. , Boor Peter , Bülow Roman David , de Vos-Geelen Judith , Iersel Liselot Valkenburg-van , Groningen Marian Clahsen-van , de Jong Evelien J.M. , Koerkamp Bas Groot , Doukas Michail , Rocha Flavio G. , Luedde Tom , Klinge Uwe , Sivakumar Shivan , Neumann Ulf , Heij Lara 
Published: January 2022

AbstractBackground & AimsPerihilar cholangiocarcinoma (pCCA) is a rare hepatobiliary malignancy. Nerve fiber invasion (NFI) shows cancer invading the nerve and is considered an aggressive feature. Nerve fiber density (NFD) consists of small nerve fibers without cancer invasion and is divided into high NFD (high numbers of small nerve fibers) or low NFD (low numbers of small nerve fibers). We aim to explore differences in immune cell populations and survival.MethodsWe applied multiplex immunofluorescence (mIF) on 47 pCCA surgically resected patients and investigated the immune cell composition in the tumor microenvironment (TME) of different nerve fiber phenotypes (NFI, high and low NFD). Extensive group comparison was carried out and the association with overall survival (OS) was assessed.ResultsThe NFI ROI was measured with highest CD68+ macrophage levels among 3 ROIs (NFI compared to tumor free p= 0.016 and to tumor p=0.034). Further, for NFI patients the density of co-inhibitory markers CD8+PD1+ and CD68+PD1+ were more abundant in the tumor rather than NFI ROI (p= 0.004 and p= 0.0029 respectively). Comparison between patients with NFD and NFI groups, the signals of co-expression of CD8+PD1+ as well as CD68+PD1+ were significantly higher in the high NFD group (p= 0.027 and p= 0.044, respectively). The OS for high NFD patients was 92 months median OS (95% CI:41-142), for low NFD patients 20 months ((95% CI: 4-36) and for NFI group of patients 19 months (95% CI 7-33). The OS for high NFD patients was significantly better compared to low NFD (p= 0.046) and NFI (p= 0.032).ConclusionsPD1+ T-cells correlate with high NFD as a prognostic biomarker, the biological pathway behind this needs to be investigated.Lay summaryNerve fibers play a dual role in the tumor microenvironment in pCCA. In our previous study, we showed that the presence of high numbers of small nerve fibers is associated with a better overall survival. In addition, we found that in high NFD patients PD1+ T-cells are significantly overexpressed. Therefore, we present high NFD as a promising prognostic biomarker.Graphical abstract
Dynamic Turnover of PI4P and PI(4,5)P2 under Hypoxia Controls Electrostatic Plasma Membrane Targeting
Authors: Lu Juan , Dong Wei , Hammond Gerald R. , Hong Yang 
Published: January 2022

SUMMARYPhosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4,5-biphosphate (PIP2) are key phosphoinositides that determine the identity of the plasma membrane (PM) and regulate numerous key biological events there. To date, mechanisms regulating the homeostasis and dynamic turnover of PM PI4P and PIP2 in response to various physiological conditions and stresses remain to be fully elucidated. Here we report that hypoxia in Drosophila induces acute and reversible depletion of PM PI4P and PIP2 that severely disrupts the electrostatic PM targeting of multiple polybasic polarity proteins. Genetically encoded ATP sensors confirmed that hypoxia induces acute and reversible reduction of cellular ATP levels which showed a strong real-time correlation with the levels of PM PI4P and PIP2 in cultured cells. By combining genetic manipulations with quantitative imaging assays we showed that PI4KIIIα, as well as Rbo/EFR3 and TTC7 that are essential for targeting PI4KIIIα to PM, are required for maintaining the homeostasis and dynamic turnover of PM PI4P and PIP2 under normoxia and hypoxia. Our results revealed that in cells challenged by energetic stresses triggered by hypoxia, ATP inhibition and possibly ischemia, dramatic turnover of PM PI4P and PIP2 could have profound impact on many cellular processes including electrostatic PM targeting of numerous polybasic proteins.
Free diffusion of PI(4,5)P2 in the plasma membrane in the presence of high density effector protein complexes
Authors: Pacheco Jonathan , Cassidy Anna C. , Zewe James P. , Wills Rachel C. , Hammond Gerald R. V. 
Published: January 2022

AbstractThe lipid phosphatidyl-D-myo-inositol-4,5-bisphosphate [PI(4,5)P2] is a master regulator of plasma membrane (PM) function. It engages effector proteins that regulate diverse traffic, transport, signaling and cytoskeletal processes that define PM structure and function. How a single class of lipid molecules independently regulate so many parallel processes remains an open question. We tested the hypothesis that spatially segregated pools of PI(4,5)P2 are associated with, and thus reserved for regulation of, different functional complexes in the PM. The mobility of PI(4,5)P2 in the membrane was measured using lipid biosensors by single particle tracking photoactivation localization microscopy (sptPALM). We found that PI(4,5)P2, and several other classes of inner PM lipids, diffuse rapidly at approximately 0.3 µm2/s with largely Brownian motion, although they spend approximately a third of their time diffusing much more slowly. Surprisingly, areas of the PM occupied by PI(4,5)P2-dependent complexes, such endoplasmic-reticulum:PM contact sites, clathrin-coated structures, and several actin cytoskeletal elements including focal adhesions, did not cause a change in PI(4,5)P2 lateral mobility. Only the spectrin and septin cytoskeletons were observed to produce a slowing of PI(4,5)P2 diffusion. We conclude that even structures with high densities of PI(4,5)P2-engaging effector proteins, such as clathrin coated pits and focal adhesions, do not corral free PI(4,5)P2, questioning a role for spatially segregated PI(4,5)P2 pools in organizing and regulating parallel PM functions.