Publications by authors named "Christian Becker"

358 Publications

Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression.

Nat Commun 2021 Oct 13;12(1):5981. Epub 2021 Oct 13.

Department of Dermatology, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany.

The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.
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http://dx.doi.org/10.1038/s41467-021-26269-wDOI Listing
October 2021

Chemical Synthesis and Semisynthesis of Lipidated Proteins.

Angew Chem Int Ed Engl 2021 Oct 6. Epub 2021 Oct 6.

The University of Sydney, School of Chemistry, Eastern Avenue, 2006, Sydney, AUSTRALIA.

Lipidation is a ubiquitous modification of peptides and proteins that can occur either co- or post-translationally. An array of different lipid classes can adorn proteins and has been shown to influence a number of crucial biological activities, including the regulation of signaling, cell-cell adhesion events, and the anchoring of proteins to lipid rafts and phospholipid membranes. Lipid modifications discovered to date include prenylation, such as S -farnesylation and S -geranylgeranylation, S - and N -palmitoylation, N -myristoylation, as well as the attachment of cholesterol, glycosylphosphatidylinositol (GPI) and phosphatidylethanolamine (PE) anchors to the C-terminus of proteins. While nature employs a range of enzymes to install lipid modifications onto proteins, the use of these for chemoenzymatic generation of lipidated proteins is often inefficient or impractical. An alternative is to harness the power of modern synthetic and semisynthetic technologies to access lipid-modified proteins in pure and homogeneously modified form. This review aims to highlight significant advances in the development of lipidation and ligation chemistry and their implementation in the synthesis and semisynthesis of homogeneously lipidated proteins that have enabled the influence of these modifications on protein structure and function to be uncovered.
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http://dx.doi.org/10.1002/anie.202111266DOI Listing
October 2021

Biomimetic and biopolymer-based enzyme encapsulation.

Enzyme Microb Technol 2021 Oct 2;150:109864. Epub 2021 Jul 2.

Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, Austria. Electronic address:

Encapsulated enzymes are stable under various conditions and used in enzyme therapy, catalysis, and biosensors. The capsules are often inspired by structures from nature such as viral capsids, DNA motifs and diatom frustules. They are based on inorganic minerals as well as soft or polymeric materials, or even a combination of these. The choice of material influences the enzyme loading and response to heat, pH and presence of proteases. This review provides a comparison of enzyme encapsulation based on these different principles with a focus on materials inspired by nature.
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http://dx.doi.org/10.1016/j.enzmictec.2021.109864DOI Listing
October 2021

Site-specific modification and segmental isotope labelling of HMGN1 reveals long-range conformational perturbations caused by posttranslational modifications.

RSC Chem Biol 2021 Apr 5;2(2):537-550. Epub 2021 Jan 5.

School of Biomedical Sciences, The University of Queensland Brisbane QLD 4072 Australia +61-7-3365-1738.

Interactions between histones, which package DNA in eukaryotes, and nuclear proteins such as the high mobility group nucleosome-binding protein HMGN1 are important for regulating access to DNA. HMGN1 is a highly charged and intrinsically disordered protein (IDP) that is modified at several sites by posttranslational modifications (PTMs) - acetylation, phosphorylation and ADP-ribosylation. These PTMs are thought to affect cellular localisation of HMGN1 and its ability to bind nucleosomes; however, little is known about how these PTMs regulate the structure and function of HMGN1 at a molecular level. Here, we combine the chemical biology tools of protein semi-synthesis and site-specific modification to generate a series of unique HMGN1 variants bearing precise PTMs at their N- or C-termini with segmental isotope labelling for NMR spectroscopy. With access to these precisely-defined variants, we show that PTMs in both the N- and C-termini cause changes in the chemical shifts and conformational populations in regions distant from the PTM sites; up to 50-60 residues upstream of the PTM site. The PTMs investigated had only minor effects on binding of HMGN1 to nucleosome core particles, suggesting that they have other regulatory roles. This study demonstrates the power of combining protein semi-synthesis for introduction of site-specific PTMs with segmental isotope labelling for structural biology, allowing us to understand the role of PTMs with atomic precision, from both structural and functional perspectives.
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http://dx.doi.org/10.1039/d0cb00175aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341956PMC
April 2021

Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

Sci Transl Med 2021 Aug;13(608)

Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in , the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls ( = 7.8 × 10). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques ( = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis ( = 5.2 × 10; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro ( < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain ( < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.
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http://dx.doi.org/10.1126/scitranslmed.abd6469DOI Listing
August 2021

Pentoxifylline for the treatment of endometriosis-associated pain and infertility.

Cochrane Database Syst Rev 2021 08 25;8:CD007677. Epub 2021 Aug 25.

Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.

Background: Endometriosis is a chronic inflammatory condition that occurs during the reproductive years. It is characterised by endometrium-like tissue developing outside the uterine cavity. This endometriotic tissue development is dependent on oestrogen produced primarily by the ovaries and partially by the endometriotic tissue itself, therefore traditional management has focused on ovarian suppression. In this review we considered the role of modulation of the immune system as an alternative approach. This is an update of a Cochrane Review previously published in 2012.

Objectives: To determine the effectiveness and safety of pentoxifylline in the management of endometriosis.  SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED on 16 December 2020, together with reference checking and contact with study authors and experts in the field to identify additional studies.

Selection Criteria: We included randomised controlled trials (RCTs) comparing pentoxifylline with placebo or no treatment, other medical treatment, or surgery in women with endometriosis. The primary outcomes were live birth rate and overall pain (as measured by a visual analogue scale (VAS) of pain, other validated scales, or dichotomous outcomes) per woman randomised. Secondary outcomes included clinical pregnancy rate, miscarriage rate, rate of recurrence, and adverse events resulting from the pentoxifylline intervention.

Data Collection And Analysis: Two review authors independently assessed studies against the inclusion criteria, extracted data, and assessed risk of bias, consulting a third review author where required. We contacted study authors as needed. We analysed dichotomous outcomes using Mantel-Haenszel risk ratios (RRs), 95% confidence intervals (CIs), and a fixed-effect model. For small numbers of events, we used a Peto odds ratio (OR) with 95% CI instead. We analysed continuous outcomes using the mean difference (MD) between groups presented with 95% CIs. We used the I statistic to evaluate heterogeneity amongst studies. We employed the GRADE approach to assess the quality of the evidence.

Main Results: We included five parallel-design RCTs involving a total of 415 women. We included one additional RCT in this update. Three studies did not specify details relating to allocation concealment, and two studies were not blinded. There were also considerable loss to follow-up, with four studies not conducting intention-to-treat analysis. We judged the quality of the evidence as very low. Pentoxifylline versus placebo No trials reported on our primary outcomes of live birth rate and overall pain. We are uncertain as to whether pentoxifylline treatment affects clinical pregnancy rate when compared to placebo (RR 1.38, 95% CI 0.91 to 2.10; 3 RCTs, n = 285; I = 0%; very low-quality evidence). The evidence suggests that if the clinical pregnancy rate with placebo is estimated to be 20%, then the rate with pentoxifylline is estimated as between 18% and 43%. We are also uncertain as to whether pentoxifylline affects the recurrence rate of endometriosis (RR 0.84, 95% CI 0.30 to 2.36; 1 RCT, n = 121; very low-quality evidence) or miscarriage rate (Peto OR 1.99, 95% CI 0.20 to 19.37; 2 RCTs, n = 164; I = 0%; very low-quality evidence). No trials reported on the effect of pentoxifylline on improvement of endometriosis-related symptoms other than pain or adverse events. Pentoxifylline versus no treatment No trials reported on live birth rate. We are uncertain as to whether pentoxifylline treatment affects overall pain when compared to no treatment at one month (MD -0.36, 95% CI -2.12 to 1.40; 1 RCT, n = 34; very low-quality evidence), two months (MD -1.25, 95% CI  -2.67 to 0.17; 1 RCT, n = 34; very low-quality evidence), or three months (MD -1.60, 95% CI -3.32 to 0.12; 1 RCT, n = 34; very low-quality evidence). No trials reported on adverse events caused by pentoxifylline or any of our other secondary outcomes. Pentoxifylline versus other medical therapies One study (n = 83) compared pentoxifylline to the combined oral contraceptive pill after laparoscopic surgery to treat endometriosis, but could not be included in the meta-analysis as it was unclear if the data were presented as +/- standard deviation and what the duration of treatment was. No trials reported on adverse events caused by pentoxifylline or any of our other secondary outcomes. Pentoxifylline versus conservative surgical treatment  No study reported on this comparison.

Authors' Conclusions: No studies reported on our primary outcome of live birth rate. Due to the very limited evidence, we are uncertain of the effects of pentoxifylline on clinical pregnancy rate, miscarriage rate, or overall pain. There is currently insufficient evidence to support the use of pentoxifylline in the management of women with endometriosis with respect to subfertility and pain relief outcomes.
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http://dx.doi.org/10.1002/14651858.CD007677.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407096PMC
August 2021

Biomimetic Silica Encapsulation of Lipid Nanodiscs and β-Sheet-Stabilized Diacylglycerol Kinase.

Bioconjug Chem 2021 08 21;32(8):1742-1752. Epub 2021 Jul 21.

Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria.

Integral membrane proteins (IMPs) comprise highly important classes of proteins such as transporters, sensors, and channels, but their investigation and biotechnological application are complicated by the difficulty to stabilize them in solution. We set out to develop a biomimetic procedure to encapsulate functional integral membrane proteins in silica to facilitate their handling under otherwise detrimental conditions and thereby extend their applicability. To this end, we designed and expressed new fusion constructs of the membrane scaffold protein MSP with silica-precipitating peptides based on the R5 sequence from the diatom . Transmission electron microscopy (TEM) and atomic force microscopy (AFM) revealed that membrane lipid nanodiscs surrounded by our MSP variants fused to an R5 peptide, so-called nanodiscs, were formed. Exposing them to silicic acid led to silica-encapsulated nanodiscs, a new material for stabilizing membrane structures and a first step toward incorporating membrane proteins in such structures. In an alternative approach, four fusion constructs based on the amphiphilic β-sheet peptide BP-1 and the R5 peptide were generated and successfully employed toward silica encapsulation of functional diacylglycerol kinase (DGK). Silica-encapsulated DGK was significantly more stable against protease exposure and incubation with simulated gastric fluid (SGF) and intestinal fluid (SIF).
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382255PMC
August 2021

A 24-generation-old founder mutation impairs splicing of RBBP8 in Pakistani families affected with Jawad syndrome.

Clin Genet 2021 10 16;100(4):486-488. Epub 2021 Jul 16.

Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Jawad syndrome is a multiple congenital anomaly and intellectual disability syndrome with mutation in RBBP8 reported only in two families. Here, we report on two new families from Pakistan and identified a previously reported variant in RBBP8, NM_002894.3:c.1808-1809delTA. We could show that this mutation impairs splicing resulting in two different abnormal transcripts. Finally, we could verify a shared haplotype among all four families and estimate the founder event to have occurred some 24 generations ago.
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http://dx.doi.org/10.1111/cge.14028DOI Listing
October 2021

HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence.

Mol Syst Biol 2021 06;17(6):e9760

Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.

Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This is perturbed once cells enter senescence and the highly abundant HMGB1 protein is depleted from nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we know little about the positioning of HMGB1 on chromatin and its nuclear roles. To address this, we mapped HMGB1 binding genome-wide in two primary cell lines. We integrated ChIP-seq and Hi-C with graph theory to uncover clustering of HMGB1-marked topological domains that harbor genes involved in paracrine senescence. Using simplified Cross-Linking and Immuno-Precipitation and functional tests, we show that HMGB1 is also a bona fide RNA-binding protein (RBP) binding hundreds of mRNAs. It presents an interactome rich in RBPs implicated in senescence regulation. The mRNAs of many of these RBPs are directly bound by HMGB1 and regulate availability of SASP-relevant transcripts. Our findings reveal a broader than hitherto assumed role for HMGB1 in coordinating chromatin folding and RNA homeostasis as part of a regulatory loop controlling cell-autonomous and paracrine senescence.
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http://dx.doi.org/10.15252/msb.20209760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224457PMC
June 2021

Digital Electrochemistry for On-Chip Heterogeneous Material Integration.

Adv Mater 2021 Jul 24;33(26):e2101272. Epub 2021 May 24.

Institute for Integrative Nanosciences, Leibniz IFW Dresden, 01069, Dresden, Germany.

Many modern electronic applications rely on functional units arranged in an active-matrix integrated on a single chip. The active-matrix allows numerous identical device pixels to be addressed within a single system. However, next-generation electronics requires heterogeneous integration of dissimilar devices, where sensors, actuators, and display pixels sense and interact with the local environment. Heterogeneous material integration allows the reduction of size, increase of functionality, and enhancement of performance; however, it is challenging since front-end fabrication technologies in microelectronics put extremely high demands on materials, fabrication protocols, and processing environments. To overcome the obstacle in heterogeneous material integration, digital electrochemistry is explored here, which site-selectively carries out electrochemical processes to deposit and address electroactive materials within the pixel array. More specifically, an amorphous indium-gallium-zinc oxide (a-IGZO) thin-film-transistor (TFT) active-matrix is used to address pixels within the matrix and locally control electrochemical reactions for material growth and actuation. The digital electrochemistry procedure is studied in-depth by using polypyrrole (PPy) as a model material. Active-matrix-driven multicolored electrochromic patterns and actuator arrays are fabricated to demonstrate the capabilities of this approach for material integration. The approach can be extended to a broad range of materials and structures, opening up a new path for advanced heterogeneous microsystem integration.
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http://dx.doi.org/10.1002/adma.202101272DOI Listing
July 2021

Reply: ICSI does not improve reproductive outcomes in autologous ovarian response cycles with non-male factor subfertility.

Hum Reprod 2021 05;36(6):1726-1727

Department of Obstetrics and Gynaecology, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK.

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http://dx.doi.org/10.1093/humrep/deab044DOI Listing
May 2021

O-GlcNAc modification of small heat shock proteins enhances their anti-amyloid chaperone activity.

Nat Chem 2021 05 15;13(5):441-450. Epub 2021 Mar 15.

Departments of Chemistry, University of Southern California, Los Angeles, CA, USA.

A major role for the intracellular post-translational modification O-GlcNAc appears to be the inhibition of protein aggregation. Most of the previous studies in this area focused on O-GlcNAc modification of the amyloid-forming proteins themselves. Here we used synthetic protein chemistry to discover that O-GlcNAc also activates the anti-amyloid activity of certain small heat shock proteins (sHSPs), a potentially more important modification event that can act broadly and substoichiometrically. More specifically, we found that O-GlcNAc increases the ability of sHSPs to block the amyloid formation of both α-synuclein and Aβ(1-42). Mechanistically, we show that O-GlcNAc near the sHSP IXI-domain prevents its ability to intramolecularly compete with substrate binding. Finally, we found that, although O-GlcNAc levels are globally reduced in Alzheimer's disease brains, the modification of relevant sHSPs is either maintained or increased, which suggests a mechanism to maintain these potentially protective O-GlcNAc modifications. Our results have important implications for neurodegenerative diseases associated with amyloid formation and potentially other areas of sHSP biology.
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http://dx.doi.org/10.1038/s41557-021-00648-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102337PMC
May 2021

A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses.

medRxiv 2021 Feb 2. Epub 2021 Feb 2.

The molecular mechanisms of chronic fatigue syndrome (CFS, or Myalgic encephalomyelitis), a disease defined by extreme, long-term fatigue, remain largely uncharacterized, and presently no molecular diagnostic test and no specific treatments exist to diagnose and treat CFS patients. While CFS has historically had an estimated prevalence of 0.1-0.5% [1], concerns of a "long hauler" version of Coronavirus disease 2019 (COVID-19) that symptomatically overlaps CFS to a significant degree and appears to occur in 10% of COVID-19 patients[2], has raised concerns of a larger spike in CFS [3]. Here, we established molecular signatures of CFS and a corresponding network-based disease context from RNA-sequencing data generated on whole blood and FACs sorted specific peripheral blood mononuclear cells (PBMCs) isolated from CFS cases and non-CFS controls. The immune cell type specific molecular signatures of CFS we identified, overlapped molecular signatures from other fatiguing illnesses, demonstrating a common molecular etiology. Further, after constructing a probabilistic causal model of the CFS gene expression data, we identified master regulator genes modulating network states associated with CFS, suggesting potential therapeutic targets for CFS.
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http://dx.doi.org/10.1101/2021.01.29.21250755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872387PMC
February 2021

Cytoskeleton-dependent clustering of membrane-bound prion protein on the cell surface.

J Biol Chem 2021 Jan-Jun;296:100359. Epub 2021 Feb 2.

Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria. Electronic address:

Prion diseases are a group of neurodegenerative disorders that infect animals and humans with proteinaceous particles called prions. Prions consist of scrapie prion protein (PrP), a misfolded version of the cellular prion protein (PrP). During disease progression, PrP replicates by interacting with PrP and inducing its conversion to PrP. Attachment of PrP to cellular membranes via a glycosylphosphatidylinositol (GPI) anchor is critical for the conversion of PrP into PrP. However, the mechanisms governing PrP conversion and replication on the membrane remain largely unclear. Here, a site-selectively modified PrP variant equipped with a fluorescent GPI anchor mimic (PrP-GPI) was employed to directly observe PrP at the cellular membrane in neuronal SH-SY5Y cells. PrP-GPI exhibits a cholesterol-dependent membrane accumulation and a cytoskeleton-dependent mobility. More specifically, inhibition of actin polymerization reduced the diffusion of PrP-GPI indicating protein clustering, which resembles the initial step of PrP aggregation and conversion into its pathogenic isoform. An intact actin cytoskeleton might therefore prevent conversion of PrP into PrP and offer new therapeutic angles.
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http://dx.doi.org/10.1016/j.jbc.2021.100359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988330PMC
August 2021

A Patternable and In Situ Formed Polymeric Zinc Blanket for a Reversible Zinc Anode in a Skin-Mountable Microbattery.

Adv Mater 2021 Feb 14;33(8):e2007497. Epub 2021 Jan 14.

Institute for Integrative Nanosciences, Leibniz IFW Dresden, Dresden, 01069, Germany.

Owing to their high safety and reversibility, aqueous microbatteries using zinc anodes and an acid electrolyte have emerged as promising candidates for wearable electronics. However, a critical limitation that prevents implementing zinc chemistry at the microscale lies in its spontaneous corrosion in an acidic electrolyte that causes a capacity loss of 40% after a ten-hour rest. Widespread anti-corrosion techniques, such as polymer coating, often retard the kinetics of zinc plating/stripping and lack spatial control at the microscale. Here, a polyimide coating that resolves this dilemma is reported. The coating prevents corrosion and hence reduces the capacity loss of a standby microbattery to 10%. The coordination of carbonyl oxygen in the polyimide with zinc ions builds up over cycling, creating a zinc blanket that minimizes the concentration gradient through the electrode/electrolyte interface and thus allows for fast kinetics and low plating/stripping overpotential. The polyimide's patternable feature energizes microbatteries in both aqueous and hydrogel electrolytes, delivering a supercapacitor-level rate performance and 400 stable cycles in the hydrogel electrolyte. Moreover, the microbattery is able to be attached to human skin and offers strong resistance to deformations, splashing, and external shock. The skin-mountable microbattery demonstrates an excellent combination of anti-corrosion, reversibility, and durability in wearables.
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http://dx.doi.org/10.1002/adma.202007497DOI Listing
February 2021

Effects of adherence to pharmacological secondary prevention after acute myocardial infarction on health care costs - an analysis of real-world data.

BMC Health Serv Res 2020 Dec 20;20(1):1145. Epub 2020 Dec 20.

AOK Bayern, Service Center of Health Care Management, Regensburg, Germany.

Background: Acute myocardial infarction (AMI), a major source of morbidity and mortality, is also associated with excess costs. Findings from previous studies were divergent regarding the effect on health care expenditure of adherence to guideline-recommended medication. However, gender-specific medication effectiveness, correlating the effectiveness of concomitant medication and variation in adherence over time, has not yet been considered.

Methods: We aim to measure the effect of adherence on health care expenditures stratified by gender from a third-party payer's perspective in a sample of statutory insured Disease Management Program participants over a follow-up period of 3-years. In 3627 AMI patients, the proportion of days covered (PDC) for four guideline-recommended medications was calculated. A generalized additive mixed model was used, taking into account inter-individual effects (mean PDC rate) and intra-individual effects (deviation from the mean PDC rate).

Results: Regarding inter-individual effects, for both sexes only anti-platelet agents had a significant negative influence indicating that higher mean PDC rates lead to higher costs. With respect to intra-individual effects, for females higher deviations from the mean PDC rate for angiotensin-converting enzyme (ACE) inhibitors, anti-platelet agents, and statins were associated with higher costs. Furthermore, for males, an increasing positive deviation from the PDC mean increases costs for β-blockers and a negative deviation decreases costs. For anti-platelet agents, an increasing deviation from the PDC-mean slightly increases costs.

Conclusion: Positive and negative deviation from the mean PDC rate, independent of how high the mean was, usually negatively affect health care expenditures. Therefore, continuity in intake of guideline-recommended medication is important to save costs.
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http://dx.doi.org/10.1186/s12913-020-05946-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751107PMC
December 2020

Correction: Correction: Multi-scale microporous silica microcapsules from gas-in water-in oil emulsions.

Soft Matter 2021 Jan 16;17(1):201. Epub 2020 Dec 16.

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.

Correction for 'Correction: Multi-scale microporous silica microcapsules from gas-in water-in oil emulsions' by Zenon Toprakcioglu et al., Soft Matter, 2020, 16, 3586-3586, DOI: .
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http://dx.doi.org/10.1039/d0sm90246bDOI Listing
January 2021

Acute Cerebrovascular Disorders and Vasculopathies Associated with Significant Mortality in SARS-CoV-2 Patients Admitted to The Intensive Care Unit in The New York Epicenter.

J Stroke Cerebrovasc Dis 2021 Feb 2;30(2):105429. Epub 2020 Nov 2.

Department of Neurology, Westchester Medical Center at New York Medical College, Valhalla, NY USA; Department of Neurosurgery, Westchester Medical Center at New York Medical College, Valhalla, NY USA; Department of Radiology, Westchester Medical Center at New York Medical College, Valhalla, NY USA.

The current Coronavirus pandemic due to the novel SARS-Cov-2 virus has proven to have systemic and multi-organ involvement with high acuity neurological conditions including acute ischemic strokes. We present a case series of consecutive COVID-19 patients with cerebrovascular disease treated at our institution including 3 cases of cerebral artery dissection including subarachnoid hemorrhage. Knowledge of the varied presentations including dissections will help treating clinicians at the bedside monitor and manage these complications preemptively.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605750PMC
February 2021

The genetic architecture of sporadic and multiple consecutive miscarriage.

Nat Commun 2020 11 25;11(1):5980. Epub 2020 Nov 25.

University of Queensland, St Lucia, QLD, Australia.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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http://dx.doi.org/10.1038/s41467-020-19742-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689465PMC
November 2020

Endometriosis and cancer: a systematic review and meta-analysis.

Hum Reprod Update 2021 Feb;27(2):393-420

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Endometriosis is an often chronic, inflammatory gynaecologic condition affecting 190 million women worldwide. Studies have reported an elevated cancer risk among patients with endometriosis. However, prior research has included methodologic issues that impede valid and robust interpretation.

Objective And Rationale: We conducted a meta-analysis of studies investigating the association between endometriosis and cancer risk and analysed the results by methodologic characteristics. We discuss the implications of cancer screening in patients and management challenges faced by clinicians.

Search Methods: We searched PubMed and Embase databases for eligible studies from inception through 24 October 2019. We included cohort and case-control studies examining the association between endometriosis and cancer risk; cross-sectional studies and case reports were excluded. Publications had to present risk/rate/odds estimates with 95% CI. Random effects meta-analysis was used to estimate summary relative risks (SRR) and CIs. Heterogeneity across studies was assessed by the Q test and I2 statistics, and publication bias using Egger's and Begg's tests. Risk of bias and quality of the included studies were assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool.

Outcomes: Forty-nine population-based case-control and cohort studies were included. Twenty-six studies were scored as having a 'serious'/'critical' risk of bias, and the remaining 23 'low'/'moderate'. Cancer-specific analyses showed a positive association between endometriosis and ovarian cancer risk (SRR = 1.93, 95% CI = 1.68-2.22; n = 24 studies) that was strongest for clear cell (SRR = 3.44, 95% CI = 2.82-4.42; n = 5 studies) and endometrioid (SRR = 2.33, 95% CI = 1.82-2.98; n = 5 studies) histotypes (Pheterogeneity < 0.0001), although with significant evidence of both heterogeneity across studies and publication bias (Egger's and Begg's P-values < 0.01). A robust association was observed between endometriosis and thyroid cancer (SRR = 1.39, 95% CI =1.24-1.57; n = 5 studies), a very small association with breast cancer (SRR = 1.04, 95% CI =1.00-1.09; n = 20 studies) and no association with colorectal cancer (SRR = 1.00, 95% CI =0.87-1.16; n = 5 studies). The association with endometrial cancer was not statistically significant (SRR = 1.23, 95% CI =0.97-1.57; n = 17 studies) overall and wholly null when restricted to prospective cohort studies (SRR = 0.99, 95% CI =0.72-1.37; n = 5 studies). The association with cutaneous melanoma was also non-significant (SRR = 1.17, 95% CI =0.97-1.41; n = 7 studies) but increased in magnitude and was statistically significant when restricted to studies with low/moderate risk of bias (SRR = 1.71, 95% CI = 1.24-2.36, n = 2 studies). The most robust finding both in terms of statistical significance and magnitude of effect was an inverse association with cervical cancer (SRR = 0.68, 95% CI =0.56-0.82; n = 4 studies); however, this result has a high potential to reflect heightened access to detection of dysplasia for women who reached an endometriosis diagnosis and is thus likely not causal. Several additional cancer types were explored based on <4 studies.

Wider Implications: Endometriosis was associated with a higher risk of ovarian and thyroid, and minimally (only 4% greater risk) with breast cancer, and with a lower risk of cervical cancer. However, this meta-analysis confirms that: a majority of studies had severe/critical risk of bias; there is impactful heterogeneity across studies-and for ovarian cancer, publication bias; and causal inference requires temporality, which in many studies was not considered. We discuss the implications of these potential associations from the perspectives of patients with endometriosis, clinicians involved in their care, and scientists investigating their long-term health risks.
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http://dx.doi.org/10.1093/humupd/dmaa045DOI Listing
February 2021

ICU Telemedicine Implementation and Risk-Adjusted Mortality Differences Between Daytime and Nighttime Coverage.

Chest 2021 04 28;159(4):1445-1451. Epub 2020 Oct 28.

eHealth Center, Westchester Medical Center Health Network, Valhalla, NY; Division of Pulmonary, Critical Care and Sleep Medicine, Westchester Medical Center Health Network, Valhalla, NY; Department of Anesthesiology, Westchester Medical Center Health Network, Valhalla, NY.

Background: ICU telemedicine augmentation has been associated with improvements in clinical and financial outcomes in many cases, but not all. Understanding this discrepancy is of interest given the clinical impact and intervention cost. A recent meta-analysis noted an association with mortality reduction and standardized mortality ratio (SMR) before ICU telemedicine implementation of > 1.

Research Question: Does ICU telemedicine implementation affect adjusted mortality outcomes? If so, in what context?

Study Design And Methods: We performed a retrospective pre-post analysis comparing before vs after ICU telemedicine implementation on the outcome of risk-adjusted ICU mortality during am vs pm admissions as well as other objective measures of ICU telemedicine involvement.

Results: One thousand five hundred eighty-one patient-stays and 14,584 patient-stays were available for analysis in the implementation period before vs after ICU telemedicine implementation, respectively. The average Acute Physiology and Chronic Health Evaluation (APACHE) IVa score was 46.6 vs 54.8 (P < .01) in the am group before ICU telemedicine implementation vs the am group after ICU telemedicine implementation, respectively. The average APACHE IVa score was 47.2 vs 56.3 (P < .01) in the pm group before ICU telemedicine implementation vs the pm group after ICU telemedicine implementation, respectively. Overall, the risk-adjusted ICU mortality was 8.7% before ICU telemedicine implementation vs 6.5% (P < .01) after implementation. When stratified by am and pm admission groups, no significant difference in risk-adjusted ICU mortality was seen in the am stratum. In the pm stratum, risk-adjusted mortality was 10.8% before ICU telemedicine implementation vs 7.0% (P < .01) after ICU telemedicine implementation. The preimplementation SMR in the am admission stratum was 0.95 vs 1.30 in the pm stratum.

Interpretation: We found a reduction in risk-adjusted ICU mortality with implementation of ICU telemedicine driven predominantly within the pm admission group. The pm admission SMR was 1.30, which may suggest an association with SMR of > 1 before ICU telemedicine implementation and mortality reduction. Future studies should seek to confirm this finding and should explore other important ICU telemedicine outcomes in the context of observed-to-expected ratios.
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http://dx.doi.org/10.1016/j.chest.2020.10.055DOI Listing
April 2021

Surgical treatment for tubal disease in women due to undergo in vitro fertilisation.

Cochrane Database Syst Rev 2020 10 22;10:CD002125. Epub 2020 Oct 22.

Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.

Background: Tubal disease accounts for 20% of infertility cases. Hydrosalpinx, caused by distal tubal occlusion leading to fluid accumulation in the tube(s), is a particularly severe form of tubal disease negatively affecting the outcomes of assisted reproductive technology (ART). It is thought that tubal surgery may improve the outcome of ART in women with hydrosalpinges.

Objectives: To assess the effectiveness and safety of tubal surgery in women with hydrosalpinges prior to undergoing conventional in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).

Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, DARE, and two trial registers on 8 January 2020, together with reference checking and contact with study authors and experts in the field to identify additional trials.

Selection Criteria: Randomised controlled trials (RCTs) comparing surgical treatment versus no surgical treatment, or comparing surgical interventions head-to-head, in women with tubal disease prior to undergoing IVF.

Data Collection And Analysis: We used Cochrane's standard methodological procedures. The primary outcomes were live birth rate (LBR) and surgical complication rate per woman randomised. Secondary outcomes included clinical, multiple and ectopic pregnancy rates, miscarriage rates and mean numbers of oocytes retrieved and of embryos obtained.

Main Results: We included 11 parallel-design RCTs, involving a total of 1386 participants. The included trials compared different types of tubal surgery (salpingectomy, tubal occlusion or transvaginal aspiration of hydrosalpingeal fluid) to no tubal surgery, or individual interventions to one another. We assessed no studies as being at low risk of bias across all domains, with the main limitations being lack of blinding, wide confidence intervals and low event and sample sizes. We used GRADE methodology to rate the quality of the evidence. Apart from one moderate-quality result in one review comparison, the evidence provided by these 11 trials ranged between very low- to low-quality. Salpingectomy versus no tubal surgery No included study reported on LBR for this comparison. We are uncertain of the effect of salpingectomy on surgical complications such as the rate of conversion to laparotomy (Peto odds ratio (OR) 5.80, 95% confidence interval (CI) 0.11 to 303.69; one RCT; n = 204; very low-quality evidence) and pelvic infection (Peto OR 5.80, 95% CI 0.11 to 303.69; one RCT; n = 204; very low-quality evidence). Salpingectomy probably increases clinical pregnancy rate (CPR) versus no surgery (risk ratio (RR) 2.02, 95% CI 1.44 to 2.82; four RCTs; n = 455; I = 42.5%; moderate-quality evidence). This suggests that in women with a CPR of approximately 19% without tubal surgery, the rate with salpingectomy lies between 27% and 52%. Proximal tubal occlusion versus no surgery No study reported on LBR and surgical complication rate for this comparison. Tubal occlusion may increase CPR compared to no tubal surgery (RR 3.21, 95% CI 1.72 to 5.99; two RCTs; n = 209; I = 0%; low-quality evidence). This suggests that with a CPR of approximately 12% without tubal surgery, the rate with tubal occlusion lies between 21% and 74%. Transvaginal aspiration of hydrosalpingeal fluid versus no surgery No study reported on LBR for this comparison, and there was insufficient evidence to identify a difference in surgical complication rate between groups (Peto OR not estimable; one RCT; n = 176). We are uncertain whether transvaginal aspiration of hydrosalpingeal fluid increases CPR compared to no tubal surgery (RR 1.67, 95% CI 1.10 to 2.55; three RCTs; n = 311; I = 0%; very low-quality evidence). Laparoscopic proximal tubal occlusion versus laparoscopic salpingectomy We are uncertain of the effect of laparoscopic proximal tubal occlusion versus laparoscopic salpingectomy on LBR (RR 1.21, 95% CI 0.76 to 1.95; one RCT; n = 165; very low-quality evidence) and CPR (RR 0.81, 95% CI 0.62 to 1.07; three RCTs; n = 347; I = 77%; very low-quality evidence). No study reported on surgical complication rate for this comparison. Transvaginal aspiration of hydrosalpingeal fluid versus laparoscopic salpingectomy No study reported on LBR for this comparison, and there was insufficient evidence to identify a difference in surgical complication rate between groups (Peto OR not estimable; one RCT; n = 160). We are uncertain of the effect of transvaginal aspiration of hydrosalpingeal fluid versus laparoscopic salpingectomy on CPR (RR 0.69, 95% CI 0.44 to 1.07; one RCT; n = 160; very low-quality evidence).

Authors' Conclusions: We found moderate-quality evidence that salpingectomy prior to ART probably increases the CPR compared to no surgery in women with hydrosalpinges. When comparing tubal occlusion to no intervention, we found that tubal occlusion may increase CPR, although the evidence was of low quality. We found insufficient evidence of any effect on procedure- or pregnancy-related adverse events when comparing tubal surgery to no intervention. Importantly, none of the studies reported on long term fertility outcomes. Further high-quality trials are required to definitely determine the impact of tubal surgery on IVF and pregnancy outcomes of women with hydrosalpinges, particularly for LBR and surgical complications; and to investigate the relative efficacy and safety of the different surgical modalities in the treatment of hydrosalpinges prior to ART.
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http://dx.doi.org/10.1002/14651858.CD002125.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094448PMC
October 2020

Specialized regulatory T cells control venous blood clot resolution through SPARC.

Blood 2021 03;137(11):1517-1526

Department of Dermatology.

The cells and mechanisms involved in blood clot resorption are only partially known. We show that regulatory T cells (Tregs) accumulate in venous blood clots and regulate thrombolysis by controlling the recruitment, differentiation and matrix metalloproteinase (MMP) activity of monocytes. We describe a clot Treg population that forms the matricellular acid- and cysteine-rich protein SPARC (secreted protein acidic and rich in cysteine) and show that SPARC enhances monocyte MMP activity and that SPARC+ Tregs are crucial for blood clot resorption. By comparing different treatment times, we define a therapeutic window of Treg expansion that accelerates clot resorption.
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http://dx.doi.org/10.1182/blood.2020005407DOI Listing
March 2021

Targeting Her2-insYVMA with Covalent Inhibitors-A Focused Compound Screening and Structure-Based Design Approach.

J Med Chem 2020 10 30;63(20):11725-11755. Epub 2020 Sep 30.

Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany.

Mutated or amplified Her2 serves as a driver of non-small cell lung cancer or mediates resistance toward the inhibition of its family member epidermal growth factor receptor with small-molecule inhibitors. To date, small-molecule inhibitors targeting Her2 which can be used in clinical routine are lacking, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds, which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion parameters as well as mass spectrometry experiments and western blot analysis substantiated our approach.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00870DOI Listing
October 2020

Targeted Activation of T Cells with IL-2-Coupled Nanoparticles.

Cells 2020 09 9;9(9). Epub 2020 Sep 9.

Department of Dermatology, Westfälische Wilhelms-University Münster, 48149 Münster, Germany.

Interleukin-2 (IL-2) is a T cell growth factor particularly required in regulatory T cell maintenance and memory T cell responses. High-dose IL-2 treatment was the first FDA-approved immunotherapy for cancer, while low-dose IL-2 administration has shown promise in allograft rejection and autoimmune and inflammatory diseases. However, its pleiotropic nature and the existence of IL-2 receptors with different binding affinity limit its therapeutic application. For an improved clinical applicability of the cytokine, a targeted receptor assignment must, therefore, be achieved. Nanoparticles allow controlling the location and dose of immunomodulating compounds and to specifically address specific receptors through targeted drug binding. In this review article we discuss the IL-2 biology and current clinical application with regard to nanoparticle-based IL-2-mediated manipulation of T cell responses in autoimmunity, chronic inflammation, and cancer.
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http://dx.doi.org/10.3390/cells9092063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565705PMC
September 2020

Alum triggers infiltration of human neutrophils ex vivo and causes lysosomal destabilization and mitochondrial membrane potential-dependent NET-formation.

FASEB J 2020 10 29;34(10):14024-14041. Epub 2020 Aug 29.

Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

Aluminium salts have been used in vaccines for decades. However, the mechanisms underlying their adjuvant effect are still unclear. Neutrophils, the first immune cells at the injection site, can release cellular DNA together with granular material, so-called neutrophil extracellular traps (NETs). In mice, NETs apparently play a role in aluminium hydroxide (alum)-adjuvant immune response to vaccines. Although no experimental data exist, this effect is assumed to be operative also in humans. As a first step to verify this knowledge in humans, we demonstrate that the injection of alum particles into human skin biopsies ex vivo leads to similar tissue infiltration of neutrophils and NET-formation. Moreover, we characterized the mechanism leading to alum-induced NET-release in human neutrophils as rapid, NADPH oxidase-independent process involving charge, phagocytosis, phagolysosomal rupture, Ca -flux, hyperpolarization of the mitochondrial membrane, and mitochondrial ROS. Extracellular flow and inhibition experiments suggested that no additional energy from oxidative phosphorylation or glycolysis is required for NET-release. This study suggests a so far unappreciated role for neutrophils in the initial phase of immune responses to alum-containing vaccines in humans and provides novel insights into bioenergetic requirements of NET-formation.
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http://dx.doi.org/10.1096/fj.202001413RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589265PMC
October 2020

Rapid Implementation and Adaptation of a Telehospitalist Service to Coordinate and Optimize Care for COVID-19 Patients.

Telemed J E Health 2021 04 14;27(4):388-396. Epub 2020 Aug 14.

Department of Internal Medicine, Westchester Medical Center Health Network and New York Medical College, Valhalla, New York, USA.

The COVID-19 pandemic poses enormous resource challenges to hospitals. Telemedicine is increasingly recognized as an attractive tool to alleviate resource strains. Herein we describe the rapid implementation and sequential process improvement (PI) of a centralized telehospitalist service to coordinate and optimize management of large number of COVID-19 patients in a tertiary and quaternary care hospital very close to the New York City epicenter. Prospective multidisciplinary PI meetings were held weekly between March 23 and May 10, 2020, and consensus service modifications were implemented for the following week. Inpatient census data, telehospitalist intervention volumes, and service utilization statistics were collected. Between March 23 and May 10, 2020, a total of 745 COVID-19 patients were admitted to the general medical wards. The telehospitalist service performed 1,136 audiovisual (AV) patient assessments, 379 best practice interventions, cohorted 108 patients, and conducted 170 remote family conversations. During the consecutive PI cycles, a number of adaptations in AV setup, care standardization, patient logistics, communication, and consultative functions were made to load balance the bedside hospitalist teams. As the COVID-19 hospital census increased to peak levels, the most value was added through facilitation of communication and collaboration between the bedside clinical teams, the infection prevention and control teams, and patient logistics team. A telehospitalist service can be rapidly implemented with basic telemedicine equipment. Processes/this functions can be sequentially adapted to quickly changing needs during conditions such as the COVID-19 pandemic that very quickly can place extraordinary strains on hospital resources.
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http://dx.doi.org/10.1089/tmj.2020.0232DOI Listing
April 2021

Machine Learning based histology phenotyping to investigate the epidemiologic and genetic basis of adipocyte morphology and cardiometabolic traits.

PLoS Comput Biol 2020 08 14;16(8):e1008044. Epub 2020 Aug 14.

Big Data Institute, University of Oxford, Oxford, United Kingdom.

Genetic studies have recently highlighted the importance of fat distribution, as well as overall adiposity, in the pathogenesis of obesity-associated diseases. Using a large study (n = 1,288) from 4 independent cohorts, we aimed to investigate the relationship between mean adipocyte area and obesity-related traits, and identify genetic factors associated with adipocyte cell size. To perform the first large-scale study of automatic adipocyte phenotyping using both histological and genetic data, we developed a deep learning-based method, the Adipocyte U-Net, to rapidly derive mean adipocyte area estimates from histology images. We validate our method using three state-of-the-art approaches; CellProfiler, Adiposoft and floating adipocytes fractions, all run blindly on two external cohorts. We observe high concordance between our method and the state-of-the-art approaches (Adipocyte U-net vs. CellProfiler: R2visceral = 0.94, P < 2.2 × 10-16, R2subcutaneous = 0.91, P < 2.2 × 10-16), and faster run times (10,000 images: 6mins vs 3.5hrs). We applied the Adipocyte U-Net to 4 cohorts with histology, genetic, and phenotypic data (total N = 820). After meta-analysis, we found that mean adipocyte area positively correlated with body mass index (BMI) (Psubq = 8.13 × 10-69, βsubq = 0.45; Pvisc = 2.5 × 10-55, βvisc = 0.49; average R2 across cohorts = 0.49) and that adipocytes in subcutaneous depots are larger than their visceral counterparts (Pmeta = 9.8 × 10-7). Lastly, we performed the largest GWAS and subsequent meta-analysis of mean adipocyte area and intra-individual adipocyte variation (N = 820). Despite having twice the number of samples than any similar study, we found no genome-wide significant associations, suggesting that larger sample sizes and a homogenous collection of adipose tissue are likely needed to identify robust genetic associations.
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http://dx.doi.org/10.1371/journal.pcbi.1008044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449405PMC
August 2020

Effects of Telemedicine ICU Intervention on Care Standardization and Patient Outcomes: An Observational Study.

Crit Care Explor 2020 Jul 15;2(7):e0165. Epub 2020 Jul 15.

eHealth Center, Westchester Medical Center Health Network, Valhalla, NY.

Objectives: Given the numerous recent changes in ICU practices and protocols, we sought to confirm whether favorable effects of telemedicine ICU interventions on ICU mortality and length of stay can be replicated by a more recent telemedicine ICU intervention.

Design Setting And Patients: Observational before-after telemedicine ICU intervention study in seven adult ICUs in two hospitals. The study included 1,403 patients in the preintervention period (October 2014 to September 2015) and 14,874 patients in the postintervention period (January 2016 to December 2018).

Intervention: Telemedicine ICU implementation.

Measurements And Main Results: ICU and hospital mortality and length of stay, best practice adherence rates, and telemedicine ICU performance metrics. Unadjusted ICU and hospital mortality and lengths of stay were not statistically significantly different. Adjustment for Acute Physiology and Chronic Health Evaluation Version IVa score, ICU type, and ICU admission time via logistic regression yielded significantly lower ICU and hospital mortality odds ratios of 0.58 (95% CI, 0.45-0.74) and 0.66 (95% CI, 0.54-0.80), respectively. When adjusting for acuity by comparing observed-over-expected length of stay ratios through Acute Physiology and Chronic Health Evaluation IVa methodology, we found significantly lower ICU and hospital length of stay in the postintervention group. ICU mortality improvements were driven by nighttime ICU admissions (odds ratio 0.45 [95% CI, 0.33-0.61]) as compared to daytime ICU admissions (odds ratio 0.81 [95% CI, 0.55-1.20]), whereas hospital mortality improvements were seen in both subgroups but more prominently in nighttime ICU admissions (odds ratio 0.57 [95% CI, 0.44-0.74]) as compared to daytime ICU admissions (odds ratio 0.73 [95% CI, 0.55-0.97]), suggesting that telemedicine ICU intervention can effectively supplement low intensity bedside staffing hours (nighttime).

Conclusions: In this pre-post observational study, telemedicine ICU intervention was associated with improvements in care standardization and decreases in ICU and hospital mortality and length of stay. The mortality benefits were mediated in part through telemedicine ICU supplementation of low intensity bedside staffing hours.
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http://dx.doi.org/10.1097/CCE.0000000000000165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365711PMC
July 2020

Endometriosis. Reply.

N Engl J Med 2020 07;383(2):194

University of Oxford, Oxford, United Kingdom.

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http://dx.doi.org/10.1056/NEJMc2013221DOI Listing
July 2020
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