Publications by authors named "Amit Bar-Or"

4,520 Publications

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Hepatitis C related cognitive impairment: impact of viral and host factors and response to therapy.

J Viral Hepat 2021 Feb 23. Epub 2021 Feb 23.

Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Chronic hepatitis C virus (HCV) infection is associated with cognitive impairment via several suggested mechanisms including direct neurotoxicity and minimal hepatic encephalopathy. The prevalence of HCV related cognitive impairment and whether it is reversed by anti-viral therapy are unknown. We aimed to assess predictors and reversibility of cognitive impairment of HCV-infected patients after successful treatment. Consecutive HCV patients treated during the EMERALD study (AbbVie 3D regimen for protease inhibitors failure) underwent neuropsychological (number connection test A [NCTA] and digital symbol test [DST]) and neurophysiological (critical flicker frequency [CFF]) tests at baseline and at 12 weeks post-treatment. Patient self-reported outcomes (PROs) were prospectively collected. Patients with a history of hepatic encephalopathy were excluded. Thirty-two patients underwent the cognitive tests at baseline. Seven of them had abnormal CFF test findings. Twenty-five (25/32, 78%) patients had repeated evaluations 3 months post-treatment. High viral loads were significantly associated with abnormal CFF across fibrosis levels (area under the ROC curve 0.817). CFF results significantly improved following viral eradication, from 40.9 (interquartile range 38.6-42.9) at baseline to 41.5 (39.8-44), P = 0.042, at follow-up. Both NCTA and DST results improved, but not significantly. There was improvement in the PROs of general health perception and vitality. The NCTA and DST results were more significantly associated with PROs than CFF. This prospective interventional study showed greater cognitive impairment in HCV patients with high viral load and demonstrated partial reversibility of HCV neurotoxicity and subsequent improvement in PROs following treatment.
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http://dx.doi.org/10.1111/jvh.13492DOI Listing
February 2021

Validation of the COVILUS score to diagnose COVID-19 in an emergency room cohort.

Anaesthesia 2021 Feb 23. Epub 2021 Feb 23.

Amiens University Hospital, Amiens, France.

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http://dx.doi.org/10.1111/anae.15450DOI Listing
February 2021

Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing.

Nat Med 2021 Feb 22. Epub 2021 Feb 22.

Department of Immunology, Weizmann Institute, Rehovot, Israel.

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.
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http://dx.doi.org/10.1038/s41591-021-01232-wDOI Listing
February 2021

Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients.

Lancet 2021 Feb 18. Epub 2021 Feb 18.

Infectious Diseases Unit, The Chaim Sheba Medical Centre, Ramat-Gan, Israel; Sakler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)00448-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906709PMC
February 2021

Relationship between parent perception of child anthropometric phenotype and body mass index change among children with developmental disabilities.

World J Pediatr 2021 Feb 19. Epub 2021 Feb 19.

University of Texas Health Science Center at Houston, School of Public Health, Dallas Campus, Dallas, TX, USA.

Background: Preschool-age children with developmental disabilities (DD) have higher prevalence of obesity than children without DD. This study aimed to explore the relationship between parent perception of their children's anthropometric phenotype and child body mass index (BMI) z score change over one school year among preschoolers with DD.

Methods: The analysis consisted of a subsample (N  =  64) of children with DD from a larger randomized controlled trial to test an obesity prevention program in the childcare center setting. Parents ranks their child's anthropometric phenotype on a visual silhouette chart on a scale from 1 (underweight) to 7 (obese) and that rank score is compared to their BMI z score change over one school year.

Results: The majority (75%) of parents with an obese child underestimated their child's anthropometric phenotype while 7% parents with a non-obese child overestimated. Parent overestimation of child anthropometric phenotype status is associated with increased BMI z score change over 1 school year among preschool-age children with disabilities.

Conclusion: Parental overestimation of child anthropometric phenotype status was associated with weight gain in preschool children with DD after one school year.
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http://dx.doi.org/10.1007/s12519-021-00420-5DOI Listing
February 2021

Polycomb complexes redundantly maintain epidermal stem cell identity during development.

Genes Dev 2021 Mar 18;35(5-6):354-366. Epub 2021 Feb 18.

Black Family Stem Cell Institute, Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

Polycomb repressive complex 1 (PRC1) and PRC2 are critical epigenetic developmental regulators. PRC1 and PRC2 largely overlap in their genomic binding and cooperate to establish repressive chromatin domains demarcated by H2AK119ub and H3K27me3. However, the functional contribution of each complex to gene repression has been a subject of debate, and understanding of its physiological significance requires further studies. Here, using the developing murine epidermis as a paradigm, we uncovered a previously unappreciated functional redundancy between Polycomb complexes. Coablation of PRC1 and PRC2 in embryonic epidermal progenitors resulted in severe defects in epidermal stratification, a phenotype not observed in the single PRC1-null or PRC2-null epidermis. Molecular dissection indicated a loss of epidermal identity that was coupled to a strong derepression of nonlineage transcription factors, otherwise repressed by either PRC1 or PRC2 in the absence of its counterpart. Ectopic expression of subsets of PRC1/2-repressed nonepidermal transcription factors in wild-type epidermal stem cells was sufficient to suppress epidermal identity genes, highlighting the importance of functional redundancy between PRC1 and PRC2. Altogether, our studies show how PRC1 and PRC2 function as two independent counterparts, thereby providing a repressive safety net that protects and preserves lineage identity.
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http://dx.doi.org/10.1101/gad.345363.120DOI Listing
March 2021

Real-world survival outcomes with immune checkpoint inhibitors in large-cell neuroendocrine tumors of lung.

J Immunother Cancer 2021 Feb;9(2)

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Little is known regarding the efficacy of immune checkpoint inhibitors (ICI) in patients with advanced large-cell neuroendocrine lung carcinoma (aLCNEC).

Methods: 125 consecutive patients with aLCNEC were identified in the electronic databases of 4 participating cancer centers. The patients were divided into group A (patients who received ICI, n=41) and group B (patients who did not receive ICI, n=84). Overall survival since advanced disease diagnosis (OS DX) and OS since ICI initiation (OS ICI) were captured.

Results: With a median follow-up of 11.8 months (mo) (IQR 7.5-17.9) and 6.0mo (IQR 3.1-10.9), 66% and 76% of patients died in groups A and B, respectively. Median OS DX was 12.4mo (95% CI 10.7 to 23.4) and 6.0mo (95% CI 4.7 to 9.4) in groups A and B, respectively (log-rank test, p=0.02). For ICI administration, HR for OS DX was 0.59 (95% CI 0.38 to 0.93, p=0.02-unadjusted), and 0.58 (95% CI 0.34 to 0.98, p=0.04-adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), presence of liver metastases and chemotherapy administration). In a propensity score matching analysis (n=74; 37 patients in each group matched for age and ECOG PS), median OS DX was 12.5 mo (95% CI 10.6 to 25.2) and 8.4 mo (95% CI 5.4 to 16.9) in matched groups A and B, respectively (log-rank test, p=0.046). OS ICI for patients receiving ICI as monotherapy (n=36) was 11.0 mo (95% CI 6.1 to 19.4).

Conclusions: With the limitations of retrospective design and small sample size, the results of this real-world cohort analysis suggest a positive impact of ICI on OS in aLCNEC.
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http://dx.doi.org/10.1136/jitc-2020-001999DOI Listing
February 2021

Kinetic modelling of high turbid water flocculation using native and surface functionalized coagulants prepared from shed-leaves of Avicennia marina plants.

Chemosphere 2021 Feb 8;272:129894. Epub 2021 Feb 8.

Analytical and Environmental Science Division & Centralized Instrument Facility, CSIR-Central Salt & Marine Chemicals Research Institute, Bhavnagar, 364 002, Gujarat, India; Academy of Scientific and Innovative Research, Ghaziabad, 201 002, Uttar Pradesh, India. Electronic address:

Coagulation performance of shed-leaves of Avicennia marina plants collected from Alang coastline, Gujarat (India) was scrutinized for the treatment of mud and starch water suspensions. For which, native, hydrochloric acid, sodium hydroxide and sodium chloride treated A. marina shed-leaves were processed with minimum environmental impact. Experiments were accomplished for the concentration of water suspensions (10-50 g/L) at the range of pH 7.0-8.0. The performances of these coagulants were assessed in terms of reduction in turbidity, pH, alkalinity, hardness, electrical conductivity and solids from water suspensions. The removal of bulk impurities was noted due to the floc formation of coagulant through hydrolysing salts, thus, resulted in the highest settlement at pH 7.82, 7.90 for mud and starch water, accordingly. Native and functionalized A. marina coagulants (AMCs) were characterized and interpreted using scanning electron microscopy, elemental analyses, energy dispersive and Fourier transform infrared spectroscopy. HCl treated AMC was relatively effective with good coagulation performance (96.76%), when compared with native and other treated AMCs. The turbidity removal by all AMCs obeyed with World Health Organization (WHO) acceptable limit of finished water, where HCl treated AMC clarified 15.15 and 16.36 NTU of mud and starch water suspensions to produce a clear water of 0.92 and 1.61 NTU, respectively. The proficiency of prepared AMCs were compared with other natural coagulants and surface functionalized (HCl > NaOH > NaCl) AMCs prepared in this study exerted better performance than the native AMC. The critical coagulation rate from the second-order kinetics were evaluated and the results were highly satisfying. Other physico-chemical parameters of water suspensions were evident for the adequate removal of impurities by non-toxic plant-based coagulants.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129894DOI Listing
February 2021

Mohs Micrographic Surgery for the Treatment of Melanoma: A Cross-Sectional Survey on the Barriers, Prevalence, and Practice.

Dermatol Surg 2021 Feb 8. Epub 2021 Feb 8.

Department of Dermatology, Oregon Health and Science University, Portland, OR Biostatistician, Knight Cancer Institute, Oregon Health and Science University, Portland, OR.

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http://dx.doi.org/10.1097/DSS.0000000000002933DOI Listing
February 2021

Diagnostic value of circulating microRNAs compared to high-sensitivity troponin T for the detection of non-ST-segment elevation myocardial infarction.

Eur Heart J Acute Cardiovasc Care 2021 Jan 4. Epub 2021 Jan 4.

Zentrum für Innere Medizin, Klinik für Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany.

Aims: To assess the diagnostic value of microRNAs (miRNAs) for the detection of non-ST-segment elevation myocardial infarction (NSTEMI).

Methods And Results: A total of 1042 patients presenting between August 2014 and April 2017 to the emergency department with the suspected acute coronary syndrome were included. Non-ST-segment elevation myocardial infarction was diagnosed per criteria of the fourth Universal definition of myocardial infarction (UDMI) using high-sensitivity troponin T (hs-cTnT). Expression levels of eleven microRNAs (miR-21, miR-22, miR-29a, miR-92a, miR-122, miR-126, miR-132, miR-133, miR-134, miR-191, and miR-423) were determined using RT-qPCR. Discrimination of NSTEMI was assessed for individual and a panel of miRNAs compared to the hs-cTnT reference using C-statistics and reclassification analysis. NSTEMI was diagnosed in 137 (13.1%) patients. The area under the curve (AUC) of the hs-cTnT based reference was 0.937. In a multivariate model, three miRNAs (miR-122, miR-133, and miR-134) were found to be associated with NSTEMI with AUCs between 0.506 and 0.656. A panel consisting of these miRNAs revealed an AUC of 0.662 for the diagnosis of NSTEMI. The AUC of the combination of the miRNA panel and troponin reference was significantly lower than the reference standard (AUC: 0.897 vs. 0.937, P = 0.006). Despite a significant improvement of NSTEMI reclassification measured by IDI and NRI, miRNAs did not improve the specificity of hs-cTnT kinetic changes for the diagnosis of NSTEMI (ΔAUC: 0.04).

Conclusion: Although single miRNAs are significantly associated with the diagnosis of NSTEMI a miRNA panel does not add diagnostic accuracy to the hs-cTnT reference considering baseline values and kinetic changes as recommended by the fourth version of UDMI.

Clinical Trials Identifier: NCT02116153.
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http://dx.doi.org/10.1093/ehjacc/zuaa034DOI Listing
January 2021

High-pressure processing-induced transcriptome response during recovery of Listeria monocytogenes.

BMC Genomics 2021 Feb 12;22(1):117. Epub 2021 Feb 12.

Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

Background: High-pressure processing (HPP) is a commonly used technique in the food industry to inactivate pathogens, including L. monocytogenes. It has been shown that L. monocytogenes is able to recover from HPP injuries and can start to grow again during long-term cold storage. To date, the gene expression profiling of L. monocytogenes during HPP damage recovery at cooling temperature has not been studied. In order identify key genes that play a role in recovery of the damage caused by HPP treatment, we performed RNA-sequencing (RNA-seq) for two L. monocytogenes strains (barotolerant RO15 and barosensitive ScottA) at nine selected time points (up to 48 h) after treatment with two pressure levels (200 and 400 MPa).

Results: The results showed that a general stress response was activated by SigB after HPP treatment. In addition, the phosphotransferase system (PTS; mostly fructose-, mannose-, galactitol-, cellobiose-, and ascorbate-specific PTS systems), protein folding, and cobalamin biosynthesis were the most upregulated genes during HPP damage recovery. We observed that cell-division-related genes (divIC, dicIVA, ftsE, and ftsX) were downregulated. By contrast, peptidoglycan-synthesis genes (murG, murC, and pbp2A) were upregulated. This indicates that cell-wall repair occurs as a part of HPP damage recovery. We also observed that prophage genes, including anti-CRISPR genes, were induced by HPP. Interestingly, a large amount of RNA-seq data (up to 85%) was mapped to Rli47, which is a non-coding RNA that is upregulated after HPP. Thus, we predicted that Rli47 plays a role in HPP damage recovery in L. monocytogenes. Moreover, gene-deletion experiments showed that amongst peptidoglycan biosynthesis genes, pbp2A mutants are more sensitive to HPP.

Conclusions: We identified several genes and mechanisms that may play a role in recovery from HPP damage of L. monocytogenes. Our study contributes to new information on pathogen inactivation by HPP.
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http://dx.doi.org/10.1186/s12864-021-07407-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881616PMC
February 2021

Psychological well-being and adjustment among type 2 diabetes patients: the role of psychological flexibility.

Psychol Health Med 2021 Feb 11:1-12. Epub 2021 Feb 11.

Head Clinical Psychologist, Psychological Service, Tel Aviv Sourasky Medical Center , Tel Aviv, Israel.

Elevated rates of psychological disorders are reported among those with type 2 diabetes (T2D). Thus, research into factors enhancing psychological aspects of well-being is critical in T2D. We examine the association between a multifaceted measure of Psychological Flexibility (PF), and its relationship to adjustment and well-being, among this population. Adults with T2D ( = 102) completed an online battery of self-reported questionnaires and were asked for demographics, general T2D features, treatment adherence, PF, adjustment, and well-being. We examined the association between PF (Psychological Flexibility Questionnaire, PFQ), adjustment to diabetes (ATT-39) and well-being (Mental Health Inventory), among adults with T2D. Greater PF was significantly associated with greater well-being, but unrelated to adjustment, which was positively associated with well-being. In a hierarchical regression analysis, perception of change as positive (one of the five PFQ factors) significantly contributed to the explained variance in well-being, beyond the contribution of adjustment. These findings indicate that positive perception of change may enhance well-being independently from adjustment to diabetes since these two constructs are distinct and independent. Such an association between PF and well-being may apply to other medical conditions. Implications for psychological intervention are discussed.
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http://dx.doi.org/10.1080/13548506.2021.1887500DOI Listing
February 2021

Combined kinesin-1 and kinesin-3 activity drives axonal trafficking of TrkB receptors in Rab6 carriers.

Dev Cell 2021 Feb 10;56(4):494-508.e7. Epub 2021 Feb 10.

Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address:

Neurons depend on proper localization of neurotrophic receptors in their distal processes for their function. The Trk family of neurotrophin receptors controls neuronal survival, differentiation, and remodeling and are well known to function as retrograde signal carriers transported from the distal axon toward the cell body. However, the mechanism driving anterograde trafficking of Trk receptors into the axon is not well established. We used microfluidic compartmental devices and inducible secretion assay to systematically investigate the retrograde and anterograde trafficking routes of TrkB receptor along the axon in rat hippocampal neurons. We show that newly synthesized TrkB receptors traffic through the secretory pathway and are directly delivered into axon. We found that these TrkB carriers associate and are regulated by Rab6. Furthermore, the combined activity of kinesin-1 and kinesin-3 is needed for the formation of axon-bound TrkB secretory carriers and their effective entry and processive anterograde transport beyond the proximal axon.
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http://dx.doi.org/10.1016/j.devcel.2021.01.010DOI Listing
February 2021

A mixture model to detect edges in sparse co-expression graphs with an application for comparing breast cancer subtypes.

PLoS One 2021 11;16(2):e0246945. Epub 2021 Feb 11.

Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, United States of America.

We develop a method to recover a gene network's structure from co-expression data, measured in terms of normalized Pearson's correlation coefficients between gene pairs. We treat these co-expression measurements as weights in the complete graph in which nodes correspond to genes. To decide which edges exist in the gene network, we fit a three-component mixture model such that the observed weights of 'null edges' follow a normal distribution with mean 0, and the non-null edges follow a mixture of two lognormal distributions, one for positively- and one for negatively-correlated pairs. We show that this so-called L2 N mixture model outperforms other methods in terms of power to detect edges, and it allows to control the false discovery rate. Importantly, our method makes no assumptions about the true network structure. We demonstrate our method, which is implemented in an R package called edgefinder, using a large dataset consisting of expression values of 12,750 genes obtained from 1,616 women. We infer the gene network structure by cancer subtype, and find insightful subtype characteristics. For example, we find thirteen pathways which are enriched in each of the cancer groups but not in the Normal group, with two of the pathways associated with autoimmune diseases and two other with graft rejection. We also find specific characteristics of different breast cancer subtypes. For example, the Luminal A network includes a single, highly connected cluster of genes, which is enriched in the human diseases category, and in the Her2 subtype network we find a distinct, and highly interconnected cluster which is uniquely enriched in drug metabolism pathways.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246945PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877669PMC
February 2021

CCR5-edited CD4 T cells augment HIV-specific immunity to enable post rebound control of HIV replication.

J Clin Invest 2021 Feb 11. Epub 2021 Feb 11.

Department of Microbiology and Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, United States of America.

Background: We performed a Phase I clinical trial that infused CCR5 gene edited CD4 T cells to determine how these T cells can better enable HIV cure strategies.

Methods: The trial addressed the method of zinc finger nuclease (ZFN) ex vivo delivery, whether CCR5 Δ32 heterozygotes preferentially benefit, the effect of CCR5 gene edited CD4 T cells on the HIV-specific T cell response, and the ability of infused CCR5 gene edited T cells to delay viral rebound during analytical treatment interruption. We enrolled 14 people living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured time to viral rebound after ART withdrawal, persistence of CCR5-edited CD4 T cells, and whether infusion of 10 billion CCR5-edited CD4 T cells augmented the HIV-specific immune response.

Results: Infusion of the CD4 T cells was well tolerated with no serious adverse events. Modest delay to the time of viral rebound was observed relative to historical controls; however, three of 14 individuals of which two were CCR5 Δ32 heterozygotes appeared to regain control of viremia before ultimately rebounding. Interestingly, only these individuals had significant restoration of HIV-specific CD8 T cell responses. Immune escape to one of these re-invigorated responses was observed at viral recrudescence, illustrating a direct link between viral control and enhanced CD8 T cell responses.

Conclusion: These findings demonstrate how CCR5 gene edited CD4 T cell infusion could aid HIV cure strategies by augmenting pre-existing HIV-specific immune responses.

Trial Registration: ClinicalTrials.gov NCT02388594FUNDING. R01AI104400 (C.H.J.), UM1AI126620 (J.L.R.) funded by NIAID, NIDA, NIMH, and NINDS; T32 grant AI007632 (C.R.M.).
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http://dx.doi.org/10.1172/JCI144486DOI Listing
February 2021

Immune responses and viral persistence in SHIV.C.CH848-infected rhesus macaques.

J Virol 2021 Feb 10. Epub 2021 Feb 10.

Tulane National Primate Research Center, Tulane University School of Medicine, Covington, Louisiana, USA

Chimeric simian/human immunodeficiency viruses (SHIVs) are widely used in nonhuman primate models to recapitulate HIV infection in humans, yet most SHIVs fail to establish persistent viral infection. We investigated immunological and virological events in rhesus macaques infected with the newly developed SHIV.C.CH848, combined with antiretroviral therapy (cART). Similar to HIV/SIV infection, SHIV.C.CH848 infection established viral reservoirs in CD4+ T cells and myeloid cells, accompanied by productive infection and depletion of CD4+ T cells in systemic and lymphoid tissues throughout SHIV infection. Despite 6-months of cART suppressed viral replication, integrated proviral DNA levels remained stable, especially in CD4+ T cells, and the viral rebound was also observed after ART interruption. Autologous neutralizing antibodies to the parental HIV-1 strain CH848 were detected, with limited viral evolution at 5 months post infection. In comparison, heterogenous neutralizing antibodies in SHIV.C.CH848-infected macaques were not detected except for one (1 of 10) animal at 2 years post infection. These findings suggest that the SHIV.C.CH848, a novel class of transmitted/founder SHIVs, can establish sustained viremia and viral reservoirs in rhesus macaques with clinical immunodeficiency consequences, providing a valuable SHIV model for HIV research. SHIVs have been extensively used in a nonhuman primate (NHP) model for HIV research. Here, we investigate viral reservoir in tissues and immune responses in an NHP model inoculated with newly generated transmitted/founder HIV-1 clade C-based SHIV.C.CH848. The data show T/F SHIVC infection of macaques more closely recapitulates the virologic and clinical features of HIV infection including persistent viremia, and viral rebound once antiretroviral therapy is discontinued. These results suggest this CCR5-tropic, SHIVC virus is valuable for testing responses to HIV vaccines and therapeutics.
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http://dx.doi.org/10.1128/JVI.02198-20DOI Listing
February 2021

Neoadjuvant chemotherapy for locoregionally advanced squamous cell carcinoma of the paranasal sinuses.

Cancer 2021 Feb 10. Epub 2021 Feb 10.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Squamous cell carcinoma is the most common type of sinonasal malignancy. Despite improvements in surgical resection and adjuvant therapy, which are considered the standard of care, the outcome for patients with locoregionally advanced disease remains poor. The objective of this study was to investigate the role of induction chemotherapy in patients with locoregionally advanced sinonasal squamous cell carcinoma and to determine the oncologic outcomes in those patients.

Methods: The study included 123 consecutive patients with previously untreated, locoregionally advanced (stage III and IV) sinonasal squamous cell carcinoma who were treated with curative intent at The University of Texas MD Anderson Cancer Center between 1988 and 2017 with induction chemotherapy followed by definitive local therapy. Patient demographics, tumor staging, treatment details, and oncologic outcomes were reviewed. The outcomes of this study included response to induction chemotherapy, recurrence, organ preservation, and survival.

Results: The median follow-up was 32.6 months (range, 12.4-240 months). Of the 123 patients, 110 (89%) had T4 disease, and 13 (11%) had T3 disease. Lymph node metastasis at the time of presentation was observed in 36 patients (29.3%). The overall stage was stage IV in 111 patients (90.2%) and stage III in 12 patients (9.8%). The chemotherapy regimen consisted of the combination of a platinum and taxanes in most cases (109 patients; 88.6%), either as a doublet (41 patients) or in combination with a third agent, such as 5-fluorouracil (34 patients), ifosfamide (26 patients), or cetuximab (8 patients). After induction chemotherapy, 71 patients (57.8%) achieved at least a partial response, and 6 patients had a complete response. Subsequent treatment after induction chemotherapy was either: 1) definitive chemoradiation or radiation followed by surgical salvage for any residual disease, or 2) surgery followed by adjuvant radiation or chemoradiation. Overall, 54 patients (49.5%) underwent surgical resection. The 2-year overall and disease-free survival rates for the whole cohort were 61.4% and 67.9%, respectively. The rate of orbital preservation was 81.5%. The recurrence rate was 26.8% (33 patients), and distant metastases occurred in 8 patients (6.5%). Patients who had at least a partial response or stable disease had significantly better overall and disease-free survival than those who had progressive disease (P = .028 and P = .021, respectively).

Conclusions: The current results indicate that a high proportion of patients with sinonasal squamous cell carcinoma achieved a favorable response to induction chemotherapy. The data suggest that response to induction chemotherapy is associated with an improved outcome and a good chance of organ preservation. The oncologic outcomes in this cohort with locally advanced (mostly T4) disease are better than those historically reported in the literature. Further study of induction chemotherapy in patients with advanced sinonasal squamous carcinoma is warranted.
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http://dx.doi.org/10.1002/cncr.33452DOI Listing
February 2021

Concentrating stroke care provision in the Czech Republic: The establishment of Stroke Centres in 2011 has led to improved outcomes.

Health Policy 2021 Jan 30. Epub 2021 Jan 30.

2nd Medical School of Charles University and Motol University Hospital, Department of Neurology, Prague, Czech Republic; Executive Board of Czech Stroke Society, Czech Neurological Society of the J. E. Purkyně Czech Medical Society, Prague, Czech Republic.

This article describes policy processes that have led to the re-organisation of stroke care in the Czech Republic since 2011, which has been part of a broader process of care concentration in several medical fields. Currently, stroke care is provided by 13 Comprehensive and 32 Primary Stroke Centres. The paper explains factors that supported the reform implementation, reviews implications, and discusses future challenges. Mandatory reporting of quality indicators, the introduction of a benchmarking system, integration with pre-hospital emergency care, and the introduction of countrywide patient triage have supported more timely treatment for stroke patients and better quality of care. Data from the Stroke Care Quality Indicators of the Czech Stroke Society show positive trends in many areas: the number of patients treated with intravenous thrombolysis quadrupled in eight years, with 26.4 % of all acute stroke patients receiving thrombolysis in 2018. Czech Republic now ranks third in Europe in the number of thrombolysis per population and second in the number of mechanical thrombectomies per population. The Czech experience provides an example of positive outcomes of concentrated stroke care, while highlighting the importance of proper implementation processes. In particular, it is essential to involve stakeholders and to provide reputational incentives through continuous benchmarking.
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http://dx.doi.org/10.1016/j.healthpol.2021.01.011DOI Listing
January 2021

Head and neck cancer exosomes drive microRNA-mediated reprogramming of local neurons.

Extracell Vesicles Circ Nucl Acids 2020 30;1:57-62. Epub 2020 Dec 30.

Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Solid tumors are complex collections of cells surrounded by benign tissues that influence and are influenced by the tumor. These surrounding cells include vasculature, immune cells, neurons, and other cell types, and are collectively known as the tumor microenvironment. Tumors manipulate their microenvironment for the benefit of the tumor. Autonomic neurons innervate and drive malignant growth in a variety of solid tumors. However, the mechanisms underlying neuron-tumor relationships are not well understood. Recently, Amit described that trophic relationships between oral cavity squamous cell carcinomas (OCSCCs) and nearby autonomic neurons arise through direct signaling between tumors and local neurons. An inducible tumor model in which 4NQO was introduced into the drinking water of knockout mice was used to model OCSCC-microenvironment interactions. Using this model, this group discovered that loss of p53 expression in OCSCC tumors resulted in increased nerve density within these tumors. This neuritogenesis was controlled by tumor-derived microRNA-laden extracellular vesicles (EVs). Specifically, EV-delivered miR-34a inhibited neuritogenesis, whereas EV-delivered miR-21 and miR-324 increased neuritogenesis. The neurons innervating p53-deficient OCSCC tumors were predominantly adrenergic and arose through the transdifferentiation of trigeminal sensory nerve fibers to adrenergic nerve fibers. This transdifferentiation corresponded with increased expression of neuron-reprogramming transcription factors, including POU5F1, KLF4, and ASCL1, which were overexpressed in the p53-deficient samples, and are proposed targets of miR-34a-mediated regulation. Human OCSCC samples enriched in adrenergic neuron markers are associated strongly with poor outcomes, thus demonstrating the relevance of these findings to cancer patients.
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http://dx.doi.org/10.20517/evcna.2020.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861575PMC
December 2020

Pembrolizumab as a monotherapy or in combination with platinum-based chemotherapy in advanced non-small cell lung cancer with PD-L1 tumor proportion score (TPS) ≥50%: real-world data.

Oncoimmunology 2021 Jan 28;10(1):1865653. Epub 2021 Jan 28.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Both pembrolizumab (P) and combination of pembrolizumab with platinum-based chemotherapy (PCT) represent standard 1-line options for advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score (TPS) ≥50%. The two strategies have never been compared in a randomized trial. 256 consecutive patients with -wild-type PD-L1 TPS ≥50% aNSCLC receiving P (group P, n = 203) or PCT (group PCT, n = 53) as a 1-line treatment were identified in the electronic databases of 4 Israeli cancer centers. Time-to-treatment discontinuation (TTD) and overall survival (OS) were assessed. Baseline characteristics were well balanced, except for age and ECOG PS differences in favor of group PCT. Median (m)TTD was 4.9 months (mo) (95% CI, 3.1-7.6) 8.0mo (95% CI, 4.7-15.6) (-0.09), mOS was 12.5mo (95% CI, 9.8-16.4) 20.4mo (95% CI, 10.8-NR) (-0.08), with P and PCT, respectively. In the propensity score matching analysis (n = 106; 53 patients in each group matched for age, sex and ECOG PS), mTTD was 7.9mo (95% CI, 2.8-12.7) 8.0mo (95% CI, 4.7-15.6) (-0.41), and mOS was 13.3mo (95% CI, 6.8-20.3) 20.4mo (95% CI, 10.8-NR) (-0.18), with P and PCT, respectively. Among various subgroups of patients examined, only in females (n = 86) mOS differed significantly between treatments (10.2mo (95% CI, 6.8-17.2) with P NR (95% CI, 11.4-NR) with PCT; -0.02). In the real-world setting, no statistically significant differences in long-term outcomes with P PCT were observed; a prospective randomized trial addressing the comparative efficacy of P and PCT in different patient subgroups is highly anticipated.:
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http://dx.doi.org/10.1080/2162402X.2020.1865653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849771PMC
January 2021

Cortical thinning and associated connectivity changes in patients with anorexia nervosa.

Transl Psychiatry 2021 Feb 4;11(1):95. Epub 2021 Feb 4.

Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, Jena University Hospital, Jena, Germany.

Structural brain abnormalities are a consistent finding in anorexia nervosa (AN) and proposed as a state biomarker of the disorder. Yet little is known about how regional structural changes affect intrinsic resting-state functional brain connectivity (rsFC). Using a cross-sectional, multimodal imaging approach, we investigated the association between regional cortical thickness abnormalities and rsFC in AN. Twenty-two acute AN patients and twenty-six age- and gender-matched healthy controls underwent a resting-state functional magnetic resonance imaging scan and cognitive tests. We performed group comparisons of whole-brain cortical thickness, seed-based rsFC, and network-based statistical (NBS) analyses. AN patients showed cortical thinning in the precuneus and inferior parietal lobules, regions involved in visuospatial memory and imagery. Cortical thickness in the precuneus correlated with nutritional state and cognitive functions in AN, strengthening the evidence for a critical role of this region in the disorder. Cortical thinning was accompanied by functional connectivity reductions in major brain networks, namely default mode, sensorimotor and visual networks. Similar to the seed-based approach, the NBS analysis revealed a single network of reduced functional connectivity in patients, comprising mainly sensorimotor- occipital regions. Our findings provide evidence that structural and functional brain abnormalities in AN are confined to specific regions and networks involved in visuospatial and somatosensory processing. We show that structural changes of the precuneus are linked to nutritional and functional states in AN, and future longitudinal research should assess how precuneus changes might be related to the evolution of the disorder.
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http://dx.doi.org/10.1038/s41398-021-01237-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862305PMC
February 2021

Cortical thinning and associated connectivity changes in patients with anorexia nervosa.

Transl Psychiatry 2021 Feb 4;11(1):95. Epub 2021 Feb 4.

Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, Jena University Hospital, Jena, Germany.

Structural brain abnormalities are a consistent finding in anorexia nervosa (AN) and proposed as a state biomarker of the disorder. Yet little is known about how regional structural changes affect intrinsic resting-state functional brain connectivity (rsFC). Using a cross-sectional, multimodal imaging approach, we investigated the association between regional cortical thickness abnormalities and rsFC in AN. Twenty-two acute AN patients and twenty-six age- and gender-matched healthy controls underwent a resting-state functional magnetic resonance imaging scan and cognitive tests. We performed group comparisons of whole-brain cortical thickness, seed-based rsFC, and network-based statistical (NBS) analyses. AN patients showed cortical thinning in the precuneus and inferior parietal lobules, regions involved in visuospatial memory and imagery. Cortical thickness in the precuneus correlated with nutritional state and cognitive functions in AN, strengthening the evidence for a critical role of this region in the disorder. Cortical thinning was accompanied by functional connectivity reductions in major brain networks, namely default mode, sensorimotor and visual networks. Similar to the seed-based approach, the NBS analysis revealed a single network of reduced functional connectivity in patients, comprising mainly sensorimotor- occipital regions. Our findings provide evidence that structural and functional brain abnormalities in AN are confined to specific regions and networks involved in visuospatial and somatosensory processing. We show that structural changes of the precuneus are linked to nutritional and functional states in AN, and future longitudinal research should assess how precuneus changes might be related to the evolution of the disorder.
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http://dx.doi.org/10.1038/s41398-021-01237-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862305PMC
February 2021

[Intracoronary imaging - an essential tool on the way to an individualized therapy of coronary artery disease?]

Ther Umsch 2021 Feb;78(1):11-15

Klinik für Kardiologie, Universitätsspital Inselspital Bern.

Intracoronary imaging - an essential tool on the way to an individualized therapy of coronary artery disease? Since decades, coronary angiography is the standard method to assess coronary anatomy and guide percutaneous coronary intervention. However, coronary angiography is limited to the lumen and a resolution of 200 - 300 micrometers. Thus, anything beyond is not detectable. Intracoronary imaging methods by means of intravascular ultrasound (IVUS) and particularly optical coherence tomography (OCT), provide incremental effects on coronary diagnostics and therapeutic decisions. Plaque burden and -composition (lipid, fibrous, calcific tissue, intramural hematoma), small intraluminal structures (thrombus), and implanted stents are uniquely detectable by intracoronary imaging. The use of these techniques inevitably leads to improved precision in coronary diagnostics and optimization of stent implantation.
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http://dx.doi.org/10.1024/0040-5930/a001231DOI Listing
February 2021

Echocardiographic measure of dynamic arterial elastance predict pressure response during norepinephrine weaning: an observational study.

Sci Rep 2021 Feb 2;11(1):2853. Epub 2021 Feb 2.

Department of Anesthesiology and Intensive Care, C.H.U, Dijon, France.

The purpose of this study was to determine whether dynamic elastance E derived from echocardiographic measurements of stroke volume variations can predict the success of a one-step decrease of norepinephrine dose. In this prospective single-center study, 39 patients with vasoplegic syndrome treated with norepinephrine and for whom the attending physician had decided to decrease norepinephrine dose and monitored by thermodilution were analyzed. E is the ratio of pulse pressure variation to stroke volume variation and was calculated from echocardiography stroke volume variations and from transpulmonary thermodilution. Pulse pressure variation was obtained from invasive arterial monitoring. Responders were defined by a decrease in mean arterial pressure (MAP) > 10% following norepinephrine decrease. The median decrease in norepinephrine was of 0.04 [0.03-0.05] µg kg min. Twelve patients (31%) were classified as pressure responders with a median decrease in MAP of 13% [12-15%]. E was lower in pressure responders (0.40 [0.24-0.57] vs 0.95 [0.77-1.09], p < 0.01). E was able to discriminate between pressure responders and non-responders with an area under the curve of 0.86 (CI [0.71 to1.0], p < 0.05). The optimal cut-off was 0.8. E calculated from the echocardiographic estimation of the stroke volume variation and the invasive arterial pulse pressure variation can be used to discriminate pressure response to norepinephrine weaning. Agreement between E calculated from echocardiography and thermodilution was poor. Echocardiographic E might be used at bedside to optimize hemodynamic treatment.
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http://dx.doi.org/10.1038/s41598-021-82408-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854654PMC
February 2021

Hormone seasonality in medical records suggests circannual endocrine circuits.

Proc Natl Acad Sci U S A 2021 Feb;118(7)

Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel;

Hormones control the major biological functions of stress response, growth, metabolism, and reproduction. In animals, these hormones show pronounced seasonality, with different set-points for different seasons. In humans, the seasonality of these hormones remains unclear, due to a lack of datasets large enough to discern common patterns and cover all hormones. Here, we analyze an Israeli health record on 46 million person-years, including millions of hormone blood tests. We find clear seasonal patterns: The effector hormones peak in winter-spring, whereas most of their upstream regulating pituitary hormones peak only months later, in summer. This delay of months is unexpected because known delays in the hormone circuits last hours. We explain the precise delays and amplitudes by proposing and testing a mechanism for the circannual clock: The gland masses grow with a timescale of months due to trophic effects of the hormones, generating a feedback circuit with a natural frequency of about a year that can entrain to the seasons. Thus, humans may show coordinated seasonal set-points with a winter-spring peak in the growth, stress, metabolism, and reproduction axes.
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http://dx.doi.org/10.1073/pnas.2003926118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896322PMC
February 2021

Post-Vaccination COVID-19 among Healthcare Workers, Israel.

Emerg Infect Dis 2021 Feb 1;27(4). Epub 2021 Feb 1.

Coronavirus disease (COVID-19) symptoms can be mistaken for vaccine-related side effects during initial days after immunization. Among 4,081 vaccinated healthcare workers in Israel, 22 (0.54%) developed COVID-19 from 1-10 days (median 3.5 days) after immunization. Clinicians should not dismiss postvaccination symptoms as vaccine-related and should promptly test for COVID-19.
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http://dx.doi.org/10.3201/eid2704.210016DOI Listing
February 2021

Long-Term Survival of Patients with Metastatic Non-Small-Cell Lung Cancer over Five Decades.

J Oncol 2021 12;2021:7836264. Epub 2021 Jan 12.

Affiliated with Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.

Objective: Novel therapeutics and supportive care improved outcomes for metastatic non-small-cell lung cancer (mNSCLC) patients. Major advances over the past five decades include the introduction of combination chemotherapy, small molecules targeting mutant proteins, especially EGFR, and more recently immunotherapy. We aim to document real-world long-term survival over the past five decades.

Methods: Survival statistics were extracted from the Survival, Epidemiology, and End Results (SEER) database for mNSCLC patients during 1973-2015. Two- and five-year survival (2yS and 5yS) were analyzed using Kaplan-Meier and proportional hazard models.

Results: The study population consisted of 280,655mNSCLC patients diagnosed during 1973-2015. Longer survival was seen in younger, female, married, Asian/Pacific Islander race, adenocarcinoma, lower grade, more recent diagnosis, higher income, and chemotherapy-treated patients. 2yS increased during the study period from 2.6% to 12.9%, and 5yS increased from 0.7% to 3.2%. 2yS of patients <50 years of age rose from 2.1% to 22.8%, and their 5yS rose from 0.7% to 6.2%. 2yS of adenocarcinoma patients improved from 2.7% to 16.2%, and their improved 5yS from 1.1% to 3.9%.

Conclusions: Between 1973 and 2015, there was a dramatic improvement in long-term survival, with an approximately five-fold increase in both 2yS and 5yS. Nonetheless, absolute numbers of long-term survivors remained low, with less than 4% living 5 years. This provides a baseline to compare long-term outcomes seen in the current generation of clinical trials.
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http://dx.doi.org/10.1155/2021/7836264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817269PMC
January 2021

Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length.

Geroscience 2021 Jan 31. Epub 2021 Jan 31.

Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.

Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.
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http://dx.doi.org/10.1007/s11357-020-00310-0DOI Listing
January 2021

Root zone warming represses foliar diseases in tomato by inducing systemic immunity.

Plant Cell Environ 2021 Jan 28. Epub 2021 Jan 28.

Department of Plant Pathology and Weed Research, Plant Protection Institute, Agricultural Research Organization, Volcani Center, Rishon LeZion, Israel.

Plants employ systemic-induced resistance as part of their defence arsenal against pathogens. In recent years, the application of mild heating has been found to induce resistance against several pathogens. In the present study, we investigated the effect of root zone warming (RZW) in promoting tomato's resistance against the necrotrophic fungus Botrytis cinerea (Bc), the hemibiotrophic bacterium Xanthomonas campestris pv. vesicatoria (Xcv) and the biotrophic fungus Oidium neolycopersici (On). We demonstrate that RZW enhances tomato's resistance to Bc, On and Xcv through a process that is dependent on salicylic acid and ethylene. RZW induced tomato immunity, resulting in increased defence gene expression, reactive oxygen species (ROS) and ethylene output when plants were challenged, even in the absence of pathogens. Overall, the results provide novel insights into the underlying mechanisms of warming-induced immune responses against phytopathogens with different lifestyles in tomato.
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http://dx.doi.org/10.1111/pce.14006DOI Listing
January 2021

Histologic Chorioamnionitis in Pregnancies Complicated by Preeclampsia and the Effect on Neonatal Outcomes.

Reprod Sci 2021 Jan 25. Epub 2021 Jan 25.

Department of Obstetrics & Gynecology, The Edith Wolfson Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Holon, Israel.

Histological chorioamnionitis (HC) is a common placental finding that represents acute/chronic inflammation and can affect neonatal outcomes. We aimed to examine the effect of HC on neonatal outcomes in pregnancies complicated by preeclampsia. All pregnancies with the diagnosis of preeclampsia at 24-42 weeks between 2008 and 2019 were reviewed. Placental lesions were classified according to the "Amsterdam" criteria. Composite adverse neonatal outcome included ≥1 early complication. Maternal and neonatal outcomes were compared between cases with and without HC. Multivariable regression analysis was performed to identify independent associations with adverse neonatal outcome. Compared to preeclampsia without HC (n=517), preeclampsia with HC (n=55) was characterized by a more advanced gestational age (p<0.001) and a higher rate of nulliparity (p=0.02). Diabetes was more prevalent in preeclampsia without HC (p=0.039) as was a history of previous preeclampsia (p=0.048). Neonates in the preeclampsia with HC group had higher rates of adverse neonatal outcome (p<0.001) and Apgar scores <7 at 5 min (p=0.034) despite a higher birthweight (p=0.005). Preeclampsia without HC was associated with smaller placentas and a higher rate of placental maternal vascular malperfusion lesions (p=0.014 and p<0.001 respectively). By multivariate analysis, gestational age and HC were independently associated with adverse neonatal outcome (aOR 0.88 95% CI 0.76-0.96, and aOR 1.33, 95% CI 1.11-3.09, respectively). In preeclampsia, concomitant HC was associated with adverse neonatal outcome despite a more advanced gestational age and higher neonatal birthweight. This inflammatory mechanism probably plays a role in a more severe subgroup of preeclampsia cases, causing an additional risk for the developing fetus.
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http://dx.doi.org/10.1007/s43032-021-00469-7DOI Listing
January 2021