Publications by authors named "Eran Segal"

194 Publications

COVID-19 dynamics after a national immunization program in Israel.

Nat Med 2021 Apr 19. Epub 2021 Apr 19.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

Studies on the real-life effect of the BNT162b2 vaccine for Coronavirus Disease 2019 (COVID-19) prevention are urgently needed. In this study, we conducted a retrospective analysis of data from the Israeli Ministry of Health collected between 28 August 2020 and 24 February 2021. We studied the temporal dynamics of the number of new COVID-19 cases and hospitalizations after the vaccination campaign, which was initiated on 20 December 2020. To distinguish the possible effects of the vaccination on cases and hospitalizations from other factors, including a third lockdown implemented on 8 January 2021, we performed several comparisons: (1) individuals aged 60 years and older prioritized to receive the vaccine first versus younger age groups; (2) the January lockdown versus the September lockdown; and (3) early-vaccinated versus late-vaccinated cities. A larger and earlier decrease in COVID-19 cases and hospitalization was observed in individuals older than 60 years, followed by younger age groups, by the order of vaccination prioritization. This pattern was not observed in the previous lockdown and was more pronounced in early-vaccinated cities. Our analysis demonstrates the real-life effect of a national vaccination campaign on the pandemic dynamics.
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http://dx.doi.org/10.1038/s41591-021-01337-2DOI Listing
April 2021

The long-term genetic stability and individual specificity of the human gut microbiome.

Cell 2021 Apr 4. Epub 2021 Apr 4.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands. Electronic address:

By following up the gut microbiome, 51 human phenotypes and plasma levels of 1,183 metabolites in 338 individuals after 4 years, we characterize microbial stability and variation in relation to host physiology. Using these individual-specific and temporally stable microbial profiles, including bacterial SNPs and structural variations, we develop a microbial fingerprinting method that shows up to 85% accuracy in classifying metagenomic samples taken 4 years apart. Application of our fingerprinting method to the independent HMP cohort results in 95% accuracy for samples taken 1 year apart. We further observe temporal changes in the abundance of multiple bacterial species, metabolic pathways, and structural variation, as well as strain replacement. We report 190 longitudinal microbial associations with host phenotypes and 519 associations with plasma metabolites. These associations are enriched for cardiometabolic traits, vitamin B, and uremic toxins. Finally, mediation analysis suggests that the gut microbiome may influence cardiometabolic health through its metabolites.
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http://dx.doi.org/10.1016/j.cell.2021.03.024DOI Listing
April 2021

Hospital load and increased COVID-19 related mortality in Israel.

Nat Commun 2021 03 26;12(1):1904. Epub 2021 Mar 26.

Department of Statistics and Operations Research, Tel Aviv University, Ramat Aviv, Israel.

The spread of Coronavirus disease 19 (COVID-19) has led to many healthcare systems being overwhelmed by the rapid emergence of new cases. Here, we study the ramifications of hospital load due to COVID-19 morbidity on in-hospital mortality of patients with COVID-19 by analyzing records of all 22,636 COVID-19 patients hospitalized in Israel from mid-July 2020 to mid-January 2021. We show that even under moderately heavy patient load (>500 countrywide hospitalized severely-ill patients; the Israeli Ministry of Health defined 800 severely-ill patients as the maximum capacity allowing adequate treatment), in-hospital mortality rate of patients with COVID-19 significantly increased compared to periods of lower patient load (250-500 severely-ill patients): 14-day mortality rates were 22.1% (Standard Error 3.1%) higher (mid-September to mid-October) and 27.2% (Standard Error 3.3%) higher (mid-December to mid-January). We further show this higher mortality rate cannot be attributed to changes in the patient population during periods of heavier load.
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http://dx.doi.org/10.1038/s41467-021-22214-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997985PMC
March 2021

Diversity and functional landscapes in the microbiota of animals in the wild.

Science 2021 04 25;372(6539). Epub 2021 Mar 25.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, 7610001 Israel.

Animals in the wild are able to subsist on pathogen-infected and poisonous food and show immunity to various diseases. These may be due to their microbiota, yet we have a poor understanding of animal microbial diversity and function. We used metagenomics to analyze the gut microbiota of more than 180 species in the wild, covering diverse classes, feeding behaviors, geographies, and traits. Using de novo metagenome assembly, we constructed and functionally annotated a database of more than 5000 genomes, comprising 1209 bacterial species of which 75% are unknown. The microbial composition, diversity, and functional content exhibit associations with animal taxonomy, diet, activity, social structure, and life span. We identify the gut microbiota of wild animals as a largely untapped resource for the discovery of therapeutics and biotechnology applications.
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http://dx.doi.org/10.1126/science.abb5352DOI Listing
April 2021

Identification of bacteria-derived HLA-bound peptides in melanoma.

Nature 2021 Apr 17;592(7852):138-143. Epub 2021 Mar 17.

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

A variety of species of bacteria are known to colonize human tumours, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.
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http://dx.doi.org/10.1038/s41586-021-03368-8DOI Listing
April 2021

Signals of hope: gauging the impact of a rapid national vaccination campaign.

Nat Rev Immunol 2021 04;21(4):198-199

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

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http://dx.doi.org/10.1038/s41577-021-00531-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953505PMC
April 2021

Prediction of Childhood Obesity from Nationwide Health Records.

J Pediatr 2021 Feb 11. Epub 2021 Feb 11.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. Electronic address:

Objective: To evaluate body mass index (BMI) acceleration patterns in children and to develop a prediction model targeted to identify children at high risk for obesity before the critical time window in which the largest increase in BMI percentile occurs.

Study Design: We analyzed electronic health records of children from Israel's largest healthcare provider from 2002 to 2018. Data included demographics, anthropometric measurements, medications, diagnoses, and laboratory tests of children and their families. Obesity was defined as BMI ≥95th percentile for age and sex. To identify the time window in which the largest annual increases in BMI z score occurs during early childhood, we first analyzed childhood BMI acceleration patterns among 417 915 adolescents. Next, we devised a model targeted to identify children at high risk before this time window, predicting obesity at 5-6 years of age based on data from the first 2 years of life of 132 262 children.

Results: Retrospective BMI analysis revealed that among adolescents with obesity, the greatest acceleration in BMI z score occurred between 2 and 4 years of age. Our model, validated temporally and geographically, accurately predicted obesity at 5-6 years old (area under the receiver operating characteristic curve of 0.803). Discrimination results on subpopulations demonstrated its robustness across the pediatric population. The model's most influential predictors included anthropometric measurements of the child and family. Other impactful predictors included ancestry and pregnancy glucose.

Conclusions: Rapid rise in the prevalence of childhood obesity warrant the development of better prevention strategies. Our model may allow an accurate identification of children at high risk of obesity.
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http://dx.doi.org/10.1016/j.jpeds.2021.02.010DOI Listing
February 2021

SARS-CoV-2 antibody testing for estimating COVID-19 prevalence in the population.

Cell Rep Med 2021 Feb 14;2(2):100191. Epub 2021 Jan 14.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

Reliable antibody testing against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to uncover the population-wide spread of coronavirus disease 2019 (COVID-19), which is critical for making informed healthcare and economic decisions. Here we review different types of antibody tests available for SARS-CoV-2 and their application for population-scale testing. Biases because of varying test accuracy, results of ongoing large-scale serological studies, and use of antibody testing for monitoring development of herd immunity are summarized. Although current SARS-CoV-2 antibody testing efforts have generated valuable insights, the accuracy of serological tests and the selection criteria for the tested cohorts need to be evaluated carefully.
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http://dx.doi.org/10.1016/j.xcrm.2021.100191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834181PMC
February 2021

The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS).

BMC Med 2021 Jan 20;19(1):13. Epub 2021 Jan 20.

Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.

Background: Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS.

Main Body: The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications.

Conclusion: Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance.
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http://dx.doi.org/10.1186/s12916-020-01885-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816375PMC
January 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Authors:
Alexander Kurilshikov Carolina Medina-Gomez Rodrigo Bacigalupe Djawad Radjabzadeh Jun Wang Ayse Demirkan Caroline I Le Roy Juan Antonio Raygoza Garay Casey T Finnicum Xingrong Liu Daria V Zhernakova Marc Jan Bonder Tue H Hansen Fabian Frost Malte C Rühlemann Williams Turpin Jee-Young Moon Han-Na Kim Kreete Lüll Elad Barkan Shiraz A Shah Myriam Fornage Joanna Szopinska-Tokov Zachary D Wallen Dmitrii Borisevich Lars Agreus Anna Andreasson Corinna Bang Larbi Bedrani Jordana T Bell Hans Bisgaard Michael Boehnke Dorret I Boomsma Robert D Burk Annique Claringbould Kenneth Croitoru Gareth E Davies Cornelia M van Duijn Liesbeth Duijts Gwen Falony Jingyuan Fu Adriaan van der Graaf Torben Hansen Georg Homuth David A Hughes Richard G Ijzerman Matthew A Jackson Vincent W V Jaddoe Marie Joossens Torben Jørgensen Daniel Keszthelyi Rob Knight Markku Laakso Matthias Laudes Lenore J Launer Wolfgang Lieb Aldons J Lusis Ad A M Masclee Henriette A Moll Zlatan Mujagic Qi Qibin Daphna Rothschild Hocheol Shin Søren J Sørensen Claire J Steves Jonathan Thorsen Nicholas J Timpson Raul Y Tito Sara Vieira-Silva Uwe Völker Henry Völzke Urmo Võsa Kaitlin H Wade Susanna Walter Kyoko Watanabe Stefan Weiss Frank U Weiss Omer Weissbrod Harm-Jan Westra Gonneke Willemsen Haydeh Payami Daisy M A E Jonkers Alejandro Arias Vasquez Eco J C de Geus Katie A Meyer Jakob Stokholm Eran Segal Elin Org Cisca Wijmenga Hyung-Lae Kim Robert C Kaplan Tim D Spector Andre G Uitterlinden Fernando Rivadeneira Andre Franke Markus M Lerch Lude Franke Serena Sanna Mauro D'Amato Oluf Pedersen Andrew D Paterson Robert Kraaij Jeroen Raes Alexandra Zhernakova

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Anosmia and other SARS-CoV-2 positive test-associated symptoms, across three national, digital surveillance platforms as the COVID-19 pandemic and response unfolded: an observation study.

medRxiv 2020 Dec 16. Epub 2020 Dec 16.

Background: Multiple participatory surveillance platforms were developed across the world in response to the COVID-19 pandemic, providing a real-time understanding of community-wide COVID-19 epidemiology. During this time, testing criteria broadened and healthcare policies matured. We sought to test whether there were consistent associations of symptoms with SARS-CoV-2 test status across three national surveillance platforms, during periods of testing and policy changes, and whether inconsistencies could better inform our understanding and future studies as the COVID-19 pandemic progresses.

Methods: Four months (1st April 2020 to 31st July 2020) of observation through three volunteer COVID-19 digital surveillance platforms targeting communities in three countries (Israel, United Kingdom, and United States). Logistic regression of self-reported symptom on self-reported SARS-CoV-2 test status (or test access), adjusted for age and sex, in each of the study cohorts. Odds ratios over time were compared to known changes in testing policies and fluctuations in COVID-19 incidence.

Findings: Anosmia/ageusia was the strongest, most consistent symptom associated with a positive COVID-19 test, based on 658325 tests (5% positive) from over 10 million respondents in three digital surveillance platforms using longitudinal and cross-sectional survey methodologies. During higher-incidence periods with broader testing criteria, core COVID-19 symptoms were more strongly associated with test status. Lower incidence periods had, overall, larger confidence intervals.

Interpretation: The strong association of anosmia/ageusia with self-reported SARS-CoV-2 test positivity is omnipresent, supporting its validity as a reliable COVID-19 signal, regardless of the participatory surveillance platform or testing policy. This analysis highlights that precise effect estimates, as well as an understanding of test access patterns to interpret differences, are best done only when incidence is high. These findings strongly support the need for testing access to be as open as possible both for real-time epidemiologic investigation and public health utility.
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http://dx.doi.org/10.1101/2020.12.15.20248096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755145PMC
December 2020

Longitudinal symptom dynamics of COVID-19 infection.

Nat Commun 2020 12 4;11(1):6208. Epub 2020 Dec 4.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

As the COVID-19 pandemic progresses, obtaining information on symptoms dynamics is of essence. Here, we extracted data from primary-care electronic health records and nationwide distributed surveys to assess the longitudinal dynamics of symptoms prior to and throughout SARS-CoV-2 infection. Information was available for 206,377 individuals, including 2471 positive cases. The two datasources were discordant, with survey data capturing most of the symptoms more sensitively. The most prevalent symptoms included fever, cough and fatigue. Loss of taste and smell 3 weeks prior to testing, either self-reported or recorded by physicians, were the most discriminative symptoms for COVID-19. Additional discriminative symptoms included self-reported headache and fatigue and a documentation of syncope, rhinorrhea and fever. Children had a significantly shorter disease duration. Several symptoms were reported weeks after recovery. By a unique integration of two datasources, our study shed light on the longitudinal course of symptoms experienced by cases in primary care.
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http://dx.doi.org/10.1038/s41467-020-20053-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718370PMC
December 2020

A reference map of potential determinants for the human serum metabolome.

Nature 2020 12 11;588(7836):135-140. Epub 2020 Nov 11.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment. The origins of specific compounds are known, including metabolites that are highly heritable, or those that are influenced by the gut microbiome, by lifestyle choices such as smoking, or by diet. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites-in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts that were not available to us when we trained the algorithms. We used feature attribution analysis to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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http://dx.doi.org/10.1038/s41586-020-2896-2DOI Listing
December 2020

Identifying gut microbes that affect human health.

Nature 2020 11;587(7834):373-374

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http://dx.doi.org/10.1038/d41586-020-03069-8DOI Listing
November 2020

A Prediction Model to Prioritize Individuals for a SARS-CoV-2 Test Built from National Symptom Surveys.

Med (N Y) 2021 Feb 10;2(2):196-208.e4. Epub 2020 Oct 10.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

Background: The gold standard for COVID-19 diagnosis is detection of viral RNA through PCR. Due to global limitations in testing capacity, effective prioritization of individuals for testing is essential.

Methods: We devised a model estimating the probability of an individual to test positive for COVID-19 based on answers to 9 simple questions that have been associated with SARS-CoV-2 infection. Our model was devised from a subsample of a national symptom survey that was answered over 2 million times in Israel in its first 2 months and a targeted survey distributed to all residents of several cities in Israel. Overall, 43,752 adults were included, from which 498 self-reported as being COVID-19 positive.

Findings: Our model was validated on a held-out set of individuals from Israel where it achieved an auROC of 0.737 (CI: 0.712-0.759) and auPR of 0.144 (CI: 0.119-0.177) and demonstrated its applicability outside of Israel in an independently collected symptom survey dataset from the US, UK, and Sweden. Our analyses revealed interactions between several symptoms and age, suggesting variation in the clinical manifestation of the disease in different age groups.

Conclusions: Our tool can be used online and without exposure to suspected patients, thus suggesting worldwide utility in combating COVID-19 by better directing the limited testing resources through prioritization of individuals for testing, thereby increasing the rate at which positive individuals can be identified. Moreover, individuals at high risk for a positive test result can be isolated prior to testing.

Funding: E.S. is supported by the Crown Human Genome Center, Larson Charitable Foundation New Scientist Fund, Else Kroener Fresenius Foundation, White Rose International Foundation, Ben B. and Joyce E. Eisenberg Foundation, Nissenbaum Family, Marcos Pinheiro de Andrade and Vanessa Buchheim, Lady Michelle Michels, and Aliza Moussaieff and grants funded by the Minerva foundation with funding from the Federal German Ministry for Education and Research and by the European Research Council and the Israel Science Foundation. H.R. is supported by the Israeli Council for Higher Education (CHE) via the Weizmann Data Science Research Center and by a research grant from Madame Olga Klein - Astrachan.
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http://dx.doi.org/10.1016/j.medj.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547576PMC
February 2021

Rationale and design of a randomised controlled trial testing the effect of personalised diet in individuals with pre-diabetes or type 2 diabetes mellitus treated with metformin.

BMJ Open 2020 10 10;10(10):e037859. Epub 2020 Oct 10.

Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

Introduction: Metformin and diets aimed at promoting healthy body weight are the first line in treating type 2 diabetes mellitus (T2DM). Clinical practice, backed by clinical trials, suggests that many individuals do not reach glycaemic targets using this approach alone. The primary aim of the Personalised Medicine in Pre-diabetes-Towards Preventing Diabetes in Individuals at Risk (PREDICT) Study is to test the efficacy of personalised diet as adjuvant to metformin in improving glycaemic control in individuals with dysglycaemia.

Methods And Analysis: PREDICT is a two-arm, parallel group, single-masked randomised controlled trial in adults with pre-diabetes or early-stage T2DM (with glycated haemoglobin (HbA1c) up to 8.0% (64 mmol/mol)), not treated with glucose-lowering medication. PREDICT is conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney). Enrolment of participants commenced in December 2018 and expected to complete in December 2021. Participants are commenced on metformin (Extended Release, titrated to a target dose of 1500 mg/day) and randomised with equal allocation to either (1) the Personalised Nutrition Project algorithm-based diet or (2) low-fat high-dietary fibre diet, designed to provide caloric restriction (75%) in individuals with body mass index >25 kg/m. Treatment duration is 6 months and participants visit the Clinical Research Facility five times over approximately 7 months. The primary outcome measure is HbA1c. The secondary outcomes are (1) time of interstitial glucose <7.8 mmol/L and (2) glycaemic variability (continuous glucose monitoring), (3) body weight, (4) fat mass and (5) abdominal visceral fat volume (dual-energy X-ray absorptiometry), serum (6) low-density lipoprotein cholesterol (7) high-density lipoprotein cholesterol and (8) triglycerides concentrations, (9) blood pressure, and (10) liver fat (Fibroscan).

Ethics And Dissemination: The study has been approved by the St Vincent's Hospital Human Research Ethics Committee (File 17/080, Sydney, Australia) and the Weizmann Institutional Review Board (File 528-3, Rehovot, Israel). The findings will be published in peer-reviewed open access medical journals.

Trial Registration Number: NCT03558867; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-037859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552859PMC
October 2020

The Gut Microbiome and Individual-Specific Responses to Diet.

mSystems 2020 Sep 29;5(5). Epub 2020 Sep 29.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

Nutritional content and timing are increasingly appreciated to constitute important human variables collectively impacting all aspects of human physiology and disease. However, person-specific mechanisms driving nutritional impacts on the human host remain incompletely understood, while current dietary recommendations remain empirical and nonpersonalized. Precision nutrition aims to harness individualized bodies of data, including the human gut microbiome, in predicting person-specific physiological responses (such as glycemic responses) to food. With these advances notwithstanding, many unknowns remain, including the long-term efficacy of such interventions in delaying or reversing human metabolic disease, mechanisms driving these dietary effects, and the extent of the contribution of the gut microbiome to these processes. We summarize these conceptual advances, while highlighting challenges and means of addressing them in the next decade of study of precision medicine, toward generation of insights that may help to evolve precision nutrition as an effective future tool in a variety of "multifactorial" human disorders.
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http://dx.doi.org/10.1128/mSystems.00665-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527138PMC
September 2020

Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome.

Cell 2020 Sep 10;182(6):1460-1473.e17. Epub 2020 Sep 10.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2020.08.007DOI Listing
September 2020

The road ahead in genetics and genomics.

Nat Rev Genet 2020 10 24;21(10):581-596. Epub 2020 Aug 24.

Center for Genome Engineering, Institute for Basic Science, Daejon, Republic of Korea.

In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone.
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http://dx.doi.org/10.1038/s41576-020-0272-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444682PMC
October 2020

[DIFFUSE ALVEOLAR BLEEDING IN A PATIENT AFTER GENERAL ANESTHESIA FOR KNEE SURGERY].

Harefuah 2020 Jun;159(6):410-413

Department of Anesthesiology and Critical Care, Assuta Medical Center, Tel-Aviv.

Introduction: A 35-year old male, generally healthy, underwent knee arthroscopy with general anesthesia with a laryngeal mask. Postoperatively, he developed decreased oxygenation and hemoptysis. A chest x-ray and a chest CT presented bilateral diffuse ground glass infiltrates. No other pathology was found. The patient was treated with oxygen enrichment, his condition quickly improved and he was discharged home on postoperative day two. The clinical picture is consistent with diffuse alveolar damage due to extreme negative alveolar pressure secondary to upper airway obstruction. This paper will discuss the differential diagnosis of diffuse alveolar bleeding, the pathophysiology of negative pressure pulmonary edema and negative pressure pulmonary hemorrhage and the recommended treatment.
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June 2020

High-throughput interrogation of programmed ribosomal frameshifting in human cells.

Nat Commun 2020 06 16;11(1):3061. Epub 2020 Jun 16.

Department of Computer Science and Applied Mathematics, Rehovot, 7610001, Israel.

Programmed ribosomal frameshifting (PRF) is the controlled slippage of the translating ribosome to an alternative frame. This process is widely employed by human viruses such as HIV and SARS coronavirus and is critical for their replication. Here, we developed a high-throughput approach to assess the frameshifting potential of a sequence. We designed and tested >12,000 sequences based on 15 viral and human PRF events, allowing us to systematically dissect the rules governing ribosomal frameshifting and discover novel regulatory inputs based on amino acid properties and tRNA availability. We assessed the natural variation in HIV gag-pol frameshifting rates by testing >500 clinical isolates and identified subtype-specific differences and associations between viral load in patients and the optimality of PRF rates. We devised computational models that accurately predict frameshifting potential and frameshifting rates, including subtle differences between HIV isolates. This approach can contribute to the development of antiviral agents targeting PRF.
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http://dx.doi.org/10.1038/s41467-020-16961-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297798PMC
June 2020

Gene Architecture and Sequence Composition Underpin Selective Dependency of Nuclear Export of Long RNAs on NXF1 and the TREX Complex.

Mol Cell 2020 07 5;79(2):251-267.e6. Epub 2020 Jun 5.

Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

The core components of the nuclear RNA export pathway are thought to be required for export of virtually all polyadenylated RNAs. Here, we depleted different proteins that act in nuclear export in human cells and quantified the transcriptome-wide consequences on RNA localization. Different genes exhibited substantially variable sensitivities, with depletion of NXF1 and TREX components causing some transcripts to become strongly retained in the nucleus while others were not affected. Specifically, NXF1 is preferentially required for export of single- or few-exon transcripts with long exons or high A/U content, whereas depletion of TREX complex components preferentially affects spliced and G/C-rich transcripts. Using massively parallel reporter assays, we identified short sequence elements that render transcripts dependent on NXF1 for their export and identified synergistic effects of splicing and NXF1. These results revise the current model of how nuclear export shapes the distribution of RNA within human cells.
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http://dx.doi.org/10.1016/j.molcel.2020.05.013DOI Listing
July 2020

The human tumor microbiome is composed of tumor type-specific intracellular bacteria.

Science 2020 05;368(6494):973-980

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.
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http://dx.doi.org/10.1126/science.aay9189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757858PMC
May 2020

Visualizing the structure and motion of the long noncoding RNA HOTAIR.

RNA 2020 05 27;26(5):629-636. Epub 2020 Feb 27.

Augmanity, Rehovot 7670308, Israel.

Long noncoding RNA molecules (lncRNAs) are estimated to account for the majority of eukaryotic genomic transcripts, and have been associated with multiple diseases in humans. However, our understanding of their structure-function relationships is scarce, with structural evidence coming mostly from indirect biochemical approaches or computational predictions. Here we describe direct visualization of the lncRNA HOTAIR (HOx Transcript AntIsense RNA) using atomic force microscopy (AFM) in nucleus-like conditions at 37°. Our observations reveal that HOTAIR has a discernible, although flexible, shape. Fast AFM scanning enabled the quantification of the motion of HOTAIR, and provided visual evidence of physical interactions with genomic DNA segments. Our report provides a biologically plausible description of the anatomy and intrinsic properties of HOTAIR, and presents a framework for studying the structural biology of lncRNAs.
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http://dx.doi.org/10.1261/rna.074633.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161352PMC
May 2020

Rich data sets could end costly drug discovery.

Authors:
Eran Segal

Nature 2020 01;577(7792):S19

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http://dx.doi.org/10.1038/d41586-020-00200-7DOI Listing
January 2020

Prediction of gestational diabetes based on nationwide electronic health records.

Nat Med 2020 01 13;26(1):71-76. Epub 2020 Jan 13.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

Gestational diabetes mellitus (GDM) poses increased risk of short- and long-term complications for mother and offspring. GDM is typically diagnosed at 24-28 weeks of gestation, but earlier detection is desirable as this may prevent or considerably reduce the risk of adverse pregnancy outcomes. Here we used a machine-learning approach to predict GDM on retrospective data of 588,622 pregnancies in Israel for which comprehensive electronic health records were available. Our models predict GDM with high accuracy even at pregnancy initiation (area under the receiver operating curve (auROC) = 0.85), substantially outperforming a baseline risk score (auROC = 0.68). We validated our results on both a future validation set and a geographical validation set from the most populated city in Israel, Jerusalem, thereby emulating real-world performance. Interrogating our model, we uncovered previously unreported risk factors, including results of previous pregnancy glucose challenge tests. Finally, we devised a simpler model based on just nine questions that a patient could answer, with only a modest reduction in accuracy (auROC = 0.80). Overall, our models may allow early-stage intervention in high-risk women, as well as a cost-effective screening approach that could avoid the need for glucose tolerance tests by identifying low-risk women. Future prospective studies and studies on additional populations are needed to assess the real-world clinical utility of the model.
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http://dx.doi.org/10.1038/s41591-019-0724-8DOI Listing
January 2020