Ronen Fluss - Academia.edu (original) (raw)

Papers by Ronen Fluss

BMJ Open

IntroductionPancreatic cancer is characterised by severe mid-back and epigastric pain caused by t... more IntroductionPancreatic cancer is characterised by severe mid-back and epigastric pain caused by tumour invasion of the coeliac nerve plexus. This pain is often poorly managed with standard treatments. This clinical trial investigates a novel approach in which high-dose radiation (radiosurgery) is targeted to the retroperitoneal coeliac plexus nerve bundle. Preliminary results from a single institution pilot trial are promising: pain relief is substantial and side effects minimal. The goals of this study are to validate these findings in an international multisetting, and investigate the impact on quality of life and functional status among patients with terminal cancer.Methods and analysisA single-arm prospective phase II clinical trial. Eligible patients are required to have severe coeliac pain of at least five on the 11-point BPI average pain scale and Eastern Cooperative Oncology Group performance status of two or better. Non-pancreatic cancers invading the coeliac plexus are als...

JAMA Network Open

ImportanceThe BNT162b2 two-dose vaccine (BioNTech/Pfizer) has high effectiveness that wanes withi... more ImportanceThe BNT162b2 two-dose vaccine (BioNTech/Pfizer) has high effectiveness that wanes within several months. The third dose is effective in mounting a significant immune response, but its durability is unknown.ObjectiveTo compare antibody waning after second and third doses and estimate the association of antibody kinetics with susceptibility to infection with the Omicron variant of SARS-CoV-2.Design, Setting, and ParticipantsIn a prospective longitudinal cohort study in a tertiary medical center in Israel, health care workers who received the BNT162b2 vaccine were followed up monthly for IgG and neutralizing antibody levels. Linear mixed models were used to compare antibody titer waning of second and third doses and to assess whether antibody dynamics were associated with Omicron transmission. Avidity, T cell activation, and microneutralization of sera against different variants of concern were assessed for a subgroup.ExposureVaccination with a booster dose of the BNT162b2 va...

Nature Immunology

As the effectiveness of a two-dose messenger RNA (mRNA) severe acute respiratory syndrome coronav... more As the effectiveness of a two-dose messenger RNA (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine regimen decreases with time, a third dose has been recommended. Here, we assessed immunogenicity, vaccine effectiveness and safety of the third BNT162b2 vaccine dose in a prospective cohort study of 12,413 healthcare workers (HCWs). Anti-RBD immunoglobulin G (IgG) levels were increased 1.7-fold after a third dose compared with following the second dose. Increased avidity from 61.1% (95% confidence interval (CI), 56.1-66.7) to 96.3% (95% CI, 94.2-98.5) resulted in a 6.1-fold increase in neutralization titer. Peri-infection humoral markers of 13 third-dose Delta variant of concern (VOC) breakthrough cases were lower compared with 52 matched controls. Vaccine effectiveness of the third dose relative to two doses was 85.6% (95% CI, 79.2-90.1). No serious adverse effects were reported. These results suggest that the third dose is superior to the second dose in both quantity and quality of IgG antibodies and safely boosts protection from infection.

BackgroundTwo doses of the BNT162b2 vaccine yielded high effectiveness that wanes within several ... more BackgroundTwo doses of the BNT162b2 vaccine yielded high effectiveness that wanes within several months. The third dose was effective in mounting a significant humoral and cellular immune response..MethodsWe followed BNT162b2-vaccinated health-care workers monthly for IgG and neutralizing antibody (NeutAb) titers. Avidity, T-cell activation and microneutralization of sera against different variants of concern (VOC) were assessed for a sub-cohort. Linear mixed models were used to compare the durability of the second and third doses, and to assess if Omicron breakthrough infections were associated with waning dynamics.ResultsOverall 3972 participants with a third dose were followed, the rate of waning of IgG and NeutAb was slower after the third (1.32%/day and 1.32%/day, respectively) compared to the second (2.26%/per day and 3.34%/day) dose. Live-neutralization of Omicron VOC was lower compared to previous strains and demonstrated similar waning from 111 (95%CI:75-166) to 26 (95%CI:1...

Clinical Infectious Diseases

Background Tolerance is the ability of bacteria to survive transient exposure to high concentrati... more Background Tolerance is the ability of bacteria to survive transient exposure to high concentrations of a bactericidal antibiotic without a change in the minimal inhibitory concentration, thereby limiting the efficacy of antimicrobials. The study sought to determine the prevalence of tolerance in a prospective cohort of E. coli bloodstream infection and to explore the association of tolerance with reinfection risk. Methods Tolerance, determined by the Tolerance Disk Test (TDtest), was tested in a prospective cohort of consecutive patient-unique E. coli bloodstream isolates and a collection of strains from patients who had recurrent blood cultures with E. coli (cohorts 1 and 2, respectively). Selected isolates were further analyzed using time-dependent killing and typed using whole-genome sequencing. Covariate data were retrieved from electronic medical records. The association between tolerance and reinfection was assessed by the Cox proportional-hazards regression and a Poisson reg...

New England Journal of Medicine, 2022

Journal of the European Academy of Dermatology and Venereology, 2022

Testicular germ-cell tumors (TGCT) are the most common cancer among young adult men. Previous stu... more Testicular germ-cell tumors (TGCT) are the most common cancer among young adult men. Previous studies suggested TGCT survivors have an increased risk for skin cancer. The goal of this study was to systematically review the literature and evidence regarding skin cancer risk among TGCT survivors compared to the general population. PubMed, Embase, Web of Science, Cochrane Databases, and reference lists were included in the search. A systematic review of all comparative studies with more than 10 TGCT survivors reporting on skin cancer incidence was performed. A meta-analysis of the Standardized Incidence Rate (SIR) was calculated by pooling study-specific log transformed estimates using the random-effects model. Risk of bias was assessed using the Newcastle - Ottawa Quality Assessment Scale. Nineteen studies that reported on 147,935 TGCT survivors were included. pooled SIR for skin cancer and for melanoma incidence among TGCT survivors was 1.93 (95% CI 1.62-2.29, P<0.0001) and 1.81 (95% CI 1.57-2.08, P<0.0001), respectively. In conclusion, compared to the general population, TGCT survivors have an increased risk for developing skin cancer and melanoma. Additional long-term studies that include TGCT survivors, additional risk factors and all subtypes of skin cancer are required.

In a prospective cohort study involving 12,413 Health Care Workers (HCW), we assessed immunogenic... more In a prospective cohort study involving 12,413 Health Care Workers (HCW), we assessed immunogenicity, vaccine-effectiveness (VE) and safety of the third BNT162b2 vaccine dose. One month after third dose, anti-RBD-IgG were induced 1.7-folds compared to one month after the second. A significant increase in avidity from 61.1% (95%CI:56.1-66.7) to 96.3% (95%CI:94.2-98.5) resulted in a 6.1-folds neutralizing antibodies induction. Linear mixed model demonstrated that the third dose elicited a greater response among HCW≥60 or those with ≥two comorbidities who had a lower response following the second dose. VE of the third dose relative to two doses was 85.6% (95% CI, 79.2-90.1%). No serious adverse effects were reported. These results suggest that the third dose is superior to the second dose in both quantity and quality of IgG-antibodies and safely boosts protection from SARS-CoV-2 infection by generating high avidity antibodies to levels that are not significantly different between healt...

Social Science Research Network, 2021

Background: Concurrent to BNT162b2 vaccine rollout in Israel, we performed a longitudinal prospec... more Background: Concurrent to BNT162b2 vaccine rollout in Israel, we performed a longitudinal prospective cohort study to assess the early antibody response and antibody kinetics after each vaccine dose among health care workers (HCW) of different ages, gender and co-morbidities. Methods: Overall 2,607 vaccinated HCW were followed for five weeks after vaccination and Immunoglobulin (Ig)M, IgA, IgG and neutralizing antibodies were measured by Beckman-coulter SARS-CoV-2 RBD IgG, ELISA-RBD and pseudo-virus neutralization assays. Scatter plot and correlation analyses, logistic and linear regression analyses and linear mixed models were used to investigate the longitudinal antibody response. Findings: The first vaccine dose elicited low IgG and neutralizing antibody response in the majority of HCW which were rapidly induced 10 and 32 folds, respectively following the second vaccine dose. High (r=0.92) correlation was detected between IgG and neutralizing titers. First dose induced IgG res...

New England Journal of Medicine, 2021

BACKGROUND Despite high vaccine coverage and effectiveness, the incidence of symptomatic infectio... more BACKGROUND Despite high vaccine coverage and effectiveness, the incidence of symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been increasing in Israel. Whether the increasing incidence of infection is due to waning immunity after the receipt of two doses of the BNT162b2 vaccine is unclear. METHODS We conducted a 6-month longitudinal prospective study involving vaccinated health care workers who were tested monthly for the presence of anti-spike IgG and neutralizing antibodies. Linear mixed models were used to assess the dynamics of antibody levels and to determine predictors of antibody levels at 6 months. RESULTS The study included 4868 participants, with 3808 being included in the linear mixed-model analyses. The level of IgG antibodies decreased at a consistent rate, whereas the neutralizing antibody level decreased rapidly for the first 3 months with a relatively slow decrease thereafter. Although IgG antibody levels were highly correlated with neutralizing antibody titers (Spearman's rank correlation between 0.68 and 0.75), the regression relationship between the IgG and neutralizing antibody levels depended on the time since receipt of the second vaccine dose. Six months after receipt of the second dose, neutralizing antibody titers were substantially lower among men than among women (ratio of means, 0.64; 95% confidence interval [CI], 0.55 to 0.75), lower among persons 65 years of age or older than among those 18 to less than 45 years of age (ratio of means, 0.58; 95% CI, 0.48 to 0.70), and lower among participants with immunosuppression than among those without immunosuppression (ratio of means, 0.30; 95% CI, 0.20 to 0.46). CONCLUSIONS Six months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.

The Lancet Respiratory Medicine, 2021

Background Concurrent with the Pfizer-BioNTech BNT162b2 COVID-19 vaccine roll-out in Israel initi... more Background Concurrent with the Pfizer-BioNTech BNT162b2 COVID-19 vaccine roll-out in Israel initiated on Dec 19, 2020, we assessed the early antibody responses and antibody kinetics after each vaccine dose in health-care workers of different ages and sexes, and with different comorbidities. Methods We did a prospective, single-centre, longitudinal cohort study at the Sheba Medical Centre (Tel-Hashomer, Israel). Eligible participants were health-care workers at the centre who had a negative anti-SARS-CoV-2 IgG assay before receiving the first dose of the intramuscular vaccine, and at least one serological antibody test after the first dose of the vaccine. Health-care workers with a positive SARS-CoV-2 PCR test before vaccination, a positive anti-SARS-CoV-2 IgG serology test before vaccination, or infection with COVID-19 after vaccination were excluded from the study. Participants were followed up weekly for 5 weeks after the first vaccine dose; a second dose was given at week 3. Serum samples were obtained at baseline and at each weekly follow-up, and antibodies were tested at 1-2 weeks after the first vaccine dose, at week 3 with the administration of the second vaccine dose, and at weeks 4-5 (ie, 1-2 weeks after the second vaccine dose). Participants with comorbidities were approached to participate in an enriched comorbidities subgroup, and at least two neutralising assays were done during the 5 weeks of follow-up in those individuals. IgG assays were done for the entire study population, whereas IgM, IgA, and neutralising antibody assays were done only in the enriched comorbidities subgroup. Concentrations of IgG greater than 0•62 sample-to-cutoff (s/co) ratio and of IgA greater than 1•1 s/co, and titres of neutralising antibodies greater than 10 were considered positive. Scatter plot and correlation analyses, logistic and linear regression analyses, and linear mixed models were used to investigate the longitudinal antibody responses.

ABSTRACTBackgroundIsraeli has vaccinated over 80% of its adult population, with two doses of the ... more ABSTRACTBackgroundIsraeli has vaccinated over 80% of its adult population, with two doses of the Pfizer BNT162b2 vaccine. This intervention has been highly successful in curtailing the coronavirus 2 outbreak. One major concern is the ability of the virus to mutate which potentially can cause SARS-CoV-2 to partially escape from the immune system. Here we evaluate the efficacy of the Pfizer vaccine against the B.1.351 variant.MethodsThe Ministry of Health, initiated sequencing of selected positive swab samples identified as being of interest. We used logistic regression, with variant type as the dependent variable, vaccination status as the main explanatory variable, controlling for age, sex, subpopulation, place of residence and time of sample, to estimate the odds ratio for a vaccinated case to have the B. 1.351 versus the B.1.1.7 variant, within vaccinated and unvaccinated persons who tested positive.FindingsThere were 19 cases of B.1.351 variant (3.2%) among those vaccinated more ...

Worldwide shortage of vaccination against SARS-CoV-2 infection while the pandemic is still uncont... more Worldwide shortage of vaccination against SARS-CoV-2 infection while the pandemic is still uncontrolled leads many states to the dilemma whether or not to vaccinate previously infected persons. Understanding the level of protection of previous infection compared to that of vaccination is critical for policy making. We analyze an updated individual-level database of the entire population of Israel to assess the protection efficacy of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19. Vaccination was highly effective with overall estimated efficacy for documented infection of 92·8% (CI:[92·6, 93·0]); hospitalization 94·2% (CI:[93·6, 94·7]); severe illness 94·4% (CI:[93·6, 95·0]); and death 93·7% (CI:[92·5, 94·7]). Similarly, the overall estimated level of protection from prior SARS-CoV-2 infection for documented infection is 94·8% (CI:[94·4, 95·1]); hospitalization 94·1% (CI:[91·...

Journal of Clinical Oncology, 2019

TPS466 Background: Many cancer patients, especially those with pancreatic cancer, suffer from sev... more TPS466 Background: Many cancer patients, especially those with pancreatic cancer, suffer from severe back/epigastric pain. Contemporary approaches (opioids, celiac blocks, systemic chemotherapy) are often inadequate. This clinical trial investigates a new approach in which high-dose radiation (radiosurgery) is focused on the retroperitoneal celiac plexus nerve bundle. Preliminary results from a single institution pilot trial NCT02356406 are promising: pain relief is substantial and side effects minimal. The main aim of the trial is to establish safety/efficacy in the setting of an international multicenter study. Exploratory analyses will examine the relationship between pain reduction and subjects’ quality-of-life, functionality, and caregiver burden. Methods: Eligibility criteria include a diagnosis of metastatic/unresectable malignancy, uncontrolled pain defined as ≥ 5 on 11-point BPI-SF scale despite analgesic use, typical retroperitoneal pain syndrome, prognosis > 8 weeks, E...

Environmental Microbiology, 2019

Predatory interactions are affected by landscape fragmentation both at the microbial and at the m... more Predatory interactions are affected by landscape fragmentation both at the microbial and at the macro-organismal scale, leading to enhanced coexistence of predator and prey. Yet, interactions between organisms may be affected by scale-dependent physical and biological phenomena. Using soil microcosms, and statistical and physical models, we show that at the microbial scale, water plays a key role in controlling predation dynamics in soils, in a thresholddependent manner related to the physical structure of the matrix, which in turn affects predation under high water contents. Under the threshold, water connectivity breaks down, leading to predator extinction. These findings are relevant to microbial interactions at large and may be helpful for devising biocontrol strategies of deleterious microorganisms. Summary Natural landscapes are both fragmented and heterogeneous, affecting the distribution of organisms, and in turn their interactions. While predation in homogeneous environments increases the probability of population extinction, fragmentation/heterogeneity promotes coexistence and enhance community stability as shown by experimentation with animals and microorganisms, and supported by theory. Patch connectivity can modulate such effects but how microbial predatory interactions are affected by water-driven connectivity is unknown. In soil, patch habitability by microorganisms, and their connectivity depend upon the water saturation degree (SD). Here, using the obligate bacterial predator Bdellovibrio bacteriovorus, and a Burkholderia prey, we show that soil spatial heterogeneity profoundly affects predatory dynamics, enhancing long-term coexistence of predator and prey in a SDthreshold dependent-manner. However, as patches and connectors cannot be distinguished in these soil matrices, metapopulations cannot be invoked to explain the dynamics of increased persistence. Using a set of experiments combined with statistical and physical models statistical and physical models we demonstrate and quantify how under full connectivity, predation is independent of the water content but depends on soil microstructure characteristics. In contrast, the SD below which predation is largely impaired corresponds to a threshold below which the water network collapses and water connectivity breaks down, preventing the bacteria to move within the soil matrix.

JNCI Cancer Spectrum, 2019

Background Improving lung cancer risk assessment is required because current early-detection scre... more Background Improving lung cancer risk assessment is required because current early-detection screening criteria miss most cases. We therefore examined the utility for lung cancer risk assessment of a DNA Repair score obtained from OGG1, MPG, and APE1 blood tests. In addition, we examined the relationship between the level of DNA repair and global gene expression. Methods We conducted a blinded case-control study with 150 non–small cell lung cancer case patients and 143 control individuals. DNA Repair activity was measured in peripheral blood mononuclear cells, and the transcriptome of nasal and bronchial cells was determined by RNA sequencing. A combined DNA Repair score was formed using logistic regression, and its correlation with disease was assessed using cross-validation; correlation of expression to DNA Repair was analyzed using Gene Ontology enrichment. Results DNA Repair score was lower in case patients than in control individuals, regardless of the case’s disease stage. Ind...

Journal of Autism and Developmental Disorders, 2019

This meta-analysis updated evidence regarding sensory over-responsivity (SOR), under-responsivity... more This meta-analysis updated evidence regarding sensory over-responsivity (SOR), under-responsivity (SUR) and seeking symptoms in individuals with autism spectrum disorders (ASDs) relative to typical controls and those with other conditions. Fifty-five questionnaire studies included 4606 individuals with ASD. Moderators tested were age, IQ, male ratio, matching group, and self-report. Compared to typical controls, effect size was large and significant for SOR, SUR, and Seeking but heterogeneous. For Seeking, age, IQ and self-report were significant moderators. Compared with developmental disorders (DDs) groups, effect size was significantly positive for SOR and Seeking; whereas compared with other clinical groups, only SOR was significant. These findings highlight the core nature of sensory symptoms in ASD and particularly SOR. Explanatory factors are yet to be revealed.

Clinical Microbiology and Infection, 2019

Objectives: The role of asymptomatic carriers in Clostridioides difficile infection (CDI) epidemi... more Objectives: The role of asymptomatic carriers in Clostridioides difficile infection (CDI) epidemiology is not fully understood. Our aim was to evaluate CD carriage prevalence on admission, associated risk factors, and the risk of developing CDI. Methods: A 10-week surveillance program for CD carriage of all medical patients admitted to the Sheba Medical Centre was implemented, utilizing an admission rectal swab PCR. Healthcare facility-onset CDI (HO-CDI) was recorded and divided into HO-CDI diagnosed in CD carriers and non-carriers. Results: A total of 4601 admissions were recorded in 3803 patients; 2368 patients had technically analysable rectal swabs, of whom 81 (3.4%) were CD carriers. A multivariate logistic regression model showed that previous hospitalization, old age (>85 years) and low Norton scores were significant independent predictors of CD carriage. Carriers were more likely to receive antimicrobial therapy during hospitalization than non-carriers were. The incidence of HO-CDI in non-carriers was 4.6 cases per 10 000 patient-days; the incidence of HO-CDI in carriers was 76.7 cases per 10 000 patient-days (RR 16.6, 95% CI 4.0e69.1, p .002). Conclusions: In a prospective study, the rate of CD carriage on admission in medical patients was 3.4%. CD carriers were older, frailer, and more likely to have been hospitalized recently. HO-CDI incidence was significantly higher among CD carriers than among non-carriers, with at least a third of CDI in screened patients developing in carriers. Targeted screening of high-risk groups for CD carriage should be further considered.

Epidemiology, 2018

Background.-Traffic-related air pollution has been linked to multiple adverse pregnancy outcomes.... more Background.-Traffic-related air pollution has been linked to multiple adverse pregnancy outcomes. However, few studies have examined pregnancy loss, targeting losses identified by hospital records, a large limitation as it does not capture events not reported to the medical system.