Background:Retroperitoneal pain syndrome seen in pancreatic cancer is a major clinical challenge. Celiac plexus radiosurgery, a new palliative technique for retroperitoneal pain syndrome, decreased pain levels in a phase II study. Here Health-Related Quality of Life (HRQOL) outcomes are reported. Methods:Evaluable patients, who were enrolled between January 2018 and December 2021, in an international single-arm Phase II ethics-approved study (NCT03323489), were included. The pre-specified secondary endpoint-change in HRQOL from baseline to 3- and 6-weeks post-treatment, was measured by the Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) version 4 questionnaire. Mean change was deemed clinically significant (CS) if the lower bound of the 95% confidence interval was above the predefined minimal clinically important difference (MCID) for that outcome. Findings:Of 90 evaluable patients, 51 (57%) and 44 (49%) had HRQOL FACT-Hep scores available at 3- and 6-weeks, compared to baseline. The majority of patients had pancreatic cancer (90%) and mean daily intravenous morphine equivalent consumption was 35.9 mg (SD 67.6).The mean increase of FACT-Hep total score from baseline was 9.3 points at 3-weeks (p = 0.0017) and 19.6 points at 6-weeks (p < 0.0001, 95% CI 13-26.3), representing a statistically significant (SS) 22% improvement from baseline, with CS demonstrated at 6-weeks. A sensitivity analysis, imputing no change from baseline in patients with missing data, demonstrated similar results. On multivariable analysis, lower baseline opioid use and baseline FACT-Hep scores were associated with an increased change in FACT-Hep from baseline to 3-weeks. Interpretation:Celiac plexus radiosurgery was associated with a SS improvement in HRQOL amongst patients with retroperitoneal pain at 3-weeks, and a SS and CS improvement at 6-weeks post intervention. Funding:This study received major financial support provided by Gateway for Cancer Research (G-17-100), additional support was provided from the Israel Cancer Association (20170128 and 20181272).

BACKGROUND:Data on drug safety in multimorbid older-adults are limited, as clinical trials often apply upper age limits and focus on individual drugs or specific combinations. We aimed to explore high-risk drug patterns in community-dwelling older-adults, and their associations with long-term mortality. METHODS:We included 1,048 participants from a longitudinal population-based cohort, all taking at least one medication. Participants were examined in 1999-2007 and followed for mortality through March 2022. Individuals with similar profiles of high-risk drugs, identified using Beers criteria as potentially inappropriate for most older adults or requiring caution, were grouped using agglomerative hierarchical clustering. Cox and competing-risk regressions were used to examine the associations of the high-risk drug patterns with all-cause and non-cancer mortality. RESULTS:The most prevalent morbidities among participants (mean age 73.3 ± 7.3 years, 55.9% women) were hypertension (55.3%) and cardiovascular diseases (45.5%), and 77.7% took at least one high-risk drug. Five distinct patterns were identified: 'None' cluster (no dominant high-risk drug); 'Calcium channel blockers' (CCBs) cluster, with high nonsteroidal anti-inflammatory drug (NSAID) prevalence; 'Renin-angiotensin-aldosterone system (RAAS) inhibitors' cluster, with a high concomitant use of sulfonylureas compared to other clusters; 'Diuretics' cluster, with a relatively high prevalence of antithrombotics and proton pump inhibitors; and 'Benzodiazepines' cluster, with a relatively high antidepressant prevalence. Clusters differed by age, sex, ethnicity, and health characteristics. In multivariable analysis, the 'Diuretics' cluster was associated with increased all-cause (HR = 1.33, 95%CI: 1.03-1.72) and non-cancer (HR = 1.41, 95%CI: 1.03-1.93) mortality compared to the 'None' cluster. The 'CCBs' cluster was associated with a greater risk for non-cancer mortality. Several drug combinations were identified as potential contributors to the increased risk observed in these clusters, including the concomitant use of NSAIDs and antihypertensives and a possible CCB-diuretic prescribing cascade. CONCLUSIONS:Examining high-risk drug patterns offers a patient-centered approach to improving evidence-based medication guidelines and facilitating early interventions for vulnerable older-adults.

BACKGROUND:Over the years, reports have associated fluoroquinolones (FQ) with seizures. The incidence and whether FQ compared to non-epileptogenic antibiotic are associated with increased risk of seizures has yet to be examined. METHODS:A retrospective observational study of hospitalized patients treated with FQ (ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin) or macrolides (MA: azithromycin or roxithromycin) between January 2009 and January 2021 in a large tertiary academic medical centre. The outcome was the occurrence of a seizure during treatment. The Naranjo scale was used to assess causality between FQ treatment and seizures. Comparative analysis was conducted using propensity score matching to correct for possible bias due to non-random selection, followed by inverse probability weighting (IPW) to estimate the difference in seizure risk between FQ and MA. RESULTS:Overall, 52 722 patients were treated with FQ during a total of 178 982 days. Mean age was 65 (±19) years and 47% were females. Thirty-three patients (0.06%) experienced a seizure, yielding an incidence of 1:5422 treatment days. Causality was deemed probable and possible among 9/33 and 24/33, respectively. The MA group composed of 8522 patients treated during 17 954 treatment days. Mean age was 65 (±21) years, 49% were females. Six (0.07%) patients experienced each a single seizure. IPW estimated OR for seizures among the FQ versus MA group was 1.44 (95%CI 0.59-3.5, P = 0.42). DISCUSSION:The incidence of FQ associated seizures among hospitalized patients is low and the risk did not significantly exceed that under macrolides. Our results provide evidence for clinicians and decision-makers when balancing fluoroquinolones risks and benefits.

Objectives: To assess whether measles infection has an impact on the rate of non-measles infectious diseases over an extended period. Methods: This retrospective matched cohort study included 532 measles-diagnosed patients who were exactly matched with 2128 individuals without a previous measles diagnosis. Adjusted OR for any allcause infectious diagnosis and any viral infection diagnosis <2 years after measles diagnosis between the measles and control groups was obtained from a conditional logistic regression model. The Cox proportional hazards model was used to estimate the hazard ratio. Results: Previous measles virus (MeV) exposure was associated with an increased risk for all-cause nonmeasles infectious disease diagnosis (OR: 1.83, 95% CI: 1.26-2.64, p 0.001), with 492 diagnoses in the MeV-exposed group and 1868 diagnoses in the control group. Additionally, previous MeV exposure was linked to a higher risk of viral infection diagnosis (OR: 1.23, 95% CI: 1.01-1.59, p < 0.05), with 302 viral infection diagnoses in the MeV-exposed group and 1107 diagnoses in the control group. The hazard ratio for viral diagnosis in the MeV-exposed group compared with the control group was 1.54 (95% CI: 1.18 -2.02, p < 0.001). Discussion: Individuals diagnosed with measles had a moderately increased risk of being diagnosed with all-cause non-measles infectious disease or viral infection. This observational individual-level study supports previous ecological and individual population-level studies.

Background Refractory upper abdominal pain or lower back pain (retroperitoneal pain syndrome) related to celiac plexus involvement characterises pancreatic and other upper gastrointestinal malignancies and is an unmet need. We hypothesised that ablative radiation delivered to the celiac plexus would decrease pain. Methods This multicentre, single-arm, phase 2 study was done at eight hospitals in five countries (Israel, Poland, Canada, the USA, and Portugal). Eligible patients aged 18 years or older with an average pain level of 5-10 on the Brief Pain Inventory short form (BPI-SF), an Eastern Cooperative Oncology Group performance status score of 0-2, and either pancreatic cancer or other tumours involving the celiac axis, received a single fraction of 25 Gy of external- beam photons to the celiac plexus. The primary endpoint was complete or partial pain response based on a reduction of the BPI-SF average pain score of 2 points or more from baseline to 3 weeks after treatment. All evaluable patients with stable pain scores were included in response assessment. The trial is registered with ClinicalTrials.gov, NCT03323489, and is complete. Findings Between Jan 3, 2018, and Dec 28, 2021, 125 patients were treated, 90 of whom were evaluable. Patients were followed up until death. Median age was 655 years (IQR 583-718), 50 (56%) were female and 40 (44%) were male, 83 (92%) had pancreatic cancer, and 77 (86%) had metastatic disease. Median baseline BPI-SF average pain score was 6 (IQR 5-7). Of the 90 evaluable patients at 3 weeks, 48 (53%; 95% CI 42-64) had at least a partial pain response. The most common grade 3-4 adverse events, irrespective of attribution, were abdominal pain (35 [28%] of 125) and fatigue (23 [18%]). 11 serious adverse events of grade 3 or worse were recorded. Two grade 3 serious adverse events were probably attributed to treatment by the local investigators (abdominal pain [n=1] and nausea [n=1]), and nine were possibly attributed to treatment (seven were grade 3: blood bilirubin increased [n=1], duodenal haemorrhage [n=2], abdominal pain [n=2], and progressive disease [n=2]; and two were grade 5: gastrointestinal bleed from suspected varices 24 days after treatment [n=1] and progressive disease [advanced pancreatic cancer] 89 days after treatment [n=1]). Interpretation Celiac plexus radiosurgery could potentially be a non-invasive palliative option for patients with retroperitoneal pain syndrome. Further investigation by means of a randomised comparison with conventional celiac block or neurolysis is warranted. Funding Gateway for Cancer Research and the Israel Cancer Association.

PURPOSE:To evaluate the utility of cervical cultures in the diagnosis and management of postpartum endometritis. METHODS:A retrospective study was conducted on 1069 cervical cultures collected from postpartum women with suspected endometritis between 2011 and 2021. Patient demographics, obstetric history, clinical parameters, and culture results were analyzed. Microorganisms were categorized into five groups based on species and virulence. Statistical analysis was performed to identify associations between risk factors, pathogens, and disease severity. RESULTS:The positivity rate for distinct microorganisms in cervical cultures was 33.1%. Escherichia coli (10.8%) and Group B Streptococcus (7.5%) were the most common isolates. Prolonged labor duration and prolonged rupture of membranes were associated with Enterobacterales infections. Elevated white blood cell count was linked to Enterobacterales and beta-hemolytic Streptococci, while the former were also associated with higher rate of postpartum clinic visit. No significant differences in disease severity were found between other microorganism groups. CONCLUSION:The study suggests that while cervical cultures can identify potential pathogens in postpartum endometritis, their clinical utility is questionable due to the polymicrobial nature of the disease and the isolation of commensal microorganisms. The lack of significant differences in disease severity across various microorganism groups raises questions regarding the contribution of distinct bacterial identification in endometritis management.

Abstract Background Despite publications assuring no increased risk for acute cardiovascular events (excluding myocarditis) and sudden death following administration of COVID19 vaccines, these issues still stir much public ado. We assessed the risk for acute cardiovascular events that require hospitalization (excluding myocarditis) and for mortality in the short-term following administration of the second dose of the Pfizer COVID19 vaccine in Israel. Methods Using a self-controlled case series (SCCS) study design and national databases, all second-dose vaccinees, who had not been diagnosed with COVID19 and who had an acute cardiovascular event (acute myocardial infarction/acute stroke/acute thromboembolic event) that required hospitalization in the 60 days following vaccine administration between Jan 11th, 2021 and Oct 31st 2021, were included. A similar analysis was carried out for mortality. The first 30 days following vaccination were defined as risk period while the next 30 days were defined as control period. The probability for an event between these periods was compared using a conditional logistic regression model, accounting for sex, age group, background morbidity and seasonal risk. Results Out of 5,700,112 second dose vaccinees, 4,163 had an acute cardiovascular event in the 60 days following vaccine administration. Following exclusion of 106 due to technical considerations, 1,979 events occurred during the risk period and 2,078 during the control period: Odds ratio, OR = 0.95, 95% confidence interval, CI 0.90–1.01, p = 0.12. Adjusted OR was similar (OR = 0.88, 95%CI 0.72–1.08). Stratifying by age showed no increased risk in any age group. Mortality assessment indicated low number of events in both periods. These results were consistent in sensitivity analyses. Conclusions There was no increased risk for acute cardiovascular events (excluding myocarditis) in the risk period compared to the control period following administration of the second dose of Pfizer COVID19 vaccine. Mortality data raised no concerns either, but may have been biased.

Introduction: Seasonality in the incidence of stroke has been examined in numerous studies, yet data on whether it differs with age are limited. To fill this gap, we utilized a largescale dataset from Israel. Patients and methods: We retrieved data of all hospitalizations for ischemic stroke (IS), transient ischemic attack (TIA) and intra cerebral hemorrhage (ICH) from 2000 to 2020. We maintained separate datasets for IS/TIA and ICH, divided into five age groups: 18-49, 50-59, 60-69, 70-79, and 80+. We modeled the monthly incidence using a generalized additive model. The seasonal effect was defined by the rate ratio (RR) of each month compared to the annual mean. Results: The analysis included 317,586 and 23,789 events of IS/TIA and ICH respectively. We found an interaction between age and seasonality, accounting for a phase shift with age in the seasonal pattern of IS/TIA incidence. For cases under 70 years, the peak was during summertime and the RRs increased with decreasing age, reaching 1.11 (95% CI 1.09-1.13) at the youngest age group. In contrast, among the elderly, a winter peak was observed and the RRs increased with age to 1.07 (95% CI 1.06-1.08) at the oldest age group. For ICH, a winter/autumn peak was identified and the RRs increased with age to 1.20 (95% CI 1.16-1.24). Conclusions: Our finding of age-dependent seasonal patterns in the occurrence of stroke, suggests closer monitoring of cardiovascular risk factors during wintertime among elderly individuals. The mechanism governing the seasonal phase shift with age in IS/TIA incidence, requires further investigation.

BACKGROUND:Hospital-at-home (HAH) is increasingly becoming an alternative for in-hospital stay in selected clinical scenarios. Nevertheless, there is still a question whether HAH could be a viable option for acutely ill patients, otherwise hospitalized in departments of general-internal medicine. METHODS:This was a retrospective matched study, conducted at a telemedicine controlled HAH department, being part of a tertiary medical center. The objective was to compare clinical outcomes of acutely ill patients (both COVID-19 and non-COVID) admitted to either in-hospital or HAH. Non-COVID patients had one of three acute infectious diseases: urinary tract infections (UTI, either lower or upper), pneumonia, or cellulitis. RESULTS:The analysis involved 159 HAH patients (64 COVID-19 and 95 non-COVID) who were compared to a matched sample of in-hospital patients (192 COVID-19 and 285 non-COVID). The median length-of-hospital stay (LOS) was 2 days shorter in the HAH for both COVID-19 patients (95% CI: 1-3; p = 0.008) and non-COVID patients (95% CI; 1-3; p < 0.001). The readmission rates within 30 days were not significantly different for both COVID-19 patients (Odds Ratio (OR) = 1; 95% CI: 0.49-2.04; p = 1) and non-COVID patients (OR = 0.7; 95% CI; 0.39-1.28; p = 0.25). The differences remained insignificant within one year. The risk of death within 30 days was significantly lower in the HAH group for COVID-19 patients (OR = 0.34; 95% CI: 0.11-0.86; p = 0.018) and non-COVID patients (OR = 0.38; 95% CI: 0.14-0.9; p = 0.019). For one year survival period, the differences were significant for COVID-19 patients (OR = 0.5; 95% CI: 0.31-0.9; p = 0.044) and insignificant for non-COVID patients (OR = 0.63; 95% CI: 0.4-1; p = 0.052). CONCLUSIONS:Care for acutely ill patients in the setting of telemedicine-based hospital at home has the potential to reduce hospitalization length without increasing readmission risk and to reduce both 30 days and one-year mortality rates.

BackgroundHealth inequities can stem from socioeconomic position (SEP) leading to poor health (social causation) or poor health resulting in lower SEP (health selection). We aimed to examine the longitudinal bidirectional SEP-health associations and identify inequity risk factors.MethodsLongitudinal Household Israeli Panel survey participants (waves 1–4), age ≥25 years, were included (N=11 461; median follow-up=3 years). Health rated on a 4-point scale was dichotomised as excellent/good and fair/poor. Predictors included SEP parameters (education, income, employment), immigration, language proficiency and population group. Mixed models accounting for survey method and household ties were used.ResultsExamining social causation, male sex (adjusted OR 1.4; 95% CI 1.1 to 1.8), being unmarried, Arab minority (OR 2.4; 95% CI 1.6 to 3.7, vs Jewish), immigration (OR 2.5; 95% CI 1.5 to 4.2, reference=native) and less than complete language proficiency (OR 2.22; 95% CI 1.50 to 3.28) were associated with fair/poor health. Higher education and income were protective, with 60% lower odds of subsequently reporting fair/poor health and 50% lower disability likelihood. Accounting for baseline health, higher education and income were associated with lower likelihood of health deterioration, while Arab minority, immigration and limited language proficiency were associated with higher likelihood. Regarding health selection, longitudinal income was lower among participants reporting poor baseline health (85%; 95% CI 73% to 100%, reference=excellent), disability (94%; 95% CI 88% to 100%), limited language proficiency (86%; 95% CI 81% to 91%, reference=full/excellent), being single (91%; 95% CI 87% to 95%, reference=married), or Arab (88%; 95% CI 83% to 92%, reference=Jews/other).ConclusionPolicy aimed at reducing health inequity should address both social causation (language, cultural, economic and social barriers to good health) and health selection (protecting income during illness and disability).

662 Background: Upper abdominal / lower back pain characterizes celiac plexus involvement from pancreatic and other cancers which may impair HRQOL; its satisfactory treatment is an unmet clinical need. We hypothesized that ablative radiation delivered to the celiac plexus would decrease pain and improve HRQOL. Methods: An international single arm Phase II study included patients with an average pain level ≥ 5/11 on the brief pain inventory (BPI), ECOG 0-2, and anatomical involvement of the celiac axis. The intervention was a single fraction of 25Gy delivered to the celiac plexus. The primary endpoint was ‘complete or partial (≥2 points) pain response’ based upon the BPI ‘average pain’ 11-point scale. Changes in Health-related QOL at 3 & 6 weeks compared to baseline were secondary endpoints as measured by FACT-Hep, > 8 point change being the minimal clinically important difference (MCID). Evaluable patients included eligible irradiated subjects, who had stable pain levels pre-treatment, and were alive 3 weeks’ post-treatment. The sample size was 90 evaluable patients, giving 90% power to show response rate ≥ 40%. Opioid usage was assessed using intravenous morphine equivalent dose. Sensitivity HRQOL analyses imputed worsened outcomes (-9 for total FACT-Hep) for missing data. Results: Between 2018 and 2022, 149 patients were enrolled, 90/125 who received treatment were evaluable. Median age was 65.5 years (range 28-88), 65% were female, 92% had pancreatic cancer, and 86% had metastatic disease. Median Zubrod PS was 1, median number of systemic treatment lines was 1 (range 0-5), and median baseline opioid use 31 mg/d. At 3 weeks, 48 (53.3%, 95% CI 42.5-63.9) had at least a partial pain, the BPI ‘average pain’ score decreased by a mean of 2.5 points at 3 weeks (86/90 reported) and 3.2 points at 6 weeks (67/90 reported), both p < 0.001. Opioid usage decreased by 0.6 mg/d at 3 weeks (NS) and 16.9 mg/d at 6 weeks (p = 0.005). The FACT-Hep total score increased by 7.8 points at 3 weeks (54/90 reported, NS diff. from 8) and 16.6 points at 6 weeks (45/90 reported, sig. > 8, p = 0.01), showing an improvement in patients’ HRQOL. Changes in FACT-Hep were especially noted in the Physical Well Being subscale. The Trial Outcome Index (sum of physical, functional & disease-specific concerns) increased markedly at 3 weeks (6.6 points, p = 0.005) after treatment and even more after 6 weeks (14.5 points, p < 0.). Sensitivity analyses demonstrated improvements in HRQOL at 3 and 6 weeks (1.1, 3.8), but these were less than MCID. Conclusions: Celiac plexus SBRT decreases pain and opioid use amongst patients with pancreatic cancer and other tumors invading the celiac axis. The treatment appears to improve HRQOL. Supported by Gateway for Cancer Research and the Israel Cancer Association. Clinical trial information: NCT03323489 .

Abstract Background Previous reports on acute cardiovascular events and sudden death following administration of COVID19 vaccines usually reported no association, but this issue still stirs much ado. We aimed to assess the risk for acute cardiovascular events that require hospitalization in the short-term following administration of the second Pfizer COVID19 vaccine dose in Israel. Methods We have used a self-controlled case series (SCCS) study design, and included second-dose vaccinees in the period from Jan 11th, 2021 to Oct 31st 2021, who had not been diagnosed with COVID19 and who had an acute cardiovascular event (acute myocardial infarction or acute stroke or acute thromboembolic event; myocarditis events excluded) that required hospitalization in the 60 days following vaccine administration. National databases (COVID19 vaccines; COVID19 infection; Hospitalizations) were used to assemble the study population. The first 30 days were defined ‘high risk period’ while the next 31-60 days were defined ‘control period’, and the risk for an acute cardiovascular event was compared between these periods using a conditional logistic regression model. Possible moderators such as: sex, age group and seasonality were included. Results Out of 5,700,112 second-dose vaccinees in the defined time period, 4,163 had an acute cardiovascular event in the 60 days following vaccine administration: 1,979 in the ‘risk period’ and 2,078 in the ‘control period’ (Odds ratio, OR = 0.95, 95% confidence interval, CI 0.90-1.01, p = 0.12). Moderation of sex, age group and recent (less than 60d prior to vaccination) acute cardiovascular event were not significant. A sensitivity analyses looking at 100 days of follow-up post-vaccination did not change these results. Conclusions We found no indication for an increased risk for an acute cardiovascular event in the 30 days (compared to 31-60 days) following administration of the second vaccine dose of Pfizer COVID19 vaccine. Key messages • We found no indication for an increased risk for an acute cardiovascular event in the 30 days (compared to 31-60 days) following administration of the second vaccine dose of Pfizer COVID19 vaccine. • These findings did not change when sensitivity analyses were used.

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.

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: [91.9, 95.7]); and severe illness 96.4% (CI: [92.5, 98.3]). Our results question the need to vaccinate previously-infected individuals.

BACKGROUND Following the emergence of the Omicron variant of concern, we investigated immunogenicity, efficacy and safety of BNT162b2 or mRNA1273 fourth dose in an open-label, clinical intervention trial. METHODS Primary end-points were safety and immunogenicity and secondary end-points were vaccine efficacy in preventing SARS-CoV-2 infections and COVID-19 symptomatic disease. The two intervention arms were compared to a matched control group. Eligible participants were healthcare-workers (HCW) vaccinated with three BNT162b2 doses, and whose IgG antibody levels were [≤]700 BAU (40-percentile). IgG and neutralizing titers, direct neutralization of live VOCs, and T-cell activation were assessed. All participants were actively screened for SARS-CoV-2 infections on a weekly basis. RESULTS Of 1050 eligible HCW, 154 and 120 were enrolled to receive BNT162b2 and mRNA1273, respectively, and compared to 426 age-matched controls. Recipients of both vaccine types had a ~9-10-fold increase in IgG and neutralizing titers within 2 weeks of vaccination and an 8-fold increase in live Omicron VOC neutralization, restoring titers to those measured after the third vaccine dose. Breakthrough infections were common, mostly very mild, yet, with high viral loads. Vaccine efficacy against infection was 30% (95%CI:-9% to 55%) and 11% (95%CI:-43% to +43%) for BNT162b2 and mRNA1273, respectively. Local and systemic adverse reactions were reported in 80% and 40%, respectively. CONCLUSIONS The fourth COVID-19 mRNA dose restores antibody titers to peak post-third dose titers. Low efficacy in preventing mild or asymptomatic Omicron infections and the infectious potential of breakthrough cases raise the urgency of next generation vaccine development.

Objective: To evaluate the effectiveness of the Pfizer BNT162b2 vaccine against the SARS-Cov-2 Beta variant. Study Design and Setting: Israel's mass vaccination program, using two doses of the Pfizer BNT162b2 vaccine, successfully curtailed the Alpha variant outbreak during winter 2020-2021, However, the virus may mutate and partially evade the immune system. To monitor this, sequencing of selected positive swab samples of interest was initiated. Comparing vaccinated with unvaccinated PCR positive persons, we estimated the odds ratio for a vaccinated case to have the Beta vs. the Alpha variant, using logistic regression, controlling for important confounders. Results: There were 19 cases of Beta variant (3.2%) among those vaccinated more than 14 days before the positive sample and 79 (3.4%) among the unvaccinated. The estimated odds ratio was 1.26 (95% CI: 0.65-2.46). Assuming the effectiveness against the Alpha variant to be 95%, the estimated effectiveness against the Beta variant was 94% (95% CI: 88%-98%). Conclusion: Despite concerns over the Beta variant, the BNT162b2 vaccine seemed to provide substantial immunity against both the Beta and the Alpha variants. From 14 days following the second vaccine dose, the effectiveness of BNT162b2 vaccine was at most marginally affected by the Beta variant. (c) 2021 Elsevier Inc. All rights reserved.

Introduction Pancreatic 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 analysis A 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 also eligible. The intervention involves irradiating the coeliac plexus using a single fraction of 25 Gy. The primary endpoint is the complete or partial pain response at 3 weeks. Secondary endpoints include pain at 6 weeks, analgesic use, hope, qualitative of life, caregiver burden and functional outcomes, all measured using validated instruments. The protocol is expected to open at a number of cancer centres across the globe, and a quality assurance programme is included. The protocol requires that 90 evaluable patients" be accrued, based upon the assumption that a third of patients are non-evaluable (e.g. due to death prior to 3-weeks post-treatment assessment, or spontaneous improvement of pain pre-treatment), it is estimated that a total of 120 patients will need to be accrued. Supported by Gateway for Cancer Research and the Israel Cancer Association. Ethics and dissemination Ethic approval for this study has been obtained at eight academic medical centres located across the Middle East, North America and Europe. Results will be disseminated through conference presentations and peer-reviewed publications. Trial registration number NCT03323489.