Search

Background Gastrointestinal (GI) leaks after cytoreductive surgery and hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC) is a known life-threatening complication that may alter patients’ outcomes. Our aim is to investigate risk factors associated with GI leaks and evaluate the impact of GI leaks on patient’s oncological outcomes. Methods A retrospective analysis of perioperative and oncological outcomes of patients with and without GI leaks after CRS/HIPEC. Results Out of 191 patients included in this study, GI leaks were identified in 17.8% (34/191) of patients. Small bowel anastomoses were the most common site (44%). Most of the GI leaks were managed conservatively and re-operation was needed in 44.1% of cases. Univariate analysis identified higher PCI (p = 0.03), higher number of packed cells transfused (p = 0.036), pelvic peritonectomy (p = 0.013), high number of anastomoses (p = 0.003) and colonic resection (p = 0.042) as factors associated with GI leaks. Multivariate analysis identified stapled anastomoses (OR 2.59, p = 0.001) and pelvic peritonectomy (OR 2.33, p = 0.044) as independent factors associated with GI leaks. Disease-free survival tended to be worse in the leak group but did not reach statistical significance (p = 0.235). The 3- and 5-year OS was 73.2% and 52.9% in the leak group compared to 75.8% and 73.2% in the non-leak group (p = 0.236). Conclusions GI leak showed no impact on overall and disease free survival after CRS/HIPEC.Avoidance of stapled reconstruction in high risk patients with high tumor burden and large number of anastomoses may yield improved outcomes.

Background: Mobile medical devices for self-patient use are a rapidly evolving section of telehealth. We examined the INSTINCT® ultrasound system, a portable, self-operated ultrasound device attach...

OBJECTIVE To evaluate outcomes of fetal reduction in twin pregnancy. SEARCH STRATEGY PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Google Scholar were searched from 1980 through December 2020. SELECTION CRITERIA Prospective or retrospective studies of pregnant women with twin gestations who had a transabdominal reduction of twin to singleton pregnancy with a comparison group of ongoing twin gestations. DATA COLLECTION AND ANALYSIS Outcomes were meta-analyzed only if reported in at least three studies. MAIN RESULTS Six studies with a pooled sample of 2867 women with a twin pregnancy of whom 624 underwent 2-to-1 reduction and 2243 did not. In the fetal reduction group, the odds of preterm birth before 34 and 37 weeks of pregnancy were lower by 36% (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.48-0.86, P

Peritoneal Cancer Index (PCI) and complete cytoreduction are the best outcome predictors following cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Lesions in critical areas, regardless of PCI, complicate surgery and impact oncological outcomes. We prospectively defined "Critical lesions" (CL) as penetrating the hepatic hilum, diaphragm at hepatic outflow, major blood vessels, pancreas, or urinary tract.Retrospective analysis of a prospective database of 352 CRS + HIPEC patients from 2015 to 2019. Excluded patients with aborted/redo operation (n = 112), or incomplete data (n = 19). Patients categorized by CL status and compared: operative time, estimated blood loss (EBL), PCI, transfusions, hospital stay, post-operative complications and mortality, overall survival (OS) and disease-free survival (DFS).Included 221 patients (78 CL; 143 no-CL). No difference in patients' characteristics: age, BMI, gender or co-morbidities noted. Operative time longer (5.3 h vs 4.3 h, p 0.01), EBL higher (769 ml vs 405 ml, p 0.01), transfusions higher (1.9 vs 0.7 Units, p 0.001) and PCI higher (15.5 vs 9.5, p 0.01) in CL. No difference in major complications. Postoperative complications, CL, OR-time and transfusions were predictive of OS in univariate analysis, while only complications remained on multivariate analysis. Median follow up of 21.4 months, 3-year DFS/OS was 22% vs 30% (p 0.037) and 73% vs 87% (p 0.014) in CL and non-CL, respectively. Despite CL complete resection, 17/38 patients (44.7%) that recurred had recurrence at previous CL site.Critical lesions complicate surgery and may be associated with poor oncological outcomes with high local recurrence rate, despite no significant difference in complications. Utilizing adjuvant or intra-operative radiation may be beneficial.

Background Cigarette smoking is an established cause of preventable death and often initiated during adolescence. We estimated the short- and long-term costs of cigarette smoking among currently smoking adolescents in Nigeria. Methods A cross-sectional survey among adolescents in Oyo state, Nigeria and a review of mortality records of patients managed for lung cancer in a tertiary facility in Ibadan, Nigeria were conducted. Short-term costs estimated were: (a) average weekly costs of purchasing cigarettes by currently smoking adolescents, and (b) costs of managing at least an episode of chronic cough occurring within 12 months of the survey. Long-term costs were limited to: (a) life-time expenditure on purchasing cigarettes, and (b) direct medical and non-medical (transportation) costs of managing lung cancer. Long-term costs were first projected to the approximate year when the adolescents (mean age:16.0 ± 1.8 years) might be diagnosed with lung cancer based on the average age at presentation with symptoms of lung cancer obtained from the records (59.8 years), and then discounted to 2020 prices. This was estimated as 44 years from the base year (2020). Costs were reported in 2020 prices in Nigerian Naira (NGN) and US dollar (USD) equivalent using the Central Bank of Nigeria, June 2020 exchange rate of USD 1: NGN 360.50. Results Approximately 3.8% of the adolescents were current cigarette smokers. Average weekly expenditure on cigarettes was NGN 306.82 ± 5.74 (USD 0.85 ± 0.02). About 26% had experienced at least an episode of chronic cough which cost them an average of NGN 1226.81 ± 6.18 (USD 3.40 ± 0.02) to manage. Total future costs of cigarette smoking in 2020 prices for the 43 adolescents who were current smokers in the event that they develop lung cancer were approximately NGN 175.7 million (USD 487.3 thousand), NGN 871.8 million (USD 2.4 million) and NGN 4.6 trillion (USD 12.7 million) at assumed annual inflation rates of 10%, 15%, and 20% respectively and discount rate of 4.25%. Conclusion The estimated economic costs of smoking were very high. Efforts to prevent smoking initiation among adolescents in our study area should be intensified. Interventions to subsidize the medical cost of health-related consequences of cigarette smoking are also required, especially as treatment costs are currently largely borne out-of-pocket.

Objectives Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields with antimitotic effects on cancerous cells. TTFields concomitant with pemetrexed and a platinum agent are approved in the US and EU as first line therapy for unresectable, locally advanced or metastatic malignant pleural mesothelioma (MPM). The goal of the current study was to characterize the mechanism of action of TTFields in MPM cell lines and animal models. Methods Human MPM cell lines MSTO-211H and NCI-H2052 were treated with TTFields to determine the frequency that elicits maximal cytotoxicity. The effect of TTFields on DNA damage and repair, and the cytotoxic effect of TTFields in combination with cisplatin and/or pemetrexed were examined. Efficacy of TTFields concomitant with cisplatin and pemetrexed was evaluated in orthotopic IL-45 and subcutaneous RN5 murine models. Results TTFields at a frequency of 150 kHz demonstrated the highest cytotoxicity to MPM cells. Application of 150 kHz TTFields resulted in increased formation of DNA double strand breaks, elevated expression of DNA damage induced cell cycle arrest proteins, and reduced expression of Fanconi Anemia (FA)-BRCA DNA repair pathway proteins. Co-treatment of TTFields with cisplatin or pemetrexed significantly increased treatment efficacy versus each modality alone, with additivity and synergy exhibited by the TTFields-pemetrexed and TTFields-cisplatin combinations, respectively. In animal models, tumor volume was significantly lower for the TTFields-cisplatin-pemetrexed combination compared to control, accompanied by increased DNA damage within the tumor. Conclusion This research demonstrated that the efficacy of TTFields for the treatment of MPM is associated with reduced expression of FA-BRCA pathway proteins and increased DNA damage. This mechanism of action is consistent with the observed synergism for TTFields-cisplatin vs additivity for TTFields-pemetrexed, as cisplatin-induced DNA damage is repaired via the FA-BRCA pathway.

Aim Patients with cancer are at an increased risk for severe coronavirus disease of 2019, thus data on the safety and efficacy of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are essential. We conducted this prospective study of patients with cancer vaccinated with BNT162b2 and monitored for antibody response and safety. The aim was to evaluate the rate of seropositivity and define predictors for non-reactive immune response. Furthermore, we evaluated the frequency and the severity of adverse events. Methods The study included patients with solid tumours undergoing anticancer treatment and immunocompetent health-care workers serving as controls. Serum titres of the receptor-binding domain (RBD) immunoglobulin G (IgG) and neutralising antibodies were measured 2–4 weeks after each vaccine dose. Results The analysis included 129 patients, of which 70.5% patients were metastatic. Patients were treated with chemotherapy (55%), immunotherapy (34.1%), biological agents (24.8%), hormonal treatment (8.5%) and radiotherapy (4.6%), that were given either alone or in combinations. The seropositivity rate among patients with cancer and controls was 32.4% versus 59.8% (p

ObjectiveTo determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP).MethodsTrio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause.ResultsGiven both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3.ConclusionsCryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

Pathological response of colorectal peritoneal metastasis (CRPM) may affect prognosis. We investigated the relationship between oncological outcomes and pathological response to chemotherapy of CRPM following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). We conducted a retrospective analysis of a prospectively maintained Peritoneal Surface Malignancies database between 2015 and 2020. Analysis included patients with CRPM who underwent a CRS/HIPEC procedure (n = 178). The cohort was divided into three groups according to the response ratio (ratio of tumor-positive specimens to the total number of specimens resected): Group A, complete response; Group B, high response ratio, and Group C, low response ratio. The group demographics were similar, but the overall complication rate was higher in Group C (65.2%) compared with Groups A (55%) and B (42.8%) [p = 0.03]. Survival correlated to response ratio; the estimated median disease-free survival of Group C was 9.1 months (5.97–12.23), 14.9 months (4.72–25.08) for Group B, and was not reached in Group A (p = 0.001). The estimated median overall survival in Group C was 35 months (26.69–43.31), and was not reached in Groups A and B (p = 0.001). The pathological response ratio to systemic therapy correlates with survival in patients undergoing CRS/HIPEC. This study supports the utilization of preoperative therapy for better patient selection, with a potential impact on survival.

This article discusses Maimonides’s rationale for the incest taboo and traces its reception in Christian and kabbalistic traditions in the thirteenth century. Tracing the reception of Maimonides’s view enables recognition of the resemblance between Maimonides and Aquinas, the ambivalent stance toward Maimonides’s explanation expressed by Nahmanides, and the incorporation of Maimonides’s reasoning in one of the most systematic and enigmatic works of kabbalistic rationalization of the commandments, the Castilian Kabbalist Joseph of Hamadan’s The Book of the Rationales of the Negative Commandments. R. Joseph’s acceptance of Maimonidean principles and his integration of them in the theurgic Kabbalah reveal a conflict in the heart of its system and teach us about an important aspect of the theory of sexuality in Kabbalah. The inquiry offered here examines the inter-relations between divergent medieval religious trends in constructing the role of sexuality. Instead of the common presentation of Kabbalah as diverging from the ascetic positions of Jewish philosophy and Christianity, this analysis will elucidate Kabbalah’s continuity with them.

Introduction The use of total neoadjuvant therapy (TNT) for locally advanced rectal cancer has been increasing in recent years, but the long-term overall survival characteristics of this approach is currently unknown. Methods We performed a retrospective study of patients with clinical stage II/III rectal cancer within the National Cancer Database. Patients who received TNT (defined as chemotherapy, followed by CRT, followed by surgery) were propensity score matched to patients who received adjuvant therapy (defined as CRT, followed by surgery, followed by chemotherapy). We compared overall survival (OS) and rates of pathologic complete response (pCR) between the two arms. Results Of the 4,300 patients in our cohort, 3,502 (81%) received adjuvant therapy and 798 (19%) received TNT. At baseline, patients who received TNT were more likely to have higher clinical T and N stages (p Conclusion In this observational study, we found TNT was not associated with a lower OS compared to standard adjuvant chemotherapy. This finding potentially reassures clinicians choosing TNT as an alternative to adjuvant chemotherapy. However, future prospective data are needed to confirm these findings. Microabstract The long-term overall survival characteristics of total neoadjuvant therapy (TNT) for locally advanced rectal cancer has not been well-defined despite its increasing popularity. In a large National Cancer Database cohort, we found that TNT was not associated with worse survival compared to historical controls.

Background The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. Patients were classified into low risk and high risk, suggesting low-risk patients may be offered only 3 months of treatment. In this study, we aimed to assess the benefit of oxaliplatin in the adjuvant setting per IDEA risk groups, using data from 3 large adjuvant phase III studies, namely Multicenter International Study of Oxaliplatin/Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC), C-07, and XELOXA. Methods Using the MOSAIC, C-07, and XELOXA previously published studies, we identified 2810 low-risk and 2124 high-risk patients with stage III colon cancer. We used Cox regression model to evaluate the magnitude of survival differences between IDEA risk groups, according to oxaliplatin use. Based on design similarity and equivalent follow-up data, MOSAIC and C-07 were pooled, whereas XELOXA was analyzed separately. Subgroup analyses were also performed for T4 and/or N2 patients. Results Individuals with IDEA low and high risk derived overall survival benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted hazard ratios of 0.79 (0.66-0.95) and 0.84 (0.71-0.99), respectively. Among individuals with IDEA high risk, those with T4 disease did not gain overall survival benefit from addition of oxaliplatin with hazard ratio of 0.95 (0.71-1.27). Similar results were demonstrated using data from the XELOXA study. Conclusion IDEA risk classification per se does not predict benefit from addition of oxaliplatin to adjuvant chemotherapy in stage III colon cancer. T4 disease may predict lack of benefit from oxaliplatin addition.

In this prospective study, we evaluated postpartum voiding dysfunction stratified by mode of delivery - vaginal delivery versus elective caesarean delivery (CD). We recruited nulliparous women carrying singleton gestation at term admitted to delivery room or elective CD. Pre-labour voiding function was assessed by recording the post-voiding residual volume (PVRV) using a bladder scan. PVRV evaluation was repeated at least 12 hours following delivery and before discharge. PVRVs were considered abnormal if ≥150 mL. PVRVs were compared between vaginal and CD. Overall, 54 women were included. Of them, 34 (63%) delivered vaginally and 20 (37%) had an elective CD. Postpartum mean PVRVs were significantly higher compared to pre-labour PVRVs (215 vs. 133 mL, p

BACKGROUND Respiratory syncytial virus (RSV) bronchiolitis is the most common lower respiratory tract disorder causing hospitalization in infants. Due to decreased hospitalization rates of premature infants following Palivizumab immune prophylaxis, the proportion of infants with chronic diseases not eligible for Palivizumab has increased. AIM To characterize infants hospitalized during 2014-2018 with RSV bronchiolitis, to compare between those with and without chronic conditions, and to identify risk factors for severe disease. METHODS This retrospective study analyzed demographic and clinical data of patients younger than 2 years admitted with bronchiolitis during four consecutive RSV seasons. RESULTS Of 1124 hospitalizations due to RSV bronchiolitis, 244 (22%) were in infants with chronic diseases. Although 20/1124 qualified for RSV prophylaxis, only eight received immune prophylaxis. Compared to otherwise healthy infants, children with chronic diseases had longer hospitalizations, median 4.8 days (interquartile range [IQR]: 3.4-8.3) versus 3.7 days (IQR: 2.7-5.1), p

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

BackgroundA novel coronavirus (COVID-19) was declared a global pandemic by the World Health Organization (WHO) in March, 2020. Until such time as a vaccine becomes available, it is important to identify the determining factors that influence the intention of the general public to accept a future COVID-19 vaccine. Consequently, we aim to explore behavioral-related factors predicting intention to receive COVID-19 vaccine among the general population using the Health Belief Model (HBM) and the Theory of Planned Behavior (TPB) model.MethodsAn online survey was conducted among adults aged 18 years and older from May 24 to June 24, 2020. The survey included socio-demographic and health-related questions, questions related to the HBM and TPB dimensions, and intention to receive COVID-19 vaccine. Associations between questionnaire variables and COVID-19 vaccination intention were assessed by univariate and multivariate analyses.ResultsEighty percent of 398 eligible respondents stated their willingness to receive COVID-19 vaccine. A unified model including HBM and TPB covariates as well as demographic and health-related factors, proved to be a powerful predictor of intention to receive COVID-19 vaccine, explaining 78% of the variance (adjusted R2 = 0.78). Men (OR=4.35, 95% CI 1.58–11.93), educated respondents (OR=3.54, 95% CI 1.44–8.67) and respondents who had received the seasonal influenza vaccine in the previous year (OR=3.31, 95% CI 1.22–9.00) stated higher intention to receive COVID-19 vaccine. Participants were more likely to be willing to get vaccinated if they reported higher levels of perceived benefits of COVID-19 vaccine (OR=4.49, 95% CI 2.79–7.22), of perceived severity of COVID-19 infection (OR=2.36, 95% CI 1.58–3.51) and of cues to action (OR=1.99, 95% CI 1.38–2.87), according to HBM, and if they reported higher levels of subjective norms (OR=3.04, 95% CI 2.15–4.30) and self-efficacy (OR=2.05, 95% CI 1.54–2.72) according to TPB. Although half of the respondents reported they had not received influenza vaccine last year, 40% of them intended to receive influenza vaccine in the coming winter and 66% of them intended to receive COVID-19 vaccine.ConclusionsProviding data on the public perspective and predicting intention for COVID-19 vaccination using HBM and TPB is important for health policy makers and healthcare providers and can help better guide compliance as the COVID-19 vaccine becomes available to the public.

Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) for colorectal cancer peritoneal metastases (CRPM) is associated with improved survival in patients with historically dismal prognosis. Nonetheless, peritoneal recurrences remain common and represent a difficult challenge in these patients' management. Repeat CRS/HIPEC is associated with even greater morbidity and its survival benefit has not yet been clearly demonstrated. We retrospectively reviewed our prospectively maintained database and aimed to assess the safety and oncological efficacy of repeat CRS/HIPEC. Two hundred thirty-two patients underwent an initial CRS/HIPEC, whereas 30 subsequently had repeat CRS/HIPEC for CRPM. Groups were similar in demographics, comorbidities, and peritoneal cancer index (PCI). No significant difference in morbidity, hospital stay, or reoperation rate was noted between initial and repeat procedures. Patients who underwent repeat CRS/HIPEC had a median overall survival of 68 months versus 51 months in patients who did not undergo repeat procedure for their peritoneal recurrence (p = 0.03). Disease-free survival (DFS) in patients after repeat and after initial procedure were similar with median of 9.6 versus 12 months, respectively (p = 0.083). Univariate analysis demonstrated that PCI, DFS, and repeat procedure displayed significant factors on outcomes in patients with peritoneal recurrences, whereas PCI > 16 and DFS remained independent predictors on multivariable analysis. Our analysis, which represents the largest series to date of repeat CRS/HIPEC for CRPM, indicates that this approach as a part of multimodal therapy is both safe and efficacious in appropriately selected patients.

Background Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5–21 years) with ASD. Methods We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and Δ9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and Δ9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI). Results Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results. Conclusions This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226

Systematic data are lacking on pediatric long COVID. This study prospectively assessed 90 children with persistent symptoms who presented to a designated multidisciplinary clinic for long COVID. In nearly 60%, symptoms were associated with functional impairment at 1-7 months after the onset of infection. A comprehensive structured evaluation revealed mild abnormal findings in approximately half the patients, mainly in the respiratory aspect.

Objective: The purpose of this study was to determine if gas tension and acidity levels could serve as biomarkers of pulp inflammatory status in primary dentition. Study design: The present study evaluated acidity level and blood partial pressures of O2 and CO2 collected from vital pulp chambers of 84 primary molars with deep carious lesions encroaching the pulp. Teeth were treated with pulpotomy or pulpectomy based on clinical judgement. Pulpectomy was performed when symptoms of spontaneous pain, difficulty in obtaining hemostasis and/or dark purple blood were present. Using a glass capillary, pulp chamber bleeding was collected and within ten minutes a neonate Astrup test was performed to determine blood gas module pH, pCO2, and pO2. Results: Eighty-four children with one affected tooth participated in the study (37 girls and 47 boys). Age ranged between 3.5 to 9-years (average: 5.3 years). Seventy-one (84%) were treated with the aid of inhalation analgesia, conscious sedation or general anesthesia. Pulpotomy was performed on 58 teeth (69%). Teeth undergoing pulpectomy revealed significant higher level of CO2 partial pressure (P= 0.002). Acidity level values (pH) were also lower but none significantly in teeth with pulpectomy (P= 0.137). Conclusions: Higher pCO2 levels was found in pulps needing pulpectomy.

Background The prognosis of gastric cancer (GC) is poor with a median overall survival (OS) of less than 12 months in advanced-stage disease. The search for distinct genetic subgroups of GC patients and predictive biomarkers is ongoing. While BRCA1 or BRCA2 germline mutations (gBRCAm) have potential therapeutic implications in ovarian, breast and pancreatic cancers, their significance in GC patients has not been established. Patients and methods A retrospective multi-center data analysis of GC patients with gBRCAm was conducted, detailing the clinical characteristics and disease course in this unique subset of patients. Results Ten GC patients with gBRCAm were identified, six of them with metastatic disease. The median OS of all ten GC patients was 47.5 (13-192) months. Median OS for patients diagnosed with operable disease was 55.5 (13-192) months and of the patients with metastatic disease (calculated from metastatic disease diagnosis) 32 (15-52) months with an exceptional 1-, 2- and 3-year survival rate of 100%, 83.3% and 50%, respectively. Conclusion These preliminary data suggest that gBRCAm in GC patients are associated with a favorable prognosis. Furthermore, gBRCAm might be a predictive biomarker to DNA-damaging agents response in GC patients, similarly to its established role in other malignancies. Further research is needed to confirm our findings.

Background Current guidelines recommend neoadjuvant chemotherapy in patients with locoregional gastric adenocarcinoma. Patients diagnosed with early stage gastric adenocarcinoma are usually managed with upfront surgical intervention. However, pathologic staging in a subset of these clinically staged patients identifies more advanced locoregional disease requiring adjuvant treatment. Therefore, identifying these patients prior to surgical intervention is critical to ensure employment of the appropriate treatment paradigm. The aim of the current study was to define patient characteristics associated with clinical understaging in early gastric cancer. Methods Using the National Cancer Database (2004–2014) we identified 3,892 individuals with clinical T1N0 gastric adenocarcinoma who underwent upfront definitive surgery, had negative surgical margins, and did not receive preoperative chemotherapy or radiotherapy. Patient characteristics were compared between those with pathologic stage T1N0 disease and those who were upstaged upon surgery. Results Twenty‐seven percent of clinical T1N0 gastric adenocarcinomas had a change in stage because of pathologically defined ≥T2 disease or positive lymph nodes. Individuals who were upstaged had a higher tumor grade compared with those with pathologic stage T1N0 disease. Specifically, 41.9% (530/1,264) of individuals with a poorly differentiated tumor were upstaged, compared with only 10.7% (70/656) with a well‐differentiated tumor. Approximately 75% of cases involved upstaging because of T misclassification. The highest percentage of upstaging was shown for tumors located at the fundus and body of the stomach. Conclusion Upstaging of clinical T1N0 gastric adenocarcinoma is characterized by higher tumor grade and is mostly a result of a change in T stage. These findings mandate thorough workup in order to identify patients with clinically staged T1N0 disease requiring preoperative chemotherapy. Implications for Practice Upstaging of clinical T1N0 gastric adenocarcinoma is characterized by higher tumor grade and is mostly a result of a change in T stage. These findings mandate thorough workup in order to identify patients with clinically staged T1N0 disease requiring preoperative chemotherapy., This article evaluates the frequency of upstaging following surgery among cT1N0 gastric cancer and defines the corresponding patient characteristics, with the goal of better identifying those patients who require preoperative chemotherapy.

INTRODUCTION The safety of neuro-axial anaesthesia (epidural/spinal) at labour of women with partial factor XI (FXI) deficiency is uncertain. Although FXI deficiency is frequent in Ashkenazi Jews, it is not routinely measured before labour. Our institute serves a large Ashkenazi population. We assumed that 10% of them have undiagnosed FXI deficiency. AIM Assess the incidence, bleeding tendency and coagulation status among Jewish Ashkenazi women with FXI deficiency that underwent neuro-axial anaesthesia at delivery. METHODS Jewish Ashkenazi women who underwent neuro-axial anaesthesia at labour completed the SSC ISTH bleeding assessment tool (BAT) and had blood drawn for coagulation tests, FXI and thrombin generation after labour. Estimation for 10 years was calculated from the 1-year sample. RESULTS We recruited 261 women during 12 months. Among them, 39 (15%) had FXI deficiency (

Coronary artery fistula (CAF) is an abnormal connection between a coronary artery and a heart chamber resulting in left-to-right shunt. A large CAF was an unexpected cause of heart failure in a 58-year-old woman who underwent transcatheter closure of the CAF with improvement in symptoms but complicated by myocardial infarction. (Level of Difficulty: Beginner.), Graphical abstract, Coronary artery fistula (CAF) is an abnormal connection between a coronary artery and a heart chamber resulting in left-to-right shunt. A large CAF…

Background Controversy surrounds the cause of the pressure gradient in patients with hypertrophic obstructive cardiomyopathy (HOCM). Left ventricular cavity obliteration (LVCO) was first described as the cause of the gradient but subsequently systolic anterior motion (SAM) of the mitral valve has been established as the cause. Nevertheless, the two gradients, though different in origin and significance, share similar characteristics. They both have a similar “dagger” profile, are obtained from the cardiac apex, are associated with a hyperdynamic left ventricle, and the gradients are worsened by Valsalva. The distinction has clinical relevance, because treating the intracavitary gradient (ICG) of LVCO as if it were a SAM‐associated gradient associated with HOCM would be inappropriate and possibly harmful. Materials and Methods To clarify the cause and characteristics of the ICG in patients with LVCO in patients without HOCM, we assessed the extent and duration of cavity obliteration, and for differentiation, we compared the spectral profiles with patients with HOCM and severe aortic stenosis (AS). Results Higher ICG is associated with a greater extent and more prolonged apposition of LV walls, and smaller left ventricular cavity size. The spectral profile of patients with AS, HOCM, and LVCO is differentiated by the peak/mean gradient ratios of 2 or less, 2–3, and 3 or greater, respectively, in >90% of patients. Most patients with LVCO without HOCM or severe LVH have an ICG

Purpose Both β1- and β2-adrenoceptor proteins were detected on the cell surface of pancreatic ductal adenocarcinoma. The current study evaluated the association between beta-blocker use and pancreatic cancer risk. Methods We conducted a nested case-control study in a large population representative database. Each pancreatic cancer case was matched with four controls based on age, sex, practice site, and duration of follow-up using incidence density sampling. Beta-blocker use was defined as any prescription prior to index date and was stratified into non-selective and selective β1 -blockers. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for pancreatic cancer risk associated with beta-blocker use was estimated using conditional logistic regression. Results The study included 4113 patients with pancreatic cancer and 16 072 matched controls. When compared to never users, there was no association between any beta-blocker use and pancreatic cancer risk (adjusted OR 1.06, 95% CI 0.97-1.16, P = .16). Analysis by receptor selectivity showed use of non-selective beta-blockers for more than 2 years was associated with a reduced pancreatic cancer risk (OR 0.75, 95% CI 0.57-1.00, P = .05). When compared to former users both users of selective β1-blockers and non-selective beta-blockers had a reduced pancreatic cancer risk (OR 0.78, 95% CI 0.67-0.90, P = .001) and (OR 0.67, 95% CI 0.49-0.92, P = .01), respectively. Conclusion Beta-blocker use was not associated with increased pancreatic cancer risk. However, long-term use of beta-blockers may be associated with decreased pancreatic cancer risk.

Global financial crises have led to the understanding that classical econometric models are limited in comprehending financial markets in extreme conditions, partially since they disregarded complex interactions within the system. Consequently, in recent years research efforts have been directed towards modeling the structure and dynamics of the underlying networks of financial ecosystems. However, difficulties in acquiring fine-grained empirical financial data, due to regulatory limitations, intellectual property and privacy control, still hinder the application of network analysis to financial markets. In this paper we study the trading of cryptocurrency tokens on top of the Ethereum Blockchain, which is the largest publicly available financial data source that has a granularity of individual trades and users, and which provides a rare opportunity to analyze and model financial behavior in an evolving market from its inception. This quickly developing economy is comprised of tens of thousands of different financial assets with an aggregated valuation of more than 500 Billion USD and typical daily volume of 30 Billion USD, and manifests highly volatile dynamics when viewed using classic market measures. However, by applying network theory methods we demonstrate clear structural properties and converging dynamics, indicating that this ecosystem functions as a single coherent financial market. These results suggest that a better understanding of traditional markets could become possible through the analysis of fine-grained, abundant and publicly available data of cryptomarkets.

Pertussis incidence in developed countries, including Israel, has increased over the past two decades despite the addition of two booster doses in children. However, as pertussis is characterized by a multi-annual periodicity, and since clinical diagnosis can miss cases, determining disease trends at the population level is challenging. To bridge this gap, we developed a simple statistical model to capture the temporal patterns of pertussis incidence in Israel. Our model was calibrated and tested using laboratory-confirmed cases of pertussis for the Israeli population between 1998 and 2019. The model identifies a clear four-year periodicity of pertussis incidence over the past two decades that is identical to the one observed in the pre-vaccine era. Accounting for this periodicity, the model shows a 325% increase in pertussis incidence from 2002 to 2014. These multi-year trends were interrupted shortly after the introduction of routine immunization of Tdap vaccine in pregnancy in 2015, after which we found a 59.7% (95% CI: 57.7-61.6%)decline in pertussis incidence and a 49.5% (36.0-61.6%) decline in hospitalizations compared to the model's projection. While this sharp decline cannot be fully attributed to the newly introduced vaccination policy, sharper reductions of 71.2% (65.6-76.1%) in incidence and 58.4% (39.6-72.7%) in hospitalizations, have been observed in infants of age two months and below - young infants that have yet to become vaccinated and are more likely to be protected by maternal vaccination. Our work suggests that Tdap vaccination during pregnancy is a promising policy for controlling pertussis. Furthermore, due to the stable periodicity of pertussis, public health decision-makers should invest continuous efforts in the implementation of this strategy with additional reinforcement in expected peak years.

Recommender systems have become extremely common in recent years and are utilized in a variety of domains such as movies, music, news, products, restaurants, and so on. While a typical recommender system bases its recommendations solely on users’ preference data collected by the system itself, the quality of recommendations can significantly be improved if several recommender systems (or vendors) share their data. However, such data sharing poses significant privacy and security challenges, both to the vendors and the users. In this article, we propose secure protocols for distributed item-based Collaborative Filtering. Our protocols allow to compute both the predicted ratings of items and their predicted rankings without compromising privacy nor predictions’ accuracy. Unlike previous solutions in which the secure protocols are executed solely by the vendors, our protocols assume the existence of a mediator that performs intermediate computations on encrypted data supplied by the vendors. Such a mediated setting is advantageous over the non-mediated one since it enables each vendor to communicate solely with the mediator. This yields reduced communication costs, and it allows each vendor to issue recommendations to its clients without being dependent on the availability and willingness of the other vendors to collaborate.

This survey assessed the attitude of paediatric dental EAPD members toward using “knee-to-knee” positioning for dental examinations and minor procedures in infants and toddlers. An anonymous electronic online questionnaire was distributed among EAPD members. The survey consisted of 12 questions and assessed demographic characteristics, professional experience and attitudes toward the use of the “knee-to-knee” position. Of the 162 respondents, 148 (91%) reported using “knee-to-knee” positioning for dental examination. In addition, 97 (63%) reported performing other procedures in the “knee-to-knee” position. Fluoride application and oral hygiene instructions were the most common procedures performed in the “knee-to-knee” position. Most of the paediatric dentists who responded to this survey reported performing dental examinations in toddlers up to 2 years old using the “knee-to-knee” position. Majority of respondents also used this position to instruct parents regarding oral hygiene and to apply fluoride varnish.

Intrahepatic cholestasis of pregnancy and preeclampsia are two major pregnancy complications. We aimed to investigate the association between intrahepatic cholestasis of pregnancy (ICP) and preeclampsia. Single-center retrospective study. Study group included 180 women (162 singletons and 18 twin gestations) who were diagnosed with ICP based on clinical presentation, elevated liver enzymes and bile acids. The reference group included 1618 women (1507 singletons and 111 twin gestations) who delivered during the study period, and were matched according to age, gravidity, parity and singleton or twin gestation. The incidence of ICP was 0.36%. The incidence of preeclampsia was higher in women with ICP compared to reference group (7.78% vs 2.41%, aOR, 3.74 95% CI 12.0–7.02, p

Label ranking tasks are concerned with the problem of ranking a finite set of labels for each instance according to their relevance. Boosting is a well-known and reliable ensemble technique that was shown to often outperform other learning algorithms. While boosting algorithms were developed for a multitude of machine learning tasks, label ranking tasks were overlooked. Herein, we present a novel boosting algorithm, $BoostLR$ , that was specifically designed for label ranking tasks. Similarly to other boosting algorithms, $BoostLR$ , proceeds in rounds, where in each round, a single weak model is trained over a sampled set of instances. Instances that were identified as harder to predict in the current round, receive a higher (boosted) weight, and therefore also a higher probability to be included in the sample of the forthcoming round. Extensive evaluation of our proposed algorithm on 24 semi-synthetic and real-world label ranking datasets concludes that our algorithm significantly outperforms the current state-of-the-art label ranking methods.

BackgroundOfranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.MethodsThis pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).ResultsEnrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91–1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3–5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.ConclusionsIn this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.Clinical trials registrationNCT02511405

Label ranking is a machine learning task that deals with mapping an instance to a ranking of labels, representing the labels’ ordered relevance to the instance. Three recent studies have suggested the use of ensembles to improve the performance of simple label ranking models. However, none of them has explicitly inspected the question of how should the results obtained by simple models be aggregated into a single combined output. While classification tasks and regression tasks typically employ trivial aggregation techniques (i.e., majority voting and averaging, respectively), the case of label ranking tasks is not straightforward. The contribution of this paper is twofold. First, we propose to apply voting rules, typically used in the field of social choice, as the aggregation technique for label ranking ensembles. Our evaluation reveals that there is no single rule that consistently outperforms all other voting rules, and that under different settings different voting rules perform the best. Second, we propose a novel aggregation method for label ranking ensembles that learns the best voting rule to be used in a given setting. An extensive evaluation of the proposed method on semi-synthetic as well as real-world datasets shows that it obtains prediction performance that is significantly higher than that of the aggregation techniques currently used by state-of-the-art label ranking ensembles.

BackgroundOn September 20, 2021, Pfizer announced encouraging effectiveness and safety results from their COVID-19 vaccine clinical trials in 5-11 years old children. This study aims to assess parents’ perceptions and intention to vaccinate their 5-11 years old children and to determine the socio-demographic, health-related and behavioral factors, as well as the role of incentives beyond these factors, in predicting this intention.MethodsA cross-sectional representative online survey among parents of children aged 5-11 years in Israel (n=1,012). The survey was carried out between September 23 and October 4, 2021, at a critical time, immediately after Pfizer’s announcement. Two multivariate regressions were performed to determine predictors of parents’ intention to vaccinate their 5-11 years old children against COVID-19 in the coming winter and how soon they intend to do so.ResultsOverall, 57% of the participants reported their intention to vaccinate their 5-11 years old children against COVID-19 in the coming winter. This intention was higher for participants over the age of 40. Perceived susceptibility, perceived benefits, perceived barriers, and cues to action, as well as two incentives - vaccine availability and receiving a ‘green pass’ - were all significant predictors of this intention. When asked about how soon they intend to vaccinate their 5-11 years old children, 27% of the participants responded immediately; 26% within three months; and 24% within more than three months. Participants having a family member suffering from a chronic disease as well as those whose children were vaccinated against influenza in the previous winter intend to vaccinate their children sooner. Perceived susceptibility, perceived severity, perceived benefits, perceived barriers, and cues to action, were all found to be significant predictors of this sense of urgency. Similar to the intention to vaccinate children in the coming winter, while vaccine availability and receiving a ‘green pass’ were found to be positive significant predictors of how soon parents intend to vaccinate their children, other incentives such as monetary rewards or monetary penalties were not found to be significant predictors. Parental concerns centered around the safety of the vaccine (64%), fear of severe side effects (60%), and fear that clinical trials and the authorization process were carried out too quickly (56%).ConclusionsThis study provides up-to-date information on the rates of the intention of parents to vaccinate their 5-11 years old children, how soon they intend to do so, and the predictors of those intentions, which is essential for health policy makers and healthcare providers for planning vaccination campaigns. Moreover, as vaccine safety and side effects were found to be key parental concerns, it is important to release post-approval safety data regarding the vaccine to the public as soon as such is available. Finally, our findings underscore the important role of vaccine accessibility and receiving a ‘green pass’ over other incentives in promoting parents’ intentions to vaccinate their children.

SummaryProtein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumors’ responses to immunotherapy. For example, immunoproteasomes – a subset of proteasomes induced by inflammatory signals – may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity.Graphical AbstractHighlightsMapping the degradation landscape in Non-Small Cell Lung Cancer (NSCLC) uncovers altered proteasome activity and compositionProteasome regulator PSME4 plays an anti-inflammatory role in NSCLC by attenuating immunoproteasome activityPSME4 restricts tumor antigen presentation and cytokine secretion, defining a ‘cold’ tumor environmentPSME4 drives tumor immune evasion and is associated with resistance to immunotherapy

Background The COVID-19 pandemic is an ongoing global healthcare crisis that negatively affects pregnant women. Although patients with an acute infection during pregnancy have been widely studied, information regarding labor and delivery while infected is sparse. The aim of the study was to ascertain maternal, obstetrical, and perinatal outcomes of women who gave birth while infected with SARS-CoV-2. Methods Patients diagnosed with COVID-19 during pregnancy at a tertiary medical center in 4/20–2/21 were identified by a retrospective database search. Those with an active intrapartum SARS-CoV-2 infection were compared with those who recovered at least 10 days before labor and delivery. Results Of the 176 women included in the study, 84 had a SARS-CoV-2 infection at the time of delivery and 92 had recovered from the infection. There was no statistically significant between-group difference in mean gestational age at delivery (39 weeks for both, p = 0.71) and overall rate of cesarean delivery (26.2% vs 17.4%, respectively, p = 0.35) or non-elective cesarean delivery (10.71% vs 4.34%, respectively, p = 0.48). In the active-infection group, the rate of severe disease was 2.4%, and of critical disease (with intensive care unit admission, mechanical ventilation, and ECMO), 3.6%, compared to zero for both in the recovered group. No differences were found between the groups in adverse perinatal outcomes. Conclusion Delivery is safe and feasible in women with active SARS-CoV-2 infection. Nevertheless, we found a non-significant trend for more severe disease and for cesarean delivery and urgent cesarean delivery (for COVID-19-related indications) in women with an intrapartum SARS-CoV-2 infection.

BackgroundThe rapid rise in hospitalizations associated with the Delta-driven COVID-19 resurgence, and the imminent risk of hospital overcrowding, led the Israeli government to initialize a national third (booster) COVID-19 vaccination campaign in early August 2021, offering the BNT162b2 mRNA vaccine to individuals who received their second dose over five months ago. However, the safety of the third (booster) dose has not been fully established yet.ObjectiveEvaluate the short-term, self-reported and physiological reactions to the third BNT162b2 mRNA COVID-19 (booster) vaccine dose.DesignA prospective observational study, in which participants are equipped with a smartwatch and fill in a daily questionnaire via a dedicated mobile application for a period of 21 days, starting seven days before the vaccination.SettingAn Israel-wide third (booster) vaccination campaign.ParticipantsA group of 1,609 (18+ years of age) recipients of at least one dose of the BNT162b2 vaccine between December 20, 2020, and September 15, 2021, out of a larger cohort of 2,912 prospective study participants. 1,344 of the participants were recipients of the third vaccine dose.MeasurementsDaily self-reported questionnaires regarding local and systemic reactions, mood level, stress level, sport duration, and sleep quality. Heart rate, heart rate variability and blood oxygen saturation level were continuously measured by Garmin Vivosmart 4 smartwatches.ResultsThe extent of systemic reactions reported following the third (booster) dose administration is similar to that reported following the second dose (p-value=0.305) and considerably greater than that reported following the first dose (p-valueLimitationsParticipants may not adequately represent the vaccinated population in Israel and elsewhere.ConclusionOur work further supports the safety of a third COVID-19 BNT162b2 mRNA (booster) vaccine dose from both a subjective and an objective perspective, particularly in individuals 65+ years of age and those with underlying medical conditions.Primary funding sourceEuropean Research Council (ERC) project #949850

ObjectivesTo review the characteristics and motivations of patients seeking second opinions, and the impact of such opinions on patient management, satisfaction and cost effectiveness.Data sourcesEmbase, Medline, PsycINFO and Health Management Information Consortium (HMIC) databases.Study designA systematic literature search was performed for terms related to second opinion and patient characteristics. Study quality was assessed using the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.Data collection/extraction methodsWe included articles focused on patient-initiated second opinions, which provided quantitative data on their impact on diagnosis, treatment, prognosis or patient satisfaction, described the characteristics or motivating factors of patients who initiated a second opinion, or the cost-effectiveness of patient-initiated second opinions.Principal findingsThirty-three articles were included in the review. 29 studies considered patient characteristics, 19 patient motivating factors, 10 patient satisfaction and 17 clinical agreement between the first and second opinion. Seeking a second opinion was more common in women, middle-age patients, more educated patients; and in people having a chronic condition, with higher income or socioeconomic status or living in central urban areas. Patients seeking a second opinion sought to gain more information or reassurance about their diagnosis or treatment. While many second opinions confirm the original diagnosis or treatment, discrepancies in opinions had a potential major impact on patient outcomes in up to 58% of cases. No studies reported on the cost effectiveness of patient initiated second opinions.ConclusionsThis review identified several demographic factors associated with seeking a second opinion, including age, gender, health status, and socioeconomic status. Differences in opinion received, and in the impact of change in opinion, varies significantly between medical specialties. More research is needed to understand the cost effectiveness of second opinions and identify patient groups most likely to benefit from second opinions.

ObjectiveTo assess the public’s intention to get vaccinated immediately after COVID-19 vaccine became available, and to determine the role of incentives beyond socio-demographic, health-related and behavioral factors, in predicting this intention.MethodsAn online survey was conducted among adults in Israel (n=461), immediately after the first COVID-19 vaccine became available (22/12/2020 to 10/1/2021). Two regressions were performed to investigate determinants of intention and sense of urgency to receive the available COVID-19 vaccine.ResultsAlthough many adults intended to receive available COVID-19 vaccine, only 65% intended to immediately receive the vaccine; 16% preferred to wait 3 months and 18% preferred to wait a year. The sense of urgency to get vaccinated differed by age, periphery-level, perceived barriers, cues to action and availability. Monetary rewards or the “green pass” incentives didn’t increase the probability of getting vaccination immediately.ConclusionsProviding data on the role of incentives in increasing the intention to immediately receive the available COVID-19 vaccine is important for health policy makers and healthcare providers. Our findings underscore the importance of COVID-19 vaccine accessibility.Practice ImplicationsHealth policy makers should consider allocating funds for making the vaccine accessible and encourage methods of persuasion, instead of investing funds in monetary incentives.

In attempts to slow down the spread of COVID-19 pandemic, countries took different measures including lockdowns. Several studies reported the effects of lockdowns on sleep mostly suggesting an increase in sleep duration during lockdowns. This is an interesting outcome as life in the modern world were associated with insufficient sleep. The present study is a systematic review and meta-analysis of work regarding sleep duration during lockdowns. We searched PubMed using the terms “COVID-19”, “SARS-CoV-2”, “lockdown”, “stay at home”, “quarantine” and “sleep” and found 262 papers. After applying exclusion criteria, we identified 26 papers (with 35 discrete studies) for the meta-analysis. A fixed effect model was used with effect sizes estimated using Cohen’s d and heterogeneity of effect sizes tested using the Cochran’s Q test statistics. Most studies (31/35) report an increase in sleep duration during lockdown periods with a mean (± STD) of 31.5 ± 21.2 minutes. Effect sizes (Cohen’s d) ranged between 0.08 and 3.34, which are considered between very small and huge. Q statistics was 4859.3 (p

Financing in Australia's public hospital works through the Australian Refined Diagnosis Related Groups (AR-DRGs) with separations to specific DRG groups based on medical diagnosis or surgical procedure, patient's age, mode of separation, clinical complexity and complications. This paper aims at assessing how the AR-DRGs reflect the efficiency and equity of the hospitals resource allocation. Using administrative data of all acute public hospital admissions and length of stay (LOS) as a proxy for hospital costs, this paper showed that patients’ socio-economic (SES) characteristics are a strong determinant of health care utilization. Our results revealed that the lower the SES, the longer the LOS and hence more utilization of the inpatient resources. Therefore, omitting SES from the risk adjusters list and solely focusing on DRG- based compensation penalizes hospitals catering to lower SES populations. Our findings further support the idea of smaller/remote hospitals based on block funding.

The long-term effect of Zinc oxide zinc sulfate (Coltosol®) dressing material on pulpotomy success and tooth survival has not yet been studied. This study compared the success rates of Zinc oxide zinc sulfate and zinc oxide eugenol as coronal dressing materials post radicular pulp amputation in primary teeth pulpotomies. This study included healthy two- to ten-year-old children who had pulpotomies on primary molars between 2012 and 2018 at the Pediatric Dentistry Clinic of the School of Dental Medicine. Data were analyzed at several follow-ups of up to 60 months. Kaplan-Meier survival curves were used to estimate survival probabilities of Zinc oxide zinc sulfate versus zinc oxide eugenol. In the 107 children included in this study, 54 teeth were filled with Zinc oxide zinc sulfate and 53 were filled with zinc oxide eugenol. Follow-up ranged from 12.2 to 73.3 months. Overall survival of Coltosol® vs. IRM filled teeth was 87.1% and 79.3%, respectively. Overall survival probabilities for Coltosol®-filled teeth at 15.5, 24 and 45 months were 95%, 89.8% and 79.7%, respectively, while for IRM they were 93.7%, 83% and 67.7%, respectively. Treatment failure rates and type of treated teeth did not differ between boys and girls (p-value = 0.77 and 0.87, respectively). Zinc oxide zinc sulfate and zinc oxide eugenol exhibited comparable high long-term success rates of up to five years (p = 0.16).

Objectives: Survival following childhood cancer has increased considerably. We examined associations of cancer therapy with the presence of Dental Developmental Anomalies (DDA)among childhood cancer survivors.Procedure: 131 children who were diagnosed with malignancies during childhood were included. Permanent teeth were examined clinically and radiographically to identify DDA: hypocalcification or hypoplasia, microdontia, root changes and hypodontia.Results: observed in 56 (46%) of 121 children, in 309 teeth (9%). Hypocalcification or hypoplasia of enamel appeared in 21 (17%) patients. Altered root development appeared in 26 patients and hypodontia affected 13(10%). Dental anomalies were observed in 36(43%) individuals who received chemotherapy and not radiation, in 20 (52.63%) who received radiotherapy, and in 15 (60%)of those who received head & neck radiotherapy. Young age (under 6 years) was associated with a higher number of malformed teeth among patients who received only chemotherapy. Various chemotherapy agents associated similarly with dental anomalies.Conclusions: Antineoplastic treatment that combines chemotherapy and radiotherapy appears to increase the risk of developing DDA. Radiation to the head and neck area particularly increases the risk of DDA. No specific chemotherapy agent was found to be associated more than the others with dental side effects.

Background Trials of the Pfizer-BioNTech BNT162b2 mRNA vaccine showed 95% efficacy in preventing symptomatic disease; however, the trials excluded immunocompromised patients (ICPs). We aim at analyzing antibody response in ICPs. Methods A prospective cohort study was conducted at Sheba Medical Center, Israel, between January and April 2020, in 1274 participants who received the vaccine, including 1002 ICPs and 272 immunocompetent healthcare workers (HCWs). Antibodies were measured two-four weeks after vaccination by SARS-CoV-2 anti–receptor binding domain IgG antibodies (RBD IgG) and pseudo-virus neutralization assays. Multivariable logistic regression analyses were used to identify factors associated with vaccine-induced antibody response. Adverse events (AEs) were monitored. Findings RBD-IgG antibodies were detected in 154/156 (98.7%) of patients with HIV, 75/90 (83.3%) with solid malignancies, 149/187 (79.7%) with myeloma, 83/111 (74.8%) following hematopoietic stem cell transplants, 25/36 (69.4%) following liver transplantation, 26/43 (60.5%) with myelodysplastic syndrome, 96/188 (51.0%) with chronic lymphocytic leukemia/non-Hodgkin's lymphoma, 50/110 (45.5%) following kidney transplantation, 15/80 (18.8%) following heart transplantation, and 269/272 (98.9%) in controls. There was a significant correlation r = 0.74 (95%CI 0.69,0.78) between RBD-binding IgG and neutralizing antibodies in all groups. Multivariate logistic regression analysis showed that age > 65 years (OR 0.41,95%CI 0.30,0.57) and underlying immunosuppression (OR 0.02,95%CI 0.01,0.07) were significantly associated with a non-reactive response of IgG antibodies. HIV patients showed a similar immunological response as healthy adults. The vaccine was safe without any episodes of rejection, graft-versus-host disease (GVHD) or allergy. Immunocompetent HCWs experienced significantly more AEs than ICPs. Interpretation Antibody response to the Pfizer-BioNTech vaccine was highly variable among different ICPs; thus, individual recommendations should be provided for the different immunosuppression states. Funding None.

Oxaliplatin is a common chemotherapy agent that is used in the treatment of multiple solid malignancies. Immune-mediated thrombocytopenia is a rare and potentially life-threatening adverse effect of oxaliplatin that is characterized by severe thrombocytopenia which may be accompanied by overt bleeding. This adverse effect is most likely mediated via anti-platelet antibodies that become reactive in the presence of oxaliplatin. Due to its rarity and severity, information is scarce regarding the effect of desensitization or attempts at rechallenge after prolonged withdrawal of oxaliplatin. This short report describes three cases of oxaliplatin immune-mediated thrombocytopenia, including a case occurring under desensitization protocol and a case of recurrence after a prolonged withdrawal. All three patients are female, have prolonged exposures to oxaliplatin and were all treated for metastatic colorectal cancer. Physicians should be aware of oxaliplatin immune-mediated thrombocytopenia as symptoms may appear rapidly. Oxaliplatin should be permanently discontinued for patients experiencing this adverse effect, as recurrence is highly likely even in the setting of desensitization.

PurposeTo compare different multi-echo combination methods for MRI quantitative susceptibility mapping (QSM). Given the current lack of consensus, we aimed to elucidate how to optimally combine multi-echo gradient-recalled echo (GRE) signal phase information, either before or after applying Laplacian-base methods (LBMs) for phase unwrapping or background field removal.MethodsMulti-echo GRE data were simulated in a numerical head phantom, and multiecho GRE images were acquired at 3 T in ten healthy volunteers. To enable image-based estimation of GRE signal noise, five volunteers were scanned twice in the same session without repositioning. Five QSM processing pipelines were designed: one applied nonlinear phase fitting over echo times (TEs) before LBMs; two applied LBMs to the TE-dependent phase and then combined multiple TEs via either TE-weighted or signal-to-noise ratio (SNR)-weighted averaging; two calculated TE-dependent susceptibility maps via either multi-step or single-step QSM and then combined multiple TEs via magnitude-weighted averaging. Results from different pipelines were compared using visual inspection; summary statistics of susceptibility in deep gray matter, white matter, and venous regions; phase noise maps (error propagation theory); and, in the healthy volunteers, regional fixed bias analysis (Bland-Altman) and regional differences between the means (nonparametric tests).ResultsNonlinearly fitting the multi-echo phase over TEs before applying LBMs provided the highest regional accuracy of χ and the lowest phase noise propagation compared to averaging the LBM-processed TE-dependent phase. This result was especially pertinent in high-susceptibility venous regions.ConclusionFor multi-echo QSM, we recommend combining the signal phase by nonlinear fitting before applying LBMs.