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Background Tixagevimab and cilgavimab, a combined monoclonal antibody (Evusheld), was granted emergency use authorization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preexposure prophylaxis in individuals with immunocompromising conditions. In this study we used population-based real-world data to evaluate the effectiveness of Evusheld in immunocompromised patients. Methods Using the computerized database of the largest healthcare provider in Israel, we identified all adult immunocompromised patients who were eligible to receive Evusheld (150 mg tixagevimab and 150 mg cilgavimab) on 15 February 2022. Patients with a documentation of a prior SARS-CoV-2 infection were excluded. A total of 703 patients who received Evusheld were propensity score matched, using a ratio of 1:4, with 2812 patients who had not received Evusheld (control group). Patients were followed through 30 June 2022 for up to 90 days for the first documentation of SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19)–related hospitalization. Results Overall, 72 patients in the Evusheld group and 377 patients in the control group had SARS-CoV-2 infection, reflecting an incidence rate of 4.18 and 5.64 per 100 person-months, respectively. The hazard ratios were 0.75 (95% confidence interval [CI]: .58–.96) for SARS-CoV-2 infection and 0.41 (95% CI: .19–.89) for COVID-19–related hospitalization in the Evusheld group compared to the control group. The magnitude of relative risk reduction of each outcome was greater in nonobese patients (P for interaction = .020 and .045, respectively). Conclusions This study suggests that Evusheld is effective in reducing the risk of SARS-CoV-2 infection and COVID-19 hospitalization in immunocompromised patients. The effectiveness of this dose appears to be greater in nonobese patients.

Background Paxlovid was granted an Emergency Use Authorization for the treatment of mild to moderate coronavirus disease 2019 (COVID-19), based on the interim analysis of the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial. Paxlovid effectiveness needs to be assessed in a noncontrolled setting. In this study we used population-based real-world data to evaluate the effectiveness of Paxlovid. Methods The database of the largest healthcare provider in Israel was used to identify all adults aged 18 years or older with first-ever positive test for severe acute respiratory syndrome coronavirus 2 between January and February 2022, who were at high risk for severe COVID-19 and had no contraindications for Paxlovid use. Patients were included irrespective of their COVID-19 vaccination status. Cox hazard regression was used to estimate the 28-day hazard ratio (HR) for severe COVID-19 or mortality with Paxlovid examined as time-dependent variable. Results Overall, 180 351 eligible patients were included; of these, only 4737 (2.6%) were treated with Paxlovid, and 135 482 (75.1%) had adequate COVID-19 vaccination status. Both Paxlovid and adequate COVID-19 vaccination status were associated with significant decrease in the rate of severe COVID-19 or mortality with adjusted HRs of 0.54 (95% confidence interval [CI], .39–.75) and 0.20 (95% CI, .17–.22), respectively. Paxlovid appears to be more effective in older patients, immunosuppressed patients, and patients with underlying neurological or cardiovascular disease (interaction P < .05 for all). No significant interaction was detected between Paxlovid treatment and COVID-19 vaccination status. Conclusions This study suggests that in the era of Omicron and in real-life settings, Paxlovid is highly effective in reducing the risk of severe COVID-19 or mortality.

To evaluate maternal and neonatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibody levels at birth after a third (booster) dose of the Pfizer-BioNTech messenger RNA (Pfizer) coronavirus disease 2019 (COVID-19) vaccine during the second trimester of pregnancy, and compare them with those in women who received two vaccine doses during the second trimester.We conducted a prospective cohort study of women admitted to the delivery ward at a single center who received the third Pfizer COVID-19 vaccine dose (booster group) at 17-30 weeks of pregnancy and who did not have previous SARS-CoV-2 infection. Maternal and neonatal antibody levels were measured on admission for delivery and in the umbilical cord blood after birth. Antibody levels for the booster group were compared with those in a historical control group of pregnant women who received their second vaccine dose (two-dose group) within the same gestational age window.Between October 2021 and February 2022, antibody levels were measured in 121 women and 109 neonates at a mean±SD of 15.3±3.9 weeks after booster vaccination. Neonatal titers measured two times higher than maternal titers, with inverse correlation between maternal and neonatal titers at birth and time interval from third vaccination. The two-dose group included 121 women and 107 neonates, with antibody levels measured at a mean±SD of 14.6±2.6 weeks after the second dose. Median [interquartile range] maternal antibody titers were higher in the booster group (4,485 [2,569-9,702] AU/mL) compared with the two-dose group (1,122 [735-1,872] AU/mL) (P.001). Furthermore, neonatal antibody titers were higher in the booster group (8,773 [5,143-18,830] AU/mL) compared with the two-dose group (3,280 [2,087-5,754] AU/mL) (P.001).Maternal and neonatal SARS-CoV-2 IgG antibody titers after second-trimester maternal Pfizer COVID-19 vaccination were significantly higher after the booster dose compared with the two-dose vaccination series. Although there is uncertainty as to whether antibody levels correlate with protection, these data support the importance of booster vaccination during pregnancy to restore maternal and neonatal protection against COVID-19.

Femtosecond laser-assisted cataract surgery (FLACS) may cause thinning of the peripapillary retinal nerve fiber layer (pRNFL) in healthy eyes.This prospective cohort study aimed to compare changes of pRNFL after FLACS using a liquid patient interface and conventional phacoemulsification cataract surgery (CPCS).Included were 261 eyes (261 patients) with age-related cataracts and no ocular diseases scheduled either for FLACS (222 eyes) or CPCS (39 eyes). FLACS was performed using a Ziemer LDV Z8 laser. Average and quadrant pRNFL thickness was measured using optical coherence tomography before surgery and at 1, 3, and 6 months postoperatively. Postoperative changes in pRNFL thickness were compared within and between groups.Mean quadrant and average pRNFL thicknesses significantly increased after both surgeries (P0.001). However, pRNFL thinning occurred after FLACS and CPCS (17% vs. 5.1%, respectively, P0.05). FLACS eyes showed a significant and stable decrease of average pRNFL thickness (P=0.057) and a gradual decrease in pRNFL thickness of all quadrants (P≤0.018). CPCS eyes showed an initial increase of pRNFL thickness, followed by a decrease only in the nasal quadrant and average pRNFL. Preoperative pRNFL thickness was associated with thinning of the temporal quadrant (P=0.04).Both FLACS and CPCS demonstrated pRNFL thinning in some healthy eyes. Although the higher rate of pRNFL thinning after FLACS compared with CPCS lacked statistical significance, a consistent decrease in pRNFL thickness occurred in all quadrants and average pRNFL of FLACS eyes, suggesting that FLACS may lead to pRNFL thinning. Eyes with thinner preoperative pRNFL may be prone to temporal quadrant thinning after FLACS.

Background Molnupiravir was granted emergency use authorization for the treatment of mild to moderate coronavirus disease 2019 (COVID-19). In this study, we used population-based real-world data to evaluate the effectiveness of molnupiravir. Methods The database of the largest healthcare provider in Israel was used to identify all adults with first-ever positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) performed in the community during January–February 2022, who were at high risk for severe COVID-19, and had no contraindications for molnupiravir use. Patients were included regardless of SARS-CoV-2 vaccination status. A total of 2661 patients who received molnupiravir were propensity score matched with 2661 patients who have not received molnupiravir (control group). Patients were followed through 10 March 2022 for up to 28 days for the first occurrence of the composite severe COVID-19 or COVID-19-specific mortality. Results The composite outcome occurred in 50 patients in the molnupiravir group and 60 patients in the control group. Molnupiravir was associated with a nonsignificant reduced risk of the composite outcome: hazard ratio, 0.83 (95% confidence interval, .57–1.21). However, subgroup analyses showed that molnupiravir was associated with a significant decrease in the risk of the composite outcome in older patients 0.54 (0.34–0.86), in females 0.41 (0.22–0.77), and in patients with inadequate COVID-19 vaccination 0.45 (0.25–0.82). The results were similar when each component of the composite outcome was examined separately. Conclusions This study suggests that in the era of Omicron and in real-life setting, molnupiravir might be effective in reducing the risk of severe COVID-19 and COVID-19-related mortality, particularly in specific subgroups.

Integrative oncology (IO) is increasingly becoming part of palliative cancer care. This study examined the correlation between an IO treatment program and rates of survival among patients with advanced gynecological cancer. Patients were referred by their oncology healthcare professionals to an integrative physician (IP) for consultation and IO treatments. Those undergoing at least 4 treatments during the 6 weeks following the consultation were considered adherence to the integrative care program (AIC), versus non-adherent (non-AIC). Survival was monitored for a period of 3 years, comparing the AIC vs. non-AIC groups, as well as controls who did not attend the IP consultation. A total of 189 patients were included: 71 in the AIC group, 44 non-AIC, and 74 controls. Overall 3-year survival was greater in the AIC group (vs. non-AIC, p = 0.012; vs. controls, p = 0.003), with no difference found between non-AIC and controls (p = 0.954). Multimodal IO programs (≥ 3 modalities) were correlated in the AIC group with greater overall 3-year survival (p = 0.027). Greater rates of survival were also found in the AIC group at 12 (p = 0.004) and 18 months (p = 0.001). When compared with the AIC group, a multivariate analysis found higher crude and adjusted hazard ratios for 3-year mortality in the non-AIC group (HR 95% CI 2.18 (1.2–3.9), p = 0.010) and controls (2.23 (1.35–3.7), p = 0.002). Adherence to an IO treatment program was associated with higher survival rates among patients with advanced gynecological cancer. Larger prospective trials are needed to explore whether the IO setting enhances patients’ resilience, coping, and adherence to oncology treatment.

In vitro studies have demonstrated rescue of CFTR function with Elexacaftor/Tezacaftor/Ivacaftor (ETI) in several mutations other than F508del. However, clinical efficacy was not tested in vivo in people with CF (pwCF) carrying mutations other than F508del. We report effects of treatment with ETI in pwCF with non-F508del mutations.We retrospectively analyzed pwCF with non-F508del mutations who received treatment with ETI. We evaluated sweat chloride, nutritional status, spirometry, antibiotic treatment, and pulmonary exacerbations (PEx), at baseline and 3-6 months after commencing treatment with ETI.We included 16 pwCF, including eight without previous use of CFTR modulators. Median time on treatment was 5.3 (range, 1.8-7.7) months. Compared to baseline, in the "naïve" group sweat chloride concentration was reduced from 113.0 (98-129) to 64.0 (32-97) mEq/L (n=7; median (IQR), p=0.018), and rate of pulmonary exacerbations declined from a median of 1.5 (IQR 1, 2.75) in the previous year to 0 (0,0) (p= 0.019) with a significant decline in annualized days with antibiotics (oral + parenteral) per year: 36 (17.5; 42) in the year before to 0 (0,0) (median (IQR), p= 0.027). Mean FEVWe demonstrate the clinical efficacy of ETI in pwCF carrying CFTR processing non-F508del mutations which are predicted to respond by in vitro studies. Our results support routine clinical use of ETI in this patient group.

Paxlovid was granted emergency use authorization for the treatment of mild to moderate COVID-19, based on the interim analysis of EPIC-HR trial. Paxlovid effectiveness needs to be assessed in a noncontrolled setting. In this study we used population-based real world data to evaluate the effectiveness of Paxlovid.The database of the largest healthcare provider in Israel was used to identify all adults aged 18 years or older with first ever positive test for SARS-CoV-2 between January and February 2022, who were at high risk for severe COVID-19 and had no contraindications for Paxlovid use. Patients were included irrespective of their COVID-19 vaccination status. Cox hazard regression was used to estimate the 28 day HR for severe COVID-19 or mortality with Paxlovid examined as time-dependent variable.Overall, 180,351 eligible were included, of them only 4,737 (2.6%) were treated with Paxlovid, and 135,482 (75.1%) had adequate COVID-19 vaccination status. Both Paxlovid and adequate COVID-19 vaccination status were associated with significant decrease in the rate of severe COVID-19 or mortality with adjusted HR 0.54 (95% CI, 0.39-0.75) and 0.20 (95% CI, 0.17-0.22), respectively. Paxlovid appears to be more effective in older patients, immunosuppressed patients, and patients with underlying neurological or cardiovascular disease (interaction p-value0.05 for all). No significant interaction was detected between Paxlovid treatment and COVID-19 vaccination status.This study suggests that in the era of omicron and in real life setting Paxlovid is highly effective in reducing the risk of severe COVID-19 or mortality.

Women with the most extensive breast density, have a 4- to 6-fold higher cancer risk than women with the lowest density. This cross-sectional study evaluated associations of cumulative mammographic density in two distinct ethnic groups with the respective age-specific breast cancer incidences in the population. The study compared four cohorts of 200 women each aged 35 to 49 and 50 to 74, representing Jewish and Arab ethnicity. Breast density measures were calculated from screening mammograms, using a thresholding software (Cumulus). Breast cancer specific incidence values were obtained from the National Cancer Registry. The percent mammographic density was lower for women aged 50 to 74 than 35 to 49 years, both for Jews: 11.7 vs 23.1 and for Arabs: 11.6 vs 18.3. In contrast, the cumulative density increased with age, from 37.30 to 181.24 in Jews, compared to 21.26 to 108.03 in Arabs. Similar trends in breast cancer incidence rates per 100 000 in the Israeli population were apparent, with an increase from 92.95 to 381.91 in Jews, compared to 48.6 to 244.44 in Arabs. Comparing cumulative density of the cohort with respective age-specific breast cancer incidence in the population yielded a highly significant correlation: Jews; r = .97, P .0001 and Arabs: r = .86, P = .007. A strong association was found between the log of cumulative density and the log of cancer incidence, as well. Our study identified correlations between cumulative mammographic density and breast cancer incidence in two distinct populations. The findings should prompt research to enhance our understanding of the pathogenesis of breast cancer, and lead to novel insights into measures of prevention.

BackgroundAirway clearance is a fundamental component of bronchiectasis care. Lung clearance index (LCI) is a measurement of ventilation inhomogeneity. Its responsiveness to long-term airway clearance is unknown. We aimed to compare two methods of daily airway clearance over 4 weeks: autogenic drainage (AD) and oscillating positive airway pressure (oPEP), and to determine effects of airway clearance on LCI and clinical outcomes.MethodsAdults with bronchiectasis naive to airway clearance were randomised to daily airway clearance with either AD or oPEP. Difference in LCI as primary outcome, spirometry, sputum volume and purulence, and quality of life were at randomisation and after 4 weeks of airway clearance.Results51 patients (32 women and 19 men, mean age 66.2±12.8 years) were randomised and 49 completed the study (25 AD and 24 oPEP). The LCI and forced expiratory volume in 1 s did not change between visits between groups (difference between groups 0.02), nor between visits in either group. Sputum quantity decreased in 12 out of 24 (50%) of the oPEP group, and in six out of 25 (24%) of the AD group (p=0.044). The “treatment burden” worsened or was unchanged in 70% of participants randomised to AD and 55% randomised to oPEP (p=0.038).ConclusionSputum quantity decreased in more participants randomised to oPEP group after 1 month of daily airway clearance, with a better treatment burden. The effects of 4 weeks of airway clearance on LCI were not significant in either treatment group.

ObjectiveThis study aimed to compare the effectiveness of pharmacological therapy with and without direct maxillary sinus saline irrigation for the management of chronic rhinosinusitis without polyps.MethodsIn this prospective randomised controlled trial, 39 non-operated patients were randomly assigned to be treated with direct maxillary sinus saline irrigation in conjunction with systemic antibiotics and topical sprays (n =24) or with pharmacological therapy alone (n =15). Endoscopy, Sino-Nasal Outcome Test and Lund–MacKay computed tomography scores were obtained before, six weeks after and one to two years after treatment.ResultsPost-treatment Lund–Mackay computed tomography scores were significantly improved in both cohorts, with no inter-cohort difference identified. Post-treatment nasal endoscopy scores were significantly improved in the study group but were similar to those measured in the control group. The Sino-Nasal Outcome Test-20 results showed improvement in both cohorts, with no difference between treatment arms.ConclusionMaxillary sinus puncture and irrigation with saline, combined with pharmacological treatment improves endoscopic findings in patients with chronic rhinosinusitis without polyps, but has no beneficial effect on symptoms and imaging findings over conservative treatment alone.

STUDY OBJECTIVE There is a need to explore how patient-tailored integrative oncology (IO) programs reduce emotional distress. This study set out to bridge the IO research gap between non-specific, quality of life-related and specific emotional-related concerns in chemotherapy-treated patients. METHODS This pragmatic, prospective and preference-controlled study examined patients attending an integrative-physician consultation and weekly IO treatments during adjuvant/neo-adjuvant chemotherapy for localized cancer. Patients choosing to attend ≥4 IO sessions (highly adherent to integrative care, AIC) were compared to low AIC patients using the ESAS (Edmonton Symptom Assessment Scale) anxiety, depression and sleep; and the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) emotional functioning scale, at baseline, 6 and 12 weeks. Emotional distress was assessed by ESAS anxiety and depression, considered as the primary study outcomes. RESULTS Of 439 participants, 260 (59%) were high-AIC and 179 low-AIC, both with similar baseline demographic and cancer-related characteristics. At 6 weeks, high-AIC patients reported greater improvement on ESAS sleep (p = 0.044); within-group improvement on ESAS anxiety and; and EORTC emotional functioning. Compared with low-AIC, high-AIC patients showed greater improvement on ESAS depression (p = 0.022) and sleep (p = 0.015) in those with high baseline ESAS anxiety scores (≥7); and ESAS anxiety (p = 0.049) for patients moderately anxious (4-6) at baseline. CONCLUSIONS High-AIC was associated with significantly reduced anxiety, depression and sleep severity at 6 weeks, especially those with high-to-moderate baseline anxiety levels. These findings reduce the research gap, suggesting specific emotional-related effects of IO.

PURPOSES Escherichia coli is one of the most common pathogens in nosocomial and community-acquired infections, but is an uncommon respiratory pathogen. However, this pathogen may at times be seen in respiratory secretions. The study aims to determine the clinical and prognostic value of E. coli in respiratory secretions. METHODS Cultures of respiratory secretions from hospitalized and outpatients between 2009 and 2016 were screened for isolation of E. coli. We defined three groups of patients: "Sensitive (S)"-growth of E. coli sensitive to all antimicrobials tested; Intermediate (I)-resistant to 1-2 antimicrobial classes; and "Resistant (R)"-resistant to at least three antibiotic classes. We compared factors associated with resistant strains and outcomes between the groups. RESULTS Eighty patients with E. coli isolates from respiratory secretions were identified while screening 177 712 (4.5: 10 000 samples). Of the E. Coli-positive cultures, 11 were from ambulatory patients, 31 patients were hospitalized and 37 were hospitalized and intubated. Ten people had bronchiectasis and 29 had COPD. Patients with resistant E. coli had significantly more hospitalization days prior to positive culture (S = 1.2 ± 1.89 days, I = 1.23 ± 1.5 days and R = 3.7 ± 5.4 days, respectively; P = 0.002). Mortality was higher in patients with a resistant strain (R) versus (I) or (S) (76.7%, 31.8% and 26.7%, respectively; P

The complex process of medical decision-making is prone also to medically extraneous influences or “non-medical” factors. We aimed to investigate the possible role of non-medical factors in doctors’ decision-making process in a telemedicine setting. Interviews with 15 physicians who work in a pediatric telemedicine service were conducted. Those included a qualitative section, in which the physicians were asked about the role of non-medical factors in their decisions. Their responses to three clinical scenarios were also analyzed. In an additional quantitative section, a random sample of 339 parent -physician consultations, held during 2014–2017, was analyzed retrospectively. Various non-medical factors were identified with respect to their possible effect on primary and secondary decisions, the accuracy of diagnosis, and “reasonability” of the decisions. Various non-medical factors were found to influence physicians’ decisions. Those factors were related to the child, the applying parent, the physician, the interaction between the doctor and parents, the shift, and to demographic considerations, and were also found to influence the ability to make an accurate diagnosis and “reasonable” decisions. Our conclusion was that non-medical factors have an impact on doctor’s decisions, even in the setting of telemedicine, and should be considered for improving medical decisions in this milieu.

OBJECTIVES The choice of a bioprosthetic valve (BV) over a mechanical valve (MV) in middle-aged adults in the mitral position is still under debate. Each valve type has benefits and drawbacks. We examined the mid-term survival of patients aged 50–70 years after BV versus MV mitral valve replacement (MVR). METHODS We conducted a multicentre, retrospective analysis of patients aged 50–70 years undergoing MVR from 2005 to December 2018 in 4 medical centres in Israel. To control for between-group differences, we used propensity-adjusted analysis. The primary end point was all-cause mortality. Secondary end points included reoperation, cerebrovascular accident and bleeding. RESULTS During the study period, 2125 MVR procedures were performed. Of these, 796 were eligible for inclusion [539 (67.8%) MV replacement and 257 (32.2%) BV]. The mean age was 61.0 ± 5.4. There were 287 deaths during 4890 person-years of follow-up. The adjusted hazard ratio was (1.13 [0.85–1.49], P = 0.672). There was also no difference in the secondary end points. Subgroup analysis of patients aged 50–64 years showed a higher risk of mortality with BV (hazard ratio = 1.50 [1.07–2.1], P = 0.018). Reoperation was a strong predictor of mortality during the study period (72.2%). CONCLUSIONS In patients aged 50–70 years, we found an interaction between age and MV or BV outcomes—those younger than 65 years gained a mortality advantage with MV, while outcomes were similar in the 65–70 age group. this supports the current guidelines recommending using MV in patients

ObjectiveClinical models such as the HAS-BLED (standing for Hypertension, Abnormal liver/renal function, Stroke history, Bleeding history or predisposition, Labile INR, Elderly, Drug/alcohol usage) were developed to predict risk of major bleeding on vitamin K antagonists/antiplatelet therapy. We aimed to develop a model that will improve the ability to predict major bleeding events in patients with non-valvular atrial fibrillation (AF) treated with new oral anticoagulants (NOACs).MethodsClalit Health Services is the largest of four integrated healthcare organisations in Israel, which insures 4.7 million patients (53% of the population). We identified in Clalit Health Services all patients with AF, new users of an NOAC (2013–2017), and followed them until first occurrence of a major bleeding event, death, switch to another oral anticoagulant, 30 days after discontinuation of NOAC or end of follow-up (31 December 2019). Importance of the candidate model variables was estimated by inclusion frequencies across forward selection algorithm applied to 50 bootstrap samples. Then, backward selection algorithm using the modified Bayesian Information Criterion for competing risks was applied to select predictors for the final model.Results47 623 patients with AF prescribed NOAC were studied. 28 055 patients with AF, initiators of apixaban (mean age 78.7, SD 9.0), were included in the first phase and had 662 major bleeding events. Nine variables were selected for inclusion in a final points-based risk-scoring system: male sex, anaemia, thrombocytopaenia (3/µL), concurrent antiplatelet therapy, hypertension, prior major bleeding, risk factors for a fall, low cholesterol level and low estimated glomerular filtration rate, with apparent area-under-curve (AUC) of 0.6546. Applicability of the model was then shown for 14 118 and 5450 patients with AF, initiators of dabigatran and rivaroxaban, where the score achieved c indices of 0.62 and 0.61, respectively.ConclusionsWe present a novel and simple risk score for prediction of major bleeding in patients with non-valvular AF treated with NOACs. Validation in additional cohorts is warranted.

Concomitant use of direct oral anticoagulants (DOACs) and medications with inhibition/induction effect on P-gp/CYP3A might increase risk of bleeding/treatment failure, respectively. We designed a nested case-control study within a Clalit cohort of patients with atrial fibrillation (AF) and a cohort of patients with venous thromboembolism, new users of a DOAC (January 1, 2010 to August 24, 2020). Propensity scores were constructed from demographic/clinical characteristics, and medications at cohort entry. Each case of: (i) serious bleeding event; (ii) stroke/systemic emboli (SE) in patients with AF; (iii) recurrent thromboembolism in patients with thromboembolism, was matched by age, sex, length of follow-up, year of cohort entry, DOAC type, and DOAC indication, to up to 20 controls. Within 89,284 patients with AF and venous thromboembolism and 126,302 patient-years of follow-up, there were 1,587 serious bleeding events. Risk of serious bleeding increased in association with concurrent prescription of P-gp/CYP3A4 inhibitors. Specifically, higher bleeding risk was associated with dabigatran-verapamil, rivaroxaban-verapamil, and rivaroxaban-amiodarone concurrent prescriptions: adjusted odds ratios (ORs) 2.29 (1.13-4.60), 2.18 (1.07-4.40), and 1.68 (1.14-2.49), respectively. There were 1,116 events of stroke/SE, in 79,302 DOAC-treated patients with AF and 118,124 patient-years of follow-up. Concomitant use of phenytoin, carbamazepine, valproic acid, or levetiracetam was associated with risk for stroke/SE: adjusted OR 2.18 (1.55-3.10). Risk of recurrent venous thromboembolism could not be assessed due to the low number of cases. Concurrent prescriptions of dabigatran or rivaroxaban with verapamil, and of rivaroxaban with amiodarone, are associated with increased risk for serious bleeding. Higher risk for stroke/SE in patients with AF is associated with concurrent prescriptions of DOACs with phenytoin, carbamazepine, valproic acid, or levetiracetam.

ObjectiveTo assess the impact of a multidisciplinary complementary and integrative medicine (CIM) intervention on physical and emotional concerns among front-line COVID-19 healthcare providers (HCPs).MethodsA multimodality CIM treatment intervention was provided by integrative practitioners to HCPs in three isolated COVID-19 departments. HCPs’ two main concerns were scored (from 0 to 6) before and following the CIM intervention using the Measure Yourself Concerns and Wellbeing questionnaire. Postintervention narratives identified reflective narratives specifying emotional and/or spiritual keywords.ResultsOf 181 HCPs undergoing at least one CIM treatment, 119 (65.7%) completed post-treatment questionnaires. While HCPs listing baseline emotional-related concerns benefited from the CIM intervention, those who did not express emotional or spiritual concerns improved even more significantly following the first session, for both leading concerns (p=0.038) and emotional-related concerns (p=0.023). Nevertheless, it was shown that following subsequent treatments HCPs who expressed emotional and spiritual concerns improved more significantly than those who did not for emotional-related concerns (p=0.017).ConclusionsA CIM intervention for front-line HCPs working in isolated COVID-19 departments can significantly impact emotional-related concerns, more so after the first treatment and among HCPs not using emotional-spiritual keywords in post-treatment narratives. Referral of HCPs to CIM programmes for improved well-being should avoid referral bias to those not expressing emotional/spiritual concerns.

Aim Condensation often occurs when providing humidified respiratory support. We examined conditions conducive to excess water formation in heated humified high-flow nasal cannula (HHHFNC). Methods An HHHFNC device, at 35 or 37°C, was attached with a nasal cannula to a reservoir and tested in five ambient conditions and flows. For Group A, tubing and collection bottle remained at room temperature (23°C). Group B, tubing and reservoir remained inside an incubator (31°C). Group C, tubing and reservoir remained at 33°C. In Group D, the HHHFNC was set to 35°C, the reservoir remained at 33°C, and the nasal cannula and tubing remained at 23°C. Group E, same as D, with HHHFNC at 37°C. Results The largest amounts of collected water were in groups A and E. Both had highest temperature differences. Median (range) was 4.9°C (4.1-6.9) and 4.0°C, collecting 38.4 (26.4-50.4) and 26.4 (19.2-50.4) ml/24 h, respectively. Smallest amounts of water were seen with lower temperature differences as in groups B, C, and D with 2.7 (1.9-4.7), 1.6 (1.2-2.1), and 2.0°C with 8.4 (0.0-33.6), 2.4 (0.0-14.4), and 9.6 (4.8-16.8) ml/24 h, respectively. Conclusion HHHFNC devices may produce clinically significant amounts of water reaching the upper airways. This may be prevented with appropriate device set-up.

Integrative oncology (IO) is increasingly becoming part of palliative cancer care. This study examined the correlation between an IO treatment program and rates of survival among patients with advanced gynecological cancer.Patients were referred by their oncology healthcare professionals to an integrative physician (IP) for consultation and IO treatments. Those undergoing at least 4 treatments during the 6 weeks following the consultation were considered adherence to the integrative care program (AIC), versus non-adherent (non-AIC). Survival was monitored for a period of 3 years, comparing the AIC vs. non-AIC groups, as well as controls who did not attend the IP consultation.A total of 189 patients were included: 71 in the AIC group, 44 non-AIC, and 74 controls. Overall 3-year survival was greater in the AIC group (vs. non-AIC, p = 0.012; vs. controls, p = 0.003), with no difference found between non-AIC and controls (p = 0.954). Multimodal IO programs (≥ 3 modalities) were correlated in the AIC group with greater overall 3-year survival (p = 0.027). Greater rates of survival were also found in the AIC group at 12 (p = 0.004) and 18 months (p = 0.001). When compared with the AIC group, a multivariate analysis found higher crude and adjusted hazard ratios for 3-year mortality in the non-AIC group (HR 95% CI 2.18 (1.2-3.9), p = 0.010) and controls (2.23 (1.35-3.7), p = 0.002).Adherence to an IO treatment program was associated with higher survival rates among patients with advanced gynecological cancer. Larger prospective trials are needed to explore whether the IO setting enhances patients' resilience, coping, and adherence to oncology treatment.

Background: Airway clearance (AWC) is a fundamental component of care in bronchiectasis, but evidence of efficacy are few. Lung clearance index (LCI) is a promising measurement of ventilation inhomogeneity. Its responsiveness to AWC has not been demonstrated. Aim: To compare effects of two methods of AWC- Autogenic Drainage (AD) and Oscillating Positive Airway Pressure (oPEP) on LCI, spirometry, sputum quantity, and quality of life. Methods: Adult patients with bronchiectasis, naive to airway clearance, were randomized and instructed to daily AWC with either AD or oPEP (Aerobika, Trudell pharma, Canada). Weekly phone calls were performed to evaluate adherence to AWC. Multiple breath washout, spirometry, sputum volume and purulence, and QOL- B questionnaire were measured at randomization and after 4 weeks of AWC. Results: 51 patients were randomized and 49 completed the study (25 AD, 24 oPEP). Adherence was 87% (oPEP) and 88% (AD). LCI and FEV1 did not change between visits in either groups. Sputum quantity decreased in 12/24 of the oPEP group, and in 6/25 (24%) of the AD group, (p=0.044). ‘Treatment burden’ was worsened or unchanged in 70% of participants randomized to AD and 55% randomized to oPEP (p=0.038). During the study, 11 participants experienced a pulmonary exacerbation (6 AD, 5 oPEP). When these participants were excluded from the analysis, LCI improved in the oPEP group only (-0.59 vs. -0.1 in the AD group), without statistical significance (p=0.45). Conclusions: Sputum quantity was improved after one month of oPEP, without an increase in treatment burden. No change in LCI was seen with AWC.

Proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) effectively reduce low-density lipoprotein cholesterol (LDL-C), improving cardiovascular outcomes in clinical trials when added to statin therapy.As real-world evidence is lacking, we aimed to evaluate treatment and adherence patterns using PCSK9i in clinical practice.We investigated 1600 patients initiating PCSK9i between January 2016 and December 2019 in a large health maintenance organization. Treatment discontinuation was defined as a gap ≥60 days between last days' supply of one prescription and the start of the next. Re-initiation rates as well as proportion of days covered (PDC) over 1-year period and attainment of lipid goals under PCSK9i, were analyzed.Evolocumab 140 mg was initiated by 50.7%, alirocumab 75 mg by 29.5% and 150 mg by 19.8%. Cumulative discontinuation rates were 28.1% after 6-months and 49.9% after 3-years. Overall, 58% of the patients that discontinued therapy have re-initiated PCSK9i (31% after 3-months from discontinuation). Mean PDC over 1-year of therapy was 56% ± 29, with PDC ≥80% evident in 29%. Of those with established cardiovascular disease (n = 991), 55% achieved LDL-C70 mg/dL and 38% LDL-C55 mg/dL. Attainment rates were lower in patients with PDC80%, baseline LDL-C190 mg/dL and in those not treated with concurrent statin therapy.In real-world practice of patients treated by PCSK9i, high proportion of early treatment discontinuation was evident, with non-negligible re-initiation rates but overall low medication coverage over time. This have contributed to sub-optimal attainment of LDL-C treatment goals, particularly observed in patients with severe hypercholesterolemia, inadequate drug adherence, and those using PCSK9i as monotherapy.

The purpose of this study was to assess the association between reduced apixaban dose and two outcomes: ischemic stroke/systemic embolism (SE) and major bleeding. We performed a retrospective cohort study within the database of the largest healthcare provider in Israel. We identified all patients diagnosed with atrial fibrillation, who started apixaban treatment between 2013 and 2017. Apixaban users were classified into three dosing regimen groups based on their renal function, age, and weight: standard dose (5 mg b.i.d.), adjusted reduced dose (2.5 mg b.i.d.), and underdosing (2.5 mg b.i.d.). Patients were followed through 2018 for the occurrence of stroke/SE and major bleeding. Of the 27,765 included patients, 13,141 (47%) adequately received standard apixaban dose, 4,739 patients (17%) received adjusted reduced dose, and 9,885 patients (36%) were classified as underdosed. The CHA2DS2-VASc score adjusted hazard ratio for ischemic stroke/SE was 1.1 (95% confidence interval (CI), 0.83-1.43) in the adjusted reduced dose group, and 1.04 (95% CI, 0.83-1.35) in the underdosing group, compared with the standard apixaban dose group. The HAS-BLED score adjusted hazard ratio for any major bleeding was 1.66 (95% CI, 1.32-2.09) in the adjusted reduced dose group, and 1.51 (95% CI, 1.24-1.83) in the underdosing group, compared with apixaban in the standard dose group. Results were similar for major gastrointestinal bleeding and intracranial hemorrhage separately. We conclude that underdosing with apixaban is very common, and may not disproportionately elevate the risk of ischemic stroke. However, albeit halving the dose, patients treated with reduced apixaban dose (adjusted or underdosing) seem to be at higher risk for major bleeding.

Non-tuberculous mycobacteria pulmonary disease (NTM-pd) commonly complicates bronchiectasis. However, clinical and radiological features of NTM-pd and bronchiectasis are very similar. We aimed to develop a radiologic prediction tool for bronchiectasis to identify NTM-pd. We reviewed clinical, laboratory and radiological data in patients with bronchiectasis. Radiologic features on CT scans and the individual components of the Bhalla scoring system were compared between people with and without NTM-pd. Logistic regression and receiver-operating curve (ROC) analysis were performed to predict NTM-pd. People with NTM-pd had more pulmonary segments with bronchiectasis (13 ± 5 vs. 11 ± 5, p = 0.03), presence of mucus plugging (47% vs. 19%, p

The aim of this study was to compare the 3-year outcome of Ex-PRESS miniature glaucoma shunt versus Ahmed glaucoma valve in pseudophakic patients.We retrospectively reviewed the records of patients with a history of clear corneal phacoemulsification alone, or failed trabeculectomy following phacoemulsification, who subsequently underwent Ahmed glaucoma valve (AGV) implantation or Ex-PRESS shunt surgery. The main outcome measure, surgical success, was defined as an intraocular pressure between 5 and 21 mm Hg and a 20% intraocular pressure reduction from baseline (with/without glaucoma medications) without glaucoma reoperation.In total, 92 patients (92 eyes) were included (43 AGV, 49 Ex-PRESS). Overall success at 3 years was 92.7% for AGV and 66.1% for Ex-PRESS (P=0.006). AGV had a higher success rate in patients with prior phacoemulsification and failed trabeculectomy (96% AGV vs. 64.1% Ex-PRESS; P=0.023). There was no difference in success rate for patients with only previous phacoemulsification (87.5% AGV vs. 69.4% Ex-PRESS; P=0.205). Glaucoma reoperation rates were 4.6% and 30.6% in the AGV and Ex-PRESS group, respectively (P=0.001). Both procedures had similar complication rates.AGV compared with Ex-PRESS shunt, had a higher success rate for secondary surgeries but not primary surgeries, in patients with prior clear corneal phacoemulsification. The AGV surgery also had a lower overall glaucoma reoperation rate.

Introduction Factor V (FV) deficiency is a rare inherited coagulation disorder associated with bleeding tendency. As a result, it has been postulated that decreased FV activity may confer protection against venous thromboembolism and atherothrombotic cardiovascular events. Materials and methods Using the electronic database of the largest health care provider in Israel, we identified all adult individuals who were tested for FV activity between January 2004 and June 2017. Subjects with liver cirrhosis or FV Leiden mutation were excluded. FV activity was classified into three predefined categories; FV activity >50%, FV activity 30–50%, and FV activity ≤30%. Patients were followed from January 2004 to June 2017 for new atherothrombotic cardiovascular events (composite of myocardial infarction, stroke, and TIA) and venous thromboembolism (VTE). Results Overall 2021 individuals were included; 83.2% had FV activity >50%, 9.6% FV activity 30–50%, and 7.2% had FV activity ≤30%. Compared to individuals with FV activity >50% the adjusted HR for atherothrombotic cardiovascular events was 1.10 (95% CI, 0.63–1.90) in those with FV activity 30–50%, and 0.95 (0.49–1.8) in those with FV activity ≤30%. None of the patients with FV activity 30–50% had VTE during follow-up; therefore those with FV activity ≤50% were classified into one group. VTE incidence was lower in those with FV activity ≤50% compared to those with FV >50% activity; adjusted HR = 0.28 (0.09–0.91). Conclusion This study suggests that decreased FV activity might be associated with decreased incidence of VTE. No significant association appears to exist between FV activity and atherothrombotic cardiovascular events.

Introduction Chronic infection is associated with adverse outcomes among people with bronchiectasis. However, it is not known which factors are associated with a bacterial infection, and with persistence of an infection after the first episode. We aimed to determine factors associated with a new infection and with chronicity of Pseudomonas aeruginosa (PA) and H. influenzae (HI), the most common organisms in bronchiectasis infection. Methods Using an Israeli population database, we identified individuals diagnosed with bronchiectasis. Cox proportional hazard models were used to assess risk factors for first isolation and Logistic regression for chronicity of infection after a first isolation of PA and HI. Results We included 1305 people with a median of 5 respiratory samples per individual. PA was initially isolated in 297 people, of whom 97 (33%) developed chronic PA infection. HI was newly identified in 169 people, of whom 39 (23%) developed chronic infection (p = 0.029). Factors associated with increased risk of a new infection with PA were COPD (HR 1.87 [1.52–2.28], previous isolation of HI (HR 1.38 [1.07–1.78]), and alcohol abuse (HR 2.22 [1.13–4.3]). Younger age was associated with increased risk of HI infection, while COPD was associated with a lower risk of HI infection. Prescription of an anti- PA antibiotic was associated with chronic PA after a new infection (OR = 1.8 [1.09–2.9], p = 0.02). A landmark analysis showed that survival was worse in people with chronic PA infection vs. single or intermittent infection (Log rank: p = 0.034) Conclusions Younger age and presence of PCD are associated with a new isolation of HI. A new infection with PA is associated with previous HI infection, PCD, COPD, and alcohol abuse. Unexpectedly, treatment with appropriate anti-PA antimicrobials was not associated with a reduced risk of chronicity.

Factor XI deficiency is one of the rare inherited coagulation factor deficiencies. However, its incidence is high within the Ashkenazi Jewish community. Because factor XI displays both procoagulant and antifibrinolytic activities, it has been postulated that an underlying cardiovascular benefit may exist with factor XI deficiency. This historical cohort study was performed using the electronic database of Clalit Health Services, the largest health care provider in Israel. All adults tested for factor XI activity between 2002 and 2014 were included in the study. Factor XI activity was classified into 3 categories: normal (activity50%), mild deficiency (activity = 30%-50%), and moderate-severe deficiency (activity ≤30%). The cohort was followed until 31 December 2015 for incidence of cardiovascular events (composite of myocardial infarction, stroke, and transient ischemic attack) and venous thromboembolism (VTE). Of the 10 193 included patients, 8958 (88.9%) had normal factor XI activity, 690 (6.8%) had mild deficiency, and 542 (5.3%) had moderate-severe deficiency. Compared with individuals with normal activity, the adjusted hazard ratio (HR) for cardiovascular events was 0.52 (95% confidence interval [CI], 0.31-0.87) in those with mild deficiency, and 0.57 (95% CI, 0.35-0.93) in those with moderate-severe factor XI deficiency. The incidence of VTE was lower in those with factor XI deficiency (activity50%) compared with those with normal activity; adjusted HR = 0.26 (95% CI, 0.08-0.84). In summary, factor XI deficiency is associated with decreased incidence of cardiovascular events and VTE.

Background: Bronchiectasis is a chronic inflammatory disease characterized by recurrent bacterial infections associated with cough, sputum production, impaired quality of life and increased mortality. In patients with chronic Pseudomonas infection, the use of long term inhaled antibiotics is recommended, although evidence for their efficacy is low- grade. Objectives: To investigate the effect of inhaled antibiotic treatment on exacerbation frequency and lung function in patients with bronchiectasis. Methods: We retrospectively collected data on patients with bronchiectasis who commenced treatment with inhaled antibiotics in a single bronchiectasis center between 2013 and 2018. Data including demographic parameters, lung function, sputum bacteria, and exacerbations were extracted from medical reports including hospital and outpatient clinics. For every patient, a comparison was made between the year prior to commencing inhaled antibiotic treatment to the time during treatment. Results: Thirty eight patients (13 men and 25 women) had complete data and fulfilled all the inclusion criteria. The mean age was 71.3 (range, 23-89). Following inhaled antibiotic treatment, there was a significant reduction in the frequency of exacerbations from 1.42 per year to 1 per year, P=0.001 (figure 1). Lung function did not change: FEV1 values before and during treatment were 60.1% and 60.4%, respectively (p= 0.747.) Conclusions: Treatment with inhaled antibiotics is associated with a reduction in the frequency of exacerbations in patients with bronchiectasis but no effect on lung function tests.

Endoscopic examination of the nasal cavity is an integral part of the assessment of patients with chronic rhinosinusitis. However, the benefit gained by performing endoscopy with respect to the patient’s medical condition has not been completely assessed. We conducted a prospective cohort in an academic medical center. Thirty-nine patients diagnosed with chronic rhinosinusitis, without polyps, whose ailment was managed conservatively with no surgical intervention. All patients underwent nasal endoscopy, a computed tomography (CT) scan rated for Lund-MacKay score, and completed a sino nasal outcome test (SNOT)-20 questionnaire. This same evaluation was repeated 6 weeks following medical treatment. The CT scan and SNOT-20 questionnaire were independent parameters to evaluate the endoscopy score in each nasal passage. Thirty-nine (28 females) patients completed the follow-up period. A total of 156 endoscopic evaluations were performed, in which 74 nasal cavities were found to have significant pathology and 82 were either normal or displayed mild pathology. The correlation with the Lund-MacKay score was poor with a positive predictive value of 68.9% (31.1% false positive and 28% false negative). However, while looking at the SNOT-20 score, corrected for repeated measures, a higher endoscopy score was associated with a higher SNOT-20 score (odds ratio = 3.53, 95% confidence interval = 1.54-8.09, P = .003). Patients with higher endoscopy scores had a greater probability for exhibiting severe symptoms. However, we could not demonstrate a strong correlation between nasal endoscopy findings and CT scan scores. Therefore, with respect to patients with chronic rhinosinusitis without polyps, nasal endoscopy could be utilized as a beneficial objective tool.

Cryptosporidium is a major threat to water supplies worldwide. Various biases and obstacles in case identification are recognized. In Israel, Cryptosporidiosis was included among notifiable diseases in 2001 in order to determine the burden of parasite-inflicted morbidity and to justify budgeting a central drinking water filtration plant.To summarize the epidemiologic features of 14 years of Cryptosporidium surveillance and to assess the effects of advanced water purification treatment on the burden of disease.From 2001 to 2014, a passive surveillance system was used. Cases were identified based on microscopic detection in stool samples. Confirmed cases were reported electronically to the Israeli Ministry of Health. Overall rates as well as age, gender, ethnicity and specific annual incidence were calculated per 100,000 population in five age groups: 0-4, 5-14, 15-44, 45-64,65 years.A total of 522 Cryptosporidium cases were reported in all six public health districts. More cases were detected among Jews and among males, and mainly in young children, with a seasonal peak during summer. The Haifa sub-district reported 69% of the cases. Most were linked to an outbreak from the summer of 2008, which was attributed to recreational swimming pool activity. Cases decreased after installation of a central filtration plant in 2007.As drinking water in Israel is treated to maximal international standards, the rationale for further inclusion of Cryptosporidium among mandatory notifiable diseases should be reconsidered. Future surveillance efforts should focus on timely detection of outbreaks using molecular high-throughput testing.

Hypertrophy of the adenoids is common in children. However, the anatomical site makes the adenoids difficult to assess, and studies evaluating the subject are ambiguous, especially with regard to the use of X-ray as an evaluation tool.To compare medical history with clinical, radiological, and endoscopic evaluations of the adenoids and compare obstructed and non-obstructed children relative to the assessment methods.A prospective comparative study was conducted with children who were suspected of having enlarged adenoids. All parents completed a medical history questionnaire and patients underwent clinical evaluation based on Nasal Obstruction Index (NOI) scores, radiological assessment based on the lateral neck X-ray adenoid-nasopharynx (A/N( ratio, and endoscopic evaluation based on anatomical relations. Spearman correlations were used for comparison between methods.We evaluated 36 patients, median age 5.33 years. Correlation measurements for clinical assessment and questionnaire (r = 0.582, P0.0001), questionnaire and endoscopy (r = 0.462, P = 0.005), and clinical assessment and nasal endoscopy (r = 0.621, P0.0001) were statistically significant. None of the parameters correlated with the radiological findings. A statistically significant difference was found between the obstructed and non-obstructed groups in both questionnaire (P = 0.004) and clinical assessment (P0.0001). However, no difference was found in X-ray measurements.Lateral neck X-ray measurements were not correlated to symptoms, signs, or endoscopic findings. Therefore, medical professionals should use lateral neck radiography when considering adenoidectomy only on a highly selective basis.

Background A fecal test followed by diagnostic colonoscopy for a positive result is a widely endorsed screening strategy for colorectal cancer (CRC). However, the relationship between the time delay from the positive test to the follow-up colonoscopy and CRC mortality has not been established. Methods From a population-based screening program, we identified CRC patients newly diagnosed from 2005 through 2015 by a positive fecal occult test followed by a colonoscopy. The primary outcome measure was CRC-specific mortality according to four categories for the time elapsed between the positive result and the subsequent colonoscopy. Results The 1749 patients underwent colonoscopies within 0–3 months (n = 981, 56.1%), 4–6 months (n = 307, 17.5%), 7–12 months (n = 157, 9.0%), and later than 12 months (n = 304, 17.4%). CRC-specific deaths according to exposure groups were: 13.8% (135 of 981) for 0–3 months, 10.7% (33 of 307) for 4–6 months (crude hazards ratio [HR] = 0.74, 95% confidence interval [CI] = 0.51 to 1.14), 11.5% (18 of 157) for 7–12 months (crude HR = 0.83, 95% CI = 0.51 to 1.42), and 22.7% (69 of 304) for longer than 12 months (crude HR = 1.40, 95% CI = 1.04 to 1.90). The only variable that was associated with mortality risk was the number of positive slides (P = .003). High positivity was twice the value in the 0–3 as the longer-than-12 months group: 51.9% vs 25.0% and similar for the 4–6 and 7–12 months groups (38.1% and 36.5%), respectively. The adjusted HRs for CRC mortality were 0.81 (95% CI = 0.55 to 1.19); 0.83 (95% CI = 0.50 to 1.41), and 1.53 (95% CI = 1.13 to 2.12, P = .006) for the 4–12, 7–12, and longer-than-12-months groups, respectively, compared with the shortest delay group. Conclusions Among screen-diagnosed CRC patients, performance of colonoscopy more than 12 months after the initial positive fecal occult blood test was associated with more advanced disease and higher mortality due to CRC.