Search

Background Symptomatic breast cancers share aggressive clinico-pathological characteristics compared to screen-detected breast cancers. We assessed the association between the method of cancer detection and genomic and clinical risk, and its effect on adjuvant chemotherapy recommendations. Patients and methods Patients with early hormone receptor positive (HR+) HER2neu-negative (HER2-) breast cancer, and known OncotypeDX Breast Recurrence Score test were included. A natural language processing (NLP) algorithm was used to identify the method of cancer detection. The clinical and genomic risks of symptomatic and screen-detected tumors were compared. Results The NLP algorithm identified the method of detection of 401 patients, with 216 (54%) diagnosed by routine screening, and the remainder secondary to symptoms. The distribution of OncotypeDX recurrence score (RS) varied between the groups. In the symptomatic group there were lower proportions of low RS (13% vs 23%) and higher proportions of high RS (24% vs. 13%) compared to the screen-detected group. Symptomatic tumors were significantly more likely to have a high clinical risk (59% vs 40%). Based on genomic and clinical risk and current guidelines, we found that women aged 50 and under, with a symptomatic cancer, had an increased probability of receiving adjuvant chemotherapy recommendation compared to women with screen-detected cancers (60% vs. 37%). Conclusions We demonstrated an association between the method of cancer detection and both genomic and clinical risk. Symptomatic breast cancer, especially in young women, remains a poor prognostic factor that should be taken into account when evaluating patient prognosis and determining adjuvant treatment plans., Highlights • Symptomatic women at diagnosis are often younger, have larger tumors and higher Ki67. • Women with symptomatic tumors have both higher genomic risk and higher clinical risk for disease recurrence. • Symptomatic presentation significantly increases the likelihood of adjuvant chemotherapy recommendation, especially among younger women. • The use of a computational approach (NLP) for extracting medical information was demonstrated to be efficient and valid.

Definity is a contrast media used to enhance the endocardium during echocardiography. Cardiac arrest as an adverse reaction to Definity is still a debate. We are presenting a rare case of a 69-year-old male patient who developed cardiopulmonary arrest immediately after Definity injection during resting echocardiography.

International audience; Purpose: To assess the variability of renal artery (RA) anatomy and presence of RA-pathology in patients with mild-to-moderate hypertension enrolled in the RADIANCE-HTN SOLO trial.Background: RADIANCE-HTN SOLO was a multicenter, international, blinded, randomized, sham-controlled trial evaluating ultrasound-based endovascular renal denervation (RDN) in patients with mild-to-moderate hypertension while off antihypertensive medications.Methods: Eligible subjects had pre-randomization renal CT- or MR- angiography (CTA, MRA) to confirm anatomic suitability and to define RA ablation sites. All images were sent for independent review for evaluation of RA anatomy and other vascular pathology.Results: A total of 324 patients underwent RA imaging (282 CTA and 42 MRA). Of those, 178 had simple anatomy with a single left and single right RA with mean diameters of 5.4 ± 0.9 and 5.1 ± 0.8 mm and mean lengths of 40.0 ± 12.9 and 52.0 ± 13.1 mm, respectively. Twenty-seven patients (8.3%) had unilateral or bilateral dual RAs with mean diameters of 4.0 ± 0.9 mm on the left and 3.9 ± 0.9 mm on the right. Forty percent (129/324) of patients had at least 1 accessory RA, with mean accessory diameters of 2.4 ± 0.8 mm on the left and 2.3 ± 0.8 mm on the right. Twenty-eight patients (8.6%) had at least 1 short (

Background Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor-necrosis-factor (TNF)α biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear. Aim To assess serologic responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC). Methods Prospective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibodies levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinaly. Results Overall 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HC. After the first vaccine dose all HC were seropositive, while ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared to non-anti-TNFα treated patients, and HC (both P, Graphical abstract

Objective We employed a multidisciplinary approach incorporating theoretical ideas, clinical experience, psychology, physiology, traditional Chinese medicine (CM), modern practice of CM, and oncology to explore the effect of patients’ repression of negative emotions and traumatic events on breast cancer (BC) pathogenesis. Methods BC female patients, older than 18 years of age, with available pathology reports who were treated at Rabin Medical Center were recruited. All participants completed questionnaires regarding medical history, behavioral tendencies, negative emotions, trauma, symptoms, and pathology (from a CM perspective). Data on tumor characteristics were collected from the pathology reports. The associations were examined using hierarchical binary logistic regressions. Results A total of 155 BC patients were enrolled. The median age was 52 years, with a range of 26–79; 95% were mothers; 28% had estrogen receptor (ER)-negative BC, 52% had progesterone receptor (PR)-negative BC, 48% had human epidermal growth factor receptor 2-negative BC, and antigen Ki-67 ≥ 20% was reported for 52% of tumors. Statistically significant associations were found between the emotional markers (sense of motherhood failure, and lack of self-fulfillment), avoidance behavior, and physical symptoms that are related to emotional repression based on CM. Significant associations were also found between variables associated with physical symptoms of emotional repression, which involves the production and accumulation of non-substantial phlegm (i.e., “high-lipid Qi-like microscopic phlegm”), avoidance behavior which unconsciously uses “high-lipid Qi-like microscopic phlegm” in order to achieve emotional repression, and tumor parameters including tumor grade, PR status, and Ki-67. Patients with higher levels of “high-lipid Qi-like microscopic phlegm” were more likely to have tumors with worse prognosis (PR-negative, higher grade, and higher Ki-67). Conclusion We demonstrated a relationship between emotional parameters, behavioral tendencies, CM parameters, and oncologic parameters in BC. Additional research is warranted to explore these associations and their relevance to clinical practice.

Background Omission errors in medical imaging can lead to missed diagnosis and harm to patients. The subject has been studied in conventional imaging, but no data is available for functional imaging in general and for PET/CT in particular. In this work, we evaluated the frequency and characteristics of perceptual omission errors in the PET component of oncologic PET/CT imaging and we analyze the hazardous scenarios prone to such modality-specific errors. Materials and methods Perceptual omission errors were collected in one tertiary center PET/CT clinic during routine PET/CT reporting over a 26-month period. The omissions were detected either in reporting follow-up PET/CT studies of the same patient or during multidisciplinary meetings. Results Significant omission errors were found in 1.2 % of the 2100 reports included in the study. The most common omissions were bone metastases and focal colon uptake. We identified six PET-specific causative factors contributing to the occurrence of omissions, and we propose solutions to minimize their influence. Conclusions The data presented here can help to promote the awareness of interpreting physicians to body areas that require higher attention and to implement reading strategies for improving the accuracy of PET/CT interpretation.

Purpose:The etiology of calcium-oxalate kidney stone formation remains elusive. Biallelic mutations in HOGA1 are responsible for primary hyperoxaluria type 3 and result in oxalate overproduction an...

Myelofibrosis (MF) is a clonal stem cell neoplasm characterized by abnormal JAK-STAT signaling, chronic inflammation, cytopenias, and risk of transformation to acute leukemia. Despite improvements in the therapeutic options for patients with MF, allogeneic hematopoietic stem cell transplantation remains the only curative treatment. We previously demonstrated multiple immunosuppressive mechanisms in patients with MF, including increased expression of programmed cell death protein 1 (PD-1) on T cells compared with healthy controls. Therefore, we conducted a multicenter, open-label, phase 2, single-arm study of pembrolizumab in patients with Dynamic International Prognostic Scoring System category of intermediate-2 or greater primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. The study followed a Simon 2-stage design and enrolled a total of 10 patients, 5 of whom had JAK2V617mutation, 2 had CALR mutation, and 6 had additional mutations. Most patients were previously treated with ruxolitinib. Pembrolizumab treatment was well tolerated, but there were no objective clinical responses, so the study closed after the first stage was completed. However, immune profiling by flow cytometry, T-cell receptor sequencing, and plasma proteomics demonstrated changes in the immune milieu of patients, which suggested improved T-cell responses that can potentially favor antitumor immunity. The fact that these changes were not reflected in a clinical response strongly suggests that combination immunotherapeutic approaches rather than monotherapy may be necessary to reverse the multifactorial mechanisms of immune suppression in myeloproliferative neoplasms. This trial was registered at www.clinicaltrials.gov as #NCT03065400.

Despite the success of antiretroviral therapy (ART) for people living with HIV, lifelong treatment is required and there is no cure. HIV can integrate in the host genome and persist for the life span of the infected cell. These latently infected cells are not recognized as foreign because they are largely transcriptionally silent, but contain replication-competent virus that drives resurgence of the infection once ART is stopped. With a combination of immune activators, neutralizing antibodies, and therapeutic vaccines, some nonhuman primate models have been cured, providing optimism for these approaches now being evaluated in human clinical trials. In vivo delivery of gene-editing tools to either target the virus, boost immunity or protect cells from infection, also holds promise for future HIV cure strategies. In this Review, we discuss advances related to HIV cure in the last 5 years, highlight remaining knowledge gaps and identify priority areas for research for the next 5 years. An effective and scalable cure strategy is a top priority for the HIV research field; this Review discusses recent advances, knowledge gaps, and priority research areas for the next 5 years.

Goal The aim of the study is to assess the incidence, risk factors and prognosis of definite stent thrombosis (ST) at 1 year in the France PCI multicenter prospective registry. Patients and methods Only patients who underwent coronary angioplasty with at least one stent implantation between 1st January 2014 and 31 December 2019 were included. The population was separated into 2 groups: the "ST" group with stent thrombosis and the "control" group without stent thrombosis. Results 35,435 patients were included. 256 patients (0.72%) presented a ST at 1 year. The rate of ST decreased significantly in acute coronary syndrome (1.5% in 2014 vs. 0.73% in 2019; p = 0.05) but not in chronic coronary syndrome (0.46% in 2014 vs 0.40%; p = 0.98). The risk factors are young age (65.8 years vs 68.2; p = 0.002), clinical context (35.27% vs 16.68%; p = 0.0001), diabetes (35.2 % vs 26.4%; p = 0.002), renal failure (11.7% vs 8%; p = 0.009) and history of coronary angioplasty (28.63% vs 21.86%; p = 0.009) and peripheral arterial disease (14.5% vs 10.1%; p = 0.021), LV dysfunction (37% vs 27.5%; p = 0.003), mean length (39.6 mm vs 31, 7mm; p Conclusion Since 2014, the incidence of ST at 1 year has been decreasing but remains stuck at a floor level of 0.54% in 2019. The battle for ST seems to have been partly won and its risk factors well identified, but its mortality is still high.

Evidence on the impact of human immunodeficiency virus (HIV) drug resistance on regimens following treatment failure is varied and inconclusive. Differential medication adherence may explain this variation. We aimed to test the association between drug resistance at first-line antiretroviral therapy (ART) switch and adherence to and virologic failure on subsequent ART. We conducted a secondary analysis of data from an open-labeled randomized trial of second-line ART (ACTG A5234). ART susceptibility was determined from study entry plasma using the Stanford Drug Resistance database version 8.7. Adherence was measured with microelectronic monitors. Three adherence variables and rates of virologic failure (HIV-1 RNA ≥1000 copies/mL) on second-line ART were compared between participants with and without resistance at first-line ART failure. Of 214 participants switching to second-line ART with baseline resistance results, 113 (53%) were men, mean age was 39 years (standard deviation 10.3), and 37 (17%) had susceptible virus at study entry. Cumulative genotypic susceptibility score (cGSS) was inversely associated with adherence, adjusted odds ratio (aOR) 0.15, 95% confidence interval (CI) (0.05–0.40), p

Aims The effect of elevated heart rate (HR) on morbidity and mortality is evident in chronic stable heart failure; data in this regard in acute decompensated heart failure (ADHF) setting are scarce. In this single‐centre study, we sought to address the prognostic value of HR and beta‐blocker dosage at discharge on all‐cause mortality among patients with heart failure and reduced ejection fraction and ADHF. Methods and results In this retrospective observational study, 2945 patients were admitted for the first time with the primary diagnosis of ADHF between January 2008 and February 2018. Patients were divided by resting HR at discharge into three groups (HR 90 b.p.m.). Evidence‐based beta‐blockers were defined as metoprolol, bisoprolol, and carvedilol. The doses of prescribed beta‐blockers were calculated into a percentage target dose of each beta‐blocker and divided to four quartiles: 0 75% of the target dose. Cox regression was used to calculate the hazard ratio for various HR categories and adjusting for clinical and laboratory variables. At discharge, 1226 patients had an HR 90 b.p.m. The 30 day mortality rate was 2.2%, 3.7%, and 12.1% (P 90 b.p.m., respectively. The adjusted hazard ratio was significantly increased only in HR above 90 b.p.m. category (hazard ratio, 2.318; 95% confidence interval, 1.794–2.996). Conclusions Patients with ADHF and an HR of

PURPOSE A growing body of evidence accumulate pointing to sex-specific differences in placental adaptation to pregnancy complications. We aimed to study if there is a difference in placental histopathology lesions, between female and male fetuses in pregnancies complicated with preeclampsia. METHODS The medical files of all patients with preeclampsia, were reviewed. Placental lesions were classified to lesions related to maternal or fetal malperfusion lesions (MVM, FVM), vascular and villous changes, and inflammatory lesions. Comparison was performed between the male and the female groups. RESULTS The study included 441 preeclamptic patients. Women in the male preeclampsia group (n = 225) had higher rate of chronic hypertension (p = 0.05) and diabetes mellitus (p

Aims To evaluate the benefit of speckle tracking radial strain imaging (STRSI)-guided left ventricular (LV) lead (LVL) positioning in cardiac resynchronization therapy (CRT) in patients (pts) with ischaemic cardiomyopathy with CRT indication. Methods and results We conducted a prospective randomized controlled trial. Patients were enrolled in nine centres with 2:1 randomization into two groups (guided vs. control). Patients underwent STRSI to identify the optimal LV position from six LV segments at midventricular level. Implantation via STRSI was attempted for recommended segment in the guided group only. Follow-up included echocardiography (6 months) and clinical evaluation (6 and 12 months). The primary endpoint was comparison % reduction in LV end-systolic volume at 6 months with baseline. Secondary endpoints included hospitalizations for heart failure and death, and improvement in additional echocardiographic measurements and quality of life score. A total of 172 patients (115 guided vs. 57 control) were enrolled. In the guided group, 60% of the implanted LV leads were adjudicated to be successfully located at the recommended segment, whereas in the control group 44% reached the best STRSI determined segment. There was no difference between the groups in any of the primary or secondary endpoints at 6 and 12 months. Conclusion Our findings suggest that echo-guided implantation of an LV lead using STRSI does not improve the clinical or echocardiographic response compared with conventional implantation.

OBJECTIVE Angiopoietins (Angs) regulate endothelial permeability. Ang-1 and 2 (Ang-1 and Ang-2) are implied in endothelial stability through an antagonism effect. The objectives of the present study were to describe and compare changes in Ang levels after transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR). DESIGN A prospective, single-center study. PARTICIPANTS Adult patients with aortic stenosis scheduled for SAVR or TAVR. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Ang-1 and Ang-2 were measured using an enzyme-linked immunosorbent assay right before surgery (T0), at the end of surgery (T1), and at day one (T2). Sixty consecutive patients (SAVR group [n = 30] and TAVR group [n = 30]) were included between January and June 2017. Ang-1 decreased significantly after both TAVR (T0: 3,663 [2,602-4,262]; T1: 1,611 [981-2,409]; T2: 1,082 [652-1,589] ng/mL; p < 0.0001) and SAVR (T0: 1,603 [975-2,849]; T1: 783 [547-1,024]; T2: 828 [460-1,227] ng/mL; p = 0.0001). Ang-2 increased significantly after SAVR (T0: 2,472 [1,502-3,622]; T1: 2,997 [1,759-3,839]; T2: 5,421 [3,557-7,087] ng/mL; p < 0.0001) but did not change markedly after TAVR (T0: 3,343 [2,661-6,272]; T1: 3,788 [2,574-5,016]; T2: 3,446 [3,029-6,313] ng/mL; p = 0.066). Among patients with paravalvular leakage, the changes in the plasma Ang-2 level and the Ang-2/Ang-1 ratio were greater. CONCLUSION SAVR induces greater alterations of Ang homeostasis than TAVR, confirming a role for the use of cardiopulmonary bypass. Paravalvular leakage after TAVR is associated with Ang changes similar to those observed with SAVR.

Introduction Inhaled therapeutics may act to directly target and attenuate lung inflammation due to COVID-19. An inhalation form of a novel biologic drug, AMP5A, is being developed as an immunomodulatory agent to treat dysregulated immune responses and is being studied in hospitalized patients to treat respiratory complications due to COVID-19. Methods A randomized, controlled, phase I trial was conducted to evaluate hospitalized adults with respiratory distress secondary to COVID-19. Patients received the standard care (SOC) for COVID-19, including respiratory therapy, corticosteroids, and antiviral therapies such as remdesivir. Patients were randomized 1:1 to inhalation treatment with AMP5A as an adjunct to SOC or to SOC alone (control). AMP5A was administered via inhalation daily for 5 days via hand-held nebulizer, non-invasive ventilator, or mechanical ventilation. Safety and clinical efficacy endpoints were evaluated. Results Forty subjects were enrolled and randomized (n = 19 AMP5A, n = 21 control). Remdesivir was used in fewer AMP5A subjects (26%) than control (52%), and dexamethasone was administered for most subjects (84% AMP5A, 71% control). The study met its primary endpoint with no AMP5A treatment-related adverse events (AEs), and the incidence and severity of AEs were comparable between groups: 18 AEs for control (8 mild, 1 moderate, 9 severe) and 19 AEs for AMP5A (7 mild, 7 moderate, 5 severe). Notably, subjects treated with AMP5A had fewer deaths (5% vs. 24%), shorter hospital stay (8 days vs. 12 days), fewer ICU admissions (21% vs. 33%), and a greater proportion with improved clinical outcomes than control. Conclusion The phase I clinical results indicate inhaled AMP5A is safe, is well tolerated, and could lead to fewer patients experiencing deterioration or death. Based on the treatment effect (i.e., reduced mortality), a phase II trial has been initiated. Trial registration Clinicaltrials.gov identifier: NCT04606784.

Approximately two thirds of veterans with posttraumatic stress disorder (PTSD) remain with the disorder following treatment. Pinpointing the per-symptom effectiveness of treatments in real-world clinical settings can highlight relevant domains for treatment augmentation and development. Baseline and posttreatment assessments of PTSD and depression were performed in 709 veterans with PTSD. PTSD remission was 39.4%. Treatment was least effective for intrusion symptoms and had no effect on flashbacks or on poor recall of traumatic features. Of veterans who remitted, 72.8% still met diagnostic criteria for at least one cluster. Poor clinical effectiveness was noted for depression; only 4.1% of the patients remitted following treatment. Treatments for veterans with PTSD show limited overall effectiveness in real-world settings. Enhancing treatment response may require enhancing provider fidelity and patient compliance with extant treatments or the development of new treatments that specifically target the symptoms of PTSD that do not respond well to extant treatments.

BACKGROUND Mohs micrographic surgery (MMS) for cutaneous melanoma is becoming more prevalent, but surgical technique varies. OBJECTIVE To define variations in published techniques for MMS for melanoma. METHODS AND MATERIALS A systematic review was performed of PubMed, EMBASE, and Scopus databases to identify all articles describing surgical techniques for MMS for melanoma. Technical details were recorded for the preoperative, intraoperative, and postoperative phases of MMS. RESULTS Twenty-four articles were included. Mohs surgeons vary in how they assess clinical margins, how wide a margin they excise on the first MMS layer, and how they process tissue to determine tumor stage and margin clearance during MMS for melanoma. CONCLUSION Mohs micrographic surgery for melanoma is performed with varied surgical techniques. To establish best practices, additional research is necessary to determine how different techniques affect outcomes.

OBJECTIVE Despite technological advances, results from various clinical trials have repeatedly shown that many individuals with type 1 diabetes (T1D) do not achieve their glycemic goals. One of the major challenges in disease management is the administration of an accurate amount of insulin for each meal that will match the expected postprandial glycemic response (PPGR). The objective of this study was to develop a prediction model for PPGR in individuals with T1D. RESEARCH DESIGN AND METHODS We recruited individuals with T1D who were using continuous glucose monitoring and continuous subcutaneous insulin infusion devices simultaneously to a prospective cohort and profiled them for 2 weeks. Participants were asked to report real-time dietary intake using a designated mobile app. We measured their PPGRs and devised machine learning algorithms for PPGR prediction, which integrate glucose measurements, insulin dosages, dietary habits, blood parameters, anthropometrics, exercise, and gut microbiota. Data of the PPGR of 900 healthy individuals to 41,371 meals were also integrated into the model. The performance of the models was evaluated with 10-fold cross validation. RESULTS A total of 121 individuals with T1D, 75 adults and 46 children, were included in the study. PPGR to 6,377 meals was measured. Our PPGR prediction model substantially outperforms a baseline model with emulation of standard of care (correlation of R = 0.59 compared with R = 0.40 for predicted and observed PPGR respectively; P < 10−10). The model was robust across different subpopulations. Feature attribution analysis revealed that glucose levels at meal initiation, glucose trend 30 min prior to meal, meal carbohydrate content, and meal’s carbohydrate-to-fat ratio were the most influential features for the model. CONCLUSIONS Our model enables a more accurate prediction of PPGR and therefore may allow a better adjustment of the required insulin dosage for meals. It can be further implemented in closed loop systems and may lead to rationally designed nutritional interventions personally tailored for individuals with T1D on the basis of meals with expected low glycemic response.

Background Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity. Methods At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case–control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity. Results Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value

The characteristics of infections following chimeric antigen receptor T (CAR-T) cells targeting CD19 in real-word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B-cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR-T cells. ECOG performance status (PS) was 2-3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram-negative rod, n = 5; Gram-positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti-CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell-associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P = .018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P = .074). Age or PS was not associated with increased risk of bacterial infection. Increase in C-reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR-T-cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome.

Background On July 30, 2021, the administration of a third (booster) dose of the BNT162b2 messenger RNA vaccine (Pfizer-BioNTech) was approved in Israel for persons who were 60 years of age or older and who had received a second dose of vaccine at least 5 months earlier. Data are needed regarding the effect of the booster dose on the rate of confirmed coronavirus 2019 disease (Covid-19) and the rate of severe illness. Methods We extracted data for the period from July 30 through August 31, 2021, from the Israeli Ministry of Health database regarding 1,137,804 persons who were 60 years of age or older and had been fully vaccinated (i.e., had received two doses of BNT162b2) at least 5 months earlier. In the primary analysis, we compared the rate of confirmed Covid-19 and the rate of severe illness between those who had received a booster injection at least 12 days earlier (booster group) and those who had not received a booster injection (nonbooster group). In a secondary analysis, we evaluated the rate of infection 4 to 6 days after the booster dose as compared with the rate at least 12 days after the booster. In all the analyses, we used Poisson regression after adjusting for possible confounding factors. Results At least 12 days after the booster dose, the rate of confirmed infection was lower in the booster group than in the nonbooster group by a factor of 11.3 (95% confidence interval [CI], 10.4 to 12.3); the rate of severe illness was lower by a factor of 19.5 (95% CI, 12.9 to 29.5). In a secondary analysis, the rate of confirmed infection at least 12 days after vaccination was lower than the rate after 4 to 6 days by a factor of 5.4 (95% CI, 4.8 to 6.1). Conclusions In this study involving participants who were 60 years of age or older and had received two doses of the BNT162b2 vaccine at least 5 months earlier, we found that the rates of confirmed Covid-19 and severe illness were substantially lower among those who received a booster (third) dose of the BNT162b2 vaccine.

BACKGROUND: Temporal lobe T2 hyperintensity has been described in association with prenatal cytomegalovirus (CMV) infection on fetal MRI. However, these findings are often perplexing with high inter-observer variability. Our objective was to evaluate temporal lobe T2 signal quantitatively in prenatal CMV infection. METHODS: In this retrospective study, 119 fetuses, of which 51 fetuses with suspected CMV exposure (29–36 weeks of gestation) based on maternal seroconversion and age-matched 68 normal controls, were included. Mean and maximal temporal lobe T2 signal were evaluated quantitatively by measuring the T2 signal in the temporal lobes relative to the amniotic fluid’s signal. Intra-observer, inter-observer variability and diagnostic performance were assessed. The occurrence of neonatal sensorineural hearing loss (SNHL) was recorded. RESULTS: Relative temporal lobe T2 signal did not change along with the examined gestational age. Of our suspected CMV cohort, 29 fetuses were positive for fetal CMV infection on polymerase chain reaction (PCR) analysis. There were no statistically significant differences in the relative mean or maximal temporal lobes T2 signal between CMV positive, CMV negative fetuses, or normal controls. No correlation was found between neonatal SNHL and temporal lobe T2 signal. CONCLUSIONS: When temporal lobe T2 signal is analyzed quantitatively, CMV infected fetuses do not present an increased signal than age-matched controls. Thus, reported subjective temporal T2 hyperintensities should be interpreted carefully and should have a limited effect on pregnancy management, especially as an isolated finding. Our study illustrates the importance of quantitative imaging in diagnostic neuroradiology.

Aim: To outline the successful development and implementation of a nurse practitioner role within a professional ballet school. Background: Nurse practitioners are well integrated into primary and acute care in Ontario, yet the role within schools and private athletic institutions is not well documented. Canada’s National Ballet School is a professional ballet school with a combination of day students and those living in residences. Students complete both dance training and academics at the School. The physical and mental health of students was identified as a key priority by the school, leading to the development of an integrated health and wellness program. To facilitate more timely access to healthcare and provide an opportunity for collaboration and consultation within the school, a plan to implement a nurse practitioner role into the school was developed. Methods: In order to develop and implement the role of the nurse practitioner within the institution, the participatory, evidence-based, patient-focused process for advanced practice nursing role development, implementation, and evaluation (PEPPA) framework was used. The first seven steps of the PEPPA framework were applied in this project. Findings: The PEPPA framework allowed for us to identify key barriers and facilitators for the role implementation and successfully implement the nurse practitioner role. While the initial plan was for a slower implementation, the COVID-19 pandemic highlighted the need for a nurse practitioner in the institution more urgently. Conclusion: The PEPPA framework provided us with an organized process for developing and implementing the nurse practitioner role at Canada’s National Ballet School.

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Purpose: Image-guided radiotherapy (IGRT) is central to the safe and effective delivery of ultrahypofractionated (UF) stereotactic body radiotherapy (SBRT) for localized prostate cancer. However, the optimal IGRT modality remains uncertain. We aim to study the safety of performing UF-SBRT using cone-beam computed tomography (CBCT) and real-time transperineal ultrasound (TPUS) monitoring. Materials and Methods: We retrospectively review the medical records of 26 patients who had received UF-SBRT for intermediate risk localized prostate cancer in our institution from October 2018 to December 2020. All patients were treated with SBRT without fiducial marker and received 35–40 Gy to the clinical target volume in 5 fractions over 2–5 weeks. CBCT was used to correct for interfraction displacement while intrafraction displacement of the prostate gland was monitored using Elekta Clarity Autoscan TPUS with 4 mm isotropic warning level. All patients also received neoadjuvant and concurrent androgen deprivation therapy for a total of 6 months. The primary endpoints were incidence of acute toxicities and patient reported urinary toxicities in terms of the International Prostate Symptom Score: before (IPSS1), at the completion of (IPSS2), and at 3–6 months (IPSS3) after SBRT. Results: All men were treated and followed up for at least 3 months after SBRT. Patients experienced transient worsening of their urinary symptoms at the end of SBRT but they usually recovered in 3–6 months afterwards. The median IPSS1, IPSS2, and IPSS3 were 12, 12.5, and 8, respectively. One patient developed grade 3 rectal bleeding which was related to underlying hemorrhoid. No other grade 3–4 acute toxicity was observed. Conclusion: It appears safe to deliver UF-SBRT without fiducial marker for prostate cancer patients using CBCT and non-invasive hybrid imaging modalities for positioning and tracking. Longer follow-up is necessary to monitor the treatment efficacy and long-term toxicities.

Background: Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods: We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided. Results: We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P < .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P < .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02). Conclusions: We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy., Supported by CERCA Programme/Generalitat de Catalunya, Health Department PERIS #SLT/002/16/00374, AGAUR-project #2017SGR1080; MCI/AEI/ERDF project #RTI2018-094049-B-I00; ERC EPIPHARM; Cellex Foundation; “la Caixa” Foundation (LCF/PR/GN18/51140001 and LCF/PR/GN18/50310007), RF-2016–02364388, Accelerator Award—Cancer Research UK/AIRC—INCAR Associazione Italiana Ricerca per la Ricerca sul Cancro (AIRC) Project 5 × 1000 no. 9962, AIRC IG 2018 id. 21724, AIRC MFAG id. 21769 and id. 20450; MIUR (Grant PRIN 2017); and RCR-2019–23669115.

OBJECTIVES/HYPOTHESIS We aim to 1) evaluate trends in adjuvant treatment of human papilloma virus (HPV)-related oropharyngeal cancer; 2) assess change in complications and functional outcomes over time; and 3) assess change in overall and disease-free survival (DFS) over time. STUDY DESIGN Retrospective analysis. METHODS Charts of patients who underwent transoral robotic surgery for HPV-related oropharyngeal cancer between 2011 and 2019 were reviewed. Trend analysis was used to compare rate of adjuvant treatment over time. The Kaplan-Meier method was conducted to analyze overall survival (OS) and DFS. RESULTS Three hundred and forty-two patients met inclusion criteria. One hundred and sixty-three (47.7%) patients underwent adjuvant radiation, and 90 (26.3%) patients underwent adjuvant chemoradiation. Rate of extranodular extension decreased significantly from 38.9% to 24.0% (P = .004). Rate of adjuvant therapy decreased significantly from 90.9% to 62.5% between 2011 and 2019 (P = .001). In patients who received adjuvant treatment, rate of adjuvant chemoradiation therapy decreased significantly from 40.0% to 20.0% (P

IntroductionPouchitis, often developing after colectomy and ileal pouch-anal anastomosis for ulcerative colitis, is highly responsive to antibiotics. Ciprofloxacin and/or metronidazole are commonly used, often for prolonged periods. We report patterns of antibiotic use, adverse events, and resistant infections in patients with pouchitis with long-term antibiotic treatment.MethodsIn a cohort of patients following pouch surgery, a retrospective nested case-control analysis was performed between 2010 and 2017. Ultra-long-term use, defined as the top 10% of users, was compared with the remaining users. Patterns of antibiotic use, adverse events, and resistant infections were analyzed.ResultsThe cohort included 205 patients with UC, of whom 167 (81.5%) used antibiotics for pouchitis, predominantly ciprofloxacin. The long-term antibiotic use rate was 18% and 42% at 5 and 20 years postsurgery, respectively. Mean antibiotic use of at least 1, 3, and 6 months/year was noted in 54 (26.3%), 31 (15.1%), and 14 (6.8%) patients, respectively. Twenty-two (13.2%) and 4 (2.4%) patients reported mild and severe (transient) adverse events, respectively, without mortalities, tendinopathies or arrhythmias. Adverse event rates for ciprofloxacin and metronidazole were 1per 10,000 and 6 per 10,000 use-days, respectively. Longer, but not ultra-long antibiotic use, was associated with mild adverse events. There was no association between antibiotic use and resistant infections. Thirteen (6.3%) patients required ileostomy procedures—more commonly in the ultra-long-term antibiotic users.ConclusionsPatients with pouchitis may require prolonged antibiotic treatment, reflecting clinical benefit and favorable safety profile. Few adverse events and resistant infections were observed with long-term antibiotics use. However, resistant microbial strains selection, which are potentially transmittable, warrants consideration of different therapeutic alternatives.

Congenital complete heart block (CCHB) affects 1 in 20,000 newborns. This study evaluates fetal and neonatal risk factors predictive of neonatal pacemaker placement in antibody-mediated complete heart block. The Children’s Hospital Los Angeles institutional fetal, pacemaker, and medical record databases were queried for confirmed SSA/SSB cases of CCHB between January 2004 and July 2019. Cases excluded were those with a diagnosis beyond the neonatal period, diagnosis of a channelopathy, or if maternal antibody status was unknown. We recorded the gestational age (GA), birth weight (BW), fetal heart rates (FHRs) of the last echocardiogram before delivery, specific neonatal ECG and echocardiogram findings, age at pacemaker placement, and mortality. Of 43 neonates identified with CCHB, 27 had confirmed maternal antibody exposure. Variables associated with neonatal pacemaker implantation were FHRs

Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.

This first-in-human phase I study (NCT03179436) investigated anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti-programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non-small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy.Patients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤ 2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumorsv1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints.Forty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7-33) among all patients, 7% (1-34) for PD-L1-positive tumors (n = 14), and 19% (5-42) for PD-L1-negative tumors (n = 21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%.Encouraging antitumor activity was observed with quavonlimab + pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1-positive and PD-L1-negative tumors. The combination was tolerable with manageable toxicities.

To assess the association between cesarean delivery and ovarian reserve, as compared to vaginal delivery. A prospective case control study conducted at a single tertiary medical center between June 2018 and June 2019. Study population included women with singleton pregnancy that underwent first cesarean delivery that were compared to women undergoing normal vaginal delivery. Women with low ovarian reserve, endometriosis, previous pelvic surgery, chronic maternal disease, and active labor were excluded. Ovarian reserve was estimated by Anti-Mullerian hormone (AMH) levels that was determined twice for each participant: up to a week before and 3 months after delivery. Primary outcome was defined as the delta in AMH levels. Data were analyzed by non-parametric tests. During the study period, 135 women were enrolled, of them 63 (47%) underwent cesarean delivery and 72 (53%) had vaginal delivery. Women in the cesarean delivery group were older (34 (31–38) vs. 32 (29–35); p = 0.001); nevertheless, AMH levels measured before delivery were comparable between the two groups (0.92 (0.51–1.79) vs. 0.95 (0.51–1.79) pg/mL; p = 0.42). AMH levels measured after delivery were more than doubled in the study and control groups (2.15 (1.24–3.05) vs. 2.62 (1.05–5.09); p = 0.50), and delta AMH levels were also found comparable (1.25 (0.61–2.22) vs. 1.59 (0.63–3.41), respectively; p = 0.43). Linear regression analysis including age, mode of delivery, gestational age at delivery, and delta hemoglobin levels revealed that only maternal age was significantly associated with delta in AMH levels (B = − 0.09, p = 0.04). Cesarean delivery does not decrease ovarian reserve as estimated by AMH.

Background: Dimethyl fumarate (DMF) demonstrated favorable benefit–risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. Objective: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0–2), then DMF (Years 3–10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. Results: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04–10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF ( n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120–0.169)), while for PBO/DMF ( n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0–2 years, 0.330 (95% CI, 0.266–0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118–0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. Conclusion: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF’s positive benefit/risk profile for long-term RRMS treatment.

The goal of this study was to explore people’s attitudes and opinions regarding addiction in Israel, among the general population and different sociodemographic categories. A national Internet-based survey (N = 2008) was conducted to examine attitudes within the adult Jewish Israeli population regarding feelings of shame, blame, alienation, and social discrimination towards people with an addiction, and opinions on treatment, awareness of resources, and public policy. Respondents held significantly negative views towards people experiencing an addiction. Women, more religious, older, and less-educated respondents expressed more stigmatizing attitudes, yet almost the same groups also expressed more supportive opinions regarding treatment and policy. Significant positive associations were found between several of these stigmatizing attitudes and supportive opinions. The association between stigmatizing attitudes and supportive opinions indicates both public support for policy change and the continued need for robust anti-stigma efforts. To improve these efforts, specific subpopulations with higher levels of stigma must be targeted. Policy makers should work towards building public health-focused policy and adapting anti-stigma efforts accordingly.

Study design A retrospective cohort study. Objectives To document the prevalence of asymptomatic bacteriuria and to characterize the resistance patterns to antibiotics among children with neurogenic bladder who require clean intermittent catheterization, with an emphasis on multidrug resistance. Setting A national referral pediatric and adolescent rehabilitation facility in Jerusalem, Israel. Methods Routine urine cultures were collected before urodynamic studies in suitable individuals during 2010-2018. None of them had symptoms of urinary tract infection at the time of specimen collection. Cultures were defined as being positive if a single bacterial species was isolated together with a growth of over 105 colony-forming units/ml. Resistance patterns were defined as extended-spectrum beta-lactamase (ESBL) and resistant to 3 antimicrobial groups (multi-drug resistant, MDR). Results In total, 281 urine cultures were available for 186 participants (median age 7 years, range 0.5-18). Etiologies for CIC included myelomeningocele (n = 137, 74%), spinal cord injury (n = 16, 9%) and caudal regression syndrome (n = 9, 5%). Vesicoureteral reflux was diagnosed in 36 participants (19%), 14 of whom were treated with prophylactic antibiotics. Asymptomatic bacteriuria was present in 217 specimens (77%, 95%CI [0.72-0.82]). The bacteria species were E. coli (71%), Klebsiella (13%), and Proteus (10%). ESBL was found in 11% of the positive cultures and MDR in 9%, yielding a total of 34 (16% of positive cultures) positive for ESBL and/or MDR bacteria. Conclusions Asymptomatic bacteriuria and resistance to antimicrobials are common in pediatric individuals who require CIC.

PURPOSE Relvar® (fluticasone furoate [FF]/vilanterol [VI]) is a once-daily inhaler with bronchodilator effect lasting 24 h. Our aim was to investigate the short- and long-term effects of FF/VI on exercise-induced asthma (EIA) in adolescents. METHODS Ninety-three adolescent asthmatics aged 12-18 years were referred for evaluation of EIA. Following a positive exercise challenge test (ECT), 22/44 were allocated to a single administration of salbutamol (400 μg) and 22/44 to FF/VI (92/22 μg) in a double-blind method. Thirty-five subjects were reassessed by repeat ECT 30-60 days of FF/VI. RESULTS Median FEV1 change post-ECT at baseline was -22.8% predicted (interquartile range [IQR] -26.1 and -18.0) for salbutamol and -21.0 (IQR -30.7 and -16.8) for FF/VI. Following bronchodilator, FEV1 improved similarly in both groups. Repeat ECT following 30-60 days of FF/VI resulted in negative ECT in 33/35 subjects; the median decrease in FEV1 of these 35 subjects was 22.6% predicted (IQR 29-18) before, and 4.6% predicted (IQR 8.7-2.5) after 30-60 days of FF/VI treatment (p

Steinberg, N, Bar-Sela, S, Moran, U, Pantanowitz, M, Waddington, G, Adams, R, Band, SS, and Funk, S. Injury prevention exercises for reduced incidence of injuries in combat soldiers. J Strength Cond Res XX(X): 000-000, 2021-The aim of this study was to determine the influence of an "all-cause injury" prevention program, focused on static-to-dynamic transitions, on injury prevalence in a military commanders course. Two cohorts of male infantry commanders were recruited (intervention [INT group], n = 196 and controls [CO group], n = 169) and tracked by a physiotherapist, who recorded any injuries that occurred during the 14-week course. Soldiers were tested precourse, midcourse, and postcourse for anthropometrics, proprioception ability, and dynamic postural balance (DPB). The INT group performed injury prevention exercises for 5 minutes, 3 times a week, and the CO group continued with their routine physical fitness sessions. The prevalence of injuries reported to the physiotherapist during the course was significantly lower for the INT group compared with the CO group (14.8 and 34.3%, respectively, p < 0.001). Similarly, rates of injury in the INT group were significantly lower than in the CO group (p < 0.001; hazard = 2.53, 95% confidence interval = 1.62-3.95). Precourse proprioception ability was significantly lower in those that became injured during the commanders course, irrespective of the group. Likewise, for DPB parameters, the injured subjects in both groups had significantly lower precourse scores than the noninjured subjects. From pretesting to midtesting, the injured soldiers in the INT group improved their ability up to the level of the noninjured subjects. A reduced prevalence of injuries was found for soldiers who completed the injury prevention program. Because the subjects soldiers injured on the course had reduced somatosensory abilities at the outset, and as these abilities can be improved by static-to-dynamic exercises, identifying at-risk soldiers and providing them with appropriate strategies for improvement beforehand is indicated.

Objectives Results of pre-post intervention studies of sepsis early warning systems have been mixed, and randomized clinical trials showing efficacy in the emergency department setting are lacking. Additionally, early warning systems can be resource-intensive and may cause unintended consequences such as antibiotic or IV fluid overuse. We assessed the impact of a pharmacist and provider facing sepsis early warning systems on timeliness of antibiotic administration and sepsis-related clinical outcomes in our setting. Design A randomized, controlled quality improvement initiative. Setting The main emergency department of an academic, safety-net healthcare system from August to December 2019. Patients Adults presenting to the emergency department. Intervention Patients were randomized to standard sepsis care or standard care augmented by the display of a sepsis early warning system-triggered flag in the electronic health record combined with electronic health record-based emergency department pharmacist notification. Measurements and main results The primary process measure was time to antibiotic administration from arrival. A total of 598 patients were included in the study over a 5-month period (285 in the intervention group and 313 in the standard care group). Time to antibiotic administration from emergency department arrival was shorter in the augmented care group than that in the standard care group (median, 2.3 hr [interquartile range, 1.4-4.7 hr] vs 3.0 hr [interquartile range, 1.6-5.5 hr]; p = 0.039). The hierarchical composite clinical outcome measure of days alive and out of hospital at 28 days was greater in the augmented care group than that in the standard care group (median, 24.1 vs 22.5 d; p = 0.011). Rates of fluid resuscitation and antibiotic utilization did not differ. Conclusions In this single-center randomized quality improvement initiative, the display of an electronic health record-based sepsis early warning system-triggered flag combined with electronic health record-based pharmacist notification was associated with shorter time to antibiotic administration without an increase in undesirable or potentially harmful clinical interventions.

Introduction Macroglossia occurs in 80% to 99% of patients with Beckwith-Wiedemann syndrome (BWS) and a variety of surgical techniques for tongue reduction are offered by surgeons. The purpose of this study is to evaluate the postoperative outcomes of the anterior “W” tongue reduction technique in patients with BWS. Methods A retrospective review was conducted of all patients diagnosed with BWS that underwent an anterior “W” tongue reduction for macroglossia in the past 7 years, performed by 2 surgeons. Demographics, procedural characteristics, perioperative outcomes, and complications were assessed. Results A total of 19 patients met inclusion criteria consisting of 8 male and 11 female patients. The mean age at the time of surgery was 405 days, mean surgeon operating time was 1.06 h, and mean length of follow-up was 467 days. Postoperative oral competence was observed in 100% of patients. There was no reported history of sleep apnea or airway compromise. Speech delay was seen in 4 patients pre- and postoperatively. Feeding issues decreased from 7 patients preoperatively to 1 patient postoperatively. Preoperative prevalence of class III malocclusion (53%) and isolated anterior open bite (26%) decreased postoperatively to 37% and 16%, respectively. The only reported complications were superficial tip wound dehiscence in 3 patients treated with nystatin antifungal therapy. None of the patients required revisional surgery. Conclusion Patients treated with the anterior “W” tongue reduction technique had low rates of perioperative complications and significant improvements in oral competence. Anterior “W” tongue reduction is safe and effective for the correction of macroglossia in patients with BWS.

We aimed to assess the incidence, clinical and biochemical course of immunotherapy-induced thyroiditis and its implication on patients' survival, based on an extensive clinical experience from a tertiary cancer center.Analyses were based on data from the electronic medical records of cancer patients treated with CPIs. Data included demographic characteristics, cancer type, Thyroid function tests (TFT), and survival.Thyroid function tests were available for 934 patients. After excluding patients with impaired baseline TFT or levothyroxine treatment, 754 euthyroid patients were included in the core analyses. Of those, 301 (39.9%) patients developed thyroid dysfunction ('thyroiditis'). Thyroiditis was more prevalent in patients with renal cell carcinoma than other types of cancer. Survival rates were comparable in patients who developed thyroiditis and in those who did not. during the 5 years follow-up period, there was a non-significant trend toward improved survival in patients who developed TD in four predefined groups: melanoma, lung cancer, renal cell carcinoma, and transitional cell carcinoma. Nevertheless, we observed a highly significant survival benefit for patients with renal cell carcinoma who developed TD (HR = 0.19, 95% CI 0.06-0.60;Thyroiditis is common, often asymptomatic, and is more prevalent in patients treated with combinations of nivolumab and PD-L1 inhibitors, and in patients with renal cell carcinoma. Thyroiditis was associated with a trend for a survival benefit, particularly in patients with renal cell carcinoma.

Objectives Using French transcatheter aortic valve replacement (TAVR) registries linked with the nationwide administrative databases, the study compared the rates of long-term mortality, bleeding, and ischemic events after TAVR in patients requiring oral anticoagulation with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs). Background The choice of optimal drug for anticoagulation after TAVR remains debated. Methods Data from the France-TAVI and FRANCE-2 registries were linked to the French national health single-payer claims database, from 2010 to 2017. Propensity score matching was used to reduce treatment-selection bias. Two primary endpoints were death from any cause (efficacy) and major bleeding (safety). Results A total of 24,581 patients who underwent TAVR were included and 8,962 (36.4%) were treated with OAC. Among anticoagulated patients, 2,180 (24.3%) were on DOACs. After propensity matching, at 3 years, mortality (hazard ratio [HR]: 1.37; 95% confidence interval [CI]: 1.12-1.67; P Conclusions In these large multicenter French TAVR registries with an exhaustive clinical follow-up, the long-term mortality and major bleeding were lower with DOACs than VKAs at discharge. The present study supports preferential use of DOACs rather than VKAs in patients requiring oral anticoagulation therapy after TAVR.

Jonathan Bar,1 Sari Godlewicz,2 Arieh Ingber,2 Eli Sprecher,1,3 Dan Slodownik1,3 1Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 2Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 3Sackler School of Medicine, Tel – Aviv University, Tel-Aviv, IsraelCorrespondence: Dan SlodownikTel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv, 6423906, IsraelTel +972 3-6973585Fax +972 3-6974998Email dans@tlvmc.gov.ilBackground: Chronic spontaneous urticaria (CSU) is a common debilitating condition. Although not completely understood, the main pathomechanism involves autoimmune-related mast-cell degranulation. Patch test (PT) is the gold standard for the diagnosis of type IV cutaneous hypersensitivity. The relevance of PT to the diagnosis of CSU is debatable.Objective: We aimed at determining the role of PT in selected patients with CSU.Methods: In this retrospective study, we reviewed cases of patients referred for patch testing at our clinic. We compared results of patients with CSU (n = 134) and patients with suspected allergic contact dermatitis (n = 680; control group).Results: Among patients in the CSU group, 3% of patients had relevant reactions to PT, indicating that contact allergen avoidance resulted in resolution of all skin findings. Metals and textile dyes were the most relevant allergens. No significant differences were found between the groups with regard to the percentage of patients with positive PT and hapten reaction profiles. Patients from the CSU group were significantly older (4.1 years on average, P < 0.05), consisted of more females, and were less likely to have atopic trait (46% vs 58%, P< 0.05).Conclusion: In some of patients, PT may assist in determining the cause of CSU.Keywords: chronic spontaneous urticaria, patch test, contact dermatitis

Background Smoking cessation in pregnancy has unique challenges. Health providers (HP) may need support to successfully implement smoking cessation care (SCC) for pregnant women (PW). We aimed to synthesize qualitative data about views of HPs and PW on SCC during pregnancy using COM-B (Capability, Opportunity, Motivation, Behaviour) framework. Methods A systematic search of online databases (MEDLINE, EMBASE, PsycINFO and CINAHL) using PRISMA guidelines. PW’s and HPs’ quotes, as well as the authors’ analysis, were extracted and double-coded (30%) using the COM-B framework. Results Thirty-two studies included research from 5 continents: 13 on HPs’ perspectives, 15 on PW’s perspectives, four papers included both. HPs’ capability and motivation were affected by role confusion and a lack of training, time, and resources to provide interventions. HPs acknowledged that advice should be delivered while taking women’s psychological state (capability) and stressors into consideration. Pregnant women’s physical capabilities to quit (e.g., increased metabolism of nicotine and dependence) was seldom addressed due to uncertainty about nicotine replacement therapy (NRT) use in pregnancy. Improving women’s motivation to quit depended on explaining the risks of smoking versus the safety of quit methods. Women considered advice from HPs during antenatal visits as effective, if accompanied by resources, peer support, feedback, and encouragement. Conclusions HPs found it challenging to provide effective SCC due to lack of training, time, and role confusion. The inability to address psychological stress in women and inadequate use of pharmacotherapy were additional barriers. These findings could aid in designing training programs that address HPs’ and PW’s attitudes and supportive campaigns for pregnant smokers.

Background This prospective study aimed to assess the reliability and validity of the Hebrew version of the forgotten joint score-12 in patients undergoing total knee arthroplasty, because it is going to be used in the Hebrew-speaking populations in Israel. Methods The English version of forgotten joint score-12 was translated into Hebrew version by using the standard procedures and in collaboration with its authors. The consecutive patients who had undergone total knee arthroplasty in a single hospital were asked to fill out the Hebrew version of forgotten joint score-12, Oxford knee score, Short Form 12, and visual analog scale. A random subgroup of 60 patients were then asked to fill out a second Hebrew version of forgotten joint score-12 at a minimum of 2-week interval. The reliability was assessed in terms of internal consistency, test-retest reliability and split-half reliability. The validity was measured in terms of the outcomes as mentioned above. Results A total of 102 patients participated in the study. The Hebrew version of forgotten joint score-12 showed high reliability. The internal consistency was excellent (Cronbachs’ α = 0.943) and test-retest reliability was high (Intraclass correlation = 0.97). The forgotten joint scores were correlated with the Oxford knee score, Short Form 12, and visual analog scale (r = 0.86, r = 0.72, and r=-0.8, respectively), indicating a high validity. Conclusions The Hebrew version of forgotten joint score-12 has excellent reliability, excellent test-retest reliability and good validity. It can be safely used for assessing outcomes of TKA.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized.

Late onset neutropenia (LON) after rituximab is a previously described complication. We aimed to assess and characterize LON after obinutuzumab, a novel anti-CD20 antibody, in the real-world setting and compare it to LON after rituximab therapy. We retrospectively analyzed 330 consecutive patients with lymphoproliferative neoplasms (rituximab-treated n = 283; obinutuzumab-treated n = 47). LON occurred in 23% patients with similar incidence in rituximab (n = 66, 23%) or obinutuzumab (n = 10, 21%) groups (p = 0.853). Patients treated for CLL and post-transplantation lymphoproliferative disease (PTLD) were at higher risk to develop LON (multivariate analysis: HR for CLL - 6.62 CI 95% 1.33-32.92; HR for PTLD 15.82 CI 95% 2.04-122.4). Febrile neutropenia was uncommon during LON and occurred in 15 patients (4.5%; rituximab (n = 14) and obinutuzumab (n = 1).These data suggest that LON after obinutuzumab treatment is as common as with rituximab. The similarities in LON after rituximab and obinutuzumab argue for a possible class effect for anti-CD20 monoclonal antibodies.

Summary Multiple myeloma (MM) patients are at excess risk for clinically significant COVID19 infection. BNT162b2 mRNA COVID19 (BNT162b2) vaccine provides effective protection against COVID19 for the general population, yet its effect in MM patients may be compromised due to disease and therapy‐related factors and was not yet evaluated. This single‐centre prospective study included MM patients tested for serological response 14–21 days post second vaccine. Vaccinated healthy volunteers served as controls. In all, 171 MM patients, median age 70 (38–94) were included; 159 active MM and 12 smouldering myeloma (SMM). Seropositive response rate (median titer) was 76% (91 U/ml) in active MM patients vs 98% (992 U/ml) in the 64 controls (P

Aims In breastfeeding women, anti-epileptic therapy can lead to infant toxicities, even with newer anti-epileptic drugs such as levetiracetam. This study assessed levetiracetam breastmilk excretion and its correlation with the maternal oral dose and serum concentrations. Methods Women with epilepsy treated with levetiracetam were recruited to this study and completed a questionnaire. Levetiracetam concentrations were determined in serial breastmilk samples (pre-dose to 12 h post-dose period) and in a single pre-dose maternal serum sample. Results Twenty breastfeeding women and 21 infants (one woman with twins; 16 fully and five partially breastfed infants) participated in this study. The trough breastmilk/serum ratio of levetiracetam was 0.98 ± 0.20. The infant levetiracetam daily dose was 5.39 ± 1.96 and 2.70 ± 0.98 mg. kg-1. d-1 , and the relative infant dose (RID) was 13.8 ± 3.1% and 6.9 ± 1.6% in the fully and partially breastfed infants, respectively. Substantial correlations between the levetiracetam dose, maternal serum and breastmilk trough concentrations, and breastmilk AUC values were found. Three women reported somnolence in their fully breastfed infants, which resolved shortly after switching to partial breastfeeding. All the infants gained weight according to their age. Conclusions Infant levetiracetam exposure via the breastmilk was close to the safety thresholds (trough breastmilk/serum ratio slightly below 1, RID > 10% in fully breastfed infants), and infant somnolescence reports could be related to exposure of the infants to levetiracetam via breastmilk. Further studies are warranted to reveal the short- and long-term safety of levetiracetam in breastfeeding.

Following vaginal hysterectomy (VH), fixation of the vaginal vault is needed to prevent post-operative recurrence/exacerbation of vault prolapse. The effectiveness of McCall culdoplasty in cases of advanced prolapse is unclear. We aimed to compare the effectiveness of McCall culdoplasty following VH in patients with mild versus advanced stages of uterine prolapse. In this retrospective study, the Pelvic Floor Distress Inventory (PFDI-20) was utilized to compare the subjective results of vaginal hysterectomy plus McCall culdoplasty between women with mild uterine prolapse stage 2 (mild prolapse group) and advanced uterine prolapse stages 3–4 (advanced prolapse group). The primary outcome, the subjective awareness of prolapse, was analyzed as well as all other aspects of PFDI-20. A sample size of 130 was calculated. The mild prolapse group consisted of 26 (19.3%) patients and the advanced prolapse group consisted of 109 (80.7%) patients. There were no differences between the groups in demographic and clinical characteristics. The rates of concomitant prolapse and incontinence surgeries, performed at the time of VH and post-operative complications. were the same between groups. The mean follow-up was more than 5 years in both groups. Awareness of prolapse was similar between the groups (11.5% in the mild prolapse group and 5.5% in the advanced prolapse group, p = 0.374). There was no significant correlation between the stage of apical prolapse before surgery and awareness of prolapse after the surgery (r = 0.0132, p = 0.879). All aspects of the PFDI-20 questionnaire were similar in the two groups. McCall culdoplasty was found to have an equal subjective effectiveness following VH in both mild and advanced stages of uterine prolapse.