Israel Medical Association Journal

Background: Real-world information regarding the use of direct oral anticoagulants therapy and the outcome in patients with renal dysfunction is limited.

Objectives: To evaluate the clinical characteristics and outcomes of patients with atrial fibrillation (AF) and severe renal dysfunction who are treated with apixaban.

Methods: A sub-analysis was conducted within a multicenter prospective cohort study. The study included consecutive eligible apixaban- or warfarin-treated patients with non-valvular AF and renal impairment (estimated glomerular filtration rate [eGFR] modification of diet in renal disease [MDRD] < 60 ml/min/BSA) were registered. All patients were prospectively followed for clinical events and over a mean period of 1 year. Our sub-analysis included the patients with 15 < eGFR MDRD < 30 ml/min/BSA. The primary outcomes at 1 year were recorded. They included mortality, stroke or systemic embolism, major bleeding, and myocardial infarction as well as their composite occurrence.

Results: The sub-analysis included 155 warfarin-treated patients and 97 apixaban-treated ones. All had 15 < eGFR MDRD < 30 ml/min/BSA. When comparing outcomes for propensity matched groups (n=76 per group) of patients treated by reduced dose apixaban or warfarin, the rates of the 1-year composite endpoint as well as mortality alone were higher among the warfarin group (30 [39.5%] vs. 14 [18.4%], P = 0.007 and 28 [36.8%] vs.12 [15.8%], P = 0.006), respectively. There was no significant difference in the rates of stroke, systemic embolism, or major bleeding.

Conclusions: Apixaban might be a reasonable alternative to warfarin in patients with severe renal impairment.

This focus article is a theoretical reflection on the ethics of allocating respirators to patients in circumstances of shortage, especially during the coronavirus disease-2019 (COVID-19) outbreak in Israel. In this article, respirators are placeholders for similar life-saving modalities in short supply, such as extracorporeal membrane oxygenation machines and intensive care unit beds.

In the article, I propose a system of triage for circumstances of scarcity of respirators. The system separates the hopeless from the curable, granting every treatable person a real chance of cure. The scarcity situation eliminates excesses of medicine, and then allocates respirators by a single scale, combining an evidence-based scoring system with risk-proportionate lottery.

The triage proposed embodies continuity and consistency with the healthcare practices in ordinary times. Yet, I suggest two regulatory modifications: one in relation to expediting review of novel and makeshift solutions and the second in relation to mandatory retrospective research on all relevant medical data and standard (as opposed to experimental) interventions that are influenced by the triage

Germany was a scientifically advanced country in the 19th and early 20th centuries, particularly in medicine, with a major interest in research and the treatment of tuberculosis. From 1933 until 1945, Nazi Germany perverted scientific research through criminal experimentations on captured prisoners of war and on "subhumans" by scientifically untrained, but politically driven, staff. This article exposes a series of failed experiments on tuberculosis in adults, experiments without scientific validity. Nonetheless, Dr. Kurt Heißmeyer repeated the experiment on Jewish children, who were murdered for the sake of personal academic ambition. It is now 75 years since liberation and the murdered children must be remembered. This observational review raises questions of medical and ethical values

Background: In April 1937 it was forbidden for German Jewish students to sit for examinations. However, a few Jewish medical students were able to continue studying at Berlin University. The order to expel all Jewish students from German Universities was published on the morning after Kristallnacht (November 1938) and was strictly imposed.

Objectives: To identity the last Jewish medical students who managed, in spite of the severe restrictions, to continue their study and apply for the examinations in Berlin from summer 1937 through 1938.

Methods: Reviews of the dissertations written in the medical faculty of Berlin during 1937–1938 identified the Jewish students. We presented their demographic and academic characteristics.

Results: Sixteen Jewish students were identified: six Germans, six Americans, and four Eastern Europeans. Their average age was 18.7 ± 1.0 years, 22.5 ± 2.0 years, and 20.8 ± 2.5 years, respectively. The last Jewish student took the exams in July 1938 and submitted a thesis one month later. One German student was half Jewish. Five gained the rights to take the examinations as foreign students by renouncing their German citizenship. They were the main group affected by the government’s restrictions. The American and the Eastern European students were more protected by law.

Conclusions: Each of those groups had different academic careers. The Americans were the last Jewish students allowed to study in Germany. It seems that they were less aware of the national socialist atmosphere in the medical faculty in Berlin during 1937–1938.

Background: The Israel National Cancer Registry (INCR) was established in 1960. Reporting has been mandatory since 1982. All neoplasms of uncertain/unknown behavior, in situ and invasive malignancies (excluding basal and squamous cell carcinomas of the skin), and benign neoplasms of the brain and central nervous system (CNS) are reportable.

Objectives: To assess completeness and timeliness of the INCR for cases diagnosed or treated in 2005.

Methods: Abstractors identified cases of in situ and invasive malignancies and tumors of benign and uncertain behavior of the brain and CNS diagnosed or treated in 2005 in the files of medical records departments, pathology and cytology laboratories, and oncology and hematology institutes in 39 Israeli medical facilities. Cases were linked to the INCR database by national identity number. Duplicate cases, and those found to be non-reportable were excluded from analysis. Completeness was calculated as the percent of reportable cases identified by the survey that were present in the registry. Timeliness was calculated as the percent of reportable cases diagnosed in 2005, which were incorporated into the registry prior to 31 December 2007.

Results: The INCR’s completeness is estimated at 93.7% for all reportable diseases, 96.8% for invasive solid tumors, and 88.0% for hematopoietic tumors. Incident cases for the calendar year 2005 were less likely to be present in the registry database than those diagnosed prior to 2005.

Conclusions: Completeness and timeliness of the INCR are high and meet international guidelines. Fully automated reporting will likely improve the quality and timeliness of INCR data.

Background: Primary spontaneous pneumothorax (PSP) tends to occur in young adults without underlying lung diseases and is usually followed by limited symptoms, while secondary spontaneous pneumothorax (SSP) is a complication of a pre-existing lung disease. Surprisingly, for such common conditions, there is a considerable inconsistency regarding management guidelines.

Objectives: To evaluate the risk factors for spontaneous pneumothoraxes and to summarize outcomes and complications based on our clinical experience.

Methods: This retrospective study group was comprised of 250 consecutive patients older than 18 years of age who were diagnosed with spontaneous pneumothorax and hospitalized at the Meir Medical Center (2004–2017). Data on demographic characteristics, indicating symptoms, chest X-rays, and chest computed tomography (CT) results were collected. Our experience and outcomes were then compared to a large multicenter study.

Results: Most of the patients were male (85%) and past or current smokers; 69% presented with PSP, while the rest were SSP. No occupational relation was noted. About 55% of the cases presented with a moderate or large pneumothorax (over 1/3 hemithorax). Most patients (56%) required chest tube drainage and 20% undergone surgery. Nearly 10% presented with a recurrent pneumothorax with the mean time to recurrence being 11 ± 20 days. Although the length of hospital stay of patients that underwent surgery was the longest (P < 0.001) for both PSP and SSP, the recurrence rate was actually reduced, suggesting some benefit for the surgical treatment option.

Conclusions: Our experience showed that the traditional approach to the PSP treatment should be further considered, as previously suggested.

Background: Lung cancer is the most common cause of cancer-related death.

Objectives: To identify changing patterns of lung cancer and its histologic subtypes among different population groups in Israel over a 25 year period.

Methods: Primary lung cancers, all types and all stages, diagnosed during 1990–2014 were recorded in the Israel National Cancer Registry database. Demographic information was retrieved from the National Population Register. Age-standardized rates for the different subgroups were calculated for each year. Joinpoint software was used to analyze trends in incidence.

Results: We identified 42,672 lung cancer cases. The most common histology was adenocarcinoma (34%), followed by squamous cell carcinoma (19%), large cell/not-otherwise-specified (19%), other histologies (15%), and small cell lung cancer (11%). The adenocarcinoma incidence rose from 25.7% to 48.2% during the examined period. Large cell/not-otherwise-specified incidence peaked around 2005–2006 and declined after. Lung cancer incidence increased significantly for the population overall and specifically in Arab females, followed by Jewish females and by Arab males. Adenocarcinoma and small cell lung cancer increased in Jewish females and in Arab males. A younger age of diagnosis was seen in Arab compared to Jewish patients.

Conclusions: Jewish females and Arab males and females living in Israel demonstrated a constant increase in lung cancer incidence, mostly in adenocarcinoma and small cell lung cancer incidence. In addition, a younger age of diagnosis in Arabs was noted. Smoking reduction interventions and screening should be implemented in those populations.

Background: Acute pulmonary embolism (PE) is considered to be one of the most common cardiovascular diseases with considerable mortality. Conflicting data imply possible role for echocardiography in assessing this disease.

Objectives: To determine which of the echo parameters best predicts short-term and long-term mortality in patients with PE.

Methods: We prospectively enrolled 235 patients who underwent computed tomography of pulmonary arteries (CTPA) and transthoracic Echocardiography (TTE) within < 24 hours. TTE included a prospectively designed detailed evaluation of the right heart including right ventricular (RV) myocardial performance index (RIMP), RV end diastolic and end systolic area, RV fractional area change, acceleration time (AT) of pulmonary flow and visual estimation. Interpretation and performance of TTE were blinded to the CTPA results.

Results: Although multiple TTE parameters were associated with PE, all had low discriminative capacity (AUC < 0.7). Parameters associated with 30-day mortality in univariate analysis were acceleration time (AT) < 81 msec (P = 0.04), stroke volume < 44 cc (P = 0.005), and RIMP > 0.42 (P = 0.05). The only RV independent echo parameter associated with poor long-term prognosis (adjusted for significant clinical, and routine echo associates of mortality) was RIMP (hazard ratio 3.0, P = 0.04). The only independent RV echo parameters associated with mortality in PE patients were RIMP (P = 0.05) and AT (P = 0.05). Addition of RIMP to nested models eliminated the significance of all other parameters assessing RV function.

Conclusions: Doppler-based parameters like pulmonary flow AT, RIMP, and stroke volume, have additive value in addition to visual RV estimation to assess prognosis in patients with PE.

Fetal complete atrioventricular block (CAVB) is usually autoimmune mediated. The risk of developing CAVB is 2% to 3% in anti-Ro/SS-A seropositive pregnancies and it increases 10 times after previous CAVB in siblings. Despite being a rare complication, CAVB carries a 20% mortality rate and substantial morbidity, as about 65% of newborns will eventually need life-long pacing. Once found, fetal CAVB is almost always irreversible, despite aggressive immunotherapy. This poor outcome prompted some research groups to address this situation. All groups followed anti-Ro/SS-A seropositive pregnancies on a weekly basis during the second trimester of pregnancy and tried to detect first degree atrioventricular block (AVB) using accurate echocardiographic tools, assuming they may characterize the initiation of the immune damage to the A-V conduction system, at which point the process might still be reversible. Some of the groups treated fetuses with first degree AVB with maternal oral fluorinated steroids. We summarized the results of all groups, including our group. We describe a case of a fetus that developed CAVB 6 days after normal sinus rhythm (NSR), who under aggressive dexamethasone therapy gradually reverted to NSR. This fetus had a previous sibling with CAVB. We assumed the immune damage to the conduction system in this small group of fetuses with a previous CAVB sibling may have occurred more quickly than usual. We therefore recommend a twice-weekly follow-up with these fetuses

Background: An association was shown between thrombocytosis and future development of several cancers.

Objectives: To investigate whether pre-treatment platelet counts correlated with clinical outcomes of patients with breast cancer.

Methods: This retrospective study included 22 patients who had been diagnosed with stage I breast cancer and were 66.8 ± 13.2 years of age. Of these, 22 with stage II were 61.6 ± 12.3 years old and 9 with stage III and IV were 64.4 ± 15.3 years old. Clinical and hematological data from the first visit to the oncology clinic were collected. The follow-up period was 12 months to 5 years.

Results: A significant difference in platelet counts was found between patients who died (187,000 ± 4000 µ/L) and those who were disease free for 5 years (248,000 ± 83,000 µ/L, P = 0.0001). A significant difference in platelet-to-lymphocyte ratio was found between patients who died and those with recurrence (192 ± 81 vs. 124 ± 71, P = 0.01). A negative correlation was found between age and lymph nodes (Ps = -0.305, P = 0.02) and staging and white blood cells count (Ps = -0.280, P = 0.04). A positive correlation was found between clinical staging and lymph nodes (Ps = 0.443, P = 0.001) and clinical staging and metastases (P = 0.308, P = 0.02).

Conclusions: Platelet counts may be a prognostic marker for breast cancer. Patients who died within 1 year had lower pre-treatment platelet count, which could represent an insidious disseminated intravascular coagulopathy cancer related consumption process.

Background: Patients with severe chronic obstructive pulmonary disease (COPD) experience frequent exacerbations and need to be hospitalized, resulting in an economic and social burden. Although data exist regarding reasons of frequent hospitalizations, there is no data available about the impact on the length of stay (LOS).

Objectives: To characterize the causes of prolonged hospitalizations in COPD patients.

Methods: A retrospective study was conducted of patients who were diagnosed and treated in the pulmonary department for severe COPD exacerbations. All patient demographic data and medical history were collected. Data regarding the disease severity were also collected (including Global Initiative for Obstructive Lung Disease [GOLD] criteria, pulmonologist follow-up, prior hospitalizations, and LOS).

Results: The study comprised 200 patients, average age 69.5 ± 10.8 years, 61% males. Of these patients, 89 (45%) were hospitalized for up to 4 days, 111 (55%) for 5 days or more, and 34 (17%) for more than 7 days. Single patients had longer LOS compared with married patients (48% vs. 34%, P = 0.044). Multivariate analysis showed that the number of prior hospital admissions in the last year was a predictor of LOS (P = 0.038, odds ratio [OR] = 0.807, 95% confidence interval [95%CI] = 0.659–0.988), as well as the use of non-invasive respiratory support by bilevel positive airway pressure (BiPAP) during the hospitalization (P = 0.024, OR = 4.662, 95%CI = 1.229–17.681).

Conclusions: Fewer previous hospitalizations due to COPD exacerbations and the need for non-invasive respiratory support by BiPAP were found as predictors of longer LOS.

Background: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA.

Objectives: To evaluate SC tocilizumab in a real-life clinical setting.

Methods: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed.

Results: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively.

Conclusions: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.