Israel Medical Association Journal

Recognizing myocarditis is a diagnostic and therapeutic challenge due to the heterogeneity of its clinical presentation and the wide range of etiologies. There is a lack of uniformity among position papers and guidelines from various professional societies regarding the definition and diagnostic workout, including recommendations for performing endomyocardial biopsy (EMB) and medical management, especially the use of immunosuppressive regimens [1-3]. Moreover, there is significant variability among medical centers in Israel in the diagnostic and therapeutic approaches to acute myocarditis. The purpose of this position paper is to present ways to standardize the management of acute myocarditis in Israel [4] by providing up-to-date definitions of the clinical categories of myocarditis, diagnostic criteria, and therapeutic approaches that correspond to the realities of our healthcare system.

In the position statement on the definition and diagnosis of acute myocarditis on page XXX of this issue of the Israel Medical Association Journal (IMAJ), we discussed contemporary criteria for definition of acute myocarditis and inflammatory cardiomyopathy [1-6]. We also addressed current diagnostic methods including indications for endomyocardial biopsy (EMB) [7-21]. In this position statement, we discuss the management approaches during hospitalization and following hospital discharge, including specific forms of myocarditis and recommendations for returning to physical activity after myocarditis [21-36].

Background: Among the most frequent complications following transcatheter aortic valve replacement (TAVR) is hemostasis imbalance that presents either as thromboembolic or bleeding. Deviations in platelet count (PC) and mean platelet volume (MPV) are markers of hemostasis imbalance.

Objectives: To determine the predictive value of pre- and post-procedural PC and MPV fL 1-year all-cause mortality in patients who underwent TAVR.

Methods: In this population-based study, we included 236 TAVR patients treated at the Tzafon Medical Center between 1 June 2015 and 31 August 2018. Routine blood samples for serum PC levels and MPV fL were taken just before the TAVR and 24-hour post-TAVR. We used backward regression models to evaluate the predictive value of PC and MPV in all-cause mortality in TAVR patients.

Results: In this study cohort, MPV levels 24-hour post-TAVR that were greater than the cohort median of 9 fL (interquartile range 8.5–9.8) were the strongest predictor of 1-year mortality (hazard ratio 1.343, 95% confidence interval 1.059–1.703, P-value 0.015). A statistically significant relationship was seen in the unadjusted regression model as well as after the adjustment for clinical variables.

Conclusions: Serum MPV levels fL 24-hour post-procedure were found to be meaningful markers in predicting 1-year all-cause mortality in patients after TAVR.

Background: The parasympathetic system and its main neurotransmitter, acetylcholine, contributes to homeostasis of inflammation. Cholinergic dysregulation is thought to contribute to the pathogenesis of inflammatory rheumatic diseases. Cholinesterase activity in patients with psoriatic arthritis (PsA) has not been investigated.

Objectives: To compare the cholinesterase activity in patients with PsA and immunocompetent controls and to explore the correlation between cholinergic status (CS) and PsA disease activity.

Methods: Serum acetylcholinesterase (AChE) and total cholinesterase activity were measured in patients with PsA (n=88) and matched controls (n=84). Cholinergic activity before and 3–6 months after the initiation of a biologic treatment was evaluated in seven patients with PsA.

Results: The levels of AChE and CS were similar in both PsA patients and controls. PsA patients treated with biologics had significantly lower levels of AChE and CS compared to patients treated with non-biologics: 447.4 vs. 526 substrate hydrolyzed/min/ml, P = 0.005, and 1360.9 vs. 1536, P = 0.029, respectively. We found an association between C-reactive protein levels, AChE activity (r = 0.291, P = 0.008), and cholinergic status (r = 0.247, P = 0.026) in patients with PsA but not in controls. No correlation between AChE activity, cholinergic status, and the indices of PsA disease activity was found. After initiating or switching biologic treatment in 7 patients, AChE levels remained stable.

Conclusions: We demonstrated similar cholinesterase activity in patients with psoriatic arthritis and controls, highlighting a potential effect of biologic treatment on cholinergic activity in patients with PsA.

Background: Up to half the patients diagnosed with acute coronavirus disease 2019 (COVID-19) presented with gastrointestinal symptoms. Gastric mucosal cells, enterocytes, and colonocytes express the viral entry receptor angiotensin-converting enzyme 2 (ACE2) and coreceptor transmembrane protease serine 2 (TMPRSS2) and are prone to infection. Direct infection of gastrointestinal epithelial cells has been demonstrated. COVID-19 disease was first diagnosed in Israel at the end of February 2020 with 842,536 confirmed cases and 6428 deaths by the end of June 2021. In our multicenter, retrospective cohort study, we looked for gastrointestinal signs and symptoms in two periods and correlated them with mortality. Period 1 included the first and second waves and the original virus. Period 2 represented the third wave and the alpha variant.

Objectives: To reveal gastrointestinal signs and symptoms in two periods and correlate them with mortality.

Methods: From 22,302 patients hospitalized in general medical centers, we randomly selected 3582 from Period 1 and 1106 from Period 2. The study was performed before vaccinations were available.

Results: Gastrointestinal signs and symptoms, diarrhea, vomiting, abdominal pain, and taste/smell loss were significantly more prevalent during Period 1. Thirty-day mortality and in-hospital mortality were significantly higher in Period 2 than in Period 1, 25.20% vs. 13.68%, and 21.17% vs. 12.87%, respectively (P < 0.001).

Conclusions: Thirty-day mortality and in-hospital mortality rates were 1.84 and 1.64 times higher from 6 November 2020 to 15 January 2021, the alpha variant, and in negative correlation with gastrointestinal symptoms.

Background: Little is known about phenotypical variations among ethnic groups in patients with Parkinson's disease (PD) in Israel. Clinical characteristics of non-Ashkenazi Jews (NAJ) are scantly described.

Objectives: To describe clinical aspects of PD in ethnic groups in Israel, focusing on NAJ and Ashkenazi Jews (AJ).

Methods: In this cross-sectional retrospective study, we collected demographic, genetic, and clinical characteristics of patients from different ethnic Jewish backgrounds. Ethnic groups included AJ; North African Jews (NAFJ); oriental Jews (OJ) originating from Iran, Iraq, and Buchara; Balkan Jews; Yemenite Jews (YJ); and Jews of mixed origin. Clinical characteristics included hyposmia, urinary complaints, constipation, and rapid eye movement sleep behavioral disorder. Cognitive complaints, motor features, levodopa-induced dyskinesia, and motor fluctuations were collected. Motor part of the MDS-UPDRS and Hoehn and Yahr scores were collected.

Results: The study comprised 174 PD Jewish patients (63.2% AJ, 56.4% males). The age at onset was 65.3 ± 10.2 years; 106 patients (60.9%) were genotyped (17 glucocerebrosidase [16.0%], 13 leucine-rich repeat kinase 2 [LRRK2] [12.3%]). Rates of hyposmia were significantly higher in AJ than NAJ (56.6% vs. 39.5%, respectively, P = 0.003). No significant differences were found in motor features in all variables. Of 13 AJ patients carrying the LRRK2 mutation, only one had hyposmia. Three patients with LRRK2 were NAJ.

Conclusions: Hyposmia is less prevalent in PD patients of NAJ origin than in AJ. The rate of hyposmia in NAFJ patients is particularly low. The rate of other non-motor features is similar between NAJ and AJ patients.

Background: Morbidly adherent placentation (MAP) increases the risk for obstetric hemorrhage. Cesarean hysterectomy is the prevalent perioperative approach. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive and relatively simple endovascular procedure to temporarily occlude the aorta and control below diaphragm bleeding in trauma. It has been effectively used to reduce obstetric hemorrhage.

Objectives: To evaluate whether REBOA during cesarean delivery (CD) in women with morbidly adherent placentation is a safe and effective treatment modality.

Methods: We introduced REBOA for CD with antepartum diagnosis of MAP in 2019 and compared these patients (RG) to a standard approach group (SAG) treated in our center over the preceding year, as a control. All relevant data were collected from patient electronic files.

Results: Estimated blood loss and transfusion rates were significantly higher in SAG; 54.5% of SAG patients received four RBC units or more vs. one administered in RG. No fresh frozen plasma, cryoprecipitate, or platelets were administered in RG vs. mean 3.63, 6, and 3.62 units, respectively in SAG. Ten SAG patients (90.9%) underwent hysterectomy vs. 3 RG patients (30%). Five SAG patients (45%) required post-surgical intensive care unit (ICU) admission vs. no RG patients. Bladder injury occurred in five SAG cases (45%) vs. 2 RG (20%). One RG patient had a thromboembolic event. Perioperative lactate levels were significantly higher in SAG patients.

Conclusions: Use of REBOA during CD in women with MAP is safe and effective in preventing massive bleeding, reducing the rate of hysterectomy, and improving patient outcome.

Background: Depression has been shown to be associated with cervical tumors (CTs), an association mostly demonstrated in studies in which temporality could not have been ascertained.

Objectives: To study the association between depression and CTs and the influence of co-morbidities of this association in a large cohort study.

Methods: A retrospective computer-based cohort study was conducted. The cohort included 357,450 female members of Maccabi Healthcare Services. The cohort was classified as depressed or non-depressed using the International Classification of Diseases 9/10 codes. For each subgroup, demographic characteristics, behavioral characteristics, co-morbidities, and CTs diagnosis were obtained. The burden of co-morbidities was defined as the sum of major co-morbidities. We used zero-inflated negative binomial regression analysis due to over-dispersion to estimate the relative risk (RR) for CTs with 95% confidence interval (95%CI).

Results: Depression was diagnosed in 15,789 women. Among this group, CTs were diagnosed in 1585 (10.0%). Among the 341,661 non-depressed, CTs were diagnosed in 4185 (1.2%). After adjustment to age and socioeconomic status, the association between depression and CTs was RR=9.2 (95%CI 8.7–9.9, P-value < 0.0001). The association between depression and CTs increased as the burden of clinical conditions increased (P-value < 0.0001).

Conclusions: Women with depression are at a higher risk for CTs, especially among those who have several co-morbidities. Tighter gynecology surveillance is crucial among these women.

Background: Group A Streptococcus (GAS), the predominant bacterial pathogen of pharyngitis, is sometimes difficult to distinguish clinically from viral pharyngitis. Despite the high prevalence of viral pharyngitis in children, antibiotic treatment is common.

Objective: To investigate the effectiveness of an antibiotic stewardship program (ASP) on antibiotic prescription in children with GAS pharyngitis (GAS-P) at a large pediatric community clinic.

Methods: Antibiotic prescription data were collected from October 2016 to March 2017 (pre-intervention period) and from October 2017 to March 2018 (post-intervention period). The intervention was a one-day seminar for primary care pediatricians on the diagnosis and treatment of GAS-P in children according to national guidelines.

Results: The overall prevalence of testing differed between the two time periods. There was a decrease in children who did not undergo any testing (from 68% to 63%), an increase in streptococcal rapid antigen detection testing (28% to 32%), and a slight increase in throat cultures (3% to 4%) (p = 0.02). There was no change in the types of antibiotics prescribed before and after the intervention (p = 0.152).

Conclusions: The ASP resulted in a slight reduction in the percentage of children who did not undergo laboratory testing for GAS-P and a slight reduction in the percentage of children who received antibiotic treatment. The ASP did not reduce the use of broad-spectrum antibiotics and macrolides.

Background: Abdominal pathology in pregnant patients is a frequent challenge for emergency department physicians. Ultrasound is the imaging modality of choice but is inconclusive in approximately one-third of cases. Magnetic resonance imaging (MRI) is becoming increasingly available, even in acute settings. Multiple studies have defined the sensitivity and specificity of MRI in this population.

Objectives: To evaluate the use of MRI findings in pregnant patients presenting with acute abdominal complaints to the emergency department.

Methods: This retrospective cohort study was conducted at a single institution. Data were collected on pregnant patients who underwent an MRI for acute abdominal complaints between 2010 and 2019 at a university center. Patient demographics, diagnosis at admission, ultrasound and MRI findings, and discharge diagnosis were recorded and evaluated.

Results: In total, 203 pregnant patients underwent an MRI for acute abdominal complaints during the study period. MRI was found without pathology in 138 cases (68%). In 65 cases (32%), the MRI showed findings that could explain the patient's clinical presentation. Patients presenting with long-standing abdominal pain (> 24 hours), fever, leukocytosis, or elevated C-reactive protein values were at a significantly increased risk of having an acute pathology. In 46 patients (22.6%), MRI findings changed the primary diagnosis and management while in 45 patients (22.1%) MRI findings improved characterization of the suspected pathology.

Conclusions: MRI is helpful when clinical and sonographic findings are inconclusive, leading to changes in patient management in more than one-fifth of patients.

Background: Treatment of gestational diabetes mellitus (GDM) has been shown to improve both maternal and neonatal outcomes. For women with GDM who require glucose-lowering medication, insulin is regarded as the drug of choice by most medical societies. Oral therapy, with metformin or glibenclamide, is a reasonable alternative in certain medical circumstances.

Objectives: To compare the efficacy and safety of insulin detemir (IDet) vs. glibenclamide for GDM when glycemic control cannot be achieved through lifestyle modification and diet.

Methods: We conducted a retrospective cohort analysis of 115 women with singleton pregnancy and GDM treated with IDet or glibenclamide. GDM was diagnosed via the two-step oral glucose tolerance test (OGTT) of 50 grams glucose, followed by 100 grams. Maternal characteristics and outcomes (preeclampsia and weight gain) and neonatal outcomes (birth weight and percentile, hypoglycemia, jaundice, and respiratory morbidity) were compared between groups.

Results: In total, 67 women received IDet and 48 glibenclamide. Maternal characteristics, weight gain, and the incidence of preeclampsia were similar in both groups. Neonatal outcomes were also similar. The proportion of large for gestational age (LGA) infants was 20.8% in the glibenclamide group compared to 14.9% in the IDet group (P = 0.04).

Conclusions: In pregnant women with GDM, glucose control on IDet yielded comparable results as on glibenclamide, except for a significantly lower rate of LGA neonates.

Background: Mucins, heavily glycosylated glycoproteins, are synthesized by mucosal surfaces and play an important role in healthy and malignant states. Changes in mucin synthesis, expression, and secretion may be a primary event or may be secondary to inflammation and carcinogenesis.

Objectives: To assess current knowledge of mucin expression in the small bowel of celiac disease (CD) patients and to determine possible associations between mucin profile and gluten-free diet.

Method: Medical literature searches of articles in English were conducted using the terms mucin and celiac. Observational studies were included. Pooled odds ratios and 95% confidence intervals were calculated.

Results: Of 31 articles initially generated by a literature search, 4 observational studies that fulfilled the inclusion criteria remained eligible for meta-analysis. These studies included 182 patients and 148 controls from four countries (Finland, Japan, Sweden, United States). Mucin expression was significantly increased in small bowel mucosa of CD patients than in normal small bowel mucosa (odds ratio [OR] 7.974, 95% confidence interval [95%CI] (1.599–39.763), P = 0.011] (random-effect model). Heterogeneity was significant: Q = 35.743, df (Q) = 7, P < 0.0001, I² = 80.416%. ORs for MUC2 and MUC5AC expression in the small bowel mucosa of untreated CD patients were 8.837, 95%CI 0.222–352.283, P = 0.247 and 21.429, 95%CI 3.883–118.255, P < 0.0001, respectively.

Conclusions: Expression of certain mucin genes in the small bowel mucosa of CD patients is increased and may serve as a diagnostic tool and assist in surveillance programs.

Background: Implantable loop recorders (ILRs) are a central tool in the evaluation of unexplained syncope. These devices record and store electrocardiograms, both automatically and on patient-dependent activation. Therefore, obtaining optimal diagnostic results relies on a patient's comprehension and collaboration.

Objectives: To evaluate the effect of ethnic background and mother-tongue language on the diagnostic yield (DY) of ILRs.

Methods: Patients at two medical centers in Israel, who had ILRs as part of syncope workup were included. Inclusion criteria were age over 18 years and an ILR for at least one year (or less if the cause of syncope was detected). Patient demographics, ethnic background, and previous medical history were recorded. All findings from ILR recordings, activation mode (manual vs. automatic), and treatment decisions (none, ablation, device implantation) were collected.

Results: The study comprised 94 patients, 62 Jews (i.e., ethnic majority) and 32 non-Jews (i.e., ethnic minority). While baseline demographic characteristics, medical history, and drug therapy were similar in both groups, Jewish patients were significantly older at the time of device implantation: 64.3 ± 16.0 years of age vs. 50.6 ± 16.9, respectively; (P < 0.001). Arrhythmias recorded in both groups as well as treatment decisions and device activation mode were similar. Total follow-up time from device implantation was longer in the non-Jewish vs. the Jewish group (17.5 ± 12.2 vs. 24.0 ± 12.4 months, respectively; P < 0.017).

Conclusions: The DY of ILR implanted for unexplained syncope did not seem to be influenced by patient's mother-tongue language or ethnicity.

Background: A limited program for kidney donation from uncontrolled donation after cardiocirculatory determination of death (uDCDD) was implemented at four hospitals in Israel in close cooperation with Magen David Adom (MDA), the national emergency medical service.

Objectives: To assess the outcome of transplantations performed between January 2017 and June 2022.

Methods: Donor data included age, sex, and cause of death. Recipient data included age, sex, and yearly serum creatinine levels. A retrospective study of out-of-hospital cardiac arrest cases treated by MDA during 2021 were analyzed to assess their compatibility as potential uDCDD donors.

Results: In total, 49 potential donors were referred to hospitals by MDA. Consent was obtained in 40 cases (83%), organ retrieval was performed in 28 cases, and 40 kidneys were transplanted from 21 donors (75% retrieval rate). At 1-year follow-up, 36 recipients had a functioning graft (4 returned to dialysis) and mean serum creatinine 1.59 ± 0.92 mg% (90% graft survival). Outcome after transplantation showed serum creatinine levels (mg%) at 2 years 1.41 ± 0.83, n=26; 3 years 1.48 ± 0.99, n=16; 4 years 1.07 ± 1.06, n=7; and 5 years 1.12 ± 0.31, n=5. One patient died of multiple myeloma at 3 years. The MDA audit revealed an unutilized pool of 125 potential cases, 90 of whom were transported to hospitals and 35 were declared dead at the scene.

Conclusions: Transplant outcomes were encouraging, suggesting that more intensive implementation of the program may increase the number of kidneys transplanted, thus shortening recipient waiting lists.

Background: Trabecular bone score (TBS) reflects vertebrae microarchitecture and assists in fracture risk assessment. The International Society of Clinical Densitometry postulates that the role of TBS in monitoring antiresorptive therapy is unclear. Whether changes in TBS correlate with bone resorption measured by bone turnover markers is not known.

Objectives: To determine whether longitudinal changes in TBS correlate with C-terminal telopeptide (CTX) of type I collagen.

Methods: Examinees with two bone mineral density (BMD) measurements were detected via the institutional database. Over 5.8% change in TBS was considered least significant and patients were grouped accordingly (increment, decrement, or unchanged). CTX, BMD, co-morbidities, incident fractures, and medication exposure were compared between the groups by Kruskal-Wallis. The correlation between TBS and BMD change and CTX in a continuous model was analyzed by Pearson's correlation coefficient.

Results: In total, 110 patients had detailed medical records. In 74.5%, TBS change was below least significant change. Two other TBS categories, fracture incidence or medication exposure, did not differ by CTX. In the continuous model, BMD and TBS change was positively correlated (r = 0.225, P = 0.018). A negative correlation was observed between BMD change and CTX. The decrease in BMD level was associated with higher CTX (r = -0.335, P = 0.004). No correlation was observed between CTX and TBS.

Conclusions: No correlation between TBS dynamics and bone resorption marker was found. Clinical interpretation and implication of longitudinal TBS changes should be further explored.