Israel Medical Association Journal

Background: The use of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAbs) is emerging for lowering low-density lipoprotein cholesterol (LDL-C). However, real-world data is lacking for their use among elderly patients.

Objective: To define the characteristics of elderly patients treated with PCSK9 mAbs and to evaluate the efficacy and tolerability compared with younger patients.

Methods: We conducted a retrospective cohort study of elderly patients (≥ 75 years at enrollment) treated with PCSK9 mAbs for primary and secondary cardiovascular prevention. Data were retrieved for demographic and clinical characteristics; indications for treatment; agents and dosages; concomitant lipid lowering treatment; LDL-C levels at baseline, 6, 12 months, and at the end of follow up. Data also included achieving LDL-C target levels and adverse effects.

Results: The cohort included 91 elderly patients and 92 younger patients, mean age 75.2 ± 3.76 and 58.9 ± 7.4 years (P < 0.0001). Most patients (82%, 80%) were in high/very high-risk categories. For almost all (98%, 99%), the indication was statin intolerance, with PCSK9 mAb monotherapy the most prevalent regimen. The average follow-up was 38.1 ± 20.5 and 30.9 ± 15.8 months (P = 0.0258). Within 6 months the LDL-C levels were reduced by 57% in the elderly group and by 59% in the control group (P = 0.2371). Only 53% and 57% reached their LDL-C target levels. No clinically significant side effects were documented.

Conclusion: PCSK9 mAbs have similar effects and are well tolerated among elderly patients as in younger patients.

Gastric perforation secondary to foreign body ingestion is rare. While obvious signs of acute abdomen usually lead to a prompt diagnosis by emergency department (ED) staff, this can be delayed in non-responsive or mentally disabled patients. An altered pain perception has been described in schizophrenia, as part of a complex phenomenon, which is thought to be unrelated to changes in nociceptive pathways. Cognitive impairment and negative symptoms may strongly influence the patient’s expression of pain [1].

On Saturday, 7 October 2023, the Jewish holiday of Simchat Torah, our entire country woke to a reality of the worst terror attacks it has ever known, despite its long history of wars and terror. These horrific attacks included killing and burning babies, children, women, men, and the elderly; raping women; beheading babies; destroying settlements; and kidnapping more than 240 civilians and soldiers. The severe traumatic events created different circles of those exposed to trauma. In each group, the intensity of the trauma was different and had different characteristics.

Background: The continuity equation (CE) used for evaluating aortic stenosis (AS) is based on values obtained from transthoracic echocardiography (TTE) with the assumption that the left ventricular outflow tract (LVOT) has a circular shape. Transesophageal echocardiography (TEE) may be used for accurate measurement of the LVOT cross-sectional area (CSA). Previous studies have focused on fusion from TEE for LVOT-CSA measurement and TTE for velocity time integrals (VTI) calculations.

Objectives: To assess aortic valve area (AVA) using parameters obtained exclusively from TEE as an alternative approach.

Methods: Thirty patients with equivocal AS based on TTE were evaluated using TEE for further assessment.

Results: The mean pressure gradient across the aortic valve (AV) was 38 ± 5.9 and 37.9 ± 7.6 mmHg in TTE and TEE, respectively, P = 0.42. LVOT-CSA was larger in TEE (3.6 ± 0.3 vs. 3.4 ± 0.3 cm², P = 0.049). VTI over the AVA was similar (98.54 ± 22.8 and 99.52 ± 24.52 cm in TTE and TEE, respectively, P = 0.608), while VTI across the LVOT was higher when measured by TTE (24.06 ± 5.8 vs. 22.03 ± 4.3 cm, P < 0.009). Using the CE, AVA was 0.82 ± 0.3 vs. 0.83 ± 0.17 cm² in TEE vs. TTE, respectively, P = 0.608. Definitive grading was achieved in all patients (26 patients defined with severe AS and 4 with moderate).

Conclusions: In equivocal cases of AS, full assessment using TEE may be a reliable modality for decision making.

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: Direct oral anticoagulants (DOACs) are the treatment of choice for patients with non-valvular atrial fibrillation; however, bleeding risk remains significant. We reported a single-center experience with 11 patients who presented with hemorrhagic cardiac tamponade while treated with DOACs.

Objectives: To evaluate the characteristics and clinical outcomes of patients under DOACs with cardiac tamponade.

Methods: We retrospectively identified 11 patients treated with DOACs admitted with pericardial tamponade in our cardiology unit during 2018–2021.

Results: The mean age was 84 ± 4 years; 7 males. Atrial fibrillation was the indication for anticoagulation in all cases. DOACs included apixaban (8 patients), dabigatran (2 patients), and rivaroxaban (1 patient). Urgent pericardiocentesis via a subxiphoid approach under echocardiography guidance was successfully performed in 10 patients. One patient was treated with urgent surgical drainage with a pericardial window. Reversal of anticoagulation using prothrombin complex concentrate and idarucizumab was given before the procedure to 6 patients treated with apixaban and one patient treated with dabigatran. One patient, initially treated with urgent pericardiocentesis, underwent pericardial window surgery due to re-accumulation of blood in the pericardium. The pericardial fluid analysis demonstrated hemopericardium. Cytology tests were negative for malignant cells in all cases. Discharge diagnoses regarding the cause of hemopericardium included pericarditis (3 patients) and idiopathic (8 patients). Medical therapy included non-steroidal anti-inflammatory drugs (1 patient), colchicine (3 patients), and steroids (3 patients). No patient died during hospitalization.

Conclusions: Hemorrhagic cardiac tamponade is a rare complication of DOACs. We found good short-term prognosis following pericardiocentesis.

Background: The neutrophil to lymphocyte ratio (NLR) has demonstrated prognostic value in various malignant conditions, including gastric adenocarcinoma. However, chemotherapy may affect NLR.

Objectives: To evaluate the prognostic value of NLR as an accessory decision-making tool in terms of operating patients after neoadjuvant chemotherapy in patients with resectable gastric cancer.

Methods: We collected oncologic, perioperative, and survival data of patients with gastric adenocarcinoma who underwent curative intent gastrectomy and D2 lymphadenectomy between 2009 and 2016. The NLR was calculated from preoperative laboratory tests and classified as high (> 4) and low (≤ 4). The t-test, chi-square, Kaplan-Meier analysis, and Cox multivariate regression models were used to assess associations of clinical, histologic, and hematological variables with survival.

Results: For 124 patients the median follow-up was 23 months (range 1–88). High NLR was associated with greater rate of local complication (r=0.268, P < 0.01). The rate of major complications (Clavien-Dindo ≥ 3) was higher in the high NLR group (28% vs. 9%, P = 0.022). Among the 53 patients who received neoadjuvant chemotherapy, those with low NLR had significantly improved disease-free survival (DFS) (49.7 vs. 27.7 months, P = 0.025). Low NLR was not significantly associated with overall survival (mean survival, 51.2 vs. 42.3 months, P = 0.19). Multivariate regression identified NLR group (P = 0.013), male gender (P = 0.04), and body mass index (P = 0.026) as independently associated with DFS.

Conclusions: Among gastric cancer patients planned for curative intent surgery who underwent neoadjuvant chemotherapy, NLR may have prognostic value, particularly regarding DFS and postoperative complications.

Global developmental delay (GDD), defined as a significant delay in two or more developmental domains (e.g., gross/fine motor, cognitive, speech/language, personal/social, activities of daily living), affects 1–3% of children. According to the Israeli Ministry of Health, thyroid function studies are not indicated in children with GDD unless there are systemic features suggestive of thyroid dysfunction (https://www.health.gov.il/hozer/mr36_2012.pdf). This approach also exists in other countries with newborn screening programs for congenital hypothyroidism.

We present the case of an infant with GDD, who despite normal newborn screening tests, underwent a repeated extended thyroid function analysis (including T₃ levels) leading to a diagnosis of Allan-Herndon-Dudley syndrome, a rare genetic neurodevelopmental syndrome.

Takotsubo syndrome (TTS) often develops following stressors such as cardiac surgery. It may be fatal in rare cases. Our 70-year-old female patient presented with a rare case of tricuspid valve papillary fibroelastoma, which was complicated by fatal TTS after successful resection. The patient had a right atrial mass that was investigated with computed tomography and transesophageal echocardiography (TTE). She was scheduled for surgery. Pathology findings were consistent with papillary fibroelastoma of the tricuspid valve. Three weeks after successful surgery, the patient was admitted due to cardiogenic shock with echocardiographic findings of apical ballooning and left ventricular outflow tract obstruction consistent with TTS. The patient died one hour after her admission despite optimal medical therapy.

Background: Diagnosing occult stress urinary incontinence (OSUI) prior to surgical intervention for pelvic organ prolapse (POP) repair may allow for adding an anti-incontinence procedure and thus prevent postoperative SUI.

Objectives: To compare preoperative detection rates for OSUI by either a multichannel urodynamic investigation or by a plain pelvic examination.

Methods: We retrospectively evaluated the medical charts of all women who underwent urodynamic investigation prior to surgical repair of advanced POP at our institution between 1 January 2006 and 31 December 2012.

Results: In total, 720 women underwent surgical POP repair during the study period, of whom 54 (7.5%) were diagnosed with OSUI preoperatively. Of these patients, 54 (100%) were detected by multichannel urodynamic investigation while only 27 (50%) were detected by a plain pelvic examination (P = 0.001). Bladder fullness during the pelvic examination was associated with higher detection rates for OSUI (P = 0.001). Women with OSUI who underwent concomitant tension-free vaginal tape and POP repair procedures did not develop de novo SUI or obstructive voiding symptoms (OVS) postoperatively.

Conclusions: Preoperative multichannel urodynamic investigation has significantly higher detection rates for OSUI than a plain pelvic examination. Utilizing this modality resulted in no cases of de novo SUI or OVS postoperatively.

Background: The chloride intracellular channel (CLIC) protein family consists of six members in humans. CLICs are unique due to their metamorphic property, displaying both soluble and integral membrane forms. The transmembrane conformation was shown to give rise to ion-channel activity in vitro. In recent years, CLICs were implicated in a growing number of physiological processes in various organ systems and associated with distinct disease states. Indeed, the founding member of the family, CLIC5, was shown to be involved in hereditary deafness and various types of cancer. Nevertheless, the natural interactants and endogenous ligands of CLIC5 have not been discovered yet.

Objectives: To find ligands that affect the biochemical properties and activity of CLIC5. We hypothesized that such ligands could serve as important tools for resolving the long-sought cellular roles of CLICs and may offer novel therapeutic avenues for CLIC-associated conditions.

Methods: Using molecular biology and biochemical methods, CLIC5 was overexpressed in Escherichia coli and purified. Next, a high-throughput differential scanning fluorimetry thermal shift assay (TSA) was established and the interaction of approximately 500 natural compounds was examined.

Results: The TSA-based screening approach developed here allows to evaluate the effect of approximately 100 compounds in parallel within approximately 1 hour. Our proof-of-concept screening yielded 11 potential hits, significantly affecting the thermal stability of CLIC5. By examining the dose-dependence of this effect, we identified a specific interaction of CLIC5 with curcumin.

Conclusions: Using the approach we developed, large libraries of small molecules can be screened efficiently to identify novel CLIC5 interactants. Considering the participation of CLIC5 in various physiological and pathological processes, uncovering ligands that inhibit or activate CLIC5 may provide tools to modulate its activity and possibly to ameliorate CLIC5-related pathologies in the future.

Hypereosinophilia is defined as the absolute eosinophilic count of above 1500 cells/µL in the peripheral blood on two separate tests taken during one month and/or the pathological confirmation of hypereosinophilia. There are many conditions that are associated with increased eosinophil counts including: parasitic infections, drug reactions, eosinophilic granulomatosis with polyangiitis, allergic reactions, drug reaction with eosinophilia and systemic symptoms (DRESS), primary immunodeficiencies (PID), eosinophilic gastrointestinal diseases (EGID), familial hypereosinophilia, and neoplasms [1]. Molecular classification may be an adjuvant in the classification of hypereosinophilia [2]. Our patient presented with hypereosinophilia as part of a paraneoplastic syndrome.

Candida species inhabit the gastrointestinal tract. Isolation of Candida from the respiratory tract has been found and reflects colonization, particularly among mechanically ventilated patients [1]. However, the existence of candida as a respiratory pathogen was previously doubted. Candida pneumonia is a rare and challenging-to-diagnose entity. We present a histopathologically confirmed case of necrotizing Candida pneumonia and lung abscess in a solid organ transplant recipient.

Background: Salmonella, Shigella, and Campylobacter are highly prevalent among children. Reports on risk factors of patients infected with all three pathogens, not simultaneously, are scarce.

Objectives: To identify risk factors for multiple infection with Salmonella, Shigella, and Campylobacter in the same child.

Methods: Using the Israel Sentinel Laboratory-Based Surveillance Network, we conducted a retrospective observational case-case–control study among children aged 0–9 years. A case was defined as a child infected with Salmonella, Shigella, and Campylobacter at different occasions between January 1999 and December 2020. A control was defined as a child infected with a single pathogen once, during the same period. Logistic regression models were applied to determine the association between multiple infections and demographic characteristics.

Results: We identified 109 cases (0.1%) infected with Salmonella, Shigella, and Campylobacter, and 86,511 controls (99.9%) infected with only one bacteria type. In a multivariable analysis, we showed that being Jewish (odds ratio [OR] 2.4, 95% confidence interval [95%CI] 1.3–4.4), having residency in Jerusalem (OR 3.2, 95%CI 1.3–7.7), or in the southern district (OR 3.7, 95%CI 1.5–8.8) were independent risk factors for multiple infection.

Conclusions: Although very rare, non-simultaneous infection with multiple bacteria does occur in Israel. National and local authorities should promote programs to encourage proper hygiene practices, which are culture-adjusted.