Israel Medical Association Journal

Background: Remnant cholesterol (RC), the cholesterol content of triglyceride-rich lipoproteins, is an emerging residual risk factor for atherosclerotic cardiovascular disease. Data on the prognostic significance after an ischemic stroke are limited.

Objectives: To investigate the association between RC and risk for cardiac events following hospitalization for an ischemic stroke.

Methods: Data were collected for 5697 patients (39.5% women) affiliated with Clalit Health Services and hospitalized with an acute ischemic stroke. Adjusted Cox-regression models were used to estimate the association between RC percentiles, calculated using a routine post-discharge lipid profile, and risk for future myocardial infarction (MI) or coronary revascularization.

Results: Mean age was 69 ± 10 years; 78% were treated by lipid-lowering therapies. During median follow-up of 22 months, a MI or coronary revascularization event occurred in 243 patients. After multivariable adjustment including lipid-lowering therapies and non-HDL-C, RC was associated with higher MI or revascularization risk: hazard ratio (95% confidence interval): 1.42 (1.10–1.85), 1.50 (1.11–2.02), 1.62 (1.09–2.40), and 1.93 (1.22–3.06), in those with RC percentiles ≥ 50th (23.3 mg/dl), ≥ 75th (31.8 mg/dl), ≥ 90th (42.1 mg/dl), and ≥ 95th (49.1 mg/dl), compared to < 50th percentile. When RC and non-HDL-C levels were discordant, the level of RC better reflected higher risk for adverse cardiac events.

Conclusions: Elevated RC following acute ischemic stroke is a risk factor for MI or coronary revascularization, independent of lipid-lowering therapies and non-HDL-C and may serve as a residual cardiovascular risk marker and potential treatment target in patients with ischemic stroke.

Background: Immunoglobulin 4 (IgG4) is the least abundant immunoglobulin in the sera of healthy individuals; however, its levels can vary in different diseases such as IgG4-related disease (high) or Sjögren's syndrome (low). While previous studies have suggested the importance of IgG4 in autoimmune diseases, the clinical and biological significance of high or low levels remains unclear.

Objectives: To investigate the association between IgG4 antibody levels and systemic sclerosis (SSc), as well as the clinical features of the disease.

Methods: We measured IgG4 levels in the sera of 74 SSc patients from the years 2000 to 2019 and compared them to IgG4 levels in 80 healthy donors from the Israeli national blood bank. We performed correlation analyses between IgG4 levels and various factors, including age, sex, disease subtype, disease duration, organs involved, and medications taken by the patients.

Results: Our findings revealed significantly lower IgG4 levels in SSc patients compared to healthy participants. SSc patients receiving steroid treatment exhibited prominently lower IgG4 levels. In addition, SSc patients with Raynaud's phenomenon tended to have lower IgG4 levels compared to those without Raynaud's phenomenon.

Conclusions: Our study demonstrates that IgG4 levels are lower in SSc patients. Further research is needed to elucidate whether this observation contributes to the etiology of the disease or if it represents a common manifestation among other autoimmune diseases.

Despite the application of recommended guideline-driven therapies and optimal medical interventions, individuals with established cardiovascular disease remain susceptible to additional cardiovascular incidents, a phenomenon referred to as residual risk. Analyses of clinical trial data reveal significant residual cardiovascular risk in all treated patients, even in the setting of optimal LDL-C reduction, thus enforcing the need to revise the algorithms beyond focusing on LDL-C levels. We present a case that highlights the problem of residual risk upon well controlled LDL-C levels and provide insights for additional measures for residual risk reduction.

Background: Coronary heart disease (CHD) patients are considered high cardiovascular risks. Guidelines recommend low-density lipoprotein cholesterol (LDL-C) target levels below 55 mg/dl with > 50% reduction from baselines. These levels can be reached by a combination of statins, ezetimibe, and anti-protein convertase subtilisin/kexin type 9 (anti-PCSK9) agents. Our clinical impression was that CHD patients do not reach LDL-C target levels, despite the wide availability.

Objectives: To evaluate whether hospitalization would result in changes in lipid lowering regimens and short-term compliance.

Methods: We conducted a retrospective cohort study using data of CHD patients who were admitted to internal medicine wards at Clalit Health Services medical centers because of anginal syndrome during 2020–2022. The data were evaluated for demographic and clinical characteristics; LDL-C level at admission, 6 months previously, and 3 months and 6–9 months after discharge; rates of reaching LDL-C target levels; and lipid lowering treatment at admission, discharge, and 6–9 months after.

Results: The cohort included 10,540 patients. One-third and three-quarters did not have lipids level measurements up to 6 months before and during hospitalization, respectively. Only one-fifth of the patients reached LDL-C values before and during admission (median LDL-C 72 mg/dl; range 53–101). Approximately half were treated with high-dose potent statins. Only 10% were treated with ezetimibe. Hospitalization did not have a clinically significant effect on short-term lipid lowering treatment or LDL-C levels.

Conclusions: Gaps were noted between guidelines and clinical practice for reaching LDL-C target levels. Further education and strict policy are needed.

Fibromyalgia is a pain-related condition common in women and is present in about 5% of the population [1]. Its treatment involves physical exercise, psychotherapy (mainly behavioral–cognitive therapy), and antidepressant/anticonvulsant use as class IA evidence treatments [1]. Although in several cases this treatment fails or loses effectiveness over time, necessitating novel therapeutical agents.

Naltrexone is an opioid antagonist drug used for opioid addiction therapy. It also has anti-inflammatory and analgesic properties when used in low dosages [2]. Our group recently wrote a systematic review of low-dose naltrexone (LDN) for treating rheumatic diseases, including fibromyalgia [3]. In all seven published articles on LDN for fibromyalgia, a benefit was observed in pain reduction and improvements in fibromyalgia questionnaires [3]. To the best of our knowledge, no study using LDN as the first option of treatment has been conducted. Therefore, in this study we aimed to evaluate the effects of LDN as the first line of therapy in patients with fibromyalgia.

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.

Background: The evaluation of syncope in emergency departments (EDs) and during hospitalization can be ineffective. The European Society of Cardiology (ESC) guidelines were established to perform the evaluation based on risk stratification.

Objectives: To investigate whether the initial screening of syncope adheres to the recent ESC guidelines.

Methods: Patients with syncope who were evaluated in our ED were included in the study and retrospectively classified based on whether they were treated according to ESC guidelines. Patients were divided into two groups according to the ESC guideline risk profile: high risk or low risk.

Results: The study included 114 patients (age 50.6 ± 21.9 years, 43% females); 74 (64.9%) had neurally mediated syncope, 11 (9.65%) had cardiac syncope, and 29 (25.45%) had an unknown cause. The low-risk group included 70 patients (61.4%), and the high-risk group included 44 (38.6%). Only 48 patients (42.1%) were evaluated according to the ESC guidelines. In fact, 22 (36.7%) of 60 hospitalizations and 41 (53.2%) of 77 head computed tomography (CT) scans were not mandatory according to guidelines. The rate of unnecessary CT scans (67.3% vs. 28.6%, respectively, P = 0.001) and unnecessary hospitalization (66.7% vs. 6.7%, respectively, P < 0.02) were higher among low-risk patients than high-risk patients. Overall, a higher percentage of high-risk patients were treated according to guidelines compared to low-risk patients (68.2% vs. 25.7% respectively, P < 0.0001).

Conclusions: Most syncope patients, particularly those with a low-risk profile, were not evaluated in accordance with the ESC guidelines.

Background: Traditionally, transesophageal echocardiography (TEE) has been performed under moderate sedation and local pharyngeal anesthesia. Respiratory complications during the TEE can occur.

Objectives: To test the effectiveness of low-dose midazolam combined with verbal sedation during TEE.

Methods: The study comprised 157 consecutive patients who underwent TEE under mild conscious sedation. All patients received local pharyngeal anesthesia and low doses of midazolam combined with verbal sedation. The course of TEE and clinical characteristics of the patients were analyzed.

Results: The mean age was 64 ± 15.3 years, 96 males (61%). In 6% of the patients, low dose midazolam in combination with verbal sedation was insufficient and propofol was administrated. In women under 65 years of age with normal renal function, there was a 40% risk of low-dose midazolam being ineffective (P = 0.0018).

Conclusions: In most patients, TEE can be conducted easily using low-dose midazolam combined with verbal sedation. Some patients need deeper sedation with anesthetic agents like propofol. These patients tended to be younger, in good general health, and more often female.

Background: Bicalutamide monotherapy (BMT) is an option for androgen deprivation therapy (ADT) in patients with low- and intermediate-risk prostate cancer (LIR-PC). Painful gynecomastia (PG) is a common side effect of BMT. Few therapeutic options are available for preventing BMT-induced PG.

Objectives: To assess the efficacy and side effects of single fraction (SF) prophylactic breast irradiation (PBI) to prevent painful gynecomastia (PG) in patients LIR-PC treated with BMT.

Methods: We reviewed the results of bilateral PBI in a prospective cohort of LIR-PC patients who received 150 mg bicalutamide daily as a first-line treatment for at least 12 months. A single fraction of 8 Gy was administered to both breasts by a stationary field of 10 × 10 cm, using 10–15 MeV electron beam. PBI was commenced on the same day as BMT, but prior to the first dose of bicalutamide. A radiotherapy treatment plan was designed to cover breast tissue by the 90% isodose line. Subsequent monthly physical examinations were scheduled for all patients during the first year of BMT to evaluate any PG symptoms.

Results: Seventy-six patients received BMT and PBI, 80% (61/76) showed no signs of PG; 20% (15/76) experienced mild gynecomastia. The main adverse effect of PBI was grade 1 radiation dermatitis.

Conclusions: PBI using a SF of 8 Gy is an effective, safe, and low-cost strategy for the prevention of BMT-induced PG in LIR-PC patients.

Background: Low back pain has been the leading cause for disability worldwide for several decades, and clinical guidelines for its management clearly emphasize a multifactorial approach. Yet, current guidelines are still not well implemented by clinicians.

Objectives: To explore the attitudes of family medicine residents regarding low back pain and to determine whether they positively correlate with their treatment approaches. To test if these attitudes can be affected by the Enhanced Transtheoretical Model Intervention (ETMI), a guideline-based workshop.

Methods: Participants completed an online questionnaire regarding their attitudes toward low back pain and clinical habits, after which they attended an online ETMI educational workshop. One month later all participants were asked to complete the questionnaire a second time. Statistical analysis was conducted to explore the attitudes of the residents and clinical approaches, as well as any associations between them, as well as possible differences pre- and post-intervention.

Results: The participants exhibited highly psychologically oriented attitudes. Correlations between the attitudes and treatment did not show consistent coherency. Results regarding the participants clinical approaches were revealed to have two distinct and opposed inclinations: biomedically and biopsychosocially. Last, results for the re-activation subscale were significantly higher post-intervention.

Conclusions: Family medicine residents seem to be highly psychologically oriented regarding low back pain; however, they do not necessarily treat their patients accordingly. Their clinical choices seem to follow two different approaches: guideline-consistent and non-guideline-consistent. An ETMI guideline-based workshop may sway their attitudes toward re-activation of patients. Further research is needed to determine whether similar results would arise in larger physician populations.

Background: Self-management, an active life routine, and adherence to physical activity are effective in the management of low back pain (LBP). However, delivering effective education and reassurance to patients can be a difficult for practitioners. The enhanced transtheoretical model intervention (ETMI) has shown to be successful and cost effective. The intervention focuses on educating practitioners to reassure patients, empower them to increase physical activity, and improve their self-efficacy.

Objectives: To assess whether ETMI can be implemented among primary care practitioners and to examine whether it reduces pain, disability, and fear avoidance as well as decreasing healthcare utilization. This protocol outlines the methodology for the implementation of ETMI through a hybrid implementation–effectiveness design.

Methods: Two qualitative and mixed-method studies provided a basis for an implementation prospective cohort study. Discussions are followed by a prospective cohort study with pre-and post-intervention measures as well as descriptions retrieving economic and therapeutic outcome data from the Maccabi Healthcare Services (MHS) databases. In addition, a fourth qualitative study was conducted at the midpoint of the implementation to evaluate the process by measuring the perceptions and practice of practitioners. The intervention group was 220 primary care practitioners and their patients (~n=10,000) from the central district of MHS. The control data was provided by other care districts with similar socioeconomic makeup (~n=40,000).

Conclusions: We evaluated the process and outcomes of the implementation of ETMI. We investigated the relationship between the care received (ETMI against treatment as usual) and healthcare utilization, costs, and patient-clinical outcomes.

Too much healthcare is prevalent, wasteful, and harmful. It consists of two separate phenomena: overdiagnosis and overuse. Overdiagnosis is the labeling of a person with a disease or abnormal condition that would not have caused the person harm if left undiscovered. Individuals derive no clinical benefit from overdiagnosis, although they may experience physical, psychological, or financial harm. It has been found that 15–30%, 20–50%, 0–67%, and 50–90% of people with screen detected breast, prostate, lung, and thyroid cancer, respectively, are overdiagnosed. Since many screening tests have trade-off between benefit and harm, a shared decision-making approach is essential. Incidental findings are very common and may also cause overdiagnosis. Overdiagnosis is recognizable in populations and not at the individual level. However, overuse is recognizable at the level of the individual practitioner. Choosing Wisely, an intervention directed at reducing low value care, now faces the challenge of developing interventions that go beyond recommendations. While some of the drivers of overdiagnosis and overuse are similar, different and parallel strategies are needed in order to reduce them. This is one of the major challenges to our health care system.

Background: The CHA₂DS₂-VASc score has been shown to predict systemic thromboembolism and mortality in certain groups in sinus rhythm (SR), similar to its predictive value with atrial fibrillation (AF).

Objectives: To compare factors of inflammation, thrombosis, platelet reactivity, and turnover in patients with high versus low CHA₂DS₂-VASc score in SR.

Methods: We enrolled consecutive patients in SR and no history of AF. Blood samples were collected for neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), immature platelet fraction (IPF%) and count (IPC), CD40 ligand, soluble P-selectin (sP-selectin) and E-selectin. IPF was measured by autoanalyzer and the other factors by ELISA.

Results: The study comprised 108 patients (age 58 ± 18 years, 63 women (58%), 28 (26%) with diabetes), In addition, 52 had high CHA₂DS₂-VASc score (³ 2 for male and ³ 3 for female) and 56 had low score. Patients with low scores were younger, with fewer co-morbidities, and smaller left atrial size. sP-selectin was higher in the high CHA₂DS₂-VASc group (45, interquartile ratio [IQR] 36–49) vs. 37 (IQR 28–46) ng/ml, P = 0.041]. Inflammatory markers were also elevated, CRP 3.1 mg/L (IQR 1.7–9.3) vs. 1.6 (IQR 0.78–5.4), P < 0.001; NLR 2.7 (IQR 2.1–3.8) vs. 2.1 (IQR 1.6–2.5), P = 0.001, respectively. There was no difference in E-selectin, CD40 ligand, IPC, or IPF% between the groups.

Conclusions: Patients in SR with high CHA₂DS₂-VASc score have higher inflammatory markers and sP-selectin. These findings may explain the higher rate of adverse cardiovascular events associated with elevated CHA₂DS₂-VASc score.

Background: Medical imaging and the resultant ionizing radiation exposure is a public concern due to the possible risk of cancer induction.

Objectives: To assess the accuracy of ultra-low-dose (ULD) chest computed tomography (CT) with denoising versus normal dose (ND) chest CT using the Lung CT Screening Reporting and Data System (Lung-RADS).

Methods: This prospective single-arm study comprised 52 patients who underwent both ND and ULD scans. Subsequently AI-based denoising methods were applied to produce a denoised ULD scan. Two chest radiologists independently and blindly assessed all scans. Each scan was assigned a Lung-RADS score and grouped as 1 + 2 and 3 + 4.

Results: The study included 30 men (58%) and 22 women (42%); mean age 69.9 ± 9 years (range 54–88). ULD scan radiation exposure was comparable on average to 3.6–4.8% of the radiation depending on patient BMI. Denoising increased signal-to-noise ratio by 27.7%. We found substantial inter-observer agreement in all scans for Lung-RADS grouping. Denoised scans performed better than ULD scans when negative likelihood ratio (LR-) was calculated (0.04–-0.08 vs. 0.08–0.12). Other than radiation changes, diameter measurement differences and part-solid nodules misclassification as a ground-glass nodule caused most Lung-RADS miscategorization.

Conclusions: When assessing asymptomatic patients for pulmonary nodules, finding a negative screen using ULD CT with denoising makes it highly unlikely for a patient to have a pulmonary nodule that requires aggressive investigation. Future studies of this technique should include larger cohorts and be considered for lung cancer screening as radiation exposure is radically reduced.