Israel Medical Association Journal

Background: In recent years, treatment for Achilles tendon rupture (ATR) went through radical changes: from the conservative non-weight bearing approach to a functional protocol. This functional protocol allows complete weight bearing after only 2 weeks by placing the foot in a plastic boot in tapered down equines and using interchangeable wedges under the heel. This change of approach has dramatically lowered the rate of re-rupture.

Objectives: To describe our preliminary results with this functional protocol and to assess outcome measures in the functional conservative treatment.

Methods: The study comprised 15 people who were evaluated clinically and by sonograph. We measured calf circumference, ankle joint range of motion (ROM), and single-leg heel-rise test (SLHRT). In addition, standard scoring methods (Achilles Tendon Rupture Score and Physical Activity Scale) were examined.

Results: In our cohort 14 people successfully gained SLHRT. The mean Achilles Tendon Rupture Score functional questionnaire and Physical Activity Scale physical activity questionnaire score was 85.6 of 100, and 4.7 of 6, respectively. There were no significant differences in ankle ROM compared to the uninjured limb. There was statistically significant reduction in the calf circumference and soleus muscle thickness sonographically.

Conclusions: It seems that the conservative functional treatment of ATR demonstrates good functional outcomes, with the patients returning to close to normal activity, although noted muscle wasting and weakness. This protocol presents a true alternative to surgery and should be considered for most non-insertional Achilles tendon tears

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.

Background: Heart failure with preserved ejection fraction (HFpEF) is a common clinical entity, with a mechanism that appears to involve endothelial dysfunction of the cardiac microcirculation. Endothelial progenitor cells (EPC) are bone marrow derived cells that are able to differentiate into functional endothelial cells and participate in endothelial surface repair.

Objectives: To compare the level and function of EPCs in patients with HFpEF compared with heart failure with reduced ejection fraction (HFrEF) and control subjects.

Methods: We enrolled 21 patients with HFpEF (LVEF ≥ 50%, age 74.5 ± 9.9 years, 43% men, 48% diabetes), 20 patients with HFrEF (LVEF < 40%, age 70 ± 11.5 years, 90% men, 60% diabetes), and 11 control subjects with cardiovascular risk factors (age 53.3 ± 6.1years, 90% men, 64% diabetes). Circulating EPC levels were evaluated by expression of vascular endothelial growth factor receptor-2 (VEGFR-2), CD34, and CD133 by flow-cytometry. EPCs colony forming units (CFUs) were quantified after 7 days in culture.

Results: The proportion of cells that co-expressed VEGFR-2 and CD34 or VEGFR-2 and CD133 was similar among the HFpEF and HFrEF groups, and significantly lower than in the control group. The number of EPC-CFUs was also similar among the two heart failure groups and significantly lower than the control group.

Conclusions: Patients with HFpEF, like HFrEF, have significant reduction in EPC level and function.

Background: Patients with type 2 diabetes mellitus (T2DM) have a high rate of cardiovascular disease (CVD). The Mediterranean diet is preferred for CVD prevention. Endothelial dysfunction is demonstrated early in T2DM.

Objectives: To study the effects of dietary intervention of T2DM patients without known CVD on endothelial function and vascular inflammation.

Methods: A prospective study enrolled 22 patients with T2DM. Patients were divided randomly into two groups: an intervention group with 12 patients (55 ± 7 years old, 6 women) and a control group with 10 patients (59 ± 10 years old, 5 women). Clinical evaluation included body mass index (BMI) and endothelial function measured by the flow mediated percent change (FMD%). Fasting blood was drawn on entry to the study and 3 months later, measuring C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), total cholesterol, triglycerides, and glycosylated hemoglobin (HbA1C%). The intervention was based on weekly telephone calls by a clinical dietitian for 3 months.

Results: In the intervention group CRP and ICAM-1 were reduced (from 4.2 ± 3.3 mg/dl to 0.4 ± 0.5 mg/dl, P = 0.01 and from 258.6 ± 98.3 ng/ml to 171.6 ± 47.7 ng/ml, P = 0.004). Endothelial function (FMD%) was improved (from 0.5 ± 8.0% to 9.5 ± 11.5%, P = 0.014). No change was observed in BMI, HbA1C%, total cholesterol, and triglycerides levels in either group.

Conclusions: Patients with T2DM on the Mediterranean diet who received a weekly telephone call for 3 months improved their endothelial function with reduction of markers of inflammation.

Background: Adnexal torsion in pregnancy is often associated with functional adnexal cysts, especially in pregnancies conceived by ovulation induction (OI) or in-vitro fertilization (IVF). During laparoscopy for adnexal de-torsion, drainage of the functional cysts can be attempted, although this procedure may cause bleeding.

Objectives: To investigate the characteristics of ovarian torsion in pregnancy associated with functional cysts and to compare the rate of torsion recurrence following de-torsion alone versus cyst drainage.

Methods: All cases of surgically diagnosed adnexal torsion occurring during pregnancy between January 2007 and April 2019 in our department were retrospectively analyzed. The cases of torsion associated with presumed functional ovarian cysts were selected. The rate of recurrent torsion during the same pregnancy was compared for de-torsion alone versus de-torsion and cyst aspiration.

Results: Of the 113 women who experienced adnexal torsion during pregnancy, 71 (67.0%) of torsion cases were caused by presumed functional ovarian cysts. Among women with torsion of functional ovarian cysts, the rate of torsion recurrence was significantly higher in patients who underwent de-torsion alone (n=28) compared to women who underwent aspiration and drainage of the ovarian cysts (n=43) (14.3% vs. 0, P = 0.021). There were no cases of intra- or post-operative bleeding in the study cohort.

Conclusions: Functional ovarian cysts are the most common adnexal pathology encountered in pregnant women with torsion. Intra-operative cyst aspiration and drainage may reduce the risk of recurrent torsion. Further multi-center studies are required to validate our data prospectively.

Background: The single-breath diffusing capacity of the lungs (DLCO_SB) test measures the extent to which carbon monoxide (CO) passes from the lung air sacs into the blood. The accessible alveolar volume (VA_SB) is measured by inert gas during a 10-second period. The single-breath transfer coefficient of the lung for carbon monoxide (KCO_SB) is the DLCO_SB divided by VA_SB. Cystic fibrosis (CF) disease comprises progressive airway obstruction with bronchiectasis and parenchyma fibrosis. Yet, the KCO_SB appears insignificant in the assessment of pulmonary function in CF.

Objectives: To challenge the precision of normal KCO_SB in CF.

Methods: The authors collected pulmonary function tests (PFT) data from 74 confirmed CF patients (mean age 26 ± 10 years) with various levels of pulmonary disease severity. Tests included spirometry, DLCO_BP, and body plethysmography (_BP). Anatomical dead space was calculated by deducting anatomical dead space from total lung capacity TLC(_BP) to establish alveolar volume (VA_BP) and to determine KCO_BP. We also included individual data of arterial pCO₂ blood-gas level.  

Results: KCO_SB values were normal or higher in most patients, regardless of patient FEV1 value (R² = 0.2204; P < 0.02). In contrast, the measurements of KCO_BP were low corresponding with low FEV1 values, and negatively correlated with the elevation of trapped air and pCO₂ levels (R² = 0.1383; P = 0.0133, P > 0.05, respectively).

Conclusions: The 10- second perfusion time of the inert gas during DLCO_SB represent the communicative alveolar volume in CF patients with advanced pulmonary disease. The findings justify the use of DLCO_SB with the deterioration of FEV1 and elevation of pCO₂ levels.

Background: Progress in the treatment of breast cancer has led to substantial improvement in survival, but at the cost of increased side effects, with cardiotoxicity being the most significant one. The commonly used definition is cancer therapeutics-related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction reduction of > 10%, to a value below 53%. Recent studies have implied that the incidence of CTRCD among patients with breast cancer is decreasing due to lower doses of anthracyclines and low association to trastuzumab and pertuzumab treatment.

Objectives: To evaluate the prevalence of CTRCD among patients with active breast cancer and to identify significant associates for its development.

Methods: Data were collected as part of the Israel Cardio-Oncology Registry, which enrolls all patients who are evaluated at the cardio-oncology clinic at our institution. Patients were divided to two groups: CTRCD and no-CTRCD.

Results: Among 103 consecutive patients, five (5%) developed CTRCD. There were no significant differences in the baseline cardiac risk factors between the groups. Significant correlations of CTRCD included treatment with trastuzumab (P = 0.001) or pertuzumab (P < 0.001), lower baseline global longitudinal strain (GLS) (P = 0.016), increased left ventricular end systolic diameter (P < 0.001), and lower e’ septal (P < 0.001).

Conclusions: CTRCD is an important concern among patients with active breast cancer, regardless of baseline risk factors, and is associated with trastuzumab and pertuzumab treatment. Early GLS evaluation may contribute to risk stratification and allow deployment of cardioprotective treatment

Background: Transanal minimally invasive surgery (TAMIS) is a single port access platform used for full thickness local excision of rectal lesions. It is an appealing alternative to a radical resection of rectum that often can cause a significant bowel dysfunction described as low anterior resection syndrome (LARS). LARS is evaluated using a validated score. Functional outcomes of patients undergoing TAMIS has not yet been evaluated using the LARS score.

Objectives: To evaluate long-term bowel function in patients who underwent TAMIS.

Methods: In this case series, all patients who underwent TAMIS in a single tertiary institute between 2011 and 2017 were retrospectively reviewed. We evaluated bowel function using the LARS score questionnaire through telephone interviews.

Results: The study consisted of 23 patients, average age of 67 ± 6.98 year; 72% were male. The median follow-up from the time of surgery was 5 years. Six patients (26.08%) had malignant type lesions. The average height of the lesion from the anal verge was 7.4 cm. The average size of the specimen was 4 cm. The total LARS score revealed that 17 patients (73.91%) had no definitive LAR syndrome following the surgery. Four patients (17.39%) fit the description of minor LARS and only two (8.69%) presented with major LARS.

Conclusions: TAMIS provides relatively good long-term functional outcomes in terms of bowel function. Further randomized studies with larger cohorts are still needed to better evaluate the outcomes.

Background: Heart failure (HF) patients with reduced ejection fraction (HFrEF) are frequently treated with sub-optimal doses of angiotensin converting enzyme-inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and beta blockers (BBs).

Objectives: To determine factors associated with attaining upper-range doses in patients with HFrEF.

Methods: We examined treatment in patients with left ventricular ejection fraction (LVEF) ≤ 40% in a community-based, dedicated heart-failure clinic. Upper-range doses were defined as ≥ 75% of target recommended doses by heart failure society guidelines.

Results: The majority of the 215 patients were men (82%); median age at presentation 73 years (interquartile range [IQR] 65–78) and LVEF of 30% (IQR 25–35%). Following the up-titration program, 41% and 35% of patients achieved upper-range doses of ACE-Is/ARBs and BBs, respectively. Higher body mass index (BMI) was the only parameter found to be associated with achieving upper-range doses of ACE-I/ARBs (odds ratio [OR] 1.13, 95% confidence interval [95%CI] 1.05–1.22, P = 0.001). More patients achieved this target as BMI increased, with a sharp decline in the highest obesity category (BMI ≥ 40 m²/kg). Attaining upper-range doses of BBs was associated with pre-existing diabetes mellitus (DM) (OR 2.6, 95%CI 1.34–5.19, P = 0.005); women were associated with attaining lower BBs doses (OR 0.34, 95%CI 0.13–0.90, P = 0.031).

Conclusions: Achieving upper-range doses of ACE-Is/ARBs and BBs in HFrEF outpatients in a treatment up-titration program were associated with greater BMI and DM, respectively. These findings may serve as benchmarks for up-titration programs.

Background: Cyclophosphamide treatment has been associated with ovarian function impairment. Co-treatment with gonadotropin-releasing hormone-analogue (GnRH-a) seems to be able to prevent this complication. However, even though data are available on neoplastic patients, limited data have been published on systemic lupus erythematosus (SLE) women cohorts

Objectives: To evaluate GnRH-a efficacy on ovarian function preservation in SLE women receiving cyclophosphamide treatment

Methods: The authors performed a retrospective study including SLE women requiring cyclophosphamide treatment and compared those treated with and without GnRH-a (case and controls, respectively). All patients were evaluated before cyclophosphamide treatment and every 3 months in the following years. Ovarian function was evaluated using hormonal profiles

Results: The study comprised 33 SLE cyclophosphamide-treated women: 18 co-treated with triptorelin and 15 controls. The mean follow-up was 8.1 ± 5.1 years (range 4–11). Premature ovarian failure (POF) prevalence was significantly lower in SLE women treated by cyclophosphamide plus triptorelin compared to controls (11.1% vs. 33.3%, P = 0.0002). The occurrence of POF was significantly associated with higher age at the time of cyclophosphamide treatment (P = 0.008). Only patients in the GnRH-a treated group had successful pregnancies

Conclusions: The study provides information about the efficacy of co-treatment with GnRH-a in SLE women receiving cyclophosphamide, as demonstrated by the lower POF incidence compared to untreated subjects, based on long-term follow-up. These results reinforce the use of GnRH-a for fertility preservation in premenopausal SLE patients treated by cyclophosphamide

Background: Cardiovascular disease (CVD) is more frequent in patients with systemic lupus erythematosus (SLE) compared with age- and sex-matched healthy subjects. SLE is an autoimmune disease that is more prevalent in women (9:1). Women tend to develop CVD in post-menopausal years; however, women with SLE may develop endothelial dysfunction and CVD at a younger age in the pre-menopausal years.

Objectives: To study the endothelial function of adult-onset SLE patients from the north of Israel (the Galilee region) and to determine whether modern management (including biological treatments) changes the risk of developing CVD.

Methods: Thirteen females with adult-onset SLE without renal involvement were recruited to this prospective study. Clinical parameters (age, height, body mass index [BMI]), laboratory parameters (C-reactive protein [CRP] and hemoglobin level), and vascular responsiveness (flow mediated diameter percent change [FMD%]) were evaluated and compared to 11 age-matched healthy females. Student's t-test was used to find differences between the two groups.

Results: No difference was observed in adult-onset SLE female patients and their age- and sex-matched controls with regard to age (42.1 ± 11.8 years vs. 36.6 ± 10.8 years, P = NS), BMI (25 ± 1.8 kg/m² vs. 25 ± 2.5 kg/m², P = NS), and hemoglobin level (11.9 ± 0.9 gr% vs. 12.7 ± 1.2 gr%, P = NS). However, a significant difference was found in CRP (2.57 ± 2.2 mg vs. 0.60 ± 0.37 mg, P = 0.001), vascular responsiveness (0.94 ± 6.6 FMD% vs. 9.2 ± 8.1 FMD%, P = 0.012), and height (165.7 ± 4.5 cm vs. 171.6 ± 5.8 cm, P = 0.009).

Conclusions: Adult-onset SLE females had impaired endothelial function even though they were treated by modern protocols.

Background: Autoimmune hepatitis (AIH) may be associated with other autoimmune diseases. Autoantibodies are common in AIH suggesting their potential role in the pathogenesis of the disease. Among these autoantibodies, thyroid autoantibodies have been reported in patients with chronic hepatitis, with greater prevalence in patients with chronic hepatitis C infection.

Objectives: To assess the prevalence of thyroid dysfunction among patients with AIH.

Methods: In this case-control, retrospective study, we examined patients diagnosed with AIH according to both the original and revised international AIH group scoring systems. Patients with other hepatic pathologies were excluded AIH was evaluated as an independent risk factor for thyroid disease by a logistic regression model. Univariate and multivariate regression analyses were conducted using hypothyroidism and hyperthyroidism as the dependent variables.

Results: Our cohort comprised 163 patients diagnosed with AIH and 1104 healthy age- and gender-matched controls. Hypothyroidism was more prevalent among those with AIH compared to controls (17.7% vs. 5%, respectively, 95% confidence interval [95%CI] 1.68–2.48, P <  0.001). Hyperthyroidism was more prevalent in AIH patients compared to controls (odds ratio 3.2% and 1.2%, respectively, 95%CI 1.68–2.47, P <  0.001). Using a multivariate logistic analysis, we found an independent association between AIH and hypothyroidism but not with hyperthyroidism.

Conclusions: Thyroid dysfunction is more prevalent in patients with AIH. Whether thyroid dysfunction is the cause or a risk factor for AIH, or vice versa, is still unclear. Screening for thyroid dysfunction is warranted after AIH is diagnosed.