Israel Medical Association Journal

Fever of unknown origin (FUO) is defined as the repeated occurrence of elevated body temperature above 38.3°C (101°F) lasting for at least 3 weeks with no clear diagnosis despite a thorough investigation of more than one-week duration. FUO cases could be categorized into three major etiologies: infectious, neoplastic, and systemic inflammatory. Despite novel diagnostic modalities, clinicians still encounter a significant number of unresolved FUO cases, accounting for as many as 50% of cases [1]. Prolonged futile FUO investigations may be a source of frustration for many clinicians [2]. We described a unique cause for FUO that shares the complexity of the diagnostic workup and emphasizes the importance of ¹⁸F-fluorodeoxyglucose positron-emission tomography/computed tomography (PET/CT) modality in the process of investigating FUO.

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.

Cannabis and cannabinoids have been known for thousands of years for their promising potential as analgesics. Chronic pain is a common complaint among many patients with rheumatic conditions. These disorders have revisited the medical approach toward cannabis and its potential role in pain relief. In addition, in recent years, information has mounted about the immunomodulatory effects of cannabis. In this review we discuss findings on the benefits cannabis may have in rheumatic and autoimmune disorders.

Background: Toward the end of 2019, the coronavirus disease-2019 (COVID-19) pandemic began to create turmoil for global health organizations. The illness, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), spreads by droplets and fomites and can rapidly lead to life-threatening lung disease, especially for the old and those with health co-morbidities. Treating orthopedic patients, who presented with COVID-19 while avoiding nosocomial transmission, became of paramount importance.

Objectives: To present relevant methods for pandemic control and hospital accommodation with emphasis on orthopedic surgery.

Methods: We searched search PubMed and Google Scholar electronic databases using the following keywords: COVID-19, SARS-CoV-2, screening tools, personal protective equipment, and surgery triage.

Results: We included 25 records in our analysis. The recommendations from these records were divided into the following categories: COVID-19 disease, managing orthopedic surgery in the COVID-19 era, general institution precautions, triage of orthopedic surgeries, preoperative assessment, surgical room setting, personal protection equipment, anesthesia, orthopedic surgery technical precautions, and department stay and rehabilitation.

Conclusions: Special accommodations tailored for each medical facility, based on disease burden and available resources can improve patient and staff safety and reduce elective surgery cancellations. This article will assist orthopedic surgeons during the COVID-19 medical crisis, and possibly for future pandemics

Background: Systemic sclerosis (SSc) is a connective tissue disease that may affect the heart and the autonomic nervous system (ANS). There is little knowledge regarding the degree of ANS involvement in SSc patients with unknown cardiac disease.

Objectives: To evaluate cardiac and pupillary autonomic functions in patients before cardiac involvement has emerged.

Methods: The study comprised 19 patients with SSc and 29 healthy controls. Heart rate variability (HRV) analysis for time and frequency domains, as well as deep breathing test and Ewing maneuvers, were performed in all patients. Automated pupillometry for the evaluation of pupillary diameter and pupillary light reflex was completed in 8 SSc patients and 21 controls.

Results: Both groups had similar characteristics, except for medications that were more commonly or solely prescribed for SSc patients. Compared with control subjects, the SSc patients had significantly lower HRV parameters of NN50 (15.8 ± 24.4 vs. 33.9 ± 33.1, P = 0.03), pNN50 (4.9 ± 7.4% vs.10.8 ± 10.8%, P = 0.03), and triangular index (11.7 ± 3.4 vs. 15.7 ± 5.8, P = 0.02). Abnormal adaptive responses in heart rate changes were recorded during deep breathing tests and Ewing maneuvers. There was no significant difference in any of the pupillometric indices or other HRV parameters within groups.

Conclusions: SSc patients may manifest cardiac autonomic dysfunction, while their autonomic pupillary function is seemingly spared. The role of certain medications, the significance of differential organ involvement, as well as the prognostic value of our findings should be evaluated in future studies

Background: Recent data regarding polymicrobial bacteremia (PMB) are lacking.

Objectives: To characterize risk factors as well as clinical, microbiological, and prognostic patterns of patients with PMB in a modern hospital setting.

Methods: A single center retrospective study including all patients diagnosed with PMB during 2013 was conducted. PMB was defined as two or more organisms cultured from the blood of the same patient within 72 hours. Patients with monomicrobial infections served as controls.

Results: There were 135 episodes (2% of all bacteremia episodes) of true PMB among 123 patients during the study period. Recent invasive procedures (odds ratio [OR] 3.59, 95% confidence interval [95%CI] 1.41–9.12, P = 0.006) and foreign bodies (OR 1.88, 95%CI 1.06–3.33, P = 0.04) were risk factors for PMB when compared with 79 patients with monomicrobial bacteremia. Central-line-associated infections were the most common infection source among patients with PMB (n=34, 28%). Enterobacteriaceae were the most commonly implicated pathogen (n=95, 77%). Non-fermenting Gram-negative bacilli were significantly more common than previously reported (n=55, 45%). Although crude 30-day mortality was higher (48% vs. 33%) in PMB patients, adjusted mortality was comparable in the two groups.

Conclusions: PMB rate in our cohort was considerably lower than in previous reports. Central-line-associated infections were more common than classic PMB sources. Mortality remained high. Strategies for early identification and better care for these patients should be pursued.

Background: Klotho is a transmembrane protein that can be shed and can act as a circulating hormone in three forms: soluble klotho (KL1 + KL2), KL1, and KL2. Klotho was discovered as a gene implicated in aging through inhibition of the IGF-I pathway. Our laboratory discovered the role of klotho as a tumor suppressor in breast cancer and other malignancies. Furthermore, we showed that the KL1 domain mediates this activity. Altered cancer cell metabolism is a hallmark of cancer and our lab demonstrated various effects of klotho on breast cancer cell metabolism. Thus, klotho inhibited glycolysis and activated adenosine monophosphate activating kinase (AMPK), an energy sensor pathway. Moreover, inhibition of AMPK reduced the tumor suppressor activity of klotho.

Objectives: To assess the effect of KL1 on breast tumor cells metabolism, as KL1 possesses the tumor suppressor activity of klotho.

Methods: We used MCF-7 breast cancer cells treated with soluble or over-expressed KL1 and klotho. Glycolysis was assessed by measuring mRNA levels of key glycolytic enzymes using reverse transcription polymerase chain reaction and by measuring lactate and glucose levels in media. The AMPK pathway was studied by monitoring AMPK phosphorylation as well as its down-stream target, acetyl-CoA carboxylase, using western blotting. Wound healing assay was used to assess cell migration.

Results: KL1 treatment reduced glycolytic enzymes mRNA levels and the activity of hexokinase, similar to klotho treatment. Furthermore, KL1 reduced glucose uptake and decreased lactate production. KL1 elevated phosphorylated acetyl-CoA carboxylase and phosphorylatedAMPK levels. Inhibition AMPK (using a mutant AMPK activator) stopped KL1 from inhibiting cell migration, suggesting AMPK underlies klotho’s tumor suppressor activity.

Conclusions: Our data indicate KL1 as a regulator of metabolic activity in breast cancer and suggest that metabolic alterations underlie KL1 tumor suppressor activities. Furthermore, as KL1 and klotho share a similar effect on cell metabolism, our results further support the central role KL1 domain plays in klotho’s tumor suppressor activity.

Background: Access-site bleeding is a common complication of transfemoral transcatheter aortic valve implantation (TAVI). Percutaneous stent-graft implantation within the femoral artery may achieve hemostasis and avert the need for more invasive surgical vascular repair; however, failure to advance a guidewire antegradely via the injured vessel may preclude stent delivery. While retrograde stent-graft delivery from the distal vasculature may potentially enable percutaneous control of bleeding, this approach has not been reported.

Objectives: To assess the feasibility of a retrograde approach for stent-graft implantation in the treatment of access-site bleeding following transfemoral TAVI.

Methods: A prospective TAVI registry was analyzed. Of 349 patients who underwent TAVI, transfemoral access was used in 332 (95%). Access-site injury requiring stent-graft implantation occurred in 56 (17%). In four patients (7%), antegrade wiring across the site of vascular injury was not possible and a retrograde approach for stent delivery was used.

Results: Distal vascular access was achieved via the superficial femoral or profunda artery. Retrograde advancement of a polymer-coated 0.035” wire to the abdominal aorta, followed by stent-graft delivery to the common femoral artery, achieved hemostasis in all cases. During a median (interquartile range) follow-up period of 198 (618) days (range 46–2455) there were no deaths and no patient required additional vascular interventions.

Conclusions: A retrograde approach for stent-graft delivery is feasible and allows percutaneous treatment of a common femoral artery injury following TAVI in patients who are not suitable for the conventional antegrade approach.

Background: Contemporary data on clinical profiles and long-term outcomes of young adults with coronary artery disease (CAD) are limited.

Objectives: To determine the risk profile, presentation, and outcomes of young adults undergoing coronary angiography.

Methods: A retrospective analysis (2000–2017) of patients aged ≤ 35 years undergoing angiography for evaluation and/or treatment of CAD was conducted.

Results: Coronary angiography was performed in 108 patients (88% males): 67 acute coronary syndrome (ACS) and 41 non-ACS chest pain syndromes. Risk factors were similar: dyslipidemia (69%), positive family history (64%), smoking (61%), obesity (39%), hypertension (32%), and diabetes (22%). Eight of the ACS patients (12%) and 29 of the non-ACS (71%) had normal coronary arteries without subsequent cardiac events. Of the 71 with angiographic evidence of CAD, long-term outcomes (114 ± 60 months) were similar in ACS compared to non-ACS presentations: revascularization 41% vs. 58%, myocardial infarction 32% vs. 33%, and all-cause death 8.5% vs. 8.3%. Familial hypercholesterolemia (FH) was diagnosed in 25% of those with CAD, with higher rates of myocardial infarction (adjusted hazard ratio [HR] 2.62, 95% confidence interval [95%CI] 1.15–5.99) and revascularization (HR 4.30, 95%CI 2.01–9.18) during follow-up. Only 17% of patients with CAD attained a low-density lipoprotein cholesterol treatment goal < 70 mg/dl.

Conclusions: CAD in young adults is associated with marked burden of traditional risk factors and high rates of future adverse cardiac events, regardless of acuity of presentation, especially in patients with FH, emphasizing the importance of detecting cardiovascular risk factors and addressing atherosclerosis at young age.

Background: Supracondylar humerus fractures are the most common elbow fractures in the pediatric population.

Objectives: To evaluate the outcomes of French's corrective osteotomy for correction of post-traumatic cubitus varus deformity in children.

Method: We conducted a retrospective review of medical charts of all patients who had undergone French's corrective osteotomy in our institution from 1998 to 2012. We recorded range of motion, cosmetic deformity, carrying angle, lateral cortex prominence index, hyperextension, and lateral cortex step before and after the surgery.

Results: Seven patients were enrolled the study. Average follow-up time was 4.6 years (range 2–9 years). An average of 18.3º of limited flexion (range 5º–35º) compared to the healthy elbow was recorded in three patients. Lateral condylar prominence was recorded in one patient. The average preoperative carrying angle was -20.5º (range -15º–30º) and postoperative angle was 9.6º (range 7º–13º). In comparison, the average carrying angle in the healthy elbow was 8.5º (range 4º–13º). No lateral cortex prominence was recorded. An average of 27.5º (range 15º–35º) of hyperextension of the distal fragment was recorded immediately postoperatively in four patients; however, during postoperative follow-up, the hyperextension was corrected spontaneously in all patients.

Conclusions: As described by French, osteotomy has the ability to correct the varus deformity only in the coronal plane. However, our research supports the assumption that hyperextension in the sagittal plane might be corrected spontaneously.

Background: Acute appendicitis (AA) is one of the most common indications for emergency abdominal surgery.

Objective: To assess the diagnostic and prognostic value of serum bilirubin and liver enzyme levels in the management of acute appendicitis.

Methods: Consecutive emergency department patients referred for a surgical consult for suspected AA were prospectively enrolled in the study. Data regarding demographic, clinical and laboratory results were recorded. Receiver operating characteristic (ROC) curve was performed for all evaluated parameters. Clinical and laboratory markers were evaluated for diagnostic accuracy and correlation to the clinical severity, histology reports, and length of hospital stay.

Results: The study was comprised of 100 consecutive patients. ROC curve analysis revealed white blood cell count, absolute neutrophils count (ANC), C-reactive protein, total-bilirubin and direct-bilirubin levels as significant factors for diagnosis of AA. The combination of serum bilirubin levels, alanine transaminase levels, and ANC yielded the highest area under the curve (0.898, 95% confidence interval 0.835–0.962, P<0.001) with a diagnostic accuracy of 86%. In addition, total and direct bilirubin levels significantly correlated with the severity of appendicitis as described in the operative and pathology reports (P < 0.01). Total and direct bilirubin also significantly correlated with the length of hospital stay (P < 0.01).

Conclusions: Serum bilirubin levels, alone or combined with other markers, may be considered as a clinical marker for AA correlating with disease existence, severity, and length of hospital stay. These findings support the routine use of serum bilirubin levels in the workup of patients with suspected AA.

Dupuytren’s disease is a common benign fibromatosis of the palmar and digital fascia. The exact pathophysiology and epidemiology of this condition have not been entirely identified. Pathologic fibrous bands cause a flexion contracture of the metacarpal phalangeal joints and proximal interphalangeal joint. Treatment includes fasciectomy, needle fasciotomy, and enzymatic fasciectomy.