[RAMBAM - WHERE MEDICINE, TECHNOLOGY AND HUMANITY INTERTWINE].

INTRODUCTION: In this issue, we present a series of articles written by Rambam's physicians, which reflect the scope of research that takes place in the hospital. This incorporates physicians, nurses and related professions, and progress in health care attained through research and technology-based medicine. A central part of our values is a combination of medicine, technology and humanity. Thanks to our unique location in close proximity to the Technion's Baruch and Ruth Rappaport Faculty of Medicine, our commitment to the combination of research and medicine has a unique impact. We invest in the development and promotion of the physician-researcher and the allied health professions involved in the research. We provide a range of research grants throughout the researchers' careers. The "Futures" grant is for a young doctor who wants to be exposed to basic or applied research under the guidance of a senior scientist. The "Ofakim" grant is intended for the senior physician in his initial steps, who is interested in establishing research activity. The "Nitzotz" grant is intended for an entrepreneur who has an idea for a product and wants to build a prototype, as a first step towards establishing a medical technology company. The "Maof" grant is intended for the nurse-investigator, and there are additional grants for other disciplines. In addition, there is a variety of national and international sources to fund research on a competitive basis in all fields, and we encourage our teams to turn to these sources. Cooperation with our neighboring universities, the Technion and the University of Haifa, with the industry around us and with other research and educational institutions, is of paramount importance for the continued development of the basic, applied and clinical research culture on our campus. We recently published an article describing the reasons why Israel has become a medical start-up country in many fields, and one of the leading reasons is the combination of clinical medicine, research and industry. The papers presented in this issue reflect our wide interest in the entire scope of medical professions. It spans internal medicine, surgery, nephrology, cardiology and cardiac surgery, genetics, organ transplantation and other topics. I wish you an interesting and joyful reading of this special issue.

Moral dilemmas faced by hospitals in time of war: the Rambam Medical Center during the second Lebanon war.

Rambam Medical Center, the only tertiary care center and largest hospital in northern Israel, was subjected to continuous rocket attacks in 2006. This extreme situation posed serious and unprecedented ethical dilemmas to the hospital management. An ambiguous situation arose that required routine patient care in a tertiary modern hospital together with implementation of emergency measures while under direct fire. The physicians responsible for hospital management at that time share some of the moral dilemmas faced, the policy they chose to follow, and offer a retrospective critical reflection in this paper. The hospital's first priority was defined as delivery of emergency surgical and medical services to the wounded from the battlefields and home front, while concomitantly providing the civilian population with all elective medical and surgical services. The need for acute medical service was even more apparent as the situation of conflict led to closure of many ambulatory clinics, while urgent or planned medical care such as open heart surgery and chemotherapy continued. The hospital management took actions to minimize risks to patients, staff, and visitors during the ongoing attacks. Wards were relocated to unused underground spaces and corridors. However due to the shortage of shielded spaces, not all wards and patients could be relocated to safer areas. Modern warfare will most likely continue to involve civilian populations and institutes, blurring the division between peaceful high-tech medicine and the rough battlefront. Hospitals in high war-risk areas must be prepared to function and deliver treatment while under fire or facing similar threats.

Performance of a novel artificial intelligence software developed to derive coronary fractional flow reserve values from diagnostic angiograms.

BACKGROUND: Although invasive measurement of fractional flow reserve (FFR) is recommended to guide revascularization, its routine use is underutilized. Recently, a novel non-invasive software that can instantaneously produce FFR values from the diagnostic angiograms, derived completely from artificial intelligence (AI) algorithms has been developed. We aim to assess the accuracy and diagnostic performance of AI-FFR in a real-world retrospective study. METHODS: Retrospective, three-center study comparing AI-FFR values with invasive pressure wire-derived FFR obtained in patients undergoing routine diagnostic angiography. The accuracy, sensitivity, and specificity of AI-FFR were analyzed. RESULTS: A total of 304 vessels from 297 patients were included. Mean invasive FFR was 0.86 vs. 0.85 AI-FFR (mean difference: -0.005, P  = 0.159). The diagnostic performance of AI-FFR demonstrated sensitivity of 91%, specificity 95%, positive predictive value 83% and negative predictive value 97%. Overall accuracy was 94% and the area under curve was 0.93 (95% CI 0.88-0.97). 105 lesions fell around the cutoff value (FFR = 0.75-0.85); in this sub-group, AI-FFR demonstrated sensitivity of 95%, and specificity 94%, with an AUC of 0.94 (95% CI 88.2-98.0). AI-FFR calculation time was 37.5 ±â€…7.4 s for each angiographic video. In 89% of cases, the software located the target lesion and in 11%, the operator manually marked the target lesion. CONCLUSION: AI-FFR calculated by an AI-based, angio-derived method, demonstrated excellent diagnostic performance against invasive FFR. AI-FFR calculation was fast with high reproducibility.

Latest Developments in Robotic Percutaneous Coronary Interventions.

Since the first robotic-assisted percutaneous coronary intervention procedure (R-PCI) was performed in 2004, there has been a steady evolution in robotic technology, combined with a growth in the number of robotic installations worldwide and operator experience. This review summarises the latest developments in R-PCI with a focus on developments in robotic technology, procedural complexity, tele-stenting and training methods, which have all contributed to the global expansion in R-PCI.

Door to balloon time in primary percutaneous coronary intervention in ST elevation myocardial infarction: every minute counts.

OBJECTIVES: This study examines relationships between door to balloon (D2B) time and subsequent admissions due to heart failure (HF), acute coronary syndrome (ACS), and mortality for up to 1 year. BACKGROUND: Current guidelines set 90-min for D2B time for primary percutaneous coronary intervention (PPCI) as a goal, which has been shown to reduce mortality and adverse events. METHODS: Using the MDclone ADAMS system integrated with our electronic medical records, we conducted retrospective analysis of all patients admitted due to ST-elevation myocardial infarction from home, without any history of HF or coronary disease, and who underwent PPCI during 2013-2019. Data on D2B time, baseline clinical and demographic characteristics, and outcomes of HF, ACS and mortality were collected. Adjusted HR for each of the outcomes was calculated by multivariate Cox model. RESULTS: A total of 826 patients were included in the final analysis. D2B had no significant effect on incidence of heart failure admissions for up to 1-year follow-up. D2B had a significant effect on mortality at 180 days, showing a 30% increase for each 30-min increase (HR 1.308; CI, 1.046-1.635) as for ACS at 90 days (HR 1.307; 1.025-1.638). The 30-min D2B cutoff showed a significant increase in ACS recurrence throughout the follow-up period at 90 days (HR 2.871, 1.239-6.648), 180 days (HR 2.607, 1.255-5.413), and 1 year (HR 1.886, 1.073-3.317). CONCLUSIONS: Patients with shorter D2B times had significantly reduced mortality and recurrence of ACS, with no effect on heart failure admission incidence.

Integrated SPECT/CT for assessment of haemodynamically significant coronary artery lesions in patients with acute coronary syndrome.

PURPOSE: Early risk stratification in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) is important since the benefit from more aggressive and costly treatment strategies is proportional to the risk of adverse clinical events. In the present study we assessed whether hybrid single photon emission computed tomography (SPECT)/coronary computed tomography angiography (CCTA) technology could be an appropriate tool in stratifying patients with NSTE-ACS. METHODS: SPECT/CCTA was performed in 90 consecutive patients with NSTE-ACS. The Thrombolysis in Myocardial Infarction risk score (TIMI-RS) was used to classify patients as low- or high-risk. Imaging was performed using SPECT/CCTA to identify haemodynamically significant lesions defined as >50% stenosis on CCTA with a reversible perfusion defect on SPECT in the corresponding territory. RESULTS: CCTA demonstrated at least one lesion with >50% stenosis in 35 of 40 high-risk patients (87%) as compared to 14 of 50 low-risk patients (35%; TIMI-RS<3; p<.0001). Of the 40 high-risk and 50 (16%) low-risk TIMI-RS patients, 16 (40%) and 8 (16%), respectively, had haemodynamically significant lesions (p=0.01). Patients defined as high-risk by a high TIMI-RS, a positive CCTA scan or both (n=45) resulted in a sensitivity of 95%, specificity of 49%, PPV of 35% and NPV of 97% for having haemodynamically significant coronary lesions. Those with normal perfusion were spared revascularization procedures, regardless of their TIMI-RS. CONCLUSION: Noninvasive assessment of coronary artery disease by SPECT/CCTA may play an important role in risk stratification of patients with NSTE-ACS by better identifying the subgroup requiring intervention.

Robotics, imaging, and artificial intelligence in the catheterisation laboratory.

The catheterisation laboratory today combines diagnosis and therapeutics, through various imaging modalities and a prolific list of interventional tools, led by balloons and stents. In this review, we focus primarily on advances in image-based coronary interventions. The X-ray images that are the primary modality for diagnosis and interventions are combined with novel tools for visualisation and display, including multi-imaging co-registration modalities with three- and four-dimensional presentations. Interpretation of the physiologic significance of coronary stenosis based on prior angiographic images is being explored and implemented. Major efforts to reduce X-ray exposure to the staff and the patients, using computer-based algorithms for image processing, and novel methods to limit the radiation spread are being explored. The use of artificial intelligence (AI) and machine learning for better patient care requires attention to universal methods for sharing and combining large data sets and for allowing interpretation and analysis of large cohorts of patients. Barriers to data sharing using integrated and universal protocols should be overcome to allow these methods to become widely applicable. Robotic catheterisation takes the physician away from the ionising radiation spot, enables coronary angioplasty and stenting without compromising safety, and may allow increased precision. Remote coronary procedures over the internet, that have been explored in virtual and animal studies and already applied to patients in a small pilot study, open possibilities for sharing experience across the world without travelling. Application of those technologies to neurovascular, and particularly stroke interventions, may be very timely in view of the need for expert neuro-interventionalists located mostly in central areas.

Real case virtual reality training prior to carotid artery stenting.

BACKGROUND: The majority of procedural training especially in interventional cardiology, still occurs on patients with direct mentoring by experienced physicians during an actual clinical procedure. In recent years there is an increase use of simulators especially for carotid artery stenting. However, most simulators use "generic" predefined cases. METHODS AND RESULT: We report here a simulation done on data of a real patient prior to intervention. The patient's specific carotid anatomy was modeled using CTA on an endovascular simulator. Pre-procedure patient-specific case rehearsal accurately predicted procedure experience. CONCLUSIONS: A case rehearsal prior to an intervention may be useful in the planning and execution of carotid artery stenting. The use of patient specific simulation helps with planning of procedure and device selection, and may lead to use of less contrast and radiation, and shorter procedure duration. These may benefit the patient with increased success and lower complication rates.

Israeli underground hospital conversion for treating COVID-19 patients.

OBJECTIVE: This paper describes how a large academic medical center solved the challenges of war preparedness and subsequently adapted them for the COVID-19 pandemic. SETTING: A 1,000-bed academic medical center in Northern Israel has faced two extreme challenges since 2006: operating under missile attack during the 2006 Second Lebanon War, and rapid establishment of a scalable infrastructure for COVID-19 patients. The first challenge led to construction of a dual-use facility: a parking lot during peacetime, and a fully functioning fortified underground emergency hospital (FUEH) in times of emergency. Several drills have confirmed readiness for various scenarios including conventional and unconventional warfare, and treating isolated patients during the Ebola and SARS threats. RESULTS: The hospital achieved preparedness for patient care during the COVID-19 pandemic, including all facilities and personnel, including infrastructure, laboratories, and innovations, to maintain standard patient care and separate COVID-19 treatment facilities. The hospital's second challenge represented by the COVID-19 pandemic led to adaptation of the FUEH as a key strategic facility in Northern Israel for treating hundreds of COVID-19 patients. Each solution was supported by innovations targeted for specific purposes and needs. CONCLUSIONS: The function and unique mechanisms used to leverage use of a dual facility was proven viable for several emergency conditions, including the COVID-19 pandemic. Infrastructure and technological flexibility is essential when planning for handling different emergencies situations.

Analyzing Medical Research Results Based on Synthetic Data and Their Relation to Real Data Results: Systematic Comparison From Five Observational Studies.

BACKGROUND: Privacy restrictions limit access to protected patient-derived health information for research purposes. Consequently, data anonymization is required to allow researchers data access for initial analysis before granting institutional review board approval. A system installed and activated at our institution enables synthetic data generation that mimics data from real electronic medical records, wherein only fictitious patients are listed. OBJECTIVE: This paper aimed to validate the results obtained when analyzing synthetic structured data for medical research. A comprehensive validation process concerning meaningful clinical questions and various types of data was conducted to assess the accuracy and precision of statistical estimates derived from synthetic patient data. METHODS: A cross-hospital project was conducted to validate results obtained from synthetic data produced for five contemporary studies on various topics. For each study, results derived from synthetic data were compared with those based on real data. In addition, repeatedly generated synthetic datasets were used to estimate the bias and stability of results obtained from synthetic data. RESULTS: This study demonstrated that results derived from synthetic data were predictive of results from real data. When the number of patients was large relative to the number of variables used, highly accurate and strongly consistent results were observed between synthetic and real data. For studies based on smaller populations that accounted for confounders and modifiers by multivariate models, predictions were of moderate accuracy, yet clear trends were correctly observed. CONCLUSIONS: The use of synthetic structured data provides a close estimate to real data results and is thus a powerful tool in shaping research hypotheses and accessing estimated analyses, without risking patient privacy. Synthetic data enable broad access to data (eg, for out-of-organization researchers), and rapid, safe, and repeatable analysis of data in hospitals or other health organizations where patient privacy is a primary value.

Calcium handling in human embryonic stem cell-derived cardiomyocytes.

The objective of the current study was to characterize calcium handling in developing human embryonic stem cell-derived cardiomyocytes (hESC-CMs). To this end, real-time polymerase chain reaction (PCR), immunocytochemistry, whole-cell voltage-clamp, and simultaneous patch-clamp/laser scanning confocal calcium imaging and surface membrane labeling with di-8-aminonaphthylethenylpridinium were used. Immunostaining studies in the hESC-CMs demonstrated the presence of the sarcoplasmic reticulum (SR) calcium release channels, ryanodine receptor-2, and inositol-1,4,5-trisphosphate (IP3) receptors. Store calcium function was manifested as action-potential-induced calcium transients. Time-to-target plots showed that these action-potential-initiated calcium transients traverse the width of the cell via a propagated wave of intracellular store calcium release. The hESC-CMs also exhibited local calcium events ("sparks") that were localized to the surface membrane. The presence of caffeine-sensitive intracellular calcium stores was manifested following application of focal, temporally limited puffs of caffeine in three different age groups: early-stage (with the initiation of beating), intermediate-stage (10 days post-beating [dpb]), and late-stage (30-40 dpb) hESC-CMs. Calcium store load gradually increased during in vitro maturation. Similarly, ryanodine application decreased the amplitude of the spontaneous calcium transients. Interestingly, the expression and function of an IP3-releasable calcium pool was also demonstrated in the hESC-CMs in experiments using caged-IP3 photolysis and antagonist application (2 microM 2-Aminoethoxydiphenyl borate). In summary, our study establishes the presence of a functional SR calcium store in early-stage hESC-CMs and shows a unique pattern of calcium handling in these cells. This study also stresses the importance of the functional characterization of hESC-CMs both for developmental studies and for the development of future myocardial cell replacement strategies. Disclosure of potential conflicts of interest is found at the end of this article.

Occluded mammary graft post-coronary bypass surgery: do we need to look for the second one? A case report.

BACKGROUND: Anatomic variations of the left internal mammary artery (LIMA) can influence coronary artery bypass surgical technique as well as posing definite difficulties in the interpretation of angiographic findings. We present an unusual anatomic variant of two LIMAs originating from the left subclavian artery discovered post-coronary artery bypass grafting surgery. CASE SUMMARY: A 60-year-old man post-LIMA grafting of the left anterior descending (LAD) coronary artery underwent diagnostic cardiac catheterization. Selective angiography revealed occluded LIMA; therefore, it was decided to proceed with percutaneous coronary intervention (PCI) to the occluded native LAD. Once antegrade flow in the LAD was restored, retrograde filling of a vessel corresponding to the previously grafted LIMA was also detected. Additional contrast injection in the left subclavian artery (LSCA) showed a second patent LIMA originating from the distal segment of the LSCA. DISCUSSION: This patient has an unusual anatomic variant of two LIMAs originating from the LCSA. The proximal rudimentary LIMA was misinterpreted as an occluded arterial graft while the second, well-developed LIMA connected to the LAD had an unusually distal origin and had therefore been overlooked. This anatomical variant should be kept in mind when the internal mammary graft seems to be occluded.

Impact of red blood cell transfusion on clinical outcomes in patients with acute myocardial infarction.

Divergent views remain regarding the safety of treating anemia with red blood cell (RBC) transfusion in patients with acute coronary syndrome (ACS). We used a prospective database to study effect of RBC transfusion in patients with acute myocardial infarction (MI; n = 2,358). Cox regression models were used to determine the association between RBC transfusion and 6-month outcomes, incorporating transfusion as a time-dependent variable. The models adjusted for baseline variables, propensity for transfusion, and nadir hemoglobin previous to the transfusion. One hundred ninety-two patients (8.1%) received RBC transfusion. Six-month mortality rates were higher in patients receiving transfusion (28.1% vs 11.7%, p <0.0001). The adjusted hazard ratio (HR) for mortality was 1.9 in transfused patients (95% confidence interval [CI] 1.3 to 2.9). Interaction between RBC transfusion and nadir hemoglobin with respect to mortality (p = 0.004) was significant. Stratified analyses showed a protective effect of transfusion in patients with nadir hemoglobin < or=8 g/dL (adjusted HR 0.13, 95% CI 0.03 to 0.65, p = 0.013). By contrast, transfusion was associated with increased mortality in patients with nadir hemoglobin >8 g/dL (adjusted HR 2.2, 95% CI 1.5 to 3.3; p <0.0001). Similar results were obtained for the composite end point of death/MI/heart failure (p for interaction = 0.04). In conclusion, RBC transfusion in patients with acute MI and hemoglobin < or =8 g/dL may be appropriate. The increased mortality observed in transfused patients with nadir hemoglobin above 8 g/dL underscores the clinical difficulty of balancing risks and benefits of RBC transfusion in the setting of ACS.

Long-term (>3 Years) outcome and predictors of clinical events after insertion of sirolimus-eluting stent in one or more native coronary arteries (from the Israeli arm of the e-Cypher registry).

The aim of this study was to evaluate long-term (3.4 years) outcomes and predictors of clinical events in patients treated with sirolimus-eluting stents in the Israeli arm of the e-Cypher registry. From July 2002 to October 2003, 488 patients from 8 medical centers in Israel were enrolled in the e-Cypher registry. Nineteen patients with interventions in venous grafts were excluded from the final analysis. Long-term follow-up was completed for 98% of the remaining patients. There were 29 cases (6.3%) of death (3.9% cardiac and 2.4% noncardiac deaths). According to the broad academic research consortium definition of stent thrombosis, there were 19 cases (4%) of stent thrombosis (incidence density 0.9 cases/100 patient-years). There were 46 cases (9.9%) of target lesion revascularization and 76 cases (16.3%) of major adverse cardiac events (combination of death, myocardial infarction, and target lesion revascularization). Independent predictors of stent thrombosis were renal failure (hazard ratio 9.6, 95% confidence interval 1.9 to 47), stent length (hazard ratio 1.1, 95% confidence interval 1 to 1.2), and the off-label use of sirolimus-eluting stents (hazard ratio 5.3, 95% confidence interval 1.2 to 24). In conclusion, during >3 years of follow-up, stent thrombosis, major adverse cardiac events, and target lesion revascularization continued at constant rates over time. Clinical parameters such as renal failure and procedural parameters such as off-label use and stent length were independent predictors of stent thrombosis.

Controlling ischemic cardiovascular disease: from basic mechanisms to clinical management.

Progress in cardiovascular disease understanding and management continues at an exponential pace. Our understanding of the molecular basis of disease is enhanced by newer molecular measurement techniques, sophisticated models of physiological protein functions, understanding of the genetic foundation for diseases, and the incorporation of population genetic tools in our clinical analysis. In this review, I discuss prevention and therapy of coronary stenosis impeding coronary flows, prevention of acute and chronic manifestation of coronary flow impairment, and interfering with myocardial manifestation of acute or chronic deprivation of coronary flow. Mechanical heart failure and arrhythmias are common causes of myocardial dysfunction that originate, in part, from the loss of myocardial tissue and function. Techniques for interfering with cardiac function, in order to address the molecular mechanisms associated with restenosis, range from pharmacologic to mechanical procedures including mechanical dilation and scaffolding of coronary stenosis. The use of stents with and without drug coating is leading the clinical world of revascularization side-by-side with cardiac bypass surgery. Other topics that are discussed here include managing myocardial damage and acute and chronic pump failure. Finally, population genetics of cardiac health and the potential for genetic therapeutic guidance in managing ischemic cardiovascular diseases are discussed.

Cardiology consultation as a gatekeeper prior to cardiac multi-detector computed tomography scan.

BACKGROUND: Multi-detector computed tomography has advanced enormously and now enables non-invasive evaluation of coronary arteries as well as cardiac anatomy, function and perfusion. However, the role of cardiac MDCT is not yet determined in the medical community and, consequently, many clinically unnecessary scans are performed solely on a self-referral basis. OBJECTIVES: To prospectively evaluate the role of a cardiologist consultation and recommendation prior to the scan, and the influence on the diagnostic yield of cardiac MDCT. METHODS: In our center a CT service was initiated, but with the prerequisite approval of a cardiologist before performance of the CT. Each individual who wanted and was willing to pay for a cardiac CT was interviewed by an experienced cardiologist who determined whether cardiac MDCT was the most appropriate next test in the cardiovascular evaluation. Subjects were classified into three groups: a) those with a normal or no prior stress test, no typical symptoms and no significant risk factors of coronary artery disease were recommended to perform a stress test or to remain under close clinical follow-up without MDCT; b) those with an equivocal stress test, atypical symptoms and/or significant risk factors were allowed to have cardiac MDCT; and c) those with positive stress test or clinically highly suspected CAD were advised to go directly to invasive coronary angiography. CT findings were categorized as normal CAD (normal calcium score and no narrowings), < 50% and > 50% CAD. RESULTS: A total of 254 people were interviewed, and in only 39 cases did the cardiologist approve the CT. However, 61 of the 215, despite our recommendation not to undergo CT, decided to have the scan. Assessment of the 100 cases that underwent MDCT showed a statistically significant better discrimination of significant CAD, according to the cardiologist's recommendation: MDCT not recommended in 3/54 (6%) vs. MDCT recommended in 12/39 (31%) vs. recommended invasive coronary angiography in 4/7 (57%)(P<0.001). CONCLUSIONS: Detection of coronary calcification, as well as MDCT angiography can provide clinically useful information if applied to suitable patient groups. It is foreseeable that MDCT angiography will become part of the routine workup in some subsets of patients with suspected CAD. Selection of patients undergoing MDCT scans by a cardiologist improves the ability of the test to stratify patients, preventing unnecessary scans in both high and low risk patients.

Relation of C-reactive protein to coronary collaterals in patients with stable angina pectoris and coronary artery disease.

The heterogeneity in the degree of collateralization among patients with coronary artery disease (CAD) is poorly understood. We sought to determine whether chronic subclinical inflammation is related to coronary collateral development in patients with chronic stable angina pectoris and obstructive CAD. High-sensitivity C-reactive protein (CRP) levels were measured in 177 patients with stable angina pectoris before coronary angiography. Multivariable logistic regression revealed an inverse graded association between CRP and the presence of coronary collaterals (Rentrop grade 1 to 3). Compared with patients in the first CRP tertile, the adjusted odds ratio for the presence of coronary collaterals was 0.70 (95% confidence interval, 0.33 to 1.52; p = 0.45) for patients in the second CRP tertile and 0.33 (95% confidence interval, 0.15 to 0.75; p = 0.008) for patients in the third CRP tertile (p for trend = 0.008). In conclusion, an inverse graded association exists between CRP and the presence of coronary collaterals in patients with stable angina pectoris.