Background: Postural tachycardia syndrome (POTS) is a common form of chronic orthostatic intolerance. The remarkable increase in heart rate (HR) upon standing is the hallmark of this syndrome. Treatment of POTS patients is challenging and includes drugs that slow the HR. Ivabradine is a selective If channel blocker designed to slow the HR, as an anti-anginal agent. In view of its ability to slow the HR, we posited that ivabradine may be an ideal medication for treating POTS patients. This report provides the results of an investigation in which we studied ivabradine’s effect on the hemodynamics and sympathovagal balance in POTS patients.
Methods: An open-label trial, without a placebo control, was performed in eight patients with POTS of two years’ standing. Characterization of symptoms, hemodynamics, autonomic function tests, and HR and blood pressure (BP) variability were determined while patients were in a supine position and during a 20-minute head-up tilt before and after a single oral dose of 7.5 mg ivabradine.
Results: Ivabradine slowed the HR of POTS patients at rest by 4±1 bpm (P<0.05). During a 5-minute head-up tilt, the HR decreased from 118±4 bpm to 101±5 bpm (P<0.01). Ivabradine did not affect the BP when patients were at rest in a supine position or in head-up tilt position. Cardiovascular vagal and sympathetic tone, extrapolated from the time and frequency domains of the HR and BP variability, were also not affected by ivabradine.
Conclusions: Ivabradine is an effective drug for slowing the HR of POTS patients at rest and during tilting, without producing significant adverse effects. Moreover, ivabradine exerts its effects without influencing the sympathovagal balance.
This brief introduction is followed by a published version of my Nobel Laureate lecture, re-published herein with the kind permission of the Nobel Foundation. Much has happened since my original research, for which that prize was awarded. Hence, I am pleased to offer a few thoughts about the future of my research and its possible impact on humankind.
Although the original work on nuclear transfer and reprogramming was done over half a century ago, advances continue to be made. In particular the Takahashi and Yamanaka induced pluripotent stem cells (iPS) procedure has opened up the field of cell replacement to a great extent. Now, more recently, further advances make this whole field come closer to actual usefulness for humans. Recently, in the UK, the government approved the use of mitochondrial replacement therapy to avoid the problems associated with genetically defective mitochondria in certain women. Although the House of Commons (members of Parliament) and the House of Lords had to debate and discuss whether to allow this kind of human therapy, I was very pleased to find that both bodies approved this procedure. This means that a patient can choose to make use of the procedure; it does not in any way force an individual to have a procedure that they are not comfortable with. In my view, this is a great advance in respect to giving patients a choice about the treatment they receive. I am told that the UK is the first country in the world to approve mitochondrial replacement therapy.
Now that the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPr) technology is being widely used and works well, one can foresee that there will be those who wish to use this technology to make genetic changes to humans. For example, if a human has a gene that makes it susceptible to infection or any other disorder, the removal of that gene might give such a person immunity from that disease. If this gene deletion is done within the germ line, the genetic change will be inherited. However, one can imagine that various people will strongly object and say that this technology should not be allowed. I would very much hope that various regulatory bodies, governments, etc. will allow the choice to remain with the individual. I can see no argument for such bodies to make a law that removes any choice whatsoever by an individual.
The number needed to treat (NNT) is a simple measure of a treatment’s impact, increasingly reported in randomized trials and observational studies. It has been found to be incorrectly calculated in several studies involving varying follow-up times. We discuss the NNT in these contexts and illustrate the concept using several published studies. The computation of the NNT is founded on the cumulative incidence of the outcome. Instead, several published studies use simple proportions that do not account for varying follow-up times, or use incidence rates per person-time. We show how these approaches can lead to erroneous values of the NNT and misleading interpretations. For example, a trial of 3,845 very elderly hypertensives randomized to a diuretic or placebo reported a NNT of 94 treated for 2 years to prevent one stroke, though the correct approach results in a NNT of 63. We also note that meta-analyses involve trials of differing lengths, but often report a single NNT. For example a meta-analysis of 22 trials of the anticholinergic tiotropium in chronic obstructive pulmonary disease reported a NNT of 16 patients “over one year,” even if the trials varied in duration from 3 to 48 months, with the more specifically computed NNTs varying widely from 72, 15, and 250 for the 3-month, 12-month, and 48-month trials, respectively. Finally, we describe the value of the NNT in assessing benefit–risk, such as low-dose aspirin use in secondary prevention, where prevention of mortality was assessed against the risk of gastrointestinal bleeding. As the “number needed to treat” becomes increasingly used in the comparative effectiveness and safety of therapies, its accurate estimation and interpretation become crucial to avoid distorting clinical, economic, and public health decisions.
Introduction. The current study evaluated the rate of ependymal enhancement and whether its presence influences survival of patients with malignant glioma (GBM).
Methods. A retrospective review of all patients who were treated in our institution from 2005 to 2011 was conducted. Data extracted from the medical records included age, date of diagnosis, co-morbidities, treatment regimen, and time of death. Magnetic resonance images (MRI) were evaluated for the presence of ependymal enhancement and its extent, and the correlation to survival was investigated.
Results. Between 2005 and 2011, 230 patients were treated for GBM. Eighty-nine patients were excluded from the study due to insufficient data, leaving 141 patients for analysis. Median age at diagnosis was 60 years. Sixty-seven (40.6%) patients had evidence of ependymal enhancement on MRI (group A), and 70 (42.4%) patients did not have evidence of enhancement. The assessment of ependymal enhancement was inconclusive due to mass effect and ventricular compression that precluded accurate assessment for 28 (17%) patients (group C). Median survival was 14 months for group A (range, 12–16 months), 15.9 months for group B (range, 14.28–17.65 months), and 11.7 months for group C (range, 6.47–16.92 months) (P>0.05). A multivariate analysis to predict survival indicated that male gender (P=0.039), hypertension (P=0.012), and biopsy only compared to complete gross tumor resection (P=0.001) were significant for poor survival.
Conclusions. Pretreatment ependymal enhancement on MRI was not found to be associated with poorer survival. These results might be due to better treatments options compared to prior reports.
Historically speaking, in many societies a select few carried the burden of preserving and transferring knowledge. While modern society has broadened the scope of education, this is not enough in the medical sciences. We must ensure that all those who pursue a career in medicine become life-long learners who will grow and contribute well beyond their years in medical school. In considering how to attain this goal, we were intrigued by the similarities between generations-old wisdom of teaching and learning methods in Jewish culture and modern educational principles. Both aim to nurture a culture of learners. Our objective was to parallel the methodologies, pedagogic directives, and demands made of students in the Jewish tradition, to the principles used in medical education today. We surveyed the traditional Jewish culture of teaching and learning. We compared it to modern medical teaching methods and looked to see what lessons might be gleaned. In the traditional Jewish community, life is focused on education, and producing “learners” is the ideal. This culture of learning was developed over the generations and many educational methods are similar to modern ones. Some of the pedagogic principles developed successfully in Jewish society should be considered for adaptation in medical education. Further comparative research could help to expand the ways in which we teach medicine.
Objective: Urology practice has undergone several changes in recent years mainly related to novel technologies introduced. We aimed to get the residents’ perspective on the current residency program in Israel and propose changes in it.
Methods: A web-based survey was distributed among urology residents.
Results: 61 residents completed the survey out of 95 to whom it was sent (64% compliance). A total of 30% replied that the 9 months of mandatory general surgery rotation contributed to their training, 48% replied it should be shortened/canceled, and 43% replied that the Step A exam (a mandatory written certifying exam) in general surgery was relevant to their training. A total of 37% thought that surgical exposure during the residency was adequate, and 28% considered their training “hands-on.” Most non-junior residents (post-graduate year 3 and beyond) reported being able to perform simple procedures such as circumcision and transurethral resections but not complex procedures such as radical and laparoscopic procedures. A total of 41% of non-junior residents practice at a urology clinic. A total of 62% of residents from centers with no robotics replied its absence harmed their training, and 85% replied they would benefit from a robotics rotation. A total of 61% of residents from centers with robotics replied its presence harmed their training, and 72% replied they would benefit from an open surgery rotation. A total of 82% of the residents participated in post-graduate courses, and 81% replied they would engage in a clinical fellowship.
Conclusion: Given the survey results we propose some changes to be considered in the residency program. These include changes in the general surgery rotation and exam, better surgical training, possible exchange rotations to expose residents to robotic and open surgery (depending on the availability of robotics in their center), greater out-patient urology clinic exposure, and possible changes in the basic science period.
Background: Estimates of lifetime cancer risk are commonly used in the clinical setting and in health-care evaluations. These measures are based on lifetime cancer risk estimates and may create an unrealistically frightening perception of cancer risk for an individual. We suggest using two new measures of cancer risk to complement the cancer lifetime risk measure, namely estimates of cancer risk from birth to a specific age or from a specific age to life expectancy.
Methods: We calculated risks using incidence density data from the Israel National Cancer Registry of 2013, applying a well-known formula for calculating risk, for a follow-up time. The joint disease-free survival probability is calculated for several age intervals, and hence the risk (i.e. 1–survival) for the intervals.
Results: The risk of cancer to age 80 in Jewish men and women, respectively, ranged from about 0.336 and 0.329 at age 0, to 0.279 and 0.237 at age 60. The risk of cancer from birth up to an age in Jewish men and women, respectively, ranged from 0 and 0 at birth to 0.088 and 0.129 at age 60. The risk of cancer to age 80 in Arab men and women, respectively, ranged from 0.298 and 0.235 at age 0 to 0.249 and 0.161 at age 60. The risk of cancer from birth up to an age in Arab men and women, respectively, ranged from 0 and 0 at age 0 to 0.074 and 0.095 at age 60. In Jewish and Arab women, breast cancer risk to age 80 decreased from about 0.127 in Jewish women at age 40 to 0.079 at age 60 and from 0.080 to 0.043 in Arab women; the risk from birth up to a specific age ranged between 0 and 0.056, and 0 and 0.040, respectively.
Conclusion: The two proposed new estimates convey important additional information to patients and physicians. These estimates are considerably lower than the frequently quoted 33% lifetime cancer risk and are more relevant to patients and physicians. Similarly, breast cancer risk estimates up to or from a specific age differ considerably from the frequently quoted lifetime risk estimates of 1 in 8 women.
An ideological case study based on medical profession norms during the Third Reich will be used to exemplify the importance of diversity in the manifestations of professional ethics. The German professional medical community banned their Jewish colleagues from treating German citizens. This included legally mandated employment discrimination and outright censure which led to a professional ethic devoid of diverse voices. While the escalation to the T-4 program and medicalized genocide was influenced by many causes, the intentional, ethnocentric-based exclusion of voices was an important contributing element to the chronicled degradation of societal mores. For illustration, six core Jewish values—life, peace, justice, mercy, scholarship, and sincerity of intention—will be detailed for their potential to inspire health-care professionals to defend and protect minorities and for readers to think critically about the role of medical professionalism in Third Reich society. The Jewish teachings highlight the inherent professional obligations physicians have toward their patients in contrast to the Third Reich’s corruption of patient-centered professionalism. More fundamentally, juxtaposing Jewish and Nazi teachings exposes the loss of perspective when a profession’s identity spurns diversity. To ensure respect for persons in all vulnerable minorities, the first step is addressing professional inclusion of minority voices.
Objectives: Peripartum cardiomyopathy (PPCM) is a serious complication of pregnancy. Studies investigating the risk factors that worsen outcomes have yielded conflicting results. The goals of this study were to describe the clinical and echocardiographic characteristics of PPCM in a single tertiary center and to determine the prognostic factors associated with persistence of left ventricular (LV) dysfunction in these women.
Study Design: This retrospective cross-sectional population-based cohort study included all patients with PPCM confirmed by echocardiography who delivered at our center from 2004 to 2014. Two groups were compared to determine long-term maternal outcome: (1) those who recovered normal LV function; and (2) those with residual systolic LV dysfunction.
Results: There were 148,994 deliveries during the study period. Of these, 89,196 patients were Bedouin and 59,798 were non-Bedouin. Forty-six patients met the PPCM study inclusion criteria. The PPCM prevalence for the total deliveries was 1:3,239. The PPCM prevalence among Bedouin patients was 1:2,787 versus non-Bedouin patients of 1:4,983 (P=0.037). None of the women had pre-existing chronic hypertension, and there was no maternal death. Patients who had severe or moderate LV dysfunction at the clinical presentation of PPCM were less likely to regain normal LV function than those with mild dysfunction (81.2% versus 56.7%, P=0.009). Based on initial echocardiogram, a trend toward residual LV dysfunction was noted in patients with a dilated left ventricle as compared to those with a non-dilated left ventricle (18.8% versus 6.7%, P=0.32). A hypokinetic right ventricle was found in 15.2% of the women who suffered from PPCM.
Conclusion: In our cohort, Bedouin women may be at increased risk for PPCM, and patients with severe LV dysfunction have a lower chance of recovery from PPCM.
The strong relationship between cardiovascular diseases (CVD), atherosclerosis, and endogenous or exogenous lipids has been recognized for decades, underestimating the contribution of other dietary components, such as amino acids, to the initiation of the underlying inflammatory disease. Recently, specific amino acids have been associated with incident cardiovascular disorders, suggesting their significant role in the pathogenesis of CVD. Special attention has been paid to the group of branched-chain amino acids (BCAA), leucine, isoleucine, and valine, since their plasma values are frequently found in high concentrations in individuals with CVD risk. Nevertheless, dietary BCAA, leucine in particular, have been associated with improved indicators of atherosclerosis. Therefore, their potential role in the process of atherogenesis and concomitant CVD development remains unclear. Macrophages play pivotal roles in the development of atherosclerosis. They can accumulate high amounts of circulating lipids, through a process known as macrophage foam cell formation, and initiate the atherogenesis process. We have recently screened for anti- or pro-atherogenic amino acids in the macrophage model system. Our study showed that glycine, cysteine, alanine, leucine, glutamate, and glutamine significantly affected macrophage atherogenicity mainly through modulation of the cellular triglyceride metabolism. The anti-atherogenic properties of glycine and leucine, and the pro-atherogenic effects of glutamine, were also confirmed in vivo. Further investigation is warranted to define the role of these amino acids in atherosclerosis and CVD, which may serve as a basis for the development of anti-atherogenic nutritional and therapeutic approaches.
