The transition of new biotechnologies into clinical trials is a critical step in approving a new drug or therapy in health care. Ethically recruiting appropriate volunteers for these clinical trials can be a challenging task for both the pharmaceutical companies and the US Food and Drug Administration. In this paper we analyze the Jewish halachic perspectives of volunteering for clinical trials by focusing on an innovative technology in reproductive medicine, mitochondrial replacement therapy. The halachic perspective encourages individuals to volunteer for such clinical trials under the ethical principles of beneficence and social responsibility, when animal studies have shown that health risks are minimal.
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.
Background: Following the announcement of actress Angelina Jolie’s prophylactic bilateral mastectomies and subsequent prophylactic oophorectomy, there has been a dramatic increase in interest in BRCA testing and prophylactic surgery.
Objective: To review current medical literature on the benefits of prophylactic mastectomy and oophorectomy among BRCA-positive women and its permissibility under Jewish law.
Results: Recent literature suggests that in BRCA-positive women who undergo prophylactic oophorectomy the risk of dying of breast cancer is reduced by 90%, the risk of dying of ovarian cancer is reduced by 95%, and the risk of dying of any cause is reduced by 77%. The risk of breast cancer is further reduced by prophylactic mastectomy. Prophylactic oophorectomy and prophylactic mastectomy pose several challenges within Jewish law that call into question the permissibility of surgery, including mutilation of a healthy organ, termination of fertility, self-wounding, and castration. A growing number of Jewish legal scholars have found grounds to permit prophylactic surgery among BRCA carriers, with some even obligating prophylactic mastectomy and oophorectomy.
Conclusion: Current data suggest a significant reduction in mortality from prophylactic mastectomy and oophorectomy in BRCA carriers. While mutilation of healthy organs is intrinsically forbidden in Jewish law, the ability to preserve human life may contravene and even mandate prophylactic surgery.
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.
OBJECTIVE: Right-sided endocarditis (RSE) accounts for 5%–10% of all cases of infective endocarditis (IE) and frequently has different etiological, pathogenetic, and clinical presentations compared with left-sided endocarditis (LSE). The aims of this study were to evaluate the epidemiologic and clinical characteristics and prognosis of RSE patients and to compare them with those of LSE patients. This study’s importance relates to the local understanding of RSE and LSE, since Israeli demographics are different compared to the Unites States and Europe with regard to intravenous drug abuse and rheumatic valvular disease prevalence.
MATERIAL AND METHODS: A retrospective cohort study of 215 patients with infective endocarditis was performed. The primary outcome was in-hospital mortality. The secondary outcomes were duration of hospitalization, recurrent hospitalization, recurrent infective endocarditis, and one-year mortality.
RESULTS: Of the 215 patients in the study, 176 had LSE and 39 had RSE. The RSE patients were younger than the LSE patients (48.1±18.9 years versus 61.8±17.0 years, P<0.001). The most common pathogen in both groups was Staphylococcus aureus, which occurred more in the RSE group (51%) versus the LSE group (19%). In-hospital mortality was lower among patients with RSE (2.6% versus 17%, P<0.037).
CONCLUSIONS: Our study demonstrated an increasing percentage of RSE compared to LSE among patients with IE. Pacemaker lead infection has become the leading cause of RSE in intravenous drug users (IVDU), although less common in Southern Israel. The etiological and clinical differences between RSE and LSE are noteworthy. Patients with RSE have a better prognosis than those with LSE.
Chemotherapy-associated myocardial toxicity is increasingly recognized with the expanding armamentari¬um of novel chemotherapeutic agents. The onset of cardiotoxicity during cancer therapy represents a major concern and often involves clinical uncertainties and complex therapeutic decisions, reflecting a compro¬mise between potential benefits and harm. Furthermore, the improved cancer survival has led to cardio¬vascular complications becoming clinically relevant, potentially contributing to premature morbidity and mortality among cancer survivors. Specific higher-risk populations of cancer patients can benefit from pre¬vention and screening measures during the course of cancer therapies. The pathobiology of chemotherapy-induced myocardial dysfunction is complex, and the individual patient risk for heart failure entails a multifactorial interaction between the selected chemotherapeutic regimen, traditional cardiovascular risk factors, and individual susceptibility. Treatment with several specific chemotherapeutic agents, including anthracyclines, proteasome inhibitors, epidermal growth factor receptor inhibitors, vascular endothelial growth factor inhibitors, and immune checkpoint inhibitors imparts increased risk for cardiotoxicity that results from specific therapy-related mechanisms. We review the pathophysiology, risk factors, and imaging considerations as well as patient surveillance, prevention, and treatment approaches to mitigate cardiotox¬icity prior, during, and after chemotherapy. The complexity of decision-making in these patients requires viable discussion and partnership between cardiologists and oncologists aiming together to eradicate cancer while preventing cardiotoxic sequelae.
