Autism spectrum disorder diagnosis using a new panel of immune- and inflammatory-related serum biomarkers: A case-control multicenter study.

Background and objectives: Children with autism spectrum disorder (ASD) present with distinctive clinical features. No objective laboratory assay has been developed to establish a diagnosis of ASD. Considering the known immunological associations with ASD, immunological biomarkers might enable ASD diagnosis and intervention at an early age when the immature brain has the highest degree of plasticity. This work aimed to identify diagnostic biomarkers discriminating between children with ASD and typically developing (TD) children. Methods: A multicenter, diagnostic case-control study trial was conducted in Israel and Canada between 2014 and 2021. In this trial, a single blood sample was collected from 102 children with ASD as defined in Diagnostic Statistical Manual of Mental Disorders [DSM)-IV (299.00) or DSM-V (299.00)], and from 97 typically developing control children aged 3-12 years. Samples were analyzed using a high-throughput, multiplexed ELISA array which quantifies 1,000 human immune/inflammatory-related proteins. Multiple logistic regression analysis was used to obtain a predictor from these results using 10-fold cross validation. Results: Twelve biomarkers were identified that provided an overall accuracy of 0.82 ± 0.09 (sensitivity: 0.87 ± 0.08; specificity: 0.77 ± 0.14) in diagnosing ASD with a threshold of 0.5. The resulting model had an area under the curve of 0.86 ± 0.06 (95% CI: 0.811-0.889). Of the 102 ASD children included in the study, 13% were negative for this signature. Most of the markers included in all models have been reported to be associated with ASD and/or autoimmune diseases. Conclusion: The identified biomarkers may serve as the basis of an objective assay for early and accurate diagnosis of ASD. In addition, the markers may shed light on ASD etiology and pathogenesis. It should be noted that this was only a pilot, case-control diagnostic study, with a high risk of bias. The findings should be validated in larger prospective cohorts of consecutive children suspected of ASD.

Israeli Position Paper: Triage Decisions for Severely Ill Patients During the COVID-19 Pandemic. Joint Commission of the Israel National Bioethics Council, the Ethics Bureau of the Israel Medical Association and Representatives from the Israeli Ministry of Health.

OBJECTIVES: This document provides an English translation of the Israeli Joint Commission's national guidelines for triaging severely ill patients during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Four subcommittees of medical, legal, ethical-social, and religious experts developed the general principles and practical medical criteria for triaging scarce life-saving resources. RESULTS: The guidelines provide an overview of general principles as well as pragmatic medical criteria and a practical triage protocol to be followed should the healthcare system be overwhelmed due to COVID-19. Issues covered include triggers for activating the guidelines, guiding ethical, legal, and religious principles, equity in access, fair distribution, transparency, consistency, palliation, medical policy prioritization, problem-solving mechanisms, and public trust. CONCLUSIONS: The Israeli consensus document and pragmatic medical triage protocol offer a societal and medical roadmap for allocating scarce resources during the COVID-19 pandemic or other disasters.

Ethical Dilemmas in Neonatology - Four Theoretical Cases and Three Monotheistic Approaches: A Pilot Study.

BACKGROUND: Israel's population is diverse, with people of different religions, many of whom seek spiritual guidance during ethical dilemmas. It is paramount for healthcare providers to be familiar with different religious approaches. OBJECTIVES: To describe the attitudes of the three major monotheistic religions when encountering four complex neonatal situations. METHODS: A questionnaire related to four simulated cases was presented to each participant: a non-viable extremely premature infant (case 1), a severely asphyxiated term infant with extensive brain damage (case 2), a small preterm infant with severe brain hemorrhage and likely extensive brain damage (case 3), and a term infant with trisomy 21 syndrome and a severe cardiac malformation (case 4). RESULTS: Major differences among the three religious opinions were found in the definition of viability and in the approach towards quality of life. CONCLUSIONS: Neonatologists must be sensitive to culture and religion when dealing with major ethical issues in the neonatal intensive care unit.

A National Survey of Attitudes of the Zionist Ultra-Orthodox Community in Israel to Organ Donation.

BACKGROUND: The Council of the Chief Rabbinate formally accepted neurologically declared death as an indication of death for all legal and religious purposes following changes made to practice parameters in order to comply with Jewish Law (halacha). This removed Jewish-legal barriers for organ donation. We surveyed the Zionist ultra-Orthodox community to identify the reasons for their continued reluctance to donate. METHODS: A questionnaire was designed to assess personal, cultural, religious, and system-related considerations relating to organ donation. A telephone survey of persons identifying themselves with the Zionist ultra-Orthodox community was conducted to include 300 respondents (150 males and 150 females). RESULTS: The response rate was 5.5% (300 of 6799 approached). While most participants (79%) agreed that organ donation improved or saved lives, a minority (25%) expressed willingness to donate. The most important inhibiting factors were related to religion, namely, importance of being buried intact (84%) and donation being against halacha (46%). Most respondents (67%) would approach a religious figure for advice, and willingness to donate increased when informed that donation was permitted (68%) and supported (63%) by orthodox religious authorities. Finally, a minority (37%) perceived the allocation process to be fair and adequately supervised (36%). CONCLUSIONS: This study identified religious and system-related constraints as important inhibiting factors to donation, factors which were potentially modifiable. Since this community relies on their religious leaders for guidance, public support by authoritative and accepted religious leaders is required to reassure the community of the legitimacy and positive aspects of organ donation.

[FORCE-FEEDING OR LIFE-SAVING? - DEALING WITH HUNGER STRIKES IN ISRAEL].

INTRODUCTION: Force feeding of fasting hunger-striking prisoners is the subject of considerable controversy in Israel and elsewhere, posing a direct conflict between two basic ethical values: that of human life and respect for autonomy. The Israel Medical Association, as well as the World Medical Association, has taken the position that force feeding of such prisoners is an act of torture and is therefore unethical. However this paper presents an opposing view, which recently became the law in Israel, that, whereas the rights of prisoners to decree a hunger strike as a form of protest should be respected, if the prolongation of the strike reaches a stage of clear and present danger to the life and health of a prisoner, the saving of the prisoner's life must take precedence over considerations of autonomy. The paper present the steps that should be taken, including extensive and empathic efforts to persuade the prisoner to end his/her fast; gaining the approval of a hospital's ethics committee; and gaining the approval of a district court judge; the feeding is to be carried out in the most humane and sensitive manner as befitting a lifesaving procedure for any patient. This position is consistent with Israel's Basic Law: Human Dignity and Liberty, Israel's Patient Rights Law, Israel's "Do not stand idly by your fellow man's blood" Law, with several Israeli court decisions and in keeping with the dominant Israeli culture. Finally, instructions for physicians who object to such measures are discussed, ascertaining the freedom of conscience as well as preserving the life of the hunger-strikers.

Care for infants born at 23 weeks gestational age: 5 years' experience from a large medical center.

OBJECTIVES: Assessing parental choice regarding care of infants born at 23 weeks' gestation. METHODS: Neonatal records review. RESULTS: During 2010-2014, of 26 births (33 infants), 13 families (17 newborns) conceded comfort care only with no survivors, while 13 families (16 babies) requested full medical care and three survived. With birth year, gender, multi-fetal pregnancy, assisted reproductive technology, religious background and specialization of physician counseling at delivery as independent variables, none significantly affected parental decision; yet, that decision impacted outcome. CONCLUSIONS: Parental choice regarding infants born at 23 weeks' gestation cannot be predicted from demographics; counseling should concentrate on local experience/outcome.

Preimplantation genetic risk reduction: a new dilemma in the era of chromosomal microarrays and exome sequencing.

New technologies are revealing genetic variants of unknown significance (VUS), raising questions about the indications that call for preimplanation genetic diagnosis (PGD). Two couples requesting PGD for VUS are presented. The first couple requested PGD for Lynch syndrome. Whole exome sequencing identified in a healthy male with a family history of Lynch-associated tumours, a MLH1 missense variant. The variant had not been reported as pathogenic, but was predicted as damaging by algorithms. The second couple had a child diagnosed with pervasive developmental disorder and intellectual disability, carrying a microduplication on chr:Xp.22.3, and a microdeletion on chr:17q21.31. The maternally inherited X linked microduplication was also present in the mother's healthy brother and daughter, whereas the chr17 microdeletion was a de-novo event. As chromosomal microarrays and whole-exome sequencing are becoming standard tests, couples are requesting PGD for these VUS. The risk of possible genetic diseases can be reduced by carrying out PGD for uncertain findings, yet will inevitably lead to the birth of affected children despite the transfer of embryos that are not carriers of the familial variants. Findings of unknown significance demand urgent discussion and guidelines for their use as a risk-reduction measure in the preimplantation setting.

Risky Treatments: A Jewish Medical Ethics Perspective.

The Jewish principle concerning a decision with regard to a dangerous treatment is as following: A patient who is estimated to die within 12 months because of a fatal illness is permitted to undergo a treatment that on the one hand may extend his life beyond 12 months, but on the other hand may hasten his death. There are, however, several limitations to this ruling related to the chances of success with the proposed treatment, the nature of the treatment, whether it is intended to be curative or merely to postpone the danger and death, whether the treatment is absolutely necessary, and others. One is not obligated to undergo a dangerous treatment, but one is permitted to do so. The permissibility to forfeit a short life expectancy in order to achieve more prolonged life applies only with the patient's consent. That consent is valid and is not considered a form of attempted suicide. Neither is a refusal to submit to treatment considered an act of suicide; the patient has the right to refuse a dangerous procedure. In all situations where a permissive ruling is granted for a patient to endanger his short life expectancy, the ruling should be arrived at after careful reflection and with the approval of the rabbinic authorities acting on the recommendation of the most expert physicians.

Controversies in faith and health care.

Differences in religious faith-based viewpoints (controversies) on the sanctity of human life, acceptable behaviour, health-care technologies and health-care services contribute to the widespread variations in health care worldwide. Faith-linked controversies include family planning, child protection (especially child marriage, female genital mutilation, and immunisation), stigma and harm reduction, violence against women, sexual and reproductive health and HIV, gender, end-of-life issues, and faith activities including prayer. Buddhism, Christianity, Hinduism, Islam, Judaism, and traditional beliefs have similarities and differences in their viewpoints. Improved understanding by health-care providers of the heterogeneity of viewpoints, both within and between faiths, and their effect on health care is important for clinical medicine, public-health programmes, and health-care policy. Increased appreciation in faith leaders of the effect of their teachings on health care is also crucial. This Series paper outlines some faith-related controversies, describes how they influence health-care provision and uptake, and identifies opportunities for research and increased interaction between faith leaders and health-care providers to improve health care.

The implementation of a protocol promoting the safe practice of brain death determination.

PURPOSE: The purpose of the study is to describe the implementation of measures introduced in Israel in 2009 to promote the safe practice of brain death determination (BDD). MATERIALS AND METHODS: The measures require (1) physicians to undergo a mandatory training course, (2) the mandatory performance of an ancillary test, and (3) retrospective examination of all BDD forms by an independent committee. Any deviations from practice parameters were noted. Surveys were also undertaken to assess (i) the attitude of local physicians to the measures and (ii) whether similar measures are in place in Europe and whether they were considered necessary. RESULTS: After implementation, the measures resulted in the absence of deviations from practice parameters over time. A majority of local physician (n = 64) felt the measures added a sense of security to BDD (73%) and ensured its proper performance (85%). The European survey (n = 20 countries) revealed (1) specialized BDD training is required in 60%, provided in 50%, while felt necessary by 80%; (2) independent supervision of BDD is performed in only one other country; and (3) BDD is performed country-wide using the same criteria in 80% while felt necessary by 95%. CONCLUSION: The measures were successfully implemented, reduced diversity in patient testing, and positively accepted by local physicians. Wider application of the measures may be appropriate as suggested by the results of a European survey and the variability of BDD reported in the literature.

What is it to do good medical ethics? An orthodox Jewish physician and ethicist's perspective.

This article, dedicated to the 40th anniversary of the Journal of Medical Ethics, approaches the question 'what does it mean to do good medical ethics?' first from a general perspective and then from the personal perspective of a Jewish Orthodox physician and ethicist who tries, both at a personal clinical level and in national and sometimes international discussions and debates, to reconcile his own religious ethical values-especially the enormous value given by Jewish ethics to the preservation of human life-with the prima facie 'principlist' moral norms of contemporary secular medical ethics, especially that of respect for patients' autonomy.

[Truth telling to patients--A discussion of Jewish sources (corrected)].

Defining truth and truth-telling to patients are central topics in philosophy, law, and psychology, with many implications in medicine. In the last hundred years, with the transition from paternalistic medicine to a system in which the patient's autonomy is emphasized, the decision on the quantity and quality of medical information to be disclosed to the patient has become more complicated and requires careful consideration and special sensitivity on the part of the doctor. The Israeli Patients' Rights Act (1996] established guidelines for medical staff about telltting the truth to patients with occasional special authority delegated to the doctor to decide for the benefit of the patient at his discretion and with the approval of the institutional ethics committee, but in practice there are difficulties in implementing the Law. This article reviews a selection of sources from Jewish tradition throughout the ages that deal with truthtelling or concealing the truth in medical contexts and other contexts. Sources are drawn from the Bible, Mishna-Talmud, and halachic Literature, from which.conclusions can be drawn regarding this issue. In our opinion, these sources yield messages and values that are also relevant to the modern medical world. This is especially true in a multi-cultural environment such as Israel that requires the physician to consider the patient's background and to communicate information in accordance with his/her will, in an efficient and sensitive manner.

[Medicine, physicians and medical ethics in Jewish tradition through the ages].

Medicine has always had a place of honor in the Jewish heritage. Since Biblical times, the sources of Judaism have valued the physician's activities and seen them as a partnership with God's deeds. Later, in the times of the Mishna and the Talmud, a model of scholars evolved who were not only learned sages but also had extensive medical and scientific knowledge. Their dealings with various issues in medical ethics were the basis for deliberation on questions that appeared throughout history on the advancement of medical science. The various sources from this period show the sages' sensitivity regarding the subject of human life, saving lives and the importance of the availability of medicine for all segments of the population. During the years following the completion of the Talmud, the medical profession was common among the Jews and they excelled in this field. Jewish doctors left behind a Legacy of values in medicine. Hebrew was considered a significant Language in the medical field and was cited in various medical texts such as in the book written by Vesalius, the "father" of modern anatomy. The rapid progress of medicine poses new challenges in bioethics. There is a need for physicians with extensive medical knowledge along with an understanding of ethical issues in order to offer solutions to new situations. Knowledge of the Jewish literature throughout the ages on a variety of subjects and the essential values which are their foundation can contribute to the modern discussion on biomedical questions. This is even more important in Israeli society where many of the laws are formed based on Jewish values. Engagement with Jewish medical ethics can help in educating physicians to have the ability to contribute to public debate and legislation in a way that would balance between the values and needs which an ethical issue raises.

[Self endangerment to save life--competing Jewish legal and moral obligations].

The obligation to help others often involves personal risk. Consequently, the scope and boundaries of this obligation can present a complex dilemma, which has practical and moral implications, even in the world of medicine. In Jewish medical ethics, the dilemma stems from a confrontation between the duty to help others according to the biblical commandment: "Do not stand idly by your fellow's blood" on the one hand, and between the right and duty of man to defend himself, which is anchored in Jewish law. This article surveys the sources of this quandary in Jewish texts throughout the ages such as the Bible, Mishnah, Talmud, and responsa literature in various contexts. The discussion highlights the essential difference between the formal demands of the law, which protects human rights of self-preservation, and the moral requirement to help others even if it may include personal risk. The sources suggest distinguishing between various levels of risk ranging from high-risk to reasonable or low risk. In this way, the classic sources, provide the foundation and the tools for grappling with modern contemporary Halachic questions such as organ transplantation, and generate a Torah value-based framework to deal with new situations that may arise in the future. It is critical to assess the level of risk and the chances for success, along with other subjective considerations, in order to ensure the optimal ethical course of action.

A safety trial of high dose glyceryl triacetate for Canavan disease.

Canavan disease (CD MIM#271900) is a rare autosomal recessive neurodegenerative disorder presenting in early infancy. The course of the disease is variable, but it is always fatal. CD is caused by mutations in the ASPA gene, which codes for the enzyme aspartoacylase (ASPA), which breaks down N-acetylaspartate (NAA) to acetate and aspartic acid. The lack of NAA-degrading enzyme activity leads to excess accumulation of NAA in the brain and deficiency of acetate, which is necessary for myelin lipid synthesis. Glyceryltriacetate (GTA) is a short-chain triglyceride with three acetate moieties on a glycerol backbone and has proven an effective acetate precursor. Intragastric administration of GTA to tremor mice results in greatly increased brain acetate levels, and improved motor functions. GTA given to infants with CD at a low dose (up to 0.25 g/kg/d) resulted in no improvement in their clinical status, but also no detectable toxicity. We present for the first time the safety profile of high dose GTA (4.5 g/kg/d) in 2 patients with CD. We treated 2 infants with CD at ages 8 months and 1 year with high dose GTA, for 4.5 and 6 months respectively. No significant side effects and no toxicity were observed. Although the treatment resulted in no motor improvement, it was well tolerated. The lack of clinical improvement might be explained mainly by the late onset of treatment, when significant brain damage was already present. Further larger studies of CD patients below age 3 months are required in order to test the long-term efficacy of this drug.

The critical role of religion: caring for the dying patient from an Orthodox Jewish perspective.

BACKGROUND AND OBJECTIVE: Culturally competent medical care for the dying patient by families and health care professionals is a challenging task especially when religious values, practices, and beliefs influence treatment decisions for patients at the end of life. This article describes end-of-life guidelines for hospital health care professionals caring for Orthodox Jewish patients and their families. Religious perspectives on advance directives, comfort care and pain control, nutrition and hydration, do not resuscitate/do not intubate (DNR/DNI), and extubation are often unfamiliar to the American medical community. DESIGN: The guidelines for the care of the dying Orthodox Jewish patient were mutually agreed upon by the authors, recognized authorities in medicine, ethics, and Jewish law, who presented their perspectives during a 1-day symposium and who participated in an active working-group session. CONCLUSIONS: Care of the religious patient close to death is enormously complex especially when balancing religious obligations, the role of the rabbi, medical procedures, and personal preferences. These guidelines address from a religious perspective profound issues such as the definition of death, organ donation, and caring for the patient at life's end. The guidelines can be useful for any hospital that serves an Orthodox Jewish population.