Mitochondrial replacement therapy (MRT) encompasses assisted reproductive technologies designed to prevent the transmission of pathogenic mitochondrial DNA (mtDNA) mutations by combining the DNA in the nucleus (nuclear genome) of the intending parents with another woman’s enucleated egg that provides healthy donor-derived mtDNA. The use of advanced genomic engineering in MRT raises distinct ethical and halachic considerations regarding the ontological status of embryos containing genetic material from more than two individuals. This paper advances an original theoretical protocol, termed biparental mitochondrial replacement therapy (Bi-MRT), that mitigates the central halachic concerns associated with multi-parent embryos. In this protocol, future advances in stem cell technology could be employed to generate an enucleated gamete-like cell containing healthy mitochondria from the husband. The meiotic spindle–chromosome complex from the wife’s oocyte could then be transplanted into this reconstituted gamete, which could be subsequently fertilized with the husband’s sperm for IVF. If technically feasible and developmentally competent, the resulting embryo could potentially be transferred to the wife for gestation. By combining the wife’s nuclear genetic contribution, gestation, and parturition with the husband’s paternal DNA, this framework isolates the third-party mitochondrial contribution as a non-maternal factor, thereby reinforcing the wife’s singular claim to halachic maternity. Biparental MRT therefore represents a theoretical framework that could potentially reduce some halachic concerns associated with conventional MRT, but substantial scientific and safety barriers remain before any clinical application could be contemplated.
The Lancet Commission on medicine, Nazism, and the Holocaust (LCmNH) presented an innovation for the moral formation of health professionals. Proposing history-informed professional identity formation (HIPIF), it envisioned a morally resilient clinician who exercises moral agency, recognizes the fragility of medicine’s core values, pursues lifelong learning in medical ethics beyond principlism, and firmly addresses antisemitism, racism, and hate. Tragically, just before its publication (November 2023), the report gained greater relevance in the wake of the October 7, 2023, Hamas massacre, which led to a surge in antisemitism, including within healthcare and medical education. Unexpected barriers, such as fear of controversy, hampered dissemination of the LCmNH recommendations. Concurrently, the author, an Israeli Jew, physician, and Co-Chair of the LCmNH, grappled with moral distress in the context of the war following October 7 and antisemitism in healthcare. These challenges triggered a reappraisal of the LCmNH moral formation proposal. This reappraisal identified moral distress, antisemitism, and inadequate institutional accountability as central issues requiring attention. The author proposes a revised approach for moral formation, integrating mechanisms to prevent and identify moral distress and antisemitism, provide care for those affected, and pair systemic accountability with individual integrity. Steps for stakeholders to promote the updated approach, along with its expected benefits, are described. A diagram and comparative table illustrate and indicate areas of focus for the proposed enhanced approach. The author also shares how his reflective inquiry, scholarly pursuit, and reappraisal of the LCmNH report worked together to foster his own resilience and generate insights that informed the proposed updated approach to moral formation.
Objective: Neuropsychiatric safety concerns about glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and tirzepatide prompted regulatory review by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). We synthesized the contemporary evidence in adults with type 2 diabetes mellitus or obesity, emphasizing study design, risk of bias, and the distinction between signal detection and causal inference. Methods: The PubMed/MEDLINE, Embase, Web of Science, and Scopus databases were searched without a lower date limit through March 15, 2026 (English, adults ≥18 years). The review was reported with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020, and the PRISMA-S and PRISMA-Harms extensions. Evidence was grouped into prespecified categories: randomized syntheses, comparative observational studies and target-trial emulations, outlier non-active-comparator studies, pharmacovigilance analyses, and regulatory reviews. Risk of bias was appraised with the Cochrane Risk of Bias 2 tool and with Risk of Bias in Non-randomised Studies of Interventions; certainty was summarized using Grading of Recommendations Assessment, Development and Evaluation. Results: Twenty studies and two regulatory reviews met the inclusion criteria. Randomized evidence, including two large 2025 meta-analyses and post hoc pooled analyses of semaglutide and tirzepatide, showed no increased risk of suicidality, depression, or anxiety, though psychiatric exclusion criteria limited generalizability. Active-comparator cohorts from the United States, Scandinavia, and the United Kingdom likewise showed no clear increase after confounding control. Passive-comparator and disproportionality analyses generated signals but could not separate drug effects from baseline psychiatric risk, obesity-related distress, or reporting bias. The EMA and FDA conclusions do not support a causal class-wide association between GLP-1 RAs and suicidal ideation or behavior. Conclusions: Evidence does not support a clinically meaningful increase in neuropsychiatric harm with GLP-1 RAs or tirzepatide in the populations studied. Surveillance remains warranted for patients with substantial psychiatric morbidity, for obesity-only populations, and for long-term rare outcomes.
Orofacial and jaw pain represents a diagnostic challenge frequently encountered across multiple medical specialties. Although odontogenic disease is a common cause of pain in the facial region, the present review focuses on non-odontogenic causes that should be considered when no clear dental source is identified or symptoms remain unexplained or persist despite appropriate dental treatment. Such pain may originate from the temporomandibular joints, masticatory muscles, cranial nerves, facial skeleton, adjacent head-and-neck structures, systemic diseases, or distant referred sources. This comprehensive review presents a systematic clinical approach to differential diagnosis, classifying non-odontogenic orofacial pain into ten distinct categories: temporomandibular joint disorders, masticatory muscle pain, skeletal disorders of the jaws, space-occupying lesions, infectious processes, neuropathic orofacial pain, idiopathic and nociplastic pain, orofacial pain resembling a presentation of primary headache, systemic diseases with orofacial mani¬festations, and referred orofacial pain from distant medical conditions. This classification aligns with the In¬ternational Classification of Orofacial Pain (ICOP-2020) while emphasizing practical clinical applicability for physicians across various specialties. Each category is characterized by unique clinical features, examination findings, and diagnostic considerations. Proper recognition of these patterns enables accurate diagnosis, appropriate treatment, and timely specialist referral when indicated. The approach emphasizes clinical assessment techniques accessible to physicians across various healthcare settings, focusing on detailed history-taking and physical examination. Identification of red flag symptoms requiring urgent evaluation is highlighted throughout. This systematic framework aims to reduce diagnostic errors, improve patient outcomes, and enhance interdisciplinary collaboration in managing complex orofacial pain presentations.
BACKGROUND:Whether a fetus can experience pain remains scientifically and clinically contested, particularly as invasive fetal procedures become more common. OBJECTIVES:To review fetal nociceptive development, the evidence and uncertainties relevant to pain perception, and the clinical rationale for fetal analgesia during invasive procedures. METHODS:We performed a targeted narrative search of PubMed/MEDLINE, Google Scholar, the Cochrane Library, reference lists, and professional society websites. The final synthesis comprised 34 core sources. RESULTS:Functional nociceptive and neuroendocrine responses to noxious stimuli are documented from the mid-second trimester and can be attenuated by fetal opioids. Early thalamic and subplate circuitry may challenge the claim that mature cortical architecture is required for all pain-related processing, but this circuitry has not been shown to be sufficient for conscious pain. Continuous endogenous fetal sedation is not supported by behavioral evidence, although the fetal neurochemical environment may modulate arousal and sensory processing. Maternal anesthesia, especially regional anesthesia, may not provide reliable fetal analgesic exposure. Professional guidance differs on the gestational age at which pain perception becomes possible. CONCLUSIONS:The clinical case for fetal analgesia should be separated from the unresolved question of conscious pain. Potential rationales include preventing possible suffering, attenuating documented physiological stress responses, and facilitating procedural stability. Decisions should therefore be based on a proportionate, procedure-specific maternal-fetal risk-benefit assessment rather than a universal precautionary default.
