Untreated Illness Research Articles

Recent advances in neuro-ophthalmology.

This review article represents a collaborative effort across continents, bringing together the latest developments in neuro-ophthalmology with a focus on innovative diagnostic and therapeutic modalities that are shaping the future of the field. Among the most significant advancements is the rise of optical coherence tomography (OCT), now recognized as an indispensable tool in neuro-ophthalmological research, providing unparalleled insights into optic nerve and central nervous system pathologies. Gene therapy, particularly for conditions such as Leber's hereditary optic neuropathy, marks a new frontier in personalized medicine, offering hope for previously untreatable conditions. The article also examines the transformative role of telemedicine and artificial intelligence (AI) in clinical practice, which are revolutionizing patient care and enhancing diagnostic precision. Furthermore, it highlights the impact of novel serological biomarkers on the understanding and management of immune-mediated optic neuritis, and discusses the introduction of new therapeutic agents like Tocilizumab and Teprotumumab, which are redefining treatment paradigms. Collectively, these advancements reflect the profound influence of modern medicine on neuro-ophthalmology, paving the way for improved patient outcomes and fostering new avenues for research and clinical practice.

Conversion surgery for esophageal and esophagogastric junction cancer.

As a result of the recent advances in first-line treatment including chemotherapy, radiation therapy, targeted therapy, and immune checkpoint inhibitor immunotherapy (ICI) for locally advanced/metastatic initially unresectable esophageal and esophagogastric junction cancer, surgery aiming at cure after initial treatment, so-called "conversion surgery" has become more common in this field. Several studies have indicated encouraging survival outcomes for patients after conversion surgery with R0 resection. However, various issues, such the utility and the safety of conversion surgery remain unclear. In this review, we will focus on the surgical treatment for initially unresectable esophageal and esophagogastric junction cancer after first- or later- line treatment and review recent evidence regarding the safety and the efficacy of conversion surgery. Multidisciplinary treatment including surgery may serve as a novel treatment strategy for esophageal and esophagogastric junction cancer, thus provide a curative treatment option and potentially contribute to better prognosis for initially untreatable diseases.

Genome editing technologies and prospects for their use in biomedicine

Genome editing technologies and their modifications are an indispensable tool for studying the functions of individual molecules, obtaining cell lines and animals with specified properties, and developing promising approaches to the therapy of previously untreatable diseases. This review covers various aspects of genome editing technologies: from their biological significance to the principles of their functioning and the most promising areas of application in basic and applied research. Particular attention is paid to discussing the limitations of genome editing technologies, as well as the legal and ethical aspects of their application to human genome modification. This review may be of interest to a wide range of readers, including researchers wishing to learn more about genome editing technologies and planning their practical application.

Disease models of Leigh syndrome: From yeast to organoids.

Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.

AAV-mediated combination gene therapy of inducible Caspase 9 and miR-199a-5p is therapeutic in hepatocellular carcinoma.

Advanced-stage hepatocellular carcinoma (HCC) remains an untreatable disease with an overall survival of less than one year. One of the critical molecular mediators contributing to increased resistance to therapy and relapse, is increased hypoxia-inducible factor 1α (HIF-1α) levels, leading to metastasis of tumor cells. Several microRNAs are known to be dysregulated and impact HIF-1α expression in HCC. An in silico analysis demonstrated that hsa-miR-199a-5p is downregulated at various stages of HCC and is known to repress HIF-1α expression. Based on this analysis, we developed a combinatorial suicide gene therapy by employing hepatotropic Adeno-associated virus-based vectors encoding an inducible caspase 9 (iCasp9) and miR-199a. The overexpression of miR-199a-5p alone significantly decreased ( ~ 2-fold vs. Mock treated cells, p < 0.05) HIF-1α mRNA levels, with a concomitant increase in cancer cell cytotoxicity in Huh7 cells in vitro and in xenograft models in vivo. To further enhance the efficacy of gene therapy, we evaluated the synergistic therapeutic effect of AAV8-miR-199a and AAV6-iCasp9 in a xenograft model of HCC. Our data revealed that mice receiving combination suicide gene therapy exhibited reduced expression of HIF-1α ( ~ 4-fold vs. Mock, p < 0.001), with a significant reduction in tumor growth when compared to mock-treated animals. These findings underscore the therapeutic potential of downregulating HIF-1α during suicide gene therapy for HCC.

A familial subtype of gambling disorder.

Although family history of psychiatric disorders has often been considered potentially useful in understanding clinical presentations in patients, it is less clear what a positive gambling family history means for people with gambling disorder. We sought to understand the clinical impact of having a first-degree relative with gambling disorder in a sample of adults with gambling disorder. Data from 455 participants (aged 18-65 years) who had participated in previous pharmacological and psychotherapeutic clinical trials for gambling disorder were pooled in a secondary analysis. Demographic and clinical variables were compared between those who did versus did not have one or more first-degree relative(s) with gambling disorder. Additionally, we examined whether a family history of gambling disorder was associated with treatment outcome. 223 (49.0%) participants had at least one first-degree family member(s) with gambling disorder. In terms of clinical variables, family history of gambling disorder was significantly associated with being female, having an earlier age of gambling onset, longer duration of untreated gambling illness, a greater likelihood of developing legal problems secondary to gambling, and higher rates of alcohol use disorder in family members. Family history of gambling disorder was also associated with a greater gambling symptom improvement frompharmacotherapy. These results indicate that gamblers with a first-degree family member with a gambling disorder may have a unique clinical presentation and better response to treatment interventions.

Quality of life (QOL) of patients with schizophrenia and epilepsy attending an outpatient clinic in a tertiary care hospital in Sri Lanka

Background: Schizophrenia and epilepsy are chronic relapsing disorders, that share common disadvantages that affects QOL.Methods: A cross-sectional descriptive study was conducted on 68 patients with schizophrenia and 68 patients with epilepsy, presenting to psychiatry and neurology clinics of the Colombo South Teaching Hospital (CSTH). The validated Sinhala and Tamil version of the WHO QOL 100 was used to assess the QOL.Results: Schizophrenia group had poorer QOL in physical (p&lt;0.05), social (p&lt;0.01), independence (p&lt;0.05) and environmental (p&lt;0.05) domains, compared to epilepsy. Longer duration of illness (&gt; 5 years) was associated with poorer QOL in the independence (p&lt;0.05) and social domains (p&lt;0.05) and longer duration of untreated illness was associated with lower QOL in the physical (p&lt;0.01) and social domains (p&lt;0.01) in schizophrenia group.Conclusions: Patients with schizophrenia had poorer QOL compared to patients with epilepsy. Longer duration of untreated illness was associated with poorer QOL in both groups.

Transdiagnostic white matter controllability deficits across patients with affective and anxiety spectrum disorders

BackgroundAffective and anxiety disorders including major depression disorder (MDD), post-traumatic stress disorder (PTSD), and social anxiety disorder (SAD) are characterized by network dysconnectivity. Network controllability quantifies the capability of specific brain regions to impact functional dynamics based on the underlying structural connectome. This study aimed to investigate transdiagnostic and illness-specific network controllability alterations across these three disorders. Materials and methodsThe study enrolled 233 currently untreated and non-comorbid subjects, including 68 MDD patients, 51 PTSD patients, 46 SAD patients, and 68 healthy controls (HCs). White matter network controllability was compared among the four groups, and its associations with symptom severity and duration of untreated illness were evaluated. ResultsCompared with HCs, patients with PTSD, MDD and SAD exhibited reduced average controllability in the somatomotor, subcortical, and default mode network, notably in brain regions such as the superior frontal gyrus, postcentral gyrus, paracentral gyrus, pallidum, posterior cingulate, and putamen. MDD and SAD patients exhibited reduced average controllability in the left lateral occipital gyrus and bilateral accumbens. SAD patients showed reduced average controllability in the dorsal attention network. These controllability changes did not correlate with illness duration or symptom severity. LimitationsThe cross-sectional design limits causal inference, and adjusting for age and sex differences may not completely eliminate their influence on the results. ConclusionThe present study revealed shared and specific alterations of network controllability in MDD, PTSD, and SAD, suggesting reduced ability of specific brain regions/networks in driving the brain system into different functional states across these disorders.

Relationship between duration of undiagnosed illness, clinical features and cognitive impairment in bipolar disorder

Purpose: It is believed that a delay in the diagnosis of bipolar disorder may adversely affect the clinical course and outcome. This study aimed to investigate the relationship between diagnostic delay and clinical variables, as well as neurocognitive and social cognitive disorders Materials and methods: Eighty-four patients with bipolar disorder in remission were included in the study. Participants were evaluated using a neuropsychological battery that assessed verbal memory and learning, visual memory and learning, verbal fluency, attention, processing speed, executive functions, working memory, and social cognition. Results: The duration of undiagnosed illness was longer in patients with bipolar II disorder, those without psychotic features, those with at least one suicide attempt, those whose first episode was depressive, and those currently on antidepressants. A significant positive correlation was found between the duration of undiagnosed illness and scores on the Controlled Oral Word Association Test, total number of episodes, hypomanic episodes, depressive episodes, and their respective durations. Conversely, a significant negative correlation was found between the duration of undiagnosed illness and both the number and duration of manic episodes. Conclusion: We found that a delay in diagnosis and treatment was associated with more recurrences in bipolar disorder, an increased number of depressive episodes, and at least one lifetime suicide attempt. However, the association between extended periods of untreated illness and poor clinical and functional outcomes did not align with cognitive impairment.

Ferroptosis Inhibition: A Key Opportunity for the Treatment of Ischemia/Reperfusion Injury in Liver Transplantation.

The outcome after liver transplantation has improved in recent years, which can be attributed to superior storage and transportation conditions of the organs, as well as better peri- and postoperative management and advancements in surgical techniques. Nevertheless, there is an increasing discrepancy between the need for organs and their availability. Consequently, the mortality rate on the waiting list is high and continues to rise. One way of counteracting this trend is to increase the use of "expanded criteria donors." This means that more and more donors will be included, especially those who are older and having additional comorbidities (eg, steatosis). A major complication of any transplantation is the occurrence of ischemia/reperfusion injury (IRI), which often leads to liver dysfunction and failure. However, there have been various promising approaches to minimize IRI in recent years, but an effective and clinically applicable method to achieve a better outcome for patients after liver transplantation is still missing. Thereby, the so-called marginal organs are predominantly affected by IRI; thus, it is crucial to develop suitable and effective treatment options for patients. Recently, regulated cell death mechanisms, particularly ferroptosis, have been implicated to play a major role in IRI, including the liver. Therefore, inhibiting this kind of cell death modality presents a promising therapeutic approach for the management of this yet untreatable condition. Thus, this review provides an overview of the role of ferroptosis in liver IRI and transplantation and discusses possible therapeutic solutions based on ferroptosis inhibition to restrain IRI in marginal organs (especially steatosis and donation after circulatory death organs).

The use of orthogonal analytical approaches to profile lipid nanoparticle physicochemical attributes

Abstract Lipid nanoparticles have become a major disruptor within the drug delivery field of complex RNA molecules. The wide applicability of prototype nanomedicines have the potential to fill clinical requirements against current untreatable diseases. The uptake and implementation of analytical technologies to evaluate these prototype nanomedicines have not experienced similar growth rates hindering the translation of LNPs. Here, we evaluate a model RNA-LNP formulation with a selection of routine, and high-resolution orthogonal analytical techniques across studies on manufacturing process parameter impact and formulation stability evaluation under refrigerated and ultra-low temperatures. We analysed model cationic RNA complexed lipid nanoparticle formulation through process impact on formulation critical quality attributes, short term refrigerated stability evaluation, and frozen storage stability using zetasizer dynamic light scattering and nanoparticle tracking analysis. We also evaluated freeze/thaw induced stress on LNP formulation using high resolution field-flow fractionation. Statistical analysis and correlations between techniques were drawn to further enhance our understanding of LNP formulation design, and physiochemical attributes to facilitate LNP formulation clinical translation.

Can infrared light really be doing what we claim it is doing? Infrared light penetration principles, practices, and limitations.

Near infrared (NIR) light has been shown to provide beneficial treatment of traumatic brain injury (TBI) and other neurological problems. This concept has spawned a plethora of commercial entities and practitioners utilizing panels of light emitting diodes (LEDs) and promising to treat patients with TBI and other disorders, who are desperate for some treatment for their untreatable conditions. Unfortunately, an LED intended to deliver photonic energy to the human brain does not necessarily do what an LED pointed at a mouse brain does. There is a problem of scale. Extensive prior research has shown that infrared light from a 0.5-watt LED will not penetrate the scalp and skull of a human. Both the properties of NIR light and the manner in which it interacts with tissue are examined. Based on these principles, the shortcomings of current approaches to treating neurological disorders with NIR light are explored. Claims of clinical benefit from low-level LED-based devices are explored and the proof of concept challenged. To date, that proof is thin with marginal benefits which are largely transient. Extensive research has shown fluence at the level of the target tissue which falls within the range of 0.9 J/cm2 to 15 J/cm2 is most effective in activating the biological processes at the cellular level which underlie direct photobiomodulation. If low-level infrared light from LED devices is not penetrating the scalp and skull, then these devices certainly are not delivering that level of fluence to the neurons of the subjacent brain. Alternative mechanisms, such as remote photobiomodulation, which may underlie the small and transient benefits for TBI symptoms reported for low-power LED-based NIR studies are presented. Actionable recommendations for the field are offered.

Rapid and sensitive determination of residual prion infectivity from prion-decontaminated surfaces.

Prion diseases are untreatable fatal transmissible neurodegenerative diseases that affect a wide range of mammals, including humans, and are caused by PrPSc, the infectious self-templating conformation of the host-encoded protein, PrPC. Prion diseases can be transmitted via surfaces (e.g., forceps, EEG electrodes) in laboratory and clinical settings. Here, we use a combination of surface swabbing and real-time quaking-induced conversion (RT-QuIC) to test for residual surface-associated prions following prion disinfection. We found that treatment of several prion-contaminated laboratory and clinically relevant surfaces with either water or 70% EtOH resulted in robust detection of surface-associated prions. In contrast, treatment of surfaces with sodium hypochlorite resulted in a failure to detect surface-associated prions. RT-QuIC analysis of prion-contaminated stainless steel wires paralleled the findings of the surface swab studies. Importantly, animal bioassay and RT-QuIC analysis of the same swab extracts are in agreement. We report on conditions that may interfere with the assay that need to be taken into consideration before using this technique. Overall, this method can be used to survey laboratory and clinical surfaces for prion infectivity following prion decontamination protocols.IMPORTANCEPrion diseases can be accidentally transmitted in clinical and occupational settings. While effective means of prion decontamination exist, methods for determining the effectiveness are only beginning to be described. Here, we analyze surface swab extracts using real-time quaking-induced conversion (RT-QuIC) to test for residual prions following prion disinfection of relevant clinical and laboratory surfaces. We found that this method can rapidly determine the efficacy of surface prion decontamination. Importantly, examination of surface extracts with RT-QuIC and animal bioassay produced similar findings, suggesting that this method can accurately assess the reduction in prion titer. We identified surface contaminants that interfere with the assay, which may be found in clinical and laboratory settings. Overall, this method can enhance clinical and laboratory prion safety measures.

Intracellular Delivery of Antisense Oligonucleotides by Tri-Branched Cyclic Disulfide Units.

Therapeutic oligonucleotides, such as antisense DNA, show promise in treating previously untreatable diseases. However, their applications are still hindered by the poor membrane permeability of naked oligonucleotides. Therefore, it is necessary to develop efficient methods for intracellular oligonucleotide delivery. Previously, our group successfully developed disulfide-based Membrane Permeable Oligonucleotides (MPON), which achieved enhanced cellular uptake and gene silencing effects through an endocytosis-free uptake mechanism. Herein, we report a new molecular design for the next generation of MPON, called trimer MPON. The trimer MPON consists of a tri-branched backbone, three α-lipoic acid units, and a spacer linker between the oligonucleotides and tri-branched cyclic disulfide unit. We describe the design, synthesis, and functional evaluation of the trimer MPON, offering new insights into the molecular design for efficient oligonucleotide delivery.

Single-cell transcriptomics identifies aberrant glomerular angiogenic signalling in the early stages of WT1 kidney disease.

WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Epidemiology, diagnosis, and management of cardiac amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by the deposition of amyloid fibrils in the myocardium. It manifests in two primary subtypes: transthyretin cardiac amyloidosis (ATTR) and immunoglobulin light chain cardiac amyloidosis (AL). ATTR is further classified into wild-type and hereditary based on transthyretin gene mutation. Advances in diagnostics and therapeutics have transformed CA from a rare and untreatable condition to a more prevalent and manageable disease. Noninvasive diagnostic tools such as electrocardiography, echocardiography, and cardiac magnetic resonance can raise suspicion for CA; bone scintigraphy can non-invasively confirm ATTR, while AL necessitates histological confirmation. The severity of ATTR and AL can be assessed through serum biomarker-based staging. Treatment approaches differ, ranging from silencing or stabilizing transthyretin and degrading amyloid fibrils in ATTR to employing anti-plasma cell therapies and autologous stem cell transplantation in AL.

Assisted death in eating disorders: a systematic review of cases and clinical rationales.

Assisted dying for reasons solely related to an eating disorder (ED) has occurred in multiple countries, including those which restrict the practice to individuals with a terminal condition. The aims of this systematic review were to (1) identify all known cases of assisted deaths among patients with EDs and (2) describe the clinical rationales used to grant patients' requests for assisted death. We conducted a systematic search of peer-reviewed studies and publicly available government reports to identify cases of assisted death in patients with EDs. In reports that included qualitative data about the case, clinical rationales were extracted and grouped into domains by qualitative content analysis. We identified 10 peer-reviewed articles and 20 government reports describing at least 60 patients with EDs who underwent assisted dying between 2012 and 2024. Clinical rationales were categorized into three domains: irremediability, terminality, and voluntary request. Reports emphasized that patients with EDs who underwent assisted death had terminal, incurable, and/or untreatable conditions and had adequate decision-making capacity to make a life-ending decision. Most government reports did not include descriptive-enough data to verify psychiatric conditions. The results of our systematic review underscore considerable gaps in the reporting of assisted death in patients with psychiatric conditions, posing substantial concerns about oversight and public safety. In many cases, the clinical rationales that were used to affirm patients with EDs were eligible for assisted death lack validity and do not cohere with empirical understanding.

The Consequences of Misdiagnosing Race-Based Trauma Response in Black Men: A Critical Examination

ABSTRACT Mental illness is a significant public health concern prevalent in America. Over one in five U.S. adults are affected, yet less than half receive treatment. Among African Americans, only one in three seek treatment with statically lower rates among Black males. Therefore, an accurate diagnosis is crucial for appropriate treatment, while misdiagnosis leads to stigma, discrimination, and untreated illness. This paper examines the implications of misdiagnosing trauma responses in Black men, highlighting systemic biases that impede suitable care and perpetuate negative narratives. The authors propose a conceptual framework incorporating historical trauma, discrimination, and traumatic stress reactions, emphasizing the need for cultural competence and humility. This framework involves public narratives that influence perceptions and judgments, reviewing research evidence, advocating for competent trauma assessments, community empowerment, and future research directions. This paper underscores the importance of understanding and addressing the unique challenges Black men face in mental health diagnosis and treatment.

O-230 The ethics of disclosing reported conditions in donor-conceived offspring to recipients of the same donor

Abstract Study question To what extent should new genetic risk information, identified after donation, be disclosed to recipients? Summary answer Withholding new genetic risk information from donor sperm recipients may sometimes be ethically justified or even preferred. What is known already In some cases, donor-conceived persons are born with (suspected) harmful genetic mutations. These occurrences may flag increased genetic risks for others if the donor is used for multiple recipients. Genetic conditions can also emerge in donors or their families after donation. Current guidelines, such as those established by the European Directorate for the Quality of Medicines &amp; HealthCare, recommend contacting recipients “in the case of a diagnosis that may seriously affect a child’s health”. However, the specific timing of such disclosures and the circumstances under which (or even whether) information may be withheld are unclear. Study design, size, duration This normative analysis draws initial insights from empirical data obtained from a quantitative study into current practices of fertility clinics and extends to a comprehensive review of academic literature and international guidelines. It evaluates current practices and explores the justifications for (not) informing recipients about (possible) genetic risks linked to their donor, guided by bioethical principles. Participants/materials, setting, methods In June 2023, an electronic questionnaire was sent to all fertility clinics in Belgium to obtain information on current practices regarding the management of genetic mutations in donor treatment. The responses from 15 clinics provided empirical insights that served as an impetus for the subsequent normative analysis. This analysis integrated the findings with normative considerations using the ‘wide reflective equilibrium’ method. Main results and the role of chance Our findings revealed considerable diversity in current practices. Some clinics always informed recipients of newly identified genetic risks (possibly) related to their donor, while others based their decision on various factors. The main arguments for disclosing this information are clinical utility (beneficence) and respect for the recipient’s autonomy. Withholding health-related information can be harmful, especially if it impedes diagnosis and treatment. Moreover, when sperm samples are reserved for additional children from the same donor, disclosure facilitates better-informed reproductive decisions. Conversely, non-disclosure is sometimes justified on the same grounds. If the recurrence risk is absent or equivalent to the general population risk level, disclosure could cause undue alarm and overtreatment. These harms may outweigh the marginal benefits of (immediate) disclosure, particularly for unconfirmed, late-onset, non-severe, and untreatable conditions. Respecting autonomy also implies recognizing the right not to know, by allowing recipients to prespecify the type of information they wish to receive (e.g., untreatable conditions). However, other factors can complicate this assessment. When early diagnosis is crucial, confirming the donor’s link to the reported condition or determining the recurrence risk may take too long. Additionally, a thorough risk analysis becomes more intricate if insemination is planned, embryos are created, or during pregnancy. Limitations, reasons for caution This analysis focuses on cases with anonymous donors and excludes situations involving identifiable and known donors. If the recipient and donor know each other, a distinct set of ethical considerations and duties may emerge. Wider implications of the findings The need for a nuanced, context-sensitive ethical framework for the disclosure of (potential) harmful genetic mutations in a donor to recipients of donor sperm is highlighted. Such a framework could inspire policy development and support ethical decision-making in fertility treatments. Trial registration number Not applicable

Addressing Confusion and Inconsistencies Surrounding the Provider Role in Medical Cannabis Programs

Abstract More than 40 states in the United States have established medical Cannabis programs that authorize the use of Cannabis for specific medical conditions. Initially, these medical Cannabis programs aimed to offer compassionate care primarily for terminal or rare, untreatable conditions. However, the scope of these programs has broadened to include nonterminal and more common conditions, including various medical and mental disorders. This expansion introduces several health care challenges: a lack of robust research evidence for many listed conditions, a sense of unpreparedness among providers, and a disparity in provider roles, expectations, and responsibilities across different states, leading to potential confusion. To address these issues, medical organizations need to develop expert consensus or guidelines that underscore evidence-based shared decision-making and patient monitoring standards. Medical education should also include such training. Concurrently, medical providers must prioritize evidence-based treatment over public opinion, exercise clinical judgment, and take responsibility for their recommendations.