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Craniotubular dysplasia, Ikegawa type (OMIM #619727) denotes the autosomal recessive skeletal disease identified in 2021 featuring blindness acquired in childhood. Five young members of four Indian families harbored a homozygous indel within TMEM53 (OMIM *619722), the gene that encodes transmembrane protein 53 (TMEM53). When intact, TMEM53 spans the nuclear envelope of osteoprogenitor cells, dampens BMP-SMAD signaling, and thereby slows bone formation. Consequently, defective TMEM53 accelerates osteogenesis. Herein, an American boy is compound heterozygous for a novel deletion and a novel missense mutation within TMEM53. His vision and sensorineural hearing became impaired. Radiographic survey revealed diploic thickening of his skull, broad calvarial and facial bones, skeletal modeling errors, vertebral body flattening, wide ribs, and osteopenia of expanded bones. DXA areal bone density (gm/cm2) Z-scores were low. His optic, auditory, and spinal canals were narrow. Mineral metabolism was intact. Serum alkaline phosphatase and osteocalcin levels were normal yet CTX was high. Iliac crest histomorphometry documented accelerated bone formation. His acute vision loss briefly improved following prednisone administration, optic canal decompression, and optic nerve sheath fenestration, but then progressed despite further surgeries and zoledronate treatment aimed to suppress bone turnover. Next generation sequencing of genes associated with elevated skeletal mass, including from high bone turnover, did not suggest an etiology. Whole genome sequencing then revealed within TMEM53: i) a paternally transmitted 54-base deletion, which included the mRNA splice acceptor site for exon 2 as well as 31 bases of exonic sequence (c. 62-23_92del), and ii) a maternally transmitted missense variant (c.650C > T, p.Ser217Leu: NM_024587.4/NP_078863.2) which is extremely rare in gnomAD (frequency = 0.000036), replaces Ser217 highly conserved across species, and is scored as damaging by SIFT and Mutation Taster. We call this new osteopathy TMEM53 craniotubular dysplasia.
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Cegueira , Proteínas de Membrana , Humanos , Masculino , Cegueira/genética , Cegueira/congênito , Proteínas de Membrana/genética , Doenças do Desenvolvimento Ósseo/genética , CriançaRESUMO
Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly, is one of the most common reasons for pediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate CH risk gene, however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated CH (totaling 2,697 parent-proband trios and 8,091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, CH, developmental delay, dysmorphic features, and other structural brain defects including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbor arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven additional patients with rare, damaging, unphased or transmitted variants of uncertain significance were also identified. NHL-domain variants of TRIM71 exhibited impaired binding to the canonical TRIM71 target CDKN1A; other variants failed to direct the subcellular localization of TRIM71 to processing bodies. Single-cell transcriptomic analysis of human embryos revealed expression of TRIM71 in early first-trimester neural stem cells of the brain. These data show TRIM71 is essential for human brain morphogenesis and that TRIM71 mutations cause a novel neurodevelopmental syndrome featuring ventriculomegaly and CH.
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This paper argues that one problem that besets black-box AI is that it lacks algorithmic justifiability. We argue that the norm of shared decision making in medical care presupposes that treatment decisions ought to be justifiable to the patient. Medical decisions are justifiable to the patient only if they are compatible with the patient's values and preferences and the patient is able to see that this is so. Patient-directed justifiability is threatened by black-box AIs because the lack of rationale provided for the decision makes it difficult for patients to ascertain whether there is adequate fit between the decision and the patient's values. This paper argues that achieving algorithmic transparency does not help patients bridge the gap between their medical decisions and values. We introduce a hypothetical model we call Justifiable AI to illustrate this argument. Justifiable AI aims at modelling normative and evaluative considerations in an explicit way so as to provide a stepping stone for patient and physician to jointly decide on a course of treatment. If our argument succeeds, we should prefer these justifiable models over alternatives if the former are available and aim to develop said models if not.
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The aim of this study was to investigate the impact of orthognathic therapy on patients' quality of life. Therefore, a systematic review was conducted including all prospective studies that compared pretherapeutic and posttherapeutic Oral Health Impact Profile (OHIP) or Overall Quality of Life (OQOL) questionnaire scores. Studies in patients with congenital deformities, clefts, or posttraumatic or cancer-associated deformities were excluded. Overall, 23 prospective studies were included; 8 used OHIP, 9 used OQOL and 6 used both questionnaires. A total of 1039 patients were identified (60.29% women, 39.71% men), with a mean age of 45.17 years. All analyzed studies showed in both OHIP and OQLQ an improvement of the quality of life in patients after orthognathic therapy. While improved scores could be observed in all investigated criteria, the studies demonstrated that social and aesthetic aspects showed the most prominent impact. Comparison of different Angle Classes showed, furthermore, that Class III patients had an even greater advantage over those with a Class II deformity. The review confirms that the quality of life in patients with orthognathic therapy improves significantly in all observed aspects. With regard to Angle Classes, Class III patients showed an even greater improvement than Class II patients.
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Cirurgia Ortognática , Procedimentos Cirúrgicos Ortognáticos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estética Dentária , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
Monitored Emergency Use of Unregistered and Experimental Interventions (MEURI) is an ethical framework developed by the WHO for using unproven interventions in public health emergencies outside the context of medical research. It is mainly intended for use when medical research would be impracticable, but there is still a need to systematically gather data about unproven interventions. As such, it is designed as something of a middle ground between clinical and research ethical frameworks.However, I argue that MEURI does not truly lie at the intersection of clinical care and research. Due to its intent, structure and oversight requirements, it takes on most of the crucial features of research, to the point that it is best understood as a form of research. As a result, cases where MEURI could practicably be applied should instead make use of existing research frameworks. For those circumstances where research is truly impracticable, a more straightforward oversight system than MEURI is needed. While existing practices of compassionate use have some applicability, proposals to make use of clinical ethics committees to oversee unproven interventions may help achieve the right balance in acting in a patient's best interests when the relevant evidence base is weak.
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PURPOSE: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants. METHODS: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model. RESULTS: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model. CONCLUSION: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity.
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RNA de Transferência , Peixe-Zebra , Animais , Humanos , Mutação , Peixe-Zebra/genética , Alvo Mecanístico do Complexo 1 de Rapamicina , Ligases , FenótipoRESUMO
The COVID-19 pandemic revealed numerous weaknesses in pandemic preparedness and response, including underfunding, inadequate surveillance, and inequitable distribution of countermeasures. To overcome these weaknesses for future pandemics, WHO released a zero draft of a pandemic treaty in February, 2023, and subsequently a revised bureau's text in May, 2023. COVID-19 made clear that pandemic prevention, preparedness, and response reflect choices and value judgements. These decisions are therefore not a purely scientific or technical exercise, but are fundamentally grounded in ethics. The latest treaty draft reflects these ethical considerations by including a section entitled Guiding Principles and Approaches. Most of these principles are ethical-they establish core values that undergird the treaty. Unfortunately, the treaty draft's set of principles are numerous, overlapping, and show inadequate coherence and consistency. We propose two improvements to this section of the draft pandemic treaty. First, key guiding ethical principles should be clearer and more precise than they currently are. Second, the link between ethical principles and policy implementation should be clearly established and define boundaries on acceptable interpretation, ensuring that signatories abide by these principles.
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COVID-19 , Pandemias , Humanos , Pandemias/prevenção & controle , Cooperação InternacionalRESUMO
With the world grappling with continued spread of monkeypox internationally, vaccines play a crucial role in mitigating the harms from infection and preventing spread. However, countries with the greatest need - particularly historically endemic countries with the highest monkeypox case-fatality rates - are not able to acquire scarce vaccines. This is unjust, and requires rectification through equitable allocation of vaccines globally. We propose applying the Fair Priority Model for such allocation, which emphasizes three key principles: 1) preventing harm; 2) prioritizing the disadvantaged; and 3) treating people with equal moral concern. Post-exposure prophylaxis (PEPV) has the most potential to mitigate harm, and so ensuring countries have sufficient supply for PEPV should be the first priority. And historically endemic countries, which face disadvantages that compound potential harms from monkeypox, should be the first recipients of such vaccines. Once sufficient supply is allocated for countries to apply PEPV, global allocation could move on to pre-exposure prophylaxis (PrEP), again prioritizing historically endemic countries first before distribution to the rest of the global community, based on projected number of cases and vulnerability to harm.
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Mpox , Profilaxia Pré-Exposição , Vacinas , Humanos , Mpox/epidemiologia , Mpox/prevenção & controle , Profilaxia Pós-Exposição , Populações VulneráveisRESUMO
Countermeasures for mpox (formerly known as monkeypox), primarily vaccines, have been in limited supply in many countries during outbreaks. Equitable allocation of scarce resources during public health emergencies is a complex challenge. Identifying the objectives and core values for the allocation of mpox countermeasures, using those values to provide guidance for priority groups and prioritisation tiers, and optimising allocation implementation are important. The fundamental values for the allocation of mpox countermeasures are: preventing death and illness; reducing the association between death or illness and unjust disparities; prioritising those who prevent harm or mitigate disparities; recognising contributions to combating an outbreak; and treating similar individuals similarly. Ethically and equitably marshalling available countermeasures requires articulating these fundamental objectives, identifying priority tiers, and recognising trade-offs between prioritising the people at the highest risk of infection and the people at the highest risk of harm if infected. These five values can provide guidance on preferable priority categories for a more ethically sound response and suggest methods for optimising allocation of countermeasures for mpox and other diseases for which countermeasures are in short supply. Properly marshalling available countermeasures will be crucial for future effective and equitable national responses to outbreaks.
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Monkeypox virus , Mpox , Humanos , Mpox/epidemiologia , Mpox/prevenção & controle , Surtos de Doenças/prevenção & controle , Saúde PúblicaRESUMO
The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development.
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Proteínas de Drosophila , Doenças do Sistema Nervoso , Adulto , Animais , Humanos , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Mutação/genética , RNA MensageiroRESUMO
This paper explores the ethical challenges in deciding whether to vaccinate individuals lacking the decision-making capacity needed to provide informed consent during a public health emergency like COVID-19. The best interests standard ordinarily governs such decisions, which under the law in jurisdictions like England, Wales and Singapore takes into account the individual's past wishes and present preferences. However, in a public health emergency, the interests of third parties become more salient: those whom the unvaccinated individual might expose to infection have an interest in the individual's being vaccinated. While current mental capacity law has not been interpreted to take such public health considerations into account, we argue that such considerations are nevertheless ethically relevant, and can legitimately be weighed up alongside other considerations such as the preferences of the individual and impacts on their health. This is most relevant for individuals lacking decision-making capacity who have previously declined or presently resist vaccination. The public health impact of vaccination may in some instances be enough to outweigh preferences of the individual and justify providing vaccination against their past or present wishes.
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The development of some COVID-19 vaccines by private companies like Moderna and Sanofi-GSK has been substantially funded by various governments. While the Sanofi CEO has previously suggested that countries that fund this development ought to be given some priority, this suggestion has not been taken seriously in the literature. Considerations of nationalism, sustainability, need, and equitability have been more extensively discussed with respect to whether and how much a country is entitled to advance purchase orders of the vaccine under conditions of absolute scarcity. Yet, little attention has been paid to whether prior investment into developing a vaccine entitles a country to some priority with respect to these orders. Moreover, while not a majority view, some survey results show that a significant minority of the populace does endorse some view like this. This article argues that the minority have a point: recognizing funder countries some priority is justified by the weak Lockean claim (WLC). According to the WLC, the fact that someone has contributed to the development of something gives them some entitlement to the resultant product. This article will defend the WLC, and address objections to the argument, including those pertaining to questions of historical injustice and medical need. This argument does not imply an unconstrained entitlement. Rather, contribution to development is one morally relevant factor that must be tempered by and weighed against potentially more substantial claims to priority based on need, equity, and other considerations.
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COVID-19 , Vacinas , Humanos , Vacinas contra COVID-19 , COVID-19/prevenção & controle , GovernoRESUMO
In "Compulsory Research in Learning Health Care: Against a Minimal Risk Limit," Robert Steel offers an argument in favor of compelling individuals to participate in some research that poses more than minimal risk. In his view, the ethics of compulsory research turns on questions of fair distribution of benefits and burdens, within a paradigm analogous to health care resource rationing. We do not dispute that it may theoretically be permissible to compel participation in certain circumstances, including those that rise above minimal risk. Nevertheless, Steel's argument for this conclusion faces several challenges that ultimately render it unconvincing in its present form. First, compulsion should be subject to a "necessity" criterion, which substantially limits its applicable scope. Second, compulsion is a prima facie rights violation that requires stronger ethical justification than Steel offers. And third, substantial structural and motivational differences between rationing and compulsion render the analogy inapt.
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Dissidências e Disputas , Alocação de Recursos para a Atenção à Saúde , Humanos , Princípios Morais , Motivação , AçoRESUMO
Autism spectrum disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders and occurs in all racial, ethnic, and socioeconomic groups. Cutting-edge technologies are contributing to understanding genetic underpinnings in ASD. The reported patient is a 32-year-old male and as an infant was noted to have microcephaly, hypospadias, pulmonary vascular anomaly, and small stature. He was diagnosed with Cornelia De Lange Syndrome (CDLS) at that time based on the clinical features. As a child, he had autistic features and intellectual disabilities and as diagnoses with autism and intellectual disability. He was referred as an adult to our neurodiversity clinic and a full exome trio sequencing with reflex to mitochondrial genes identified a de novo variant of uncertain significance in a candidate gene, DCAF1. The specific variant was c.137 C > T (p.Thr46Ile) in exon 4 in the DCAF1 gene. In silico analysis supports a deleterious effect on protein structure/function. DCAF1 participates with DDB1 and CUL4 as a part of the E3 ubiquitin ligase complex. The E3 ligase complex has been associated with a syndromic form of X-linked intellectual disability. The DDB1/CUL4 E3 ubiquitination complex plays a role in methylation-dependent ubiquitination. Next, a methylation study identified a signature similar to the methylation pattern found in X- linked intellectual disability type 93. This is associated with variants of the BRWD3 gene, which is linked with the functioning of the DDB1/CUL4 E3 ubiquitination complex. Taken together, this suggests that the de novo DCAF1 variant may be a newly identified molecular cause of autism and intellectual disability.
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Neurodevelopmental disorders have steadily increased in incidence in the United States. Over the past decade, there have been significant changes in clinical diagnoses and treatments some of which are due to the increasing adoption of pharmacogenomics (PGx) by clinicians. In this pilot study, a multidisciplinary team at the Arkansas Children's Hospital North West consulted on 27 patients referred for difficult-to-manage neurodevelopmental and/or neurobehavioral disorders. The 27 patients were evaluated by the team using records review, team discussion, and pharmacogenetic testing. OneOme RightMed® (Minneapolis, MN, USA) and the Arkansas Children's Hospital comprehensive PGx test were used for drug prescribing guidance. Of the 27 patients' predicted phenotypes, the normal metabolizer was 11 (40.8%) for CYP2C19 and 16 (59.3%) for CYP2D6. For the neurodevelopmental disorders, the most common comorbid conditions included attention-deficit hyperactivity disorder (66.7%), anxiety disorder (59.3%), and autism (40.7%). Following the team assessment and PGx testing, 66.7% of the patients had actionable medication recommendations. This included continuing current therapy, suggesting an appropriate alternative medication, starting a new therapy, or adding adjunct therapy (based on their current medication use). Moreover, 25.9% of patients phenoconverted to a CYP2D6 poor metabolizer. This retrospective chart review pilot study highlights the value of a multidisciplinary treatment approach to deliver precision healthcare by improving physician clinical decisions and potentially impacting patient outcomes. It also shows the feasibility to implement PGx testing in neurodevelopmental/neurobehavioral disorders.
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The success of digital COVID-19 contact tracing requires a strategy that successfully addresses the digital divide-inequitable access to technology such as smartphones. Lack of access both undermines the degree of social benefit achieved by the use of tracing apps, and exacerbates existing social and health inequities because those who lack access are likely to already be disadvantaged. Recently, Singapore has introduced portable tracing wearables (with the same functionality as a contact tracing app) to address the equity gap and promote public health. We argue that governments have an ethical obligation to ensure fair access to the protective benefits of contract tracing during the pandemic and that wearables are an effective way of addressing some important equity issues. The most contentious issues about contact tracing apps have been the potential infringements of privacy and individual liberty, especially where the use of apps or other technology (such as wearables or QR codes) is required for access to certain spaces. Here we argue that wearables, as opposed to apps alone, will make a digital contact tracing mandate more practical and explain some conditions under which such a mandate would be justified. We focus on Singapore as a case study that has recently deployed contact tracing wearables nationally, but also reference debate about wearables in Australia and New Zealand. Our analysis will be relevant to counties trialling similar portable tracing wearables.