Advancing disability-inclusive climate research and action, climate justice, and climate-resilient development.

Globally, more than 1 billion people with disabilities are disproportionately and differentially at risk from the climate crisis. Yet there is a notable absence of climate policy, programming, and research at the intersection of disability and climate change. Advancing climate justice urgently requires accelerated disability-inclusive climate action. We present pivotal research recommendations and guidance to advance disability-inclusive climate research and responses identified by a global interdisciplinary group of experts in disability, climate change, sustainable development, public health, environmental justice, humanitarianism, gender, Indigeneity, mental health, law, and planetary health. Climate-resilient development is a framework for enabling universal sustainable development. Advancing inclusive climate-resilient development requires a disability human rights approach that deepens understanding of how societal choices and actions-characterised by meaningful participation, inclusion, knowledge diversity in decision making, and co-design by and with people with disabilities and their representative organisations-build collective climate resilience benefiting disability communities and society at large while advancing planetary health.

Administration of a Bacterial Lysate to the Airway Compartment Is Sufficient to Inhibit Allergen-Induced Lung Eosinophilia in Germ-free Mice.

The nexus between eosinophils and microbes is attracting increasing attention. We previously showed that airway administration of sterile microbial products contained in dust collected from traditional dairy farms virtually abrogated broncho-alveolar lavage (BAL) eosinophilia and other cardinal asthma phenotypes in allergen-sensitized specific pathogen-free (SPF) mice. Interestingly, comparable inhibition of allergen-induced BAL eosinophilia and promotion of airway barrier integrity were found upon administration of a sterile, pharmacological grade bacterial lysate, OM-85, to the airway compartment of allergen-sensitized SPF mice. Here we asked whether intrinsic properties of airway-delivered microbial products were sufficient to inhibit allergic lung inflammation or whether these effects were mediated by reprogramming of the host microbiota. We compared germ-free (GF) mice and offspring of GF mice associated with healthy mouse gut microbiota and maintained under SPF conditions for multiple generations (Ex-GF mice). These mice were treated intra-nasally with OM-85 and evaluated in the OVA and Alternaria models of allergic asthma focusing primarily on BAL eosinophilia. Levels of allergen-induced BAL eosinophilia were comparable in GF and conventionalized Ex-GF mice. Airway administration of the OM-85 bacterial lysate was sufficient to inhibit allergen-induced lung eosinophilia in both Ex-GF and GF mice, suggesting that host microbiota are not required for the protective effects of bacterial products in these models and local airway exposure to microbial products is an effective source of protection. OM-85-dependent inhibition of BAL eosinophilia in GF mice was accompanied by suppression of lung type-2 cytokines and eosinophil-attracting chemokines, suggesting that OM-85 may work at least by decreasing eosinophil lung recruitment.

The Pulmonary Endothelial Glycocalyx Modifications in Glypican 1 Knockout Mice Do Not Affect Lung Endothelial Function in Physiological Conditions.

The endothelial glycocalyx is a dynamic signaling surface layer that is involved in the maintenance of cellular homeostasis. The glycocalyx has a very diverse composition, with glycoproteins, proteoglycans, and glycosaminoglycans interacting with each other to form a mesh-like structure. Due to its highly interactive nature, little is known about the relative contribution of each glycocalyx constituent to its overall function. Investigating the individual roles of the glycocalyx components to cellular functions and system physiology is challenging, as the genetic manipulation of animals that target specific glycocalyx components may result in the development of a modified glycocalyx. Thus, it is crucial that genetically modified animal models for glycocalyx components are characterized and validated before the development of mechanistic studies. Among the glycocalyx components, glypican 1, which acts through eNOS-dependent mechanisms, has recently emerged as a player in cardiovascular diseases. Whether glypican 1 regulates eNOS in physiological conditions is unclear. Herein, we assessed how the deletion of glypican 1 affects the development of the pulmonary endothelial glycocalyx and the impact on eNOS activity and endothelial function. Male and female 5-9-week-old wild-type and glypican 1 knockout mice were used. Transmission electron microscopy, immunofluorescence, and immunoblotting assessed the glycocalyx structure and composition. eNOS activation and content were assessed by immunoblotting; nitric oxide production was assessed by the Griess reaction. The pulmonary phenotype was evaluated by histological signs of lung injury, in vivo measurement of lung mechanics, and pulmonary ventilation. Glypican 1 knockout mice showed a modified glycocalyx with increased glycocalyx thickness and heparan sulfate content and decreased expression of syndecan 4. These alterations were associated with decreased phosphorylation of eNOS at S1177. The production of nitric oxides was not affected by the deletion of glypican 1, and the endothelial barrier was preserved in glypican 1 knockout mice. Pulmonary compliance was decreased, and pulmonary ventilation was unaltered in glypican 1 knockout mice. Collectively, these data indicate that the deletion of glypican 1 may result in the modification of the glycocalyx without affecting basal lung endothelial function, validating this mouse model as a tool for mechanistic studies that investigate the role of glypican 1 in lung endothelial function.

Assessing the implementation of user-centred design standards on assistive technology for persons with visual impairments: a systematic review.

Despite scientific and technological advances in the field of assistive technology (AT) for people with visual impairment (VI), technological designs are frequently based on a poor understanding of the physical and social context of use, resulting in devices that are less than optimal for their intended beneficiaries. To resolve this situation, user-centred approaches in the development process of AT have been widely adopted in recent years. However, there is a lack of systematization on the application of this approach. This systematic review registered in PROSPERO (CRD42022307466), assesses the application of the ISO 9241-210 human-centred design principles in allegedly "user-centred designed" AT developments for persons with VI (see Supplementary PROSPERO Protocol). The results point to a wide variation of the depth of understanding of user needs, a poor characterization of the application of the User Centred Design (UCD) approach in the initial design phases or in the early prototyping, and a vague description of user feedback and device iteration. Among the principles set out in ISO 9241-210, the application of 5.6: "the design team includes multidisciplinary skills and perspectives" is the one for which the least evidence is found. The results show there is not enough evidence to fully assess the impact of UCD in (1) promoting innovation regarding AT products and practices, and (2) Judging if AT produced following such standards is leading to better user access, wellbeing outcomes and satisfaction. To address this gap it is necessary to, first, generate better implementation of UCD in AT development and second, to strengthen evidence regarding the implementation and outcomes of using UCD for AT. To better engage with the realities of persons with VI, we propose capacity building across development teams regarding UCD, its principles and components; better planning for UCD implementation; and cross-fertilization across engineering disciplines and social and clinical science. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=307466 PROSPERO (CRD42022307466).

Asthma-protective agents in dust from traditional farm environments.

BACKGROUND: Growing up on traditional European or US Amish dairy farms in close contact with cows and hay protects children against asthma, and airway administration of extracts from dust collected from cowsheds of those farms prevents allergic asthma in mice. OBJECTIVES: This study sought to begin identifying farm-derived asthma-protective agents. METHODS: Our work unfolded along 2 unbiased and independent but complementary discovery paths. Dust extracts (DEs) from protective and nonprotective farms (European and Amish cowsheds vs European sheep sheds) were analyzed by comparative nuclear magnetic resonance profiling and differential proteomics. Bioactivity-guided size fractionation focused on protective Amish cowshed DEs. Multiple in vitro and in vivo functional assays were used in both paths. Some of the proteins thus identified were characterized by in-solution and in-gel sodium dodecyl sulfate-polyacrylamide gel electrophoresis enzymatic digestion/peptide mapping followed by liquid chromatography/mass spectrometry. The cargo carried by these proteins was analyzed by untargeted liquid chromatography-high-resolution mass spectrometry. RESULTS: Twelve carrier proteins of animal and plant origin, including the bovine lipocalins Bos d 2 and odorant binding protein, were enriched in DEs from protective European cowsheds. A potent asthma-protective fraction of Amish cowshed DEs (≈0.5% of the total carbon content of unfractionated extracts) contained 7 animal and plant proteins, including Bos d 2 and odorant binding protein loaded with fatty acid metabolites from plants, bacteria, and fungi. CONCLUSIONS: Animals and plants from traditional farms produce proteins that transport hydrophobic microbial and plant metabolites. When delivered to mucosal surfaces, these agents might regulate airway responses.

The United Nations convention on the rights of persons with disabilities, neuroscience, and criminal legal capacity.

The United Nations Convention on the Rights of Persons with Disabilities requires states parties to 'recognize that persons with disabilities enjoy legal capacity on an equal basis with others in all aspects of life.' This mandate has sparked debate about the interpretation of legal capacity, including within the criminal context as applied to the retrogressively named 'insanity defense.' Yet, under-examined are two questions: First, what defenses should defendants with psychosocial disabilities be able to invoke during criminal prosecutions? Second, what kind of evidence is consistent with, on the one hand, determining a defendant's decision-making capacity to establish culpability and, on the other hand, the right to equal recognition before the law? Developments in neuroscience offer a unique prism to grapple with these issues. We argue that neuroscientific evidence of impaired decision-making, insofar as it presents valid and interpretable diagnostic information, can be a useful tool for influencing judicial decision-making and outcomes in criminal court. In doing so, we oppose the argument espoused by significant members of the global disability rights community that bioscientific evidence of psychosocial disability should be inadmissible to negate criminal responsibility. Such a position risks more defendants being punished harshly, sentenced to death, and placed in solitary confinement.

Redox regulation of RAD51 Cys319 and homologous recombination by peroxiredoxin 1.

RAD51 is a critical recombinase that functions in concert with auxiliary mediator proteins to direct the homologous recombination (HR) DNA repair pathway. We show that Cys319 RAD51 possesses nucleophilic characteristics and is important for irradiation-induced RAD51 foci formation and resistance to inhibitors of poly (ADP-ribose) polymerase (PARP). We have previously identified that cysteine (Cys) oxidation of proteins can be important for activity and modulated via binding to peroxiredoxin 1 (PRDX1). PRDX1 reduces peroxides and coordinates the signaling actions of protein binding partners. Loss of PRDX1 inhibits irradiation-induced RAD51 foci formation and represses HR DNA repair. PRDX1-deficient human breast cancer cells and mouse embryonic fibroblasts display disrupted RAD51 foci formation and decreased HR, resulting in increased DNA damage and sensitization of cells to irradiation. Following irradiation cells deficient in PRDX1 had increased incorporation of the sulfenylation probe DAz-2 in RAD51 Cys319, a functionally-significant, thiol that PRDX1 is critical for maintaining in a reduced state. Molecular dynamics (MD) simulations of dT-DNA bound to a non-oxidized RAD51 protein showed tight binding throughout the simulation, while dT-DNA dissociated from an oxidized Cys319 RAD51 filament. These novel data establish RAD51 Cys319 as a functionally-significant site for the redox regulation of HR and cellular responses to IR.

Ethical and Public Health Considerations for Integrating Physicians with Mental Disability into the Physician Workforce.

Stigma against mental disability within the medical field continues to impose significant barriers on physicians and trainees. Here, we examine several implications of this stigma and propose steps toward greater inclusion of persons with mental disabilities in the physician workforce.

Airway administration of OM-85, a bacterial lysate, blocks experimental asthma by targeting dendritic cells and the epithelium/IL-33/ILC2 axis.

BACKGROUND: Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral administration of OM-85, a standardized lysate of human airways bacteria, is widely used empirically to prevent respiratory infections and a clinical trial is testing its ability to prevent asthma in high-risk children. We previously showed that intranasal administration of microbial products from farm environments abrogates experimental allergic asthma. OBJECTIVES: We sought to investigate whether direct administration of OM-85 to the airway compartment protects against experimental allergic asthma; and to identify protective cellular and molecular mechanisms activated through this natural route. METHODS: Different strains of mice sensitized and challenged with ovalbumin or Alternaria received OM-85 intranasally, and cardinal cellular and molecular asthma phenotypes were measured. Airway transfer experiments assessed whether OM-85-treated dendritic cells protect allergen-sensitized, OM-85-naive mice against asthma. RESULTS: Airway OM-85 administration suppressed allergic asthma in all models acting on multiple innate and adaptive immune targets: the airway epithelium/IL-33/ILC2 axis, lung allergen-induced type 2 responses, and dendritic cells whose Myd88/Trif-dependent tolerogenic reprogramming was sufficient to transfer OM-85-induced asthma protection. CONCLUSIONS: We provide the first demonstration that administering a standardized bacterial lysate to the airway compartment protects from experimental allergic asthma by engaging multiple immune pathways. Because protection required a cumulative dose 27- to 46-fold lower than the one reportedly active through the oral route, the efficacy of intranasal OM-85 administration may reflect its direct access to the airway mucosal networks controlling the initiation and development of allergic asthma.

The OM-85 bacterial lysate inhibits SARS-CoV-2 infection of epithelial cells by downregulating SARS-CoV-2 receptor expression.

BACKGROUND: Treatments for coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are urgently needed but remain limited. SARS-CoV-2 infects cells through interactions of its spike (S) protein with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) on host cells. Multiple cells and organs are targeted, particularly airway epithelial cells. OM-85, a standardized lysate of human airway bacteria with strong immunomodulating properties and an impeccable safety profile, is widely used to prevent recurrent respiratory infections. We found that airway OM-85 administration inhibits Ace2 and Tmprss2 transcription in the mouse lung, suggesting that OM-85 might hinder SARS-CoV-2/host cell interactions. OBJECTIVES: We sought to investigate whether and how OM-85 treatment protects nonhuman primate and human epithelial cells against SARS-CoV-2. METHODS: ACE2 and TMPRSS2 mRNA and protein expression, cell binding of SARS-CoV-2 S1 protein, cell entry of SARS-CoV-2 S protein-pseudotyped lentiviral particles, and SARS-CoV-2 cell infection were measured in kidney, lung, and intestinal epithelial cell lines, primary human bronchial epithelial cells, and ACE2-transfected HEK293T cells treated with OM-85 in vitro. RESULTS: OM-85 significantly downregulated ACE2 and TMPRSS2 transcription and surface ACE2 protein expression in epithelial cell lines and primary bronchial epithelial cells. OM-85 also strongly inhibited SARS-CoV-2 S1 protein binding to, SARS-CoV-2 S protein-pseudotyped lentivirus entry into, and SARS-CoV-2 infection of epithelial cells. These effects of OM-85 appeared to depend on SARS-CoV-2 receptor downregulation. CONCLUSIONS: OM-85 inhibits SARS-CoV-2 epithelial cell infection in vitro by downregulating SARS-CoV-2 receptor expression. Further studies are warranted to assess whether OM-85 may prevent and/or reduce the severity of coronavirus disease 2019.

How Should Clinicians Minimize Harms and Maximize Benefits When Diagnosing and Treating Disorders Without Biomarkers?

Ethical obligations to minimize harms and maximize benefits of diagnosis and treatment of disorders without biomarkers include navigating difficult-to-measure, perhaps clinically inexplicable, symptoms. Among potential harms are public stigma, self-stigma, label avoidance, and the negative influence these stigmas have on self-esteem, quality of life, employment, and housing. Among potential benefits are patients becoming active agents in managing their illnesses, social acceptance, and access to evidence-based treatments. Ethical complexities clinicians face when trying to develop treatment plans while heeding key details from patients' narrative accounts prompt questions about how to best adhere to evidence in understudied domains of medicine.

Erasing Workers' Identities: Comment on Blanck, Hyseni, and Altunkol Wise's National Study of the Legal Profession.

"Bring your whole self to work" remains a common mantra of supporters of workplace diversity, equity, and inclusion ("DEI").1 For example, disability rights advocates have long contended that hiding or downplaying one's disability from one's colleagues at work "create[s] an invisible layer of additional work for the individual" in being accepted at the job and negatively affects productivity.2 LGBTQ+ rights advocates have raised similar points, noting that hiding or downplaying one's sexual orientation or gender identity from one's colleagues hinders internal advancement of LGBTQ+ workers.3 As recently as 2019, however, a Deloitte study found that sixty-one percent of workers hid or downplayed one or more of their identities from their colleagues at work.4.

The Role of Grandparents in Israeli Muslim Families with Intellectually Disabled Fathers: Social Workers' Perspectives.

Within Israeli Muslim society, men with intellectual disabilities are likely to marry nondisabled women through arranged marriages and create families. This article explores the role of grandparents with these families from the perspective of each family's social worker. A thematic analysis was conducted of 19 semistructured interviews with Muslim social workers serving Muslim families with intellectually disabled fathers. Consistent with cultural norms, paternal grandparents are extremely involved in the lives of these couples and hold responsibilities in many aspects of these couples' family lives. Social workers reported that the nondisabled wives, however, viewed the engagement as intrusive and controlling. Maternal grandparents' contributions were crucially supportive, albeit limited by Muslim cultural norms that placed households under paternal family control. Social workers had conflicted feelings regarding paternal grandparent involvement. Social workers working with Muslim fathers with intellectual disabilities should promote supportive paternal grandparent involvement and ensure that such engagement does not undermine the autonomy or well-being of the nondisabled mothers. Practice guidelines are presented.

The Treatment of Disability under Crisis Standards of Care: An Empirical and Normative Analysis of Change over Time during COVID-19.

CONTEXT: COVID-19 has prompted debates between bioethicists and disability activists about Crisis Standards of Care plans (CSCs), triage protocols determining the allocation of scarce lifesaving care. METHODS: We examine CSCs in 35 states and code how they approach disability, comparing states that have revised their plans over time to those that have not. We offer ethical and legal analyses evaluating to what extent changes to state policy aligned with disability rights law and ethics during the early pandemic and subsequently as stakeholder engagement grew. FINDINGS: While disability rights views were not well represented in CSCs that were not updated or updated early in the pandemic, states that revised their plans later in the pandemic were more aligned with advocate priorities. However, many CSCs continue to include concerning provisions, especially the reliance on long-term survival, which implicates considerations of both disability rights and racial justice. CONCLUSIONS: The disability rights movement's successes in influencing state triage policy should inform future CSCs and set the stage for further work on how stakeholders influence bioethics policy debates. We offer thoughts for examining bioethics policy making reflecting the processes by which activists seek policy change and the tension policy makers face between expert delegation and mediating values conflicts.