Gender and uveitis in patients with multiple sclerosis.

Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is more commonly seen in women. It has been associated with both anterior and intermediate uveitis as well as retinal vasculitis. Ocular inflammation may develop concurrent with, prior to, or after the development of neurologic signs and symptoms. Patients with MS have an approximately 1% chance of developing intraocular inflammation. Patients with intermediate uveitis have an 8-12% risk of being diagnosed with MS. This risk is higher in females and in those with bilateral disease. This should be kept in mind when evaluating patients with uveitis, particularly in those patients for whom TNF inhibitor therapy is being considered, as these agents may worsen demyelinating disease

Gender and Uveitis in Patients with Multiple Sclerosis

Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is more commonly seen in women. It has been associated with both anterior and intermediate uveitis as well as retinal vasculitis. Ocular inflammation may develop concurrent with, prior to, or after the development of neurologic signs and symptoms. Patients with MS have an approximately 1% chance of developing intraocular inflammation. Patients with intermediate uveitis have an 8–12% risk of being diagnosed with MS. This risk is higher in females and in those with bilateral disease. This should be kept in mind when evaluating patients with uveitis, particularly in those patients for whom TNF inhibitor therapy is being considered, as these agents may worsen demyelinating disease

Ethical, legal, and social issues in the Earth BioGenome Project.

The Earth BioGenome Project (EBP) is an audacious endeavor to obtain whole-genome sequences of representatives from all eukaryotic species on Earth. In addition to the project's technical and organizational challenges, it also faces complicated ethical, legal, and social issues. This paper, from members of the EBP's Ethical, Legal, and Social Issues (ELSI) Committee, catalogs these ELSI concerns arising from EBP. These include legal issues, such as sample collection and permitting; the applicability of international treaties, such as the Convention on Biological Diversity and the Nagoya Protocol; intellectual property; sample accessioning; and biosecurity and ethical issues, such as sampling from the territories of Indigenous peoples and local communities, the protection of endangered species, and cross-border collections, among several others. We also comment on the intersection of digital sequence information and data rights. More broadly, this list of ethical, legal, and social issues for large-scale genomic sequencing projects may be useful in the consideration of ethical frameworks for future projects. While we do not-and cannot-provide simple, overarching solutions for all the issues raised here, we conclude our perspective by beginning to chart a path forward for EBP's work

Ethical, legal, and social issues in the Earth BioGenome Project

The Earth BioGenome Project (EBP) is an audacious endeavor to obtain whole-genome sequences of representatives from all eukaryotic species on Earth. In addition to the project’s technical and organizational challenges, it also faces complicated ethical, legal, and social issues. This paper, from members of the EBP’s Ethical, Legal, and Social Issues (ELSI) Committee, catalogs these ELSI concerns arising from EBP. These include legal issues, such as sample collection and permitting; the applicability of international treaties, such as the Convention on Biological Diversity and the Nagoya Protocol; intellectual property; sample accessioning; and biosecurity and ethical issues, such as sampling from the territories of Indigenous peoples and local communities, the protection of endangered species, and cross-border collections, among several others. We also comment on the intersection of digital sequence information and data rights. More broadly, this list of ethical, legal, and social issues for large-scale genomic sequencing projects may be useful in the consideration of ethical frameworks for future projects. While we do not—and cannot—provide simple, overarching solutions for all the issues raised here, we conclude our perspective by beginning to chart a path forward for EBP’s work

Climate Change, Human Health, and Resilience in the Holocene

Climate change is an indisputable threat to human health, especially for societies already confronted with rising social inequality, political and economic uncertainty, and a cascade of concurrent environmental challenges. Archaeological data about past climate and environment provide an important source of evidence about the potential challenges humans face and the long-term outcomes of alternative short-term adaptive strategies. Evidence from well-dated archaeological human skeletons and mummified remains speaks directly to patterns of human health over time through changing circumstances. Here, we describe variation in human epidemiological patterns in the context of past rapid climate change (RCC) events and other periods of past environmental change. Case studies confirm that human communities responded to environmental changes in diverse ways depending on historical, sociocultural, and biological contingencies. Certain factors, such as social inequality and disproportionate access to resources in large, complex societies may influence the probability of major sociopolitical disruptions and reorganizations—commonly known as “collapse.” This survey of Holocene human–environmental relations demonstrates how flexibility, variation, and maintenance of Indigenous knowledge can be mitigating factors in the face of environmental challenges. Although contemporary climate change is more rapid and of greater magnitude than the RCC events and other environmental changes we discuss here, these lessons from the past provide clarity about potential priorities for equitable, sustainable development and the constraints of modernity we must address

Climate change, human health, and resilience in the Holocene

Climate change is an indisputable threat to human health, especially for societies already confronted with rising social inequality, political and economic uncertainty, and a cascade of concurrent environmental challenges. Archaeological data about past climate and environment provide an important source of evidence about the potential challenges humans face and the long-term outcomes of alternative short-term adaptive strategies. Evidence from well-dated archaeological human skeletons and mummified remains speaks directly to patterns of human health over time through changing circumstances. Here, we describe variation in human epidemiological patterns in the context of past rapid climate change (RCC) events and other periods of past environmental change. Case studies confirm that human communities responded to environmental changes in diverse ways depending on historical, sociocultural, and biological contingencies. Certain factors, such as social inequality and disproportionate access to resources in large, complex societies may influence the probability of major sociopolitical disruptions and reorganizations—commonly known as “collapse.” This survey of Holocene human–environmental relations demonstrates how flexibility, variation, and maintenance of Indigenous knowledge can be mitigating factors in the face of environmental challenges. Although contemporary climate change is more rapid and of greater magnitude than the RCC events and other environmental changes we discuss here, these lessons from the past provide clarity about potential priorities for equitable, sustainable development and the constraints of modernity we must address

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Relentless placoid chorioretinitis: A review of four cases in pediatric and young adult patients with a discussion of therapeutic strategies

IntroductionRelentless placoid chorioretinitis (RPC) is a rare, bilateral disease of the retinal pigment epithelium. The clinical course is prolonged and relapsing. No standard treatment has been established to date. The purpose of this case series is to report four cases of RPC in pediatric and young adult patients in which varying treatments were used, comparing them to previously published cases.MethodsA literature review was conducted to investigate currently published presentations and treatment options for RPC. A multicenter retrospective chart review was also performed on four consecutive patients. These patients were diagnosed with RPC because of new chorioretinitis lesions continuing to appear without or despite therapy for 5–36 months (2 patients), with a clinical course prolonged and relapsing, or because of the atypical location of the multiple lesions (>50) extending from the posterior pole to the equator and mid-peripheral retina (all four patients), which were not consistent with other entities like acute posterior multifocal placoid pigment epitheliopathy and serpiginous choroiditis.ResultsAll four cases of RPC received oral or IV steroids acutely, and three of these patients were transitioned to a steroid-sparing agent and biologic therapy: anti-TNF alpha or anti-IL-6. Quiescence of the chorioretinitis lesions was obtained after 7 months, 1 month, and 36 months; however, the latter had issues with treatment adherence. Mycophenolate mofetil was insufficient to control the disease in one patient, but tocilizumab and infliximab thereafter were effective after cessation of adalimumab due to side effects. Adalimumab when started the first month after the presentation was effective in controlling the disease in one patient. After the failure of interferon-alpha-2a, one patient displayed long-term control with infliximab. One patient did not require a steroid-sparing agent after oral prednisone taper as there was no evidence of progression or recurrence.ConclusionThis case series adds to the current knowledge regarding potential treatments for RPC, specifically the use of anti-TNF-alpha treatment and anti-IL-6 tocilizumab. In this case study, relapses of RPC were found among patients on mycophenolate mofetil and interferon-alpha-2a, and one case did not relapse on oral steroids without a steroid-sparing agent. Our findings suggest that adalimumab, infliximab, and tocilizumab may be useful medications to obtain quiescence of RPC

Gene Therapy in a Humanized Mouse Model of Familial Hypercholesterolemia Leads to Marked Regression of Atherosclerosis

Familial hypercholesterolemia (FH) is an autosomal codominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Homozygous FH patients (hoFH) have severe hypercholesterolemia leading to life threatening atherosclerosis in childhood and adolescence. Mice with germ line interruptions in the Ldlr and Apobec1 genes (Ldlr(-/-)Apobec1(-/-)) simulate metabolic and clinical aspects of hoFH, including atherogenesis on a chow diet.In this study, vectors based on adeno-associated virus 8 (AAV8) were used to deliver the gene for mouse Ldlr (mLDLR) to the livers of Ldlr(-/-)Apobec1(-/-) mice. A single intravenous injection of AAV8.mLDLR was found to significantly reduce plasma cholesterol and non-HDL cholesterol levels in chow-fed animals at doses as low as 3×10(9) genome copies/mouse. Whereas Ldlr(-/-)Apobec1(-/-) mice fed a western-type diet and injected with a control AAV8.null vector experienced a further 65% progression in atherosclerosis over 2 months compared with baseline mice, Ldlr(-/-)Apobec1(-/-) mice treated with AAV8.mLDLR realized an 87% regression of atherosclerotic lesions after 3 months compared to baseline mice. Immunohistochemical analyses revealed a substantial remodeling of atherosclerotic lesions.Collectively, the results presented herein suggest that AAV8-based gene therapy for FH may be feasible and support further development of this approach. The pre-clinical data from these studies will enable for the effective translation of gene therapy into the clinic for treatment of FH