Intrathecal B-cell activation in LGI1 antibody encephalitis.

ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies

Patent Clutter

Patent claims are supposed to clearly and succinctly describe the patented invention, and only the patented invention. This Article hypothesizes that a substantial amount of language in patent claims is in fact not about the core invention, which may contribute to well-documented problems with patent claims. I analyze the claims of 40,000 patents and applications, and document the proliferation of “clutter”—language in patent claims that is not about the invention. Although claims are supposed to be exclusively about the invention, clutter appears across industries and makes up approximately 25% of claim language. Patent clutter may contribute several major problems in patent law. Extensive clutter makes patent claims harder to search. Excessive language in patent claims may be the result of over-claiming—when patentees describe potential corollaries they do not possess—thereby making the patent so broad in scope as to be invalid. More generally, it strains the comprehensibility of patents and burdens the resources of patent examiners. After arguing that patent clutter may contribute to these various problems, this Article turns to reforms. Rejections based on prolix, lack of enablement, and lack of written description can be crafted to dispose of the worst offenders, and better algorithms and different litigation rules can allow the patent system to adapt (and even benefit from) the remaining uses of excess language. The Article additionally generates important theoretical insights. Claims are often thought of as entirely synonymous with the invention and all elements of the claim are thought to relate equally strongly to the invention. This Article suggests empirically that these assumptions do not hold in practice, and offers a framework for restructuring conceptions of the relationship between claims and the invention

Regulation in the Shadows of Private Law

With proponents of deregulation ascendant, both domestically and around the world, private regulation appears to be an attractive solution to a seemingly intractable problem—assuming it is or can be effective. This Article adds an important corrective to standard accounts of private legal regulation and its effectiveness. Existing scholarship generally looks to the formal contract terms as the key to understanding private regulation and to evaluating its impact. This practice needs to be rethought. The relationship between contracting parties, as well as the regulatory authority that one party exerts over the other, can be quite different than the relationship described by the formal contract terms. This Article illustrates the problem with the scholarly assumption that formal contract language reliably describes the private regulatory relationships they establish. It does so through an in-depth analysis of a form of private contracting with great regulatory potential: the loan guarantees and associated political risk insurance policies underwritten by the World Bank. Such policies are purchased by corporations to mitigate the risks associated with doing business in under-regulated jurisdictions. Because, on their face, the terms of these policies require socially responsible corporate behavior, they appear to be a promising form of private regulation, succeeding in imposing significant obligations on corporations that traditional public regulation has failed to mandate. But these formal terms reveal little about the true nature of the private regulatory relationships they create. Even though the policy terms themselves are unlikely ever to be formally enforced, the policyholders often have significant incentives to go above and beyond the contract requirements if requested to do so by the underwriter. But whether they are in fact being asked to do so, and whether they are in fact complying if they are being asked, is unclear. The World Bank provides considerable transparency surrounding the terms of its policies and the process for obtaining them. However, little information is available regarding its post-contracting interactions with policyholder corporations. Providing data about these interactions could be done relatively easily and without infringing upon the confidentiality interests that it, and its policyholders, may have. To the extent that entities like the World Bank are serious about their corporate social responsibility policies, it is imperative that information about the actual contracting relationship—and not just the formal contract terms—be made available

Understanding Pasefika perceptions and experiences of the school system in Years 7 to 10 : a thesis presented in partial fulfilment of the requirements for the degree of Master of Education at Massey University, Palmerston North, New Zealand

Drawing on questionnaires and interviews of Pasefika students, their parents, and teachers, this case study provides an understanding of their perceptions and experiences of the school system in Years 7 to 10 within a family resource framework. Essentially, the financial, social and cultural resources available to Pasefika students within the context of their family's cultural capital, and their prior cognitive ability and non-cognitive dispositions have greater influence on their engagement and success at school than their culture or ethnicity. Respondents' suggestions for changes to enhance schooling and the social and educational needs of Pasefika students, including the support for a middle-school structure and provision of an extra year prior to NCEA qualifications, reiterate similar multivariate recommendations and findings of other studies

Theory- and evidence-based best practices for physical activity counseling for adults with spinal cord injury

This project used a systematic and integrated knowledge translation (IKT) approach to co-create theory- and evidence-based best practices for physical activity counseling for adults with spinal cord injury (SCI). Guided by the IKT Guiding Principles, we meaningfully engaged research users throughout this project. A systematic approach was used. An international, multidisciplinary expert panel (n = 15), including SCI researchers, counselors, and people with SCI, was established. Panel members participated in two online meetings to discuss the best practices by drawing upon new knowledge regarding counselor-client interactions, current evidence, and members’ own experiences. We used concepts from key literature on SCI-specific physical activity counseling and health behavior change theories. An external group of experts completed an online survey to test the clarity, usability and appropriateness of the best practices. The best practices document includes an introduction, the best practices, things to keep in mind, and a glossary. Best practices focused on how to deliver a conversation and what to discuss during a conversation. Examples include: build rapport, use a client-centred approach following the spirit of motivational interviewing, understand your client’s physical activity barriers, and share the SCI physical activity guidelines. External experts (n = 25) rated the best practices on average as clear, useful, and appropriate. We present the first systematically co-developed theory- and evidence-based best practices for SCI physical activity counseling. The implementation of the best practices will be supported by developing training modules. These new best practices can contribute to optimizing SCI physical activity counseling services across settings.</p

TCR Convergence in Individuals Treated With Immune Checkpoint Inhibition for Cancer.

Tumor antigen-driven selection may expand T cells having T cell receptors (TCRs) of shared antigen specificity but different amino acid or nucleotide sequence in a process known as TCR convergence. Substitution sequencing errors introduced by TCRβ (TCRB) repertoire sequencing may create artifacts resembling TCR convergence. Given the anticipated differences in substitution error rates across different next-generation sequencing platforms, the choice of platform could be consequential. To test this, we performed TCRB sequencing on the same peripheral blood mononuclear cells (PBMC) from individuals with cancer receiving anti-CTLA-4 or anti-PD-1 using an Illumina-based approach (Sequenta) and an Ion Torrent-based approach (Oncomine TCRB-LR). While both approaches found similar TCR diversity, clonality, and clonal overlap, we found that Illumina-based sequencing resulted in higher TCR convergence than with the Ion Torrent approach. To build upon this initial observation we conducted a systematic comparison of Illumina-based TCRB sequencing assays, including those employing molecular barcodes, with the Oncomine assay, revealing differences in the frequency of convergent events, purportedly artifactual rearrangements, and sensitivity of detection. Finally, we applied the Ion Torrent-based approach to evaluate clonality and convergence in a cohort of individuals receiving anti-CTLA-4 blockade for cancer. We found that clonality and convergence independently predicted response and could be combined to improve the accuracy of a logistic regression classifier. These results demonstrate the importance of the sequencing platform in assessing TCRB convergence

Sherlock Holmes Meets Rube Goldberg: Fixing the Entry-into-Force Provisions of the Comprehensive Nuclear Test Ban Treaty

The Comprehensive Nuclear Test Ban Treaty (CTBT) is widely heralded as the most important international legal instrument for arresting the nuclear arms race and impeding further nuclear proliferation. Concluded in 1996, the treaty has been signed by 183 countries and ratified by 166. But it has not yet entered into force, because of its unique requirement that it not become operational for any state until it has been ratified by all forty-four countries designated in its Annex 2. Thirty-six of those Annex 2 states have ratified, but there is little prospect that all of the other eight (including the United States, China, India, Pakistan, and North Korea) will do so in the foreseeable future. In the meantime, certain parts of the CTBT are being provisionally applied, but other critical aspects are in abeyance, and the world\u27s unrequited demand for a fully effective legal prohibition on nuclear weapons testing has jeopardized the global nuclear security architecture. This Article proposes a novel work-around, to achieve early implementation of the CTBT. Interested states should negotiate a second treaty, styled as an Implementing Agreement, through which they could promptly effectuate the CTBT among themselves, even if some Annex 2 states remained outside the regime. This approach would free the CTBT from the tyranny of a veto power currently held by each of the Annex 2 states, and would allow the treaty to grow organically, building toward eventual universal acceptance by entering into force now for a sizeable coalition of the willing—as other important treaties have traditionally done. The legal mechanism for creating such an Implementing Agreement is unusual and cumbersome, but it follows an important international law precedent. The 1982 Law of the Sea Convention achieved widespread acceptance, but it, too, required substantial modification before its entry into force. There, the participating states successfully fashioned a 1994 Implementing Agreement to revise important elements. That document provides a useful template for the CTBT to emulate. This Article offers a draft of a CTBT Implementing Agreement, explaining how its waiver provisions would operate and how it would provide interested states a variety of alternative mechanisms for establishing a prompt, durable, and legally binding test ban regime