Vigabatrin-Induced Peripheral Visual Field Defects in Patients With Refractory Partial Epilepsy

Purpose: Vigabatrin can cause retinopathy, resulting in bilateral visual field constriction. Previous analyses of results from a prospective, observational study assessing vigabatrin-induced visual field constriction (described below) employed a partially subjective interpretation of static perimetery. In an effort to affirm these previous findings through more objective, quantitative methodology, we now report data from a subset analysis of refractory partial epilepsy patients in the study who underwent Goldmann kinetic perimetry. Methods: Patients aged ≥8 years with refractory partial seizures were enrolled and grouped: those receiving vigabatrin for ≥6 months (Group I); those who had received vigabatrin for ≥6 months and then had discontinued for ≥6 months (Group II); and those naïve to vigabatrin (Group III). Patients underwent static or kinetic perimetry or both every 4–6 months for ≤3 years. For kinetic perimetry, the temporal and nasal visual fields were measured along the horizontal meridian with the largest (V4e, IV4e) and smallest (I2e, I1e) isopters, respectively. Results: Of 735 patients enrolled, 341 had Goldmann perimetry data. Of these, 258 received vigabatrin. Sixteen percent of vigabatrin-exposed patients had moderate visual field defects (30°–60° retained temporal vision), and 3% had severe defects (\u3c30° retained temporal vision). Visual function questionnaire results indicated a weak correlation between visual field constriction severity and visual symptoms. Conclusions: These results affirm both an analysis of the same study based primarily on static perimetry and findings from cross-sectional studies. The present analysis verifies that visual field constriction, when it occurs, is most often mild or moderate and is not associated with symptoms of abnormal visual function. The clinical decision to prescribe vigabatrin should be based on a benefit-risk analysis for each individual patient

Progressive and biased divergent evolution underpins the origin and diversification of peridinin dinoflagellate plastids

Dinoflagellates are algae of tremendous importance to ecosystems and to public health. The cell biology and genome organization of dinoflagellate species is highly unusual. For example, the plastid genomes of peridinin-containing dinoflagellates encode only a minimal number of genes arranged on small elements termed "minicircles". Previous studies of peridinin plastid genes have found evidence for divergent sequence evolution, including extensive substitutions, novel insertions and deletions, and use of alternative translation initiation codons. Understanding the extent of this divergent evolution has been hampered by the lack of characterized peridinin plastid sequences. We have identified over 300 previously unannotated peridinin plastid mRNAs from published transcriptome projects, vastly increasing the number of sequences available. Using these data, we have produced a well-resolved phylogeny of peridinin plastid lineages, which uncovers several novel relationships within the dinoflagellates. This enables us to define changes to plastid sequences that occurred early in dinoflagellate evolution, and that have contributed to the subsequent diversification of individual dinoflagellate clades. We find that the origin of the peridinin dinoflagellates was specifically accompanied by elevations both in the overall number of substitutions that occurred on plastid sequences, and in the Ka/Ks ratio associated with plastid sequences, consistent with changes in selective pressure. These substitutions, alongside other changes, have accumulated progressively in individual peridinin plastid lineages. Throughout our entire dataset, we identify a persistent bias toward non-synonymous substitutions occurring on sequences encoding photosystem I subunits and stromal regions of peridinin plastid proteins, which may have underpinned the evolution of this unusual organelle.Wellcome Trus

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.Leona M. and Harry B. Helmsley Charitable Trust (3-SRA-2014-285-M-R)United States. National Institutes of Health (EB000244)United States. National Institutes of Health (EB000351)United States. National Institutes of Health (DE013023)United States. National Institutes of Health (CA151884)United States. National Institutes of Health (P41EB015871-27)National Cancer Institute (U.S.) (P30-CA14051

Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website

Progressive and Biased Divergent Evolution Underpins the Origin and Diversification of Peridinin Dinoflagellate Plastids.

Dinoflagellates are algae of tremendous importance to ecosystems and to public health. The cell biology and genome organization of dinoflagellate species is highly unusual. For example, the plastid genomes of peridinin-containing dinoflagellates encode only a minimal number of genes arranged on small elements termed "minicircles". Previous studies of peridinin plastid genes have found evidence for divergent sequence evolution, including extensive substitutions, novel insertions and deletions, and use of alternative translation initiation codons. Understanding the extent of this divergent evolution has been hampered by the lack of characterized peridinin plastid sequences. We have identified over 300 previously unannotated peridinin plastid mRNAs from published transcriptome projects, vastly increasing the number of sequences available. Using these data, we have produced a well-resolved phylogeny of peridinin plastid lineages, which uncovers several novel relationships within the dinoflagellates. This enables us to define changes to plastid sequences that occurred early in dinoflagellate evolution, and that have contributed to the subsequent diversification of individual dinoflagellate clades. We find that the origin of the peridinin dinoflagellates was specifically accompanied by elevations both in the overall number of substitutions that occurred on plastid sequences, and in the Ka/Ks ratio associated with plastid sequences, consistent with changes in selective pressure. These substitutions, alongside other changes, have accumulated progressively in individual peridinin plastid lineages. Throughout our entire dataset, we identify a persistent bias toward non-synonymous substitutions occurring on sequences encoding photosystem I subunits and stromal regions of peridinin plastid proteins, which may have underpinned the evolution of this unusual organelle.Wellcome Trus

Patch Test Results Among Older Adults: A Retrospective Analysis of the North American Contact Dermatitis Group Data (2009-2020)

Allergic contact dermatitis (ACD) in older adults (OA) represents a significant health burden, but few studies examine the prevalence and characteristics of contact allergy and ACD in this population. To compare positive and clinically relevant patch test results in OA versus younger adults (YA) and children. Retrospective analysis of patch test results obtained in OA (≥65 years), YA (19-64 years), and children (≤18 years) by the North American Contact Dermatitis Group, 2009 to 2020. Of 28,177 patients patch tested, 5366 (19.0%) were OA. OA were more likely to have a final primary diagnosis of ACD as compared with YA (50.8% vs 49.2%,  = 0.035) and children (44.6%,  \u3c 0.0001). The primary site of dermatitis also differed by age group, with OA having a higher proportion of dermatitis affecting the trunk, scalp, anogenital region, and under clothing, and a lower proportion of dermatitis affecting the face, lips, and feet. Retrospective design, lack of follow-up, and referral population. OA were as likely and were statistically even more likely to have a final primary diagnosis of ACD compared with YA and children. Anatomic site of dermatitis also differed by age group. This underscores the need for patch testing in OA when ACD is suspected

Patch Testing to Paraphenylenediamine: The North American Contact Dermatitis Group Experience (1994-2018)

Paraphenylenediamine (PPD) is an aromatic amine dye that may cause allergic contact dermatitis. This study examines the epidemiology of allergic patch test reactions to PPD. This retrospective analysis characterizes individuals tested to PPD (1% petrolatum) by the North American Contact Dermatitis Group (1994-2018). Demographics and dermatitis site(s) were compared between PPD-allergic and PPD-negative patients. PPD reactions were analyzed by reaction strength, clinical relevance, occupational relatedness, and source as well as coreactivity with structurally related compounds. Of 54,917 patients tested to PPD, 3095 (5.6%) had an allergic patch test reaction. Compared with PPD-negative patients, PPD-allergic patients had significantly greater odds of age \u3e40 years (odds ratio [OR] 1.55 [95% confidence interval; CI 1.43-1.69]) and female gender (OR 1.52 [95% CI 1.41-1.66]), but lower odds of being White (OR 0.66 [95% CI 0.60-0.71]). The most common primary anatomic sites of dermatitis were face (25.5%), hands (21.9%), and scattered/generalized pattern (15.5%). Over half (55.3%) of PPD reactions were ++ or +++ at the final reading and 60.9% were currently relevant. Common exposure sources included hair dye (73.5%) and clothing/shoes/apparel (3.9%). Occupationally related reactions occurred in 8.3%, most commonly in hairdressers/cosmetologists (72.8%). The most common coreactions were benzocaine (11.3%), -isopropyl-\u27-phenyl--phenylenediamine (6.7%), disperse dye mix (6.5%), and black rubber mix (5.1%). The 24-year percentage of allergic reactions to PPD was 5.6%. PPD allergy was associated with female gender and age \u3e40 years. PPD allergic patients were less likely to be White. Allergic reactions were usually clinically relevant and hair dye was the most frequently identified source