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Safety and outcomes data on eculizumab for generalized myasthenia gravis (gMG) in clinical practice remain limited. Outcomes and concomitant medication use may differ in practice compared with clinical trials. We analyzed the clinical and safety outcomes of patients who received eculizumab at our institutions.Patients with acetylcholine receptor antibody positive (AChR+) gMG, who received ≥1 dose of eculizumab and had ≥1 follow-up before December 10, 2021, were identified. Data were abstracted by chart review. Outcomes included MG Foundation of America Post Intervention Status (MGFA-PIS), Clinical Classification (MGFA-CC), MG-Activities of Daily Living (MG-ADL), concurrent immunomodulatory therapy use, and adverse events.Twelve patients were included. Mean age at eculizumab initiation was 57.4 y (range, 21-77). Eight had refractory MG. Four had history of thymoma and thymectomy. A mean of 3.2 (range, 2-5) immunomodulatory therapies were previously tried. Mean follow-up duration was 18 mo (range, 2-21.6). Clinical improvement occurred rapidly; MGFA-PIS was improved in 80%, and MGFA-CC improved in 83% at 1 mo. Mean MG-ADL decreased from 8.7 to 2.8 at 1 mo, and remainedClinical improvement occurred in most patients after eculizumab initiation, beginning as quickly as 1 mo. Steroids were tapered and maintenance IVIG and PLEX were discontinued in most. Eculizumab had a favorable safety profile even when combined with other immunosuppressants.

Fabry disease (FD) is a pan-ethnic, X-linked, progressive lysosomal storage disorder caused by pathogenic mutations in the GLA gene. Published case reports and abstracts suggest that decreased reproductive fitness may occur in males with FD. In order to understand the impact of FD on reproductive fitness and increase the accuracy of reproductive genetic counseling, this study examines a large, multi-centered population of individuals with FD to determine if males have reduced reproductive fitness. Study data were collected on 376 patients through two, gender-specific surveys distributed across the United States and Canada. The number of biological live-born children among individuals with FD was compared to statistics from the general population. Information was also collected on reduced sperm count, depression, pain, use of assisted reproductive technology, and reproductive choice. On average, females affected by FD had more biological live-born children (1.8) than males affected by FD (1.1). However, males affected by FD had an increased mean number of biological children (1.1) compared to the mean number of biological children fathered by men in the United States (0.9). Sixteen of the 134 males with FD reported oligospermia, which suggests that an infertility work up may be indicated for males having difficulty impregnating their partners. In our large multicenter sample, males and females with FD do not exhibit reduced reproductive fitness; on average they have more biological children than the general population in the United States. This information should assist clinicians in providing accurate reproductive genetic counseling and treatment for individuals with FD.

Objective: Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD). Methods: Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p Results: Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 ± 14.9 (range 9.6–72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2.7 cm 3 (interquartile range 1.8–4.0). Age (β 0.02, p = 0.008) and history of stroke (β 1.13, p = 0.02) were independently associated with lnWMHV. However, WMH burden—as well as WMHV predictors—varied by decade of life in this cohort of patients with FD ( p Conclusions: In this largest-to-date cohort of patients with FD who had volumetric analysis of MRI, age and prior stroke independently predicted the burden of WMH. The 4th decade of life appears to be critical in progression of WMH burden, as novel predictors of WMHV emerged in patients aged 31–40 years. Future studies to elucidate the biology of WMH in FD and its role as potential MRI marker of disease progression are needed.

Background Fabry disease is an X-linked lysosomal storage disorder that causes progressive complications within the kidneys, brain, and heart. Ocular manifestations of this disease are often present at a very young age, thereby facilitating early diagnosis, before the signs and symptoms of renal disease, stroke, or hypertrophic cardiomyopathy. Early diagnosis by the eye care provider may eventually reduce the morbidity and mortality of this disease through the institution of therapy before the development of sclerotic end organ damage. This study evaluated 23 Fabry-affected members of a single cohort for the presence of ocular signs of Fabry disease. Methods Twenty-three patients of a single family were seen on a single day. Patients were given comprehensive ophthalmic examinations and completed a health and lifestyle questionnaire. Results Eight hemizygous men (mean age, 32.3 years) and 15 heterozygous women (mean age, 26.9 years) from a single family of 43 known Fabry patients were evaluated. Corneal verticillata was present in all patients. Additional findings in the male patients included anterior capsule opacity (25% total) and Fabry cataract (12.5%). Thinning of the retinal nerve fiber layer was observed in one man whose medical history was significant for stroke. Conjunctival and/or retinal vessel tortuosity was present in the majority of patients (62.5% and 75% of hemizygotes, respectively; 40% and 13.3% heterozygotes, respectively). Additional findings in the women included anterior capsule opacity. The majority of patients (87.5% hemizygotes, 60% heterozygotes) felt Fabry disease had an impact on their quality of life. Conclusions All evaluated patients who had Fabry disease had corneal verticillata, which generally does not affect vision and is readily recognizable by slit lamp examination. Greater than 60% showed conjunctival and/or retinal vessel tortuosity. The eye care provider can play a crucial role in the early recognition of ocular manifestations of Fabry disease and decrease both the time to accurate diagnosis and the delay in the institution of disease-modifying therapy.

The Northeastern/Central Pennsylvania Interprofessional Education Coalition (NECPA IPEC) is a coalition of faculty from multiple smaller academic institutions with a mission to promote interprofessional education. An interprofessional learning program was organized, which involved 676 learners from 10 different institutions representing 16 unique professions, and took place at seven different institutions simultaneously. The program was a 3-hour long summit which focused on the management of a patient with ischemic stroke. A questionnaire consisting of the Interprofessional Education Perception Scale (IEPS) questionnaire (pre-post summit), Likert-type questions, and open comment questions explored the learners' perceptions of the session and their attitudes toward interprofessional learning. Responses were analyzed using descriptive statistics and statistical tests for difference and qualitative thematic coding. The attitude of learners toward interprofessional education (as measured by the IEPS) was quite high even prior to the summit, so there were no significant changes after the summit. However, a high percentage of learners and facilitators agreed that the summit met its objective and was effective. In addition, the thematic analysis of the open-ended questions confirmed that students learned from the experience with a sense of the core competencies of interprofessional education and practice. A collaborative approach to delivering interprofessional learning is time and work intensive but beneficial to learners.

New mapping approaches construct ordered restriction maps from fluorescence microscope images of individual, endonuclease-digested DNA molecules. In optical mapping, molecules are elongated and fixed onto derivatized glass surfaces, preserving biochemical accessibility and fragment order after enzymatic digestion. Measurements of relative fluorescence intensity and apparent length determine the sizes of restriction fragments, enabling ordered map construction without electrophoretic analysis. The optical mapping system reported here is based on our physical characterization of an effect using fluid flows developed within tiny, evaporating droplets to elongate and fix DNA molecules onto derivatized surfaces. Such evaporation-driven molecular fixation produces well elongated molecules accessible to restriction endonucleases, and notably, DNA polymerase I. We then developed the robotic means to grid DNA spots in well defined arrays that are digested and analyzed in parallel. To effectively harness this effect for high-throughput genome mapping, we developed: ( i ) machine vision and automatic image acquisition techniques to work with fixed, digested molecules within gridded samples, and ( ii ) Bayesian inference approaches that are used to analyze machine vision data, automatically producing high-resolution restriction maps from images of individual DNA molecules. The aggregate significance of this work is the development of an integrated system for mapping small insert clones allowing biochemical data obtained from engineered ensembles of individual molecules to be automatically accumulated and analyzed for map construction. These approaches are sufficiently general for varied biochemical analyses of individual molecules using statistically meaningful population sizes.

We examined the feasibility of recruiting US adults ≥45 years old with Fabry disease (FD) for telephone assessments of cognitive functioning. A case–control design matched each FD participant on age, sex, race, and education to four participants from a population-based study. Fifty-four participants with FD age 46–72 years were matched to 216 controls. Standardized cognitive assessments, quality of life (QOL), and medical histories were obtained by phone, supplemented by objective indices of comorbidities. Normalized scores on six cognitive tasks were calculated. On the individual tasks, scores on list recall and semantic fluency were significantly lower among FD participants (p-values

Identification and comprehensive care of individuals who have Fabry disease (FD) requires a multidisciplinary approach inclusive of genetic testing, test interpretation, genetic counseling, long term disease symptom monitoring, treatment recommendations, and coordination of therapy. The purpose of this document is to provide health care professionals with guidelines for testing, care coordination, identification of psychosocial issues, and to facilitate a better understanding of disease treatment expert recommendations for patients with Fabry disease. These recommendations are the opinions of a multicenter working group of genetic counselors, medical geneticists, and other health professionals with expertise in Fabry disease counseling, as well as representatives/founders of the two United States based Fabry disease patient advocacy groups who are themselves affected by Fabry disease. The recommendations are U.S. Preventive Task Force Class III, and they are based on clinical experience, a review of pertinent English-language articles, and reports of expert committees. This document reviews the genetics of Fabry disease, the indications for genetic testing, interpretation of results, psychosocial considerations, and references to professional and patient resources.

To refine the linkage map of mouse Chromosome (Chr) 12 and to define better the homology relationships between it and human chrs 2p and 14q, nine new anonymous DNA markers of Chr 12 were identified, and mouse loci homologous to the human D14S17, CHGA, HSPA2, RRM2, TPO, and ZFP50 ("KUP") genes were defined. The inheritance of DNA variants associated with these markers was followed in progeny of a reciprocal backcross between the C57BL/6J and SWR/J laboratory mouse strains and in recombinant inbred (RI) strains of mice. These data, combined with results of previous analyses of the backcross, allowed the construction of a 22-marker multilocus linkage map that spanned 58 cM. Use of this map to anchor the RI typing data collected in this and previous studies allowed the construction of a 79-marker map that spanned 66 cM and the identification of a framework of unambiguously ordered, extensively typed markers that should facilitate the use of RI mice in testing new markers for possible linkage to Chr 12.

The pathogenesis of 46 XX true hermaphroditism is uncertain and the role of the SRY gene in ovotestis development has not been thoroughly evaluated. We ascertained the presence of the SRY gene and SRY protein in the ovotestis.We evaluated 8 ovotestes by cytogenetic analysis of fibroblast cell culture and analysis of gonadal tissue by polymerase chain reaction to detect the SRY gene and by immunohistochemistry with a monoclonal antibody to human recombinant SRY protein.Fibroblast culture of the ovotestes demonstrated a 46XX karyotype. By polymerase chain reaction all 8 ovotestes demonstrated the SRY gene at low levels. By immunohistochemistry SRY protein was detected in all ovotestes, predominantly in Sertoli and germ cells.The SRY gene has a role in ovotestis genesis. Mosaicism with a Y bearing cell line in the gonad is a possible explanation and further study is warranted.

The unicellular parasite Plasmodium falciparum is the cause of human malaria, resulting in 1.7–2.5 million deaths each year1. To develop new means to treat or prevent malaria, the Malaria Genome Consortium was formed to sequence and annotate the entire 24.6-Mb genome2. The plan, already underway, is to sequence libraries created from chromosomal DNA separated by pulsed-field gel electrophoresis (PFGE). The AT-rich genome of P. falciparum presents problems in terms of reliable library construction and the relative paucity of dense physical markers or extensive genetic resources. To deal with these problems, we reasoned that a high-resolution, ordered restriction map covering the entire genome could serve as a scaffold for the alignment and verification of sequence contigs developed by members of the consortium. Thus optical mapping was advanced to use simply extracted, unfractionated genomic DNA as its principal substrate. Ordered restriction maps (BamHI and NheI) derived from single molecules were assembled into 14 deep contigs corresponding to the molecular karyotype determined by PFGE (ref. 3).

The asymmetric unit membrane (AUM) of the apical surface of mammalian urinary bladder epithelium contains several major integral membrane proteins, including uroplakins IA and IB (both 27 kDa), II (15 kDa), and III (47 kDa). These proteins are synthesized only in terminally differentiated bladder epithelial cells. They are encoded by separate genes and, except for uroplakins IA and IB, appear to be unrelated in their amino acid sequences. The genes encoding these uroplakins were mapped to chromosomes of cattle through their segregation in a panel of bovine x rodent somatic cell hybrids. Genes for uroplakins IA, IB, and II were mapped to bovine (BTA) Chromosomes (Chrs) 18 (UPK1A), 1 (UPK1B), and 15 (UPK2), respectively. Two bovine genomic DNA sequences reactive with a uroplakin III cDNA probe were identified and mapped to BTA 6 (UPK3A) and 5 (UPK3B). We have also mapped genes for uroplakins IA and II in mice, to the proximal regions of mouse Chr 7 (Upk1a) and 9 (Upk2), respectively, by analyzing the inheritance of restriction fragment length variants in recombinant inbred mouse strains. These assignments are consistent with linkage relationships known to be conserved between cattle and mice. The mouse genes for uroplakins IB and III were not mapped because the mouse genomic DNA fragments reactive with each probe were invariant among the inbred strains tested. Although the stoichiometry of AUM proteins is nearly constant, the fact that the uroplakin genes are unlinked indicates that their expression must be independently regulated. Our results also suggest likely positions for two human uroplakin genes and should facilitate further analysis of their possible involvement in disease.