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Morquio syndrome A (Mucopolysaccharidosis IVA, MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficiency of N-acetyl-galactosamine-6-sulfatase (GALNS) which catabolizes the glycosaminoglycans (GAG), keratan sulfate and chondroitin-6-sulfate. Homozygous or compound heterozygous pathogenic variants in the GALNS result in the deficiency of the enzyme and consequent GAG accumulations. DNA sequence and copy number analysis of the GALNS coding region fails to identify biallelic causative pathogenic variants in up to 15% of patients with Morquio syndrome A. RNA transcript analysis was performed to identify pathogenic alterations in two unrelated families with Morquio syndrome A in whom a single heterozygous or no pathogenic alteration was detected by standard analysis of the GALNS gene. RNA sequencing and quantitative expression analysis identified the overabundance of an aberrant GALNS transcript isoform and a reduction of the clinically relevant isoform (NM_000512.4) in the Morquio syndrome A patients from both families. The aberrant isoform (ENST00000568613.1) was produced by alternative splicing and contained intronic sequence that was likely a cryptic exon predicted to result in a reading frame shift and generation of a premature termination codon. These findings indicated that the aberrant splicing is likely the novel molecular defect in our patients. RNA transcript analysis could be useful to identify pathogenic alterations and increase the yield of molecular diagnosis in patients with Morquio syndrome A whose genetic variants are not found by standard sequencing or gene dosage analysis.

PurposeAccording to the Williams Institute, 1.4 million U.S. adults identify as transgender. Many experience health care disparities. Professional organizations call for medical education to improve transgender care, but what curricula are being delivered is unknown. The goal of this study was to conduct the first comprehensive, national survey of transgender health care curricula in physician assistant (PA) education.MethodThe authors sent a questionnaire to program directors (PDs) at all 236 U.S. PA programs in June 2018. They categorized programs as those that currently deliver at least 1 hour of transgender health content and those who do not (Teaching/Not Teaching). They examined differences between Teaching and Not Teaching programs using chi-square tests, and they evaluated comments for themes.ResultsThe response rate was 100%. Of the 236 programs, 202 (85.6%) teach transgender content and 34 (14.4%) do not. According to PDs, most transgender content was delivered in medical interviewing (44.1%) or women's health (31.4%) and the most common transgender health topics included differentiating between sex and gender and between behavior and identity (78.8%), followed by health disparities (77.5%) and barriers to care (75.0%). PDs most commonly cited a lack of time (51.3%) and faculty knowledge (35.6%) as barriers for teaching transgender health topics. Half of the PDs (50.4%) ranked transgender health as very or extremely important. The authors detected statistically significant differences between Teaching and Not Teaching programs based on geographic region (P = .01), perceived importance (P ≤ .001), and presence of knowledgeable faculty (P = .01). Presence of knowledgeable faculty was significantly associated with perceived importance (P = .01).ConclusionsThis is the first comprehensive, nationwide survey of transgender health education in U.S. PA programs. A key finding is that the presence of expert faculty is significantly associated with delivery and perc

Multi-party computation (MPC) is a way of computing on private data without revealing the data itself. To do this, data is "secret-shared" amongst a set of mutually-distrusting parties, which perform local computations and interactive processes to evaluate a function. MPC protocols are diverse and offer a variety of different security guarantees, and employ different methodologies to optimize for different aspects of the evaluation. The goal of this work is to show how to reduce communication costs involved in different areas of MPC. An access structure defines which sets of parties a so-called adversary can corrupt such that the inputs remain private and the outputs are revealed to the right parties; one type of access structure is called Q2, under which assumption there are many classical results on what sorts of functions can be evaluated. One of the contributions of this work is to show how special "error-detection" properties that apply in the context of Q2 access structures can be used to define MPC protocols that improve on the efficiency of classical results. In the so-called preprocessing model, parties evaluate a function on random inputs, and later "derandomize" using the real (private) inputs. This model is popular in MPC as function evaluation is expensive, whereas derandomization is cheap. In this thesis, a generic method is given for outsourcing preprocessing to a set of servers, which means that low-powered clients who wish to evaluate functions on their data can do so. The final contribution is a protocol that allows parties to mix two different MPC techniques called garbled circuits and secret-sharing in a secure way, even when the adversary deviates arbitrarily from the protocol description. Mixing these methods is useful as they optimize for different aspects of computation.

Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl-/H+ exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.

Sialuria, a rare inborn error of metabolism, was diagnosed in a healthy 12-year-old boy through whole exome sequencing. The patient had experienced mild delays of speech and motor development, as well as persistent hepatomegaly. Identification of the 8th individual with this disorder, prompted follow-up of the mother-son pair of patients diagnosed over 15years ago. Hepatomegaly was confirmed in the now 19-year-old son, but in the 46-year-old mother a clinically silent liver tumor was detected by ultrasound and MRI. The tumor was characterized as an intrahepatic cholangiocarcinoma (IHCC) and DNA analysis of both tumor and normal liver tissue confirmed the original GNE mutation. As the maternal grandmother in the latter family died at age 49years of a liver tumor, a retrospective study of the remaining pathology slides was conducted and confirmed it to have been an IHCC as well. The overall observation generated the hypothesis that sialuria may predispose to development of this form of liver cancer. As proof of sialuria in the grandmother could not be obtained, an alternate cause of IHCC cannot be ruled out. In a series of 102 patients with IHCC, not a single instance was found with the allosteric site mutation in the GNE gene. This confirms that sialuria is rare even in a selected group of patients, but does not invalidate the concern that sialuria may be a risk factor for IHCC.

Construction of a school room installation and immersive performance as part of Dirt Babylon Glebe Park (commissioned by Robyn Archer for the Centenary of Canberra) in collaboration with Rebecca Rutter and ex- Splinters artists, November 2013

We argue that the limit of the propagation of the heap effects of a source code modification is determined by the aliasing structure of method parameters in a trace of the method calls that cross a boundary which partitions the heap. Further, that this aliasing structure is sufficient to uniquely determine the state of the part of the heap which has not been affected. And we give a definition of what it means for a part of the heap to be unaffected by a source code modification. This can be used to determine the correctness of a refactoring.

We argue that the limit of the propagation of the heap effects of a source code modification is determined by the aliasing structure of method parameters in a trace of the method calls that cross a boundary which partitions the heap. Further, that this aliasing structure is sufficient to uniquely determine the state of the part of the heap which has not been affected. And we give a definition of what it means for a part of the heap to be unaffected by a source code modification. This can be used to determine the correctness of a refactoring.

The Orchard Sports Injury Classification System (OSICS) is one of the world’s most commonly used systems for coding injury diagnoses in sports injury surveillance systems. Its major strengths are that it has wide usage, has codes specific to sports medicine and that it is free to use. Literature searches and stakeholder consultations were made to assess the uptake of OSICS and to develop new versions. OSICS was commonly used in the sports of football (soccer), Australian football, rugby union, cricket and tennis. It is referenced in international papers in three sports and used in four commercially available computerised injury management systems. Suggested injury categories for the major sports are presented. New versions OSICS 9 (three digit codes) and OSICS 10.1 (four digit codes) are presented. OSICS is a potentially helpful component of a comprehensive sports injury surveillance system, but many other components are required. Choices made in developing these components should ideally be agreed upon by groups of researchers in consensus statements.

John Orchard1, Katherine Rae1, John Brooks2, Martin Hägglund3, Lluis Til4, David Wales5, Tim Wood61Sports Medicine at Sydney University, Sydney NSW Australia; 2Rugby Football Union, Twickenham, England, UK; 3Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; 4FC Barcelona, Barcelona, Catalonia, Spain; 5Arsenal FC, Highbury, England, UK; 6Tennis Australia, Melbourne, Vic, AustraliaAbstract: The Orchard Sports Injury Classification System (OSICS) is one of the world’s most commonly used systems for coding injury diagnoses in sports injury surveillance systems. Its major strengths are that it has wide usage, has codes specific to sports medicine and that it is free to use. Literature searches and stakeholder consultations were made to assess the uptake of OSICS and to develop new versions. OSICS was commonly used in the sports of football (soccer), Australian football, rugby union, cricket and tennis. It is referenced in international papers in three sports and used in four commercially available computerised injury management systems. Suggested injury categories for the major sports are presented. New versions OSICS 9 (three digit codes) and OSICS 10.1 (four digit codes) are presented. OSICS is a potentially helpful component of a comprehensive sports injury surveillance system, but many other components are required. Choices made in developing these components should ideally be agreed upon by groups of researchers in consensus statements.Keywords: sports injury classification, epidemiology, surveillance, coding

The haematopoietic cytokine family of signalling molecules comprises a variety of polypeptides which have pleiotropic effects on cell differentiation, tissue development and homeostasis. The family includes several interleukins, a variety of growth and colony stimulating factors, erythropoietin, leukaemia inhibitory factor, ciliary neurotrophic factor, the interferons, as well as leptin, prolactin and growth hormone. The receptors for a large number of cytokines have been cloned and shown to be membrane-spanning glycoproteins with their amino termini in the extracellular space. On the basis of their possession of certain structural similarities these have been grouped together into the haematopoietic cytokine / interferon (HCI) receptor family. This thesis concerns the mechanism of signal transduction of the HCI receptors. The regulation of reporter gene transcription by growth hormone in cultured cell lines has been established as a model system for the study of cytokine signal transduction. Using a combination of gel mobility shift assays and reporter gene constructs we have identified an element in the growth hormone-regulated serine protease inhibitor (SPI) 2.1 promoter which shares sequence similarity with STAT (signal transducer and activator of transcription) transcription factor response elements found in a variety of cytokine-regulated gene promoters. Growth hormone treatment of cells in culture and rat liver was found to result in the stimulation of STAT 5-binding to this element. This was the first demonstration of growth hormone-dependent activation of a clearly defined transcription factor. STAT 5, but not STATs 1 or 3, was found to be capable of mediating growth hormone's effect on transcription of a reporter gene containing the SPI 2.1 STAT response element. In addition to the growth hormone receptor, the ligand-bound receptors for prolactin and erythropoietin were also found to stimulate gene transcription via the SPI 2.1 STAT response element. This