Previously undiagnosed genetic disease in adult patient with hepatic masses and reported history of congenital hyperinsulinism.

Glycogen storage disease type 1A (GSD1A), also known as Von Gierke's disease, is a rare autosomal recessive disorder affecting glycogen metabolism in the liver. It most commonly presents in infancy with hypoglycaemia and failure to thrive, but cases have been reported as undiagnosed until adulthood. A woman in her early 20s with diabetes mellitus presented with right upper quadrant pain and was found to have several haemorrhagic hepatic adenomas. This patient had insulin-dependent diabetes since a pancreatectomy at age 9 months due to continued episodes of hypoglycaemia and suspected insulinoma. During the hospital stay, the hepatic adenomas were embolised, but significant lactic acidosis and hypoglycaemia continued. Further workup revealed a chronic lactic acid level, during several hospital stays, of above 5 mmol/L. After cytology of hepatic tissue ruled out hepatocellular carcinoma, the patient was discharged and recommended to follow-up for genetic testing, which confirmed the diagnosis of GSD1A.

External Rotation of the Shoulder against Resistance as a Clinical Sign to Aid in the Diagnosis of Acromioclavicular Injury.

Introduction: Acromioclavicular joint (ACJ) injuries account for more than 40% of all sports-related shoulder injuries. Early and effective diagnosis is crucial with surgical intervention favored over non-operative management in high-grade injury. At present diagnosis is primarily by plain radiography with a clear lack of good clinical examination techniques. This study aims to describe external rotation against resistance (ERAR) as a means of ACJ injury assessment. Case Report: This case report describes three patients who presented to a local tertiary hospital with sporting injuries. In all cases, plain radiography demonstrated ACJ injury. Patients performed ERAR with the elbow by the side and flexed to 90° to assess for increase in ACJ deformity and coracoclavicular (CC) distance. The cases reported include two acute and one chronic ACJ injury. In all cases, this physical examination technique resulted in increased ACJ deformity and CC distance. This examination technique was well tolerated in all patients. All three patients underwent operative fixation and achieved excellent clinical outcomes. Conclusion: In our experience, external rotation of the shoulder against resistance is a well-tolerated examination technique which has demonstrated good clinical utility, aiding in the diagnosis of moderate to high-grade ACJ injury. While this clinical examination technique may aid in the diagnosis of high-grade ACJ injury, the authors strongly recommend further clinical and radiological confirmation before the diagnosis of acute traumatic shoulder injuries.

RIvER Clinic: Rethinking Incarceration and Empowering Recovery-An Innovative Postincarceration Care Delivery Model Implemented During the COVID-19 Pandemic.

The Rethinking Incarceration and Empowering Recovery (RIvER) Clinic was launched in June 2021 to address the health disparities experienced during and after incarceration. The RIvER Clinic's multidisciplinary, community-centered team engages patients during jail detention and after release via telehealth, collocated in community locations, on a mobile van, and in clinic. The clinic serves as a bridge between incarceration and the establishment of permanent health care and social services in the community. In 2022, a total of 479 visits were completed. The clinic provided multidisciplinary substance use support to all eligible patients, paying for 104 medication for opioid use disorder (MOUD) prescriptions for uninsured patients. Twenty-five percent of patients were transitioned to community-based care, and less than 5% of patients were reincarcerated. Despite some limitations, results demonstrate that the RIvER Clinic is successfully reintegrating a marginalized population into its community. The purpose of this article is to describe the implementation and preliminary outcomes of this postincarceration clinic.

Loss-of-function variants in JPH1 cause congenital myopathy with prominent facial involvement.

Background: Weakness of facial, ocular, and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca 2+ homeostasis can contribute to disease pathology. Methods: We analysed exome and genome sequencing data from three unrelated individuals with congenital myopathy characterised by striking facial, ocular, and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-seq data of one proband and performed gene expression outlier analysis in 129 samples. Results: The three probands had remarkably similar clinical presentation with prominent facial, ocular, and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but most prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatiguability. While muscle biopsy on light microscopy did not show any obvious morphological abnormalities, ultrastructural analysis showed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum. DNA sequencing identified three unique homozygous loss of function variants in JPH1 , encoding junctophilin-1 in the three families; a stop-gain (c.354C>A; p.Tyr118*) and two frameshift (c.373del p.Asp125Thrfs*30 and c.1738del; p.Leu580Trpfs*16) variants. Muscle RNA-seq showed strong downregulation of JPH1 in the F3 proband. Conclusions: Junctophilin-1 is critical to the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of JPH1 results in a congenital myopathy with prominent facial, bulbar and ocular involvement. Key message: This study identified novel homozygous loss-of-function variants in the JPH1 gene, linking them to a unique form of congenital myopathy characterised by severe facial and ocular symptoms. Our research sheds light on the critical impact on junctophilin-1 function in skeletal muscle triad junction formation and the consequences of its disruption resulting in a myopathic phenotype. What is already known on this topic: Previous studies have shown that pathogenic variants in genes encoding triad proteins lead to various myopathic phenotypes, with clinical presentations often involving muscle weakness and myopathic facies. The triad structure is essential for excitation-contraction (EC) coupling and calcium homeostasis and is a key element in muscle physiology. What this study adds and how this study might affect research practice or policy: This study establishes that homozygous loss-of-function mutations in JPH1 cause a congenital myopathy predominantly affecting facial and ocular muscles. This study also provides clinical insights that may aid the clinicians in diagnosing similar genetically unresolved cases.

Ependymoma-like tumor with mesenchymal differentiation (ELTMD) with ZFTA:NCOA1 fusion: A diagnostic challenge.

Ependymal tumors are classified based on their location, histology, and molecular characteristics. Supratentorial ependymomas (ST-EPNs) are a group of circumscribed supratentorial gliomas, which usually have pathogenic fusions involving either zinc finger translocation associated (ZFTA) (formerly C11orf95) or YAP1. A subtype of ependymoma was recently described and labeled ependymoma-like tumors with mesenchymal differentiation (ELTMDs). We describe a case of a 5-year-old boy who presented with a right frontal tumor. The diagnosis was challenging, and a correct diagnosis could only be reached after reanalysis of methylation data with a more recent version of the classifier and RNA fusion testing, which revealed ZFTA:NCOA1 (nuclear receptor coactivator 1) fusion. There are only a handful of cases of this entity, which is being reported for its rarity and the diagnostic challenge it poses.

Organizational Health Literacy and Health Among New York State Medicaid Members.

BACKGROUND: The definition of health literacy has recently expanded beyond the idea of individual skills to include the system and environment the individual interacts with to receive care, known as organizational health literacy (OHL). However, neither the prevalence of OHL nor the impact of OHL on individuals' perceptions of their health and healthcare have been examined in New York's Medicaid managed care population. OBJECTIVE: This study aimed to estimate the prevalence of organizational health literacy in the New York State (NYS) Medicaid Managed Care (MMC) program. METHODS: A brief measure to assess organizational health literacy was developed from responses to two questions in the 2018 NYS Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. Generalized Estimating Equation models were developed to analyze the association between organizational health literacy and three aspects of perceptions of health and health care, controlling for demographic differences and clustering effects from health insurance plans. Missing data were handled using multiple imputation. KEY RESULTS: Among 3,598 members included in the study, 20% of the MMC members reported inadequate organizational health literacy. These members were more likely to be older, less educated, from racial and ethnic minority groups, and less fluent with English. They are more likely to have poorer self-reported health (odds ratio [OR] 1.49), lower perceived access to health care (OR 6.97), and lower satisfaction with their health care (OR 6.49) than members who did not report inadequate organizational health literacy. CONCLUSIONS: Our results suggest that a proportion of the NYS MMC population faces inadequate organizational health literacy, which can present a barrier to health care access and result in patients having a significantly poorer health care experience. Using an existing data source that is part of existing data collection allows for routine assessment of organizational health literacy, which can help inform health plans about areas for potential improvement. [HLRP: Health Literacy Research and Practice. 2023;7(3):e154-e164.].

PLAIN LANGUAGE SUMMARY: Our study looked at the impact of organizational health literacy on the perceptions of health and health care of NYS Medicaid Managed Care population. We used existing CAHPS questions to assess organizational health literacy and found that lower organizational health literacy led to worse perceptions of health and health care. This article illustrates an opportunity to demonstrate how organizational health literacy can be measured with annual CAHPS collections.

Proteomic investigation of ALS motor cortex identifies known and novel pathogenetic mechanisms.

The key pathological feature in ALS is death of motor neurones from the brain and spinal cord, but the molecular mechanisms underlying this degeneration remain unknown. Quantifying the motor cortex proteome in autopsy brain and comparing tissues from ALS cases and non-ALS controls is critical to understanding these mechanisms. We used Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) to characterize the proteomes of the motor cortex from ALS cases (n = 8) and control subjects (n = 8). A total of 1427 proteins were identified at a critical local false discovery rate < 5%; 187 of these exhibited significant expression differences between ALS cases and controls. Of these, 91 proteins were significantly upregulated and 96 proteins were significantly downregulated. Bioinformatics analysis revealed that these proteins are involved in molecular transport, protein trafficking, free radical scavenging, lipid metabolism, cell death and survival, nucleic acid metabolism, inflammatory response or amino acid metabolism and carbohydrate metabolism. Differentially expressed proteins were subjected to pathway analysis. This revealed abnormalities in pathways involving mitochondrial function, sirtuin signaling, oxidative phosphorylation, glycolysis, phagosome maturation, SNARE signaling, redox regulation and several others. Core analysis revealed mitochondrial dysfunction to be the top canonical pathway. The top-enriched networks involved JNK activation and inhibition of AKT signaling, suggesting that disruption of these signaling pathways could lead to demise of motor neurons in the ALS motor cortex.

Implementation of DNA Methylation Array Profiling in Pediatric Central Nervous System Tumors: The AIM BRAIN Project: An Australian and New Zealand Children's Haematology/Oncology Group Study.

DNA methylation array profiling for classifying pediatric central nervous system (CNS) tumors is a valuable adjunct to histopathology. However, unbiased prospective and interlaboratory validation studies have been lacking. The AIM BRAIN diagnostic trial involving 11 pediatric cancer centers in Australia and New Zealand was designed to test the feasibility of routine clinical testing and ran in parallel with the Molecular Neuropathology 2.0 (MNP2.0) study at Deutsches Krebsforschungszentrum (German Cancer Research Center). CNS tumors from 269 pediatric patients were prospectively tested on Illumina EPIC arrays, including 104 cases co-enrolled on MNP2.0. Using MNP classifier versions 11b4 and 12.5, we report classifications with a probability score ≥0.90 in 176 of 265 (66.4%) and 213 of 269 (79.2%) cases, respectively. Significant diagnostic information was obtained in 130 of 176 (74%) for 11b4, and 12 of 174 (7%) classifications were discordant with histopathology. Cases prospectively co-enrolled on MNP2.0 gave concordant classifications (99%) and score thresholds (93%), demonstrating excellent test reproducibility and sensitivity. Overall, DNA methylation profiling is a robust single workflow technique with an acceptable diagnostic yield that is considerably enhanced by the extensive subgroup and copy number profile information generated by the platform. The platform has excellent test reproducibility and sensitivity and contributes significantly to CNS tumor diagnosis.

A dual-core NMR system for field-cycling singlet assisted diffusion NMR.

Long-lived singlet spin order offers the possibility to extend the spin memory by more than an order of magnitude. This enhancement can be used, among other applications, to assist NMR diffusion experiments in porous media where the extended lifetime of singlet spin order can be used to gain information about structural features of the medium as well as the dynamics of the imbibed phase. Other than offering the possibility to explore longer diffusion times of the order of many minutes that, for example, gives unprecedented access to tortuosity in structures with interconnected pores, singlet order has the important advantage to be immune to the internal field gradients generated by magnetic susceptibility inhomogeneities. These inhomogeneities, however, are responsible for very short T2 decay constants in high magnetic field and this precludes access to the singlet order in the first instance. To overcome this difficulty and take advantage of singlet order in diffusion experiments in porous media, we have here developed a dual-core system with radiofrequency and 3-axis pulsed field gradients facilities in low magnetic field, for preparation and manipulation of singlet order and a probe, in high magnetic field, for polarisation and detection. The system operates in field-cycling and can be used for a variety of NMR experiments including diffusion tensor imaging (both singlet assisted and not). In this paper we present and discuss the new hardware and its calibration, and demonstrate its capabilities through a variety of examples.

Fatal granulomatous amebic encephalitis initially presenting with a cutaneous lesion.

We present a case of a 66-year-old man with a cutaneous Balamuthia mandrillaris lesion that progressed to fatal granulomatous amoebic encephalitis. We provide a summary of Australian cases and describe the clinical features and approach to diagnosing this rare but devastating condition, including the importance of PCR for diagnosis.

The effect of weight compared to BMI on patient reported outcomes at long term follow up of primary total hip arthroplasty.

Introduction: Obesity has been linked to the development of osteoarthritis meaning that a large portion of arthroplasty patients are overweight or obese. Whilst the short-term complications associated with obesity are well described there is a paucity of evidence on the effect of weight compared to BMI for long term functional outcomes of total hip replacements (THR). The aim of this study was to investigate the influence of BMI and weight on long-term patient reported outcome measures following primary THR. Methods: 846 patients who underwent primary THR at the Royal Adelaide Hospital between 2000 and 2009 had a pre-operative height and weight recorded. Patient reported outcome measures (PROMs) were completed at 1, 5 and greater than 10 years follow-up. Categorical comparison of PROMs was performed for patients in weight categories of 0-65 kg, 65-80 kg, 80-95 kg, 95-110 kg and >110 kg; and BMI categories as per the WHO Classifications. Results: There was no difference in absolute or change in PROMs for any weight category. BMI did not have an effect on the change in (HHS), however there was a statistically significant decrease in absolute (HHS) values at 1 and 5 years with increasing obesity. 65 patients underwent revision within the first ten years. Conclusion: The results from this study confirm for the first time that there was no impact of weight or BMI on the change in long-term PROMs of THR. There remains a need for larger registry studies to investigate the effect of weight and BMI on long-term patient outcomes and revision rate.

Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition.

BACKGROUND: Medulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups based on gene expression and genomic features. Single-cell transcriptome studies have defined the cellular states underlying each MB subgroup; however, the spatial organisation of these diverse cell states and how this impacts response to therapy remains to be determined. METHODS: Here, we used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of MB and show that cells specific to a transcriptional state or spatial location are pivotal for CDK4/6 inhibitor, Palbociclib, treatment response. We integrated spatial gene expression with histological annotation and single-cell gene expression data from MB, developing an analysis strategy to spatially map cell type responses within the hybrid system of human and mouse cells and their interface within an intact brain tumour section. RESULTS: We distinguish neoplastic and non-neoplastic cells within tumours and from the surrounding cerebellar tissue, further refining pathological annotation. We identify a regional response to Palbociclib, with reduced proliferation and induced neuronal differentiation in both treated tumours. Additionally, we resolve at a cellular resolution a distinct tumour interface where the tumour contacts neighbouring mouse brain tissue consisting of abundant astrocytes and microglia and continues to proliferate despite Palbociclib treatment. CONCLUSIONS: Our data highlight the power of using spatial transcriptomics to characterise the response of a tumour to a targeted therapy and provide further insights into the molecular and cellular basis underlying the response and resistance to CDK4/6 inhibitors in SHH MB.

Point-of-care ultrasound in diagnosis and management of congestive nephropathy.

Congestive nephropathy is kidney dysfunction caused by the impact of elevated venous pressures on renal hemodynamics. As a part of cardiorenal syndrome, the diagnosis is usually made based on history and physical examination, with findings such as jugular venous distension, a third heart sound, and vital signs as supporting findings. More recently, however, these once though objective measures have come under scrutiny for their accuracy. At the same time, bedside ultrasound has increased in popularity and is routinely being used by clinicians to take some of the guess work out of making the diagnosis of volume overload and venous congestion. In this mini-review, we will discuss some of the traditional methods used to measure venous congestion, describe the role of point-of-care ultrasound and how it can ameliorate a clinician's evaluation, and offer a description of venous excess ultrasound score, a relatively novel scoring technique used to objectively quantify congestion. While there is a paucity of published large scale clinical trials evaluating the potential benefit of ultrasonography in venous congestion compared to gold standard invasive measurements, more study is underway to solidify the role of this objective measure in daily clinical practice.

Change in CT-measured acetabular bone density following total hip arthroplasty: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Assessing peri-acetabular bone quality is valuable for optimizing the outcomes of primary total hip arthroplasty (THA) as preservation of good quality bone stock likely affects implant stability. The aim of this study was to perform a meta-analysis of peri-acetabular bone mineral density (BMD) changes over time measured using quantitative computer tomography (CT) and, second, to investigate the influence of age, sex, and fixation on the change in BMD over time. METHODS: A systematic search of Embase, Scopus, Web of Science, and PubMed databases identified 19 studies that measured BMD using CT following THA. The regions of interest (ROI), reporting of BMD results, and scan protocols were extracted. A meta-analysis of BMD was performed on 12 studies that reported measurements immediately postoperatively and at follow-up. RESULTS: The meta-analysis determined that periacetabular BMD around both cemented and uncemented components decreases over time. The amount of BMD loss increased relative to proximity of the acetabular component. There was a greater decrease in cortical BMD over time in females and cancellous BMD for young patients of any sex. CONCLUSION: Peri-acetabular BMD decreases at different rates relative to its proximity to the acetabular component. Cancellous BMD decreases more in young patients and cortical bone decreases more in females. Standardized reporting parameters and suggested ROI to measure peri-acetabular BMD are proposed, to enable comparison between implant and patient variables in the future.

Case report: Adult-onset limb girdle muscular dystrophy in sibling pair due to novel homozygous LAMA2 missense variant.

Recessive pathogenic variants in the laminin subunit alpha 2 (LAMA2) gene cause a spectrum of disease ranging from severe congenital muscular dystrophy to later-onset limb girdle muscular dystrophy (LGMDR23). The phenotype of LGMDR23 is characterized by slowly progressive proximal limb weakness, contractures, raised creatine kinase, and sometimes distinctive cerebral white matter changes and/or epilepsy. We present two siblings, born to consanguineous parents, who developed adult-onset LGMDR23 associated with typical cerebral white matter changes and who both later developed dementia. The male proband also had epilepsy and upper motor neuron signs when he presented at age 72. Merosin immunohistochemistry and Western blot on muscle biopsies taken from both subjects was normal. Whole exome sequencing revealed a previously unreported homozygous missense variant in LAMA2 [Chr6(GRCh38):g.129297734G>A; NM_000426.3:c.2906G>A; p.(Cys969Tyr)] in the proband. The same homozygous LAMA2 variant was confirmed by Sanger sequencing in the proband's affected sister. These findings expand the genotypic and phenotypic spectrum of LGMDR23.

Germline pathogenic SMARCA4 variants in neuroblastoma.

Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodelling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcaemic type, atypical teratoid and malignant rhabdoid tumour, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma (NBL), including 4 previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4 Median age at diagnosis was 5 years (range 2 months-26 years); nine were male; and eight of nine cases had tumour location information in the adrenal gland. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor. Altogether, these findings strongly suggest that NBL should be included in the spectrum of SMARCA4-associated tumours.

Impact of computed tomography metal artifact reduction protocol on periprosthetic tissue characterization after total hip arthroplasty: A cadaveric study.

Metal artifact reduction (MAR) has improved computed tomography (CT) imaging of total hip arthroplasty (THA) but the assessment of osteolysis and implant to bone contact relies on the accurate depiction of bone defects, cancellous bone, and cement. This study evaluates the impact of available single and dual-energy protocols on periprosthetic tissue characterization in a cadaveric phantom. Bilateral THA was performed on a fresh frozen cadaveric pelvis with simulated osteolytic cavities. CT acquisitions with projection-based MAR and noise equivalence were performed using single energy 140 kVp, single energy 150 kVp with 0.6 mm tin filtration, and dual-energy at 100/150 kVp with 0.6 mm tin filtration, from which simulated energies were extracted. Image subtraction, segmentation, region of interest histograms, and line profiles were used to characterize tissue density and separation. Tissue densities were heavily dependent on the energy profile of the protocol. Cancellous bone ranged from 182 to 45 HU and cement from 1012 to 131 HU using 140 kVp compared to dual-energy with weighted high energy tube, respectively. Spectral separation between cancellous bone, osteolytic defect, and cement was reduced for all protocols compared with 140 kVp. Spectral overlap was most severe using dual-energy with heavily weighted high-energy tubes. Dual-energy algorithms reduced trabecular contrast within the cancellous bone and cortical edge response. Although the dual-energy acquisition has been proposed as an additive to projection-based MAR techniques in THA, reduced density and contrast in clinically relevant periprosthetic tissue compared to 140 kVp single energy may limit its use in characterizing periprosthetic tissues.