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Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 62 pedigrees (58%), including 41 novel and 53 reported variants in IRD genes. For 58 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In eight pedigrees (13%) we observed atypical causal variants, i.e. unexpected genotype(s), including 5 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 21% of cases. Among the novel mutations, 75% were detected in Mexican and 53% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 48% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.

Background: Observational Alzheimer's disease (AD) cohorts including the Australian, Biomarkers, Imaging and Lifestyle (AIBL) Study have enhanced our understanding of AD. The generalizability of findings from AIBL to the general population has yet to be studied. Objective: We aimed to compare characteristics of people with AD dementia in AIBL to 1) the general population of older Australians using pharmacological treatment for AD dementia, and to 2) the general population of older Australians who self-reported a diagnosis of dementia. Methods: Descriptive study comparing people aged 65 years of over (1) in AIBL that had a diagnosis of AD dementia, (2) dispensed with pharmacological treatment for AD in Australia in 2021 linked to the Australian census in 2021 (refer to as PBS/census), (3) self-reported a diagnosis of dementia in the 2021 Australian census (refer to as dementia/census). Baseline characteristics included age, sex, highest education attainment, primary language, and medical co-morbidities. Results: Participants in AIBL were younger, had more years of education, and had a lower culturally and linguistically diverse (CALD) population compared to the PBS/census cohort and dementia/census cohort (mean age±standard deviation – AIBL 79±7 years, PBS/census 81±7, p < 0.001, dementia/census 83±8, p < 0.001; greater than 12 years of education AIBL 40%, PBS/census 35%, p = 0.020, dementia/census 29%, p < 0.001; CALD – AIBL 3%, PBS/census 20%, p < 0.001, dementia/census 22%, p < 0.001). Conclusions: Our findings suggest that care should be taken regarding the generalizability of AIBL in CALD populations and the interpretation of results on the natural history of AD. [ABSTRACT FROM AUTHOR]

Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Little is known about the molecular pathways that precipitate IMT formation. Here, we report the identification of somatic mutations in UPF1, a gene that encodes an essential component of the nonsense-mediated RNA decay (NMD) pathway, in 13 of 15 pulmonary IMT samples. The majority of mutations occurred in a specific region of UPF1 and triggered UPF1 alternative splicing. Several mRNA targets of the NMD pathway were upregulated in IMT samples, indicating that the UPF1 mutations led to reduced NMD magnitude. These upregulated NMD targets included NIK mRNA, which encodes a potent activator of NF-κB. In human lung cells, UPF1 depletion increased expression of chemokine-encoding genes in a NIK-dependent manner. Elevated chemokines and IgE class switching events were observed in IMT samples, consistent with NIK upregulation in these tumors. Together, these results support a model in which UPF1 mutations downregulate NMD, leading to NIK-dependent NF-κB induction, which contributes to the immune infiltration that is characteristic of IMTs. The molecular link between the NMD pathway and IMTs has implications for the diagnosis and treatment of these tumors.

Background: Residential InReach presents an alternative to hospital admission for aged care residents swabbed for coronavirus disease 2019 (COVID‐19), although relative outcomes remain unknown. Aims: To compare rates and predictors of 28‐day mortality for aged care residents seen by InReach with COVID‐19, or 'suspected COVID‐19' (sCOVID), including hospital versus InReach‐based care. Methods: Prospective observational study of consecutive patients referred to a Victorian InReach service meeting COVID‐19 testing criteria between April and October 2020 (prevaccine availability). COVID‐19 was determined by positive polymerase chain reaction testing on nasopharyngeal swab. sCOVID‐19 was defined as meeting symptomatic Victorian Government testing criteria but persistently swab negative. Results: There were no significant differences in age, sex, Clinical Frailty Score (CFS) or Charlson Comorbidity Index (CCI) between 152 patients with COVID‐19 and 118 patients with sCOVID. Similar results were found for 28‐day mortality between patients with COVID‐19 (35/152, 23%) and sCOVID (32/118, 27%) (P = 0.4). For the combined cohort, 28‐day mortality was associated with initial oxygen saturation (P < 0.001), delirium (P < 0.001), hospital transfer for acuity (P = 0.02; but not public health/facility reasons), CFS (P = 0.04), prior ischaemic heart disease (P = 0.01) and dementia (P = 0.02). For patients with COVID‐19, 28‐day mortality was associated with initial oxygen saturation (P = 0.02), delirium (P < 0.001) and hospital transfer for acuity (P = 0.01), but not public health/facility reasons. Conclusion: Unvaccinated aged care residents meeting COVID‐19 testing criteria seen by InReach during a pandemic experience high mortality rates, including with negative swab result. Residents remaining within‐facility (with InReach) experienced similar adjusted mortality odds to residents transferred to hospital for public health/facility‐based reasons, and lower than those transferred for clinical acuity. [ABSTRACT FROM AUTHOR]

Background and Aim: Risk stratification is recommended in all patients with acute variceal bleeding (AVB). It remains unclear whether liver disease severity or upper gastrointestinal bleeding (UGIB) scoring algorithms offer superior predictive ability. We aimed to validate the AIMS65 score as a predictor of mortality in AVB, and to compare AIMS65 with established UGIB and liver disease severity risk stratification scores. Methods: International Classification of Diseases, Tenth Revision codes identified patients presenting with AVB to three tertiary centers over a 48‐month period. Patients were risk‐stratified using AIMS65, Rockall, pre‐endoscopy Rockall, Child‐Pugh, Model for End‐stage Liver Disease (MELD) and United Kingdom MELD (UKELD) scores. Primary outcomes were inpatient and 6‐week mortality and inpatient rebleeding. Results: Two hundred and twenty‐three patients were included. Inpatient and 6‐week mortality were 13.9% and 15.5% respectively. Prediction of inpatient mortality by AIMS65 (area under the receiver‐operating characteristic curve [AUROC: 0.84]) was equivalent to UGIB (Rockall: 0.79, pre‐Rockall: 0.78) and liver risk scores (MELD: 0.81, UKELD: 0.79, Child‐Pugh: 0.78). AIMS65 score ≥3 best defined high‐ and low‐risk groups for inpatient mortality (mortality 37.7% vs 4.9%). AIMS65 (AUROC: 0.62) was equivalent to UGIB risk scores (pre‐Rockall: 0.64, Rockall: 0.70) in predicting inpatient rebleeding and superior to liver risk scores (MELD: 0.56, UKELD: 0.57, Child‐Pugh: 0.60). Conclusions: AIMS65 is equivalent to established UGIB and liver disease severity risk stratification scores in predicting mortality, and superior to liver scores in predicting rebleeding. [ABSTRACT FROM AUTHOR]

The article discusses balancing act between state policing and individual privacy interests in state and federal courts, along with incorporation of a search-protocol requirement into mobile device search warrants. Topics discussed include ruling of the U.S. Supreme Court in the case Riley v. California, requiring search warrants from law enforcement officers to search a mobile device, issues in lower courts over it and applicability of analogizing computer search warrant to mobile devices.

Background Aims Methods Results Conclusions Cerebral microbleeds (CMBs) are small brain haemorrhages, identified by magnetic resonance imaging (MRI). They indicate potential for cognitive decline and mortality in memory clinic attendees. The presence of more than four CMBs is exclusionary for some clinical trials of disease‐modifying therapies for Alzheimer's disease (AD). The prevalence and clinical relevance of CMBs in Australian memory clinic populations has not been reported.To highlight the prevalence of CMBs in an Australian memory clinic cohort and explore associations with diagnoses, topography and cognitive performance.We conducted a retrospective cohort study of 393 patients who attended a memory clinic (CDAMS) in Melbourne, Australia from January 2014 to December 2016 who underwent brain MRI. Data collected included age, gender, clinical diagnosis and cognitive scores. Univariable and multivariable regression analyses were performed to identify associations of CMBs with clinical and cognitive findings.The prevalence of CMBs was 27% (n=107) with good inter‐rater reliability (κ=0.75). CMBs were significantly associated with increasing age. Prevalence of CMBs was higher in people with mild cognitive impairment (MCI) (32%) and dementia (39%) compared with other diagnostic groups (p<0.001). Lobar‐predominant CMB distribution was associated with AD diagnosis. Presence of multiple CMBs was associated with poorer cognitive performance overall.CMBs are common in an Australian memory clinic population and are associated with poorer cognitive performance. “Real world” prevalence of CMBs may limit accessibility to disease‐modifying therapies for many people. [ABSTRACT FROM AUTHOR]

Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Little is known about the molecular pathways that precipitate IMT formation. Here, we report the identification of somatic mutations in UPF1, a gene that encodes an essential component of the nonsense-mediated RNA decay (NMD) pathway, in 13 of 15 pulmonary IMT samples. The majority of mutations occurred in a specific region of UPF1 and triggered UPF1 alternative splicing. Several mRNA targets of the NMD pathway were upregulated in IMT samples, indicating that the UPF1 mutations led to reduced NMD magnitude. These upregulated NMD targets included NIK mRNA, which encodes a potent activator of NF-κB. In human lung cells, UPF1 depletion increased expression of chemokine-encoding genes in a NIK-dependent manner. Elevated chemokines and IgE class switching events were observed in IMT samples, consistent with NIK upregulation in these tumors. Together, these results support a model in which UPF1 mutations downregulate NMD, leading to NIK-dependent NF-κB induction, which contributes to the immune infiltration that is characteristic of IMTs. The molecular link between the NMD pathway and IMTs has implications for the diagnosis and treatment of these tumors. [ABSTRACT FROM AUTHOR]