The Garvan Institute of Medical Research is an Australian biomedical research institute located in Darlinghurst, Sydney, New South Wales. Founded in 1963 by the Sisters of Charity as a research department of St Vincent's Hospital, it is now one of Australia's largest medical research institutions, with approximately 750 scientists, students and support staff. The executive director of the institute since 2018 is Professor Chris Goodnow FAA, FRS.In 2014 the institute became one of only three organisations in the world – and the only one outside the United States – able to sequence the human genome at a base cost below US$1,000 each (the $1,000 genome) when it purchased the next generation of genome sequencing equipment, which is capable of sequencing 350 genomes a week (18,000 a year).
The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). The resource comprised 906,359 women and men (66.9
Evidence of benefit for pancreatic ductal adenocarcinoma (PDAC) surveillance is accumulating, including earlier staging, extended survival, and improved psychological function. This study aimed to assess the 5-year psychological impact of high-risk PDAC surveillance, performed at St Vincent’s Hospital, Sydney, Australia. Participants were offered annual endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI), with frequency increasing if clinically indicated. The impact of event scale (IES), comprising intrusion and avoidance subscales, and the psychological consequences questionnaire (PCQ), which assesses emotional, physical and social domains, were administered at baseline, 1-month, 1-year and 5-years post-baseline EUS. Generalized linear mixed-effects models were used to assess for differences in reported outcomes. Of the 143 participants under surveillance, 108 underwent annual investigations, and 35 had one or more episode(s) of intensified surveillance. Overall, screening compliance was high, though understandably, increased deferrals occurred during COVID-19 pandemic restrictions. Two participants were diagnosed with pancreatic neoplasms and half had pre-malignant pancreatic lesions that remained stable (n = 45) or showed progression (n = 28). There was a significant reduction in IES intrusion and an increase in positive PCQ emotional, physical and total scores at 5-years. Negative PCQ scores remained stable compared to baseline. There was no difference in IES, negative PCQ or positive PCQ scores based on EUS/MRI findings. Individuals undergoing intensified surveillance reported significantly lower positive PCQ physical and total scores, but there was no difference in negative PCQ or IES scores. These data provide reassurance regarding the acceptability and psychological safety of PDAC surveillance, despite frequent abnormal findings and intensified investigation.
BACKGROUND:Dual anti-human epidermal growth factor receptor 2 (HER2) therapy plus chemotherapy followed by maintenance treatment with HER2-targeted and endocrine therapies is standard first-line treatment for hormone-receptor-positive, HER2-positive metastatic breast cancer. On the basis of preclinical and clinical data, the addition of palbociclib (a selective inhibitor of cyclin-dependent kinases 4 and 6) may overcome resistance to both endocrine and HER2-directed therapies. METHODS:In this phase 3, open-label, randomized trial, we enrolled patients with hormone-receptor-positive, HER2-positive metastatic breast cancer who did not have disease progression after four to eight cycles of chemotherapy plus HER2-targeted therapy. Patients were randomly assigned in a 1:1 ratio to receive maintenance HER2-targeted and endocrine therapies with or without palbociclib. The primary end point was investigator-assessed progression-free survival. Secondary end points included the objective response, clinical benefit, safety, and overall survival. RESULTS:A total of 518 patients underwent randomization: 261 were assigned to receive palbociclib and 257 to receive standard therapy. At a median follow-up of 53.5 months, patients in the palbociclib group had significantly longer progression-free survival than those in the standard-therapy group (median duration, 44.3 months vs. 29.1 months; hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; two-sided P = 0.02). Grade 3 and 4 adverse events, predominantly from neutropenia, occurred in 79.7% and 10.0% of the patients, respectively, in the palbociclib group, as compared with 30.6% and 3.6% of the patients, respectively, in the standard-therapy group. CONCLUSIONS:The addition of palbociclib to maintenance anti-HER2 and endocrine therapies led to a significant improvement in progression-free survival over standard therapy, with increased toxic effects, mainly neutropenia. (Funded by Pfizer and others; PATINA ClinicalTrials.gov number, NCT02947685.).
Cardiovascular risk factors contribute to the majority of dementia cases, with about 20% directly attributable to vascular cognitive impairment and dementia (VCID). VCID treatment developments have been slow compared with Alzheimer’s disease (AD), which now has several FDA-approved symptom- and disease-modifying agents. In the second part of this JACC Seminar Series, advances and new perspectives on the management and prevention of VCID are reviewed. There is reasonable evidence that cognitive enhancers (donepezil, galantamine, and memantine) modestly improve cognition in vascular dementia (VaD), the most severe form of VCID, especially if there is associated AD pathology. Antidepressants may benefit those with depression and stroke, but they have poor efficacy in those with depression and VaD alone. Behavioral, social, and environmental interventions are first-line therapies for managing VCID-associated agitation and psychosis. Second-line antipsychotics have not been trialed in those with VaD alone, but are beneficial where AD and VaD co-exist, with risperidone and quetiapine effective in reducing psychosis and agitation. Primary prevention of VCID includes identifying and managing cardiometabolic risk factors along with manifestations of covert cerebrovascular disease. Both primary and secondary VCID prevention involve management of cardiovascular risks, specifically hypertension, diabetes mellitus, smoking, atrial fibrillation, obesity, and sedentariness. Management of vascular risk factors may moderately reduce the risk of incident cognitive impairment. Novel interventions currently being evaluated in clinical trials are discussed. The discovery and utilization of VCID and AD biomarkers will enhance the specificity and effectiveness of interventions such that a precision-medicine approach to disease-specific medical therapy may be taken.
Mucosal-associated invariant T cells (MAIT cells) mediate tissue homeostasis and antimicrobial immunity. However, the cells that express major histocompatibility complex (MHC) class I-related protein 1 (MR1) and present microbial vitamin B-derived antigens (VitBAg) to MAIT cells remain unknown. We found that MR1 expression varied across tissues and cell types. Macrophages from the lung and peritoneal cavity expressed the highest levels of MR1 and were the most efficient at capturing and presenting VitBAg to MAIT cells. Expression of MR1 in macrophages was regulated transcriptionally and induced by the tissue environment and microbiota. Depletion of MR1 in macrophages, dendritic cells, and monocytes changed the composition of the microbiota and impaired MAIT cell responses against bacterial infection. We concluded that macrophages are key for MR1 antigen presentation and MAIT cell immunity.
