CRISPR applications for Duchenne muscular dystrophy: From animal models to potential therapies.

CRISPR gene-editing technology creates precise and permanent modifications to DNA. It has significantly advanced our ability to generate animal disease models for use in biomedical research and also has potential to revolutionize the treatment of genetic disorders. Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disease that could potentially benefit from the development of CRISPR therapy.

Alterations in Acute Lymphoblastic Leukemia: Molecular Insights for Superior Precision Medicine Strategies.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from immature lymphocytes that show uncontrolled proliferation and arrested differentiation. Genomic alterations affecting Janus kinase 2 () correlate with some of the poorest outcomes within the Philadelphia-like subtype of ALL. Given the success of kinase inhibitors in the treatment of chronic myeloid leukemia, the discovery of activating point mutations and fusion genes in ALL, was a breakthrough for potential targeted therapies.

Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia.

Tyrosine kinase inhibitors (TKIs) have revolutionised the management of chronic myeloid leukaemia (CML), with the disease now having a five-year survival rate over 80%. The primary focus in the treatment of CML has been on improving the specificity and potency of TKIs to inhibit the activation of the BCR::ABL1 kinase and/or overcoming resistance driven by mutations in the BCR::ABL1 oncogene. However, this approach may be limited in a significant proportion of patients who develop TKI resistance despite the effective inhibition of BCR::ABL1.

Urinary Tract Infection in Overactive Bladder: An Update on Pathophysiological Mechanisms.

Overactive bladder (OAB) is a clinical syndrome defined by urinary urgency, increased daytime urinary frequency and/or nocturia, with or without urinary incontinence, that affects approximately 11% of the western population. OAB is accepted as an idiopathic disorder, and is charactersied clinically in the absence of other organic diseases, including urinary tract infection. Despite this, a growing body of research provides evidence that a significant proportion of OAB patients have active bladder infection.

Sex-Related Differences in Long-Term Outcomes After Early-Onset Myocardial Infarction.

Importance: There is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure.

Methods: A nationwide study involving 125 Italian Coronary Care Units recruited 2,000 patients between 1998 and 2002 hospitalized for a type I myocardial infarction before the age of 45 years (male, = 1,778 (88.9%).

Distal femoral arthroplasty for native knee fractures : results from the Australian Orthopaedic Association National Joint Replacement Registry.

Aims: The aim of this study was to investigate the rate of revision for distal femoral arthroplasty (DFA) performed as a primary procedure for native knee fractures using data from the Australian Orthopaedic Association National Joint Arthroplasty Registry (AOANJRR).

Methods: Data from the AOANJRR were obtained for DFA performed as primary procedures for native knee fractures from 1 September 1999 to 31 December 2020. Pathological fractures and revision for failed internal fixation were excluded.

Housing and health: an updated glossary.

Recent crises have underscored the importance that housing has in sustaining good health and, equally, its potential to harm health. Considering this and building on Howden-Chapman's early glossary of housing and health and the WHO Housing and Health Guidelines, this paper introduces a range of housing and health-related terms, reflecting almost 20 years of development in the field. It defines key concepts currently used in research, policy and practice to describe housing in relation to health and health inequalities.

Investigating the association between infertility and psychological distress using Australian Longitudinal Study on Women's Health (ALSWH).

Infertility affects millions of people globally. Although an estimated 1 in 6 couples in Australia are unable to conceive without medical intervention, little is known about the mental health impacts of infertility. This study investigated how infertility impacts the mental health of women.

Asciminib for chronic myeloid leukaemia: Next questions.

Recent approval of asciminib, a novel "specifically targeting the ABL myristoyl pocket" (STAMP) BCR-ABL1 inhibitor, for the treatment of chronic myeloid leukaemia (CML) patients who have either failed ≥2 lines of therapy or have the T315I mutation, has provided clinicians with a wider selection of potentially effective treatment options. Asciminib has the attractive twin attributes of high potency directed against BCR-ABL1 and good tolerability based on its limited off-target effects. However, it is unclear exactly where asciminib will be positioned amongst the other available tyrosine kinase inhibitors (TKIs), especially ponatinib which is also available for the same indications.

TGR5 agonists induce peripheral and central hypersensitivity to bladder distension.

The mechanisms underlying chronic bladder conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder syndrome (OAB) are incompletely understood. However, targeting specific receptors mediating neuronal sensitivity to specific stimuli is an emerging treatment strategy. Recently, irritant-sensing receptors including the bile acid receptor TGR5, have been identified within the viscera and are thought to play a key role in neuronal hypersensitivity.

A Comparison of Revision Rates and Dislocation After Primary Total Hip Arthroplasty with 28, 32, and 36-mm Femoral Heads and Different Cup Sizes: An Analysis of 188,591 Primary Total Hip Arthroplasties.

This article was updated on August 17, 2022, because of previous errors, which were discovered after the preliminary version of the article was posted online. On page 1462, in the first sentence of the Abstract section entitled "Results," the phrase that had read "and 36-mm heads had fewer dislocations than 28-mm (HR = 0.33 [95% CI, 0.

A Prospective, Longitudinal Study of the Influence of Obesity on Total Knee Arthroplasty Revision Rate: Results from the Australian Orthopaedic Association National Joint Replacement Registry.

Background: The aim of this study was to investigate the relationship of obesity with all-cause revision and revision for infection, loosening, instability, and pain after total knee arthroplasty (TKA) performed in Australia.

Methods: Data for patients undergoing primary TKA for osteoarthritis from January 1, 2015, to December 31, 2020, were obtained from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). The rates of all-cause revision and revision for infection, loosening, instability, and pain were compared for non-obese patients (body mass index [BMI], 18.

Dialysis modality utilization patterns and mortality in older persons initiating dialysis in Australia and New Zealand.

Aim: The benefits of dialysis in the older population remain highly debated, particularly for certain dialysis modalities. This study aimed to explore the dialysis modality utilization patterns between in-centre haemodialysis (ICHD), peritoneal dialysis (PD) and home haemodialysis (HHD) and their association with outcomes in older persons.

Methods: Older persons (≥75 years) initiating dialysis in Australia and New Zealand from 1999 to 2018 reported to the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry were included.

Automated Coronary Optical Coherence Tomography Feature Extraction with Application to Three-Dimensional Reconstruction.

Coronary optical coherence tomography (OCT) is an intravascular, near-infrared light-based imaging modality capable of reaching axial resolutions of 10-20 µm. This resolution allows for accurate determination of high-risk plaque features, such as thin cap fibroatheroma; however, visualization of morphological features alone still provides unreliable positive predictive capability for plaque progression or future major adverse cardiovascular events (MACE). Biomechanical simulation could assist in this prediction, but this requires extracting morphological features from intravascular imaging to construct accurate three-dimensional (3D) simulations of patients' arteries.

Between-hospital and between-surgeon variation in thresholds for hip and knee replacement.

Background: Total hip replacement (THR) and total knee replacement (TKR) are cost-effective interventions to reduce pain and disability associated with osteoarthritis, however there is no clear guidelines available to determine appropriate patient selection and the timing of surgery. This prospective cohort study aimed to evaluate the hospital- and surgeon-level variation in the severity of patient-reported symptoms prior to THR and TKR.

Methods: Patients undergoing primary THR (n = 4330) or TKR (n = 7054) for osteoarthritis who participated in a national registry-led Patient Reported Outcome Measures (PROMs) pilot program were included in the analysis.

Total shoulder replacement stems in osteoarthritis-short, long, or reverse? An analysis of the impact of crosslinked polyethylene.

Background: The 2021 Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) report indicated that total shoulder replacement using both midhead (TMH) length humeral components and reverse arthroplasty (RTSA) had a lower revision rate than stemmed humeral components in anatomic total shoulder arthroplasty (aTSA)-for all prosthesis types and diagnoses. However, there are many factors that affect the outcome of total shoulder replacement, including stem length and polarity, polyethylene type, and glenoid fixation (cemented vs. cementless).

Fc gamma receptor is not required for in vivo processing of radio- and drug-conjugates of the dead tumor cell-targeting monoclonal antibody, APOMAB®.

The Fc region of a monoclonal antibody (mAb) can play a crucial role in its biodistribution and therapeutic activity. The chimeric mAb, chDAB4 (APOMAB®), which binds to dead tumor cells after DNA-damaging anticancer treatment, has been studied pre-clinically in both diagnostic and therapeutic applications in cancer. Given that macrophages contribute to the tumor accumulation of chDAB4 and its potency as an antibody drug conjugate in vivo, we next wanted to determine whether the Fc region of the chDAB4 mAb also contributed.

Outcomes following venetoclax-based treatment in therapy-related myeloid neoplasms.

Therapy-related myeloid neoplasms (t-MN) are aggressive malignancies in need of effective therapies. The BCL-2 inhibitor venetoclax represents a paradigm shift in the treatment of acute myeloid leukemia. However, the effectiveness of venetoclax has not been studied in a large cohort of t-MN.

The Cell Type-Specific 5hmC Landscape and Dynamics of Healthy Human Hematopoiesis and TET2-Mutant Preleukemia.

Unlabelled: The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human hematopoietic stem and progenitor cells (HSPC).

Obesity is associated with an increased risk of undergoing knee replacement in Australia.

Background: Obesity is associated with the development of knee osteoarthritis (OA). The aim of this study was to examine the incidence of obesity in patients undergoing knee replacement (KR) for OA in Australia compared to the incidence of obesity in the general population.

Methods: A cohort study was conducted, comparing data from the Australian Bureau of Statistics (ABS) 2017-2018 National Health Survey with data from the National Joint Replacement Registry.

Unravelling Prostate Cancer Heterogeneity Using Spatial Approaches to Lipidomics and Transcriptomics.

Due to advances in the detection and management of prostate cancer over the past 20 years, most cases of localised disease are now potentially curable by surgery or radiotherapy, or amenable to active surveillance without treatment. However, this has given rise to a new dilemma for disease management; the inability to distinguish indolent from lethal, aggressive forms of prostate cancer, leading to substantial overtreatment of some patients and delayed intervention for others. Driving this uncertainty is the critical deficit of novel targets for systemic therapy and of validated biomarkers that can inform treatment decision-making and to select and monitor therapy.