Chunky Mitral Annular Calcification: Caseoma or a Tumor?

Mitral annular calcification (MAC) is relatively common in clinical practice. Females are more often affected than males. Patients with end-stage renal disease have MAC relatively more commonly than the general population. Patients with MAC often develop conduction system disturbances, including advanced atrioventricular blocks. They are also more likely to develop various arrhythmias, including atrial fibrillation. Caseous mitral annulus calcification is a variant of MAC that often looks like a cardiac tumor on an echocardiogram and needs to be differentiated.

Lymphatic expression of the proliferation marker Ki67 is linked to sentinel node positivity, recurrence and mortality in primary cutaneous melanoma.

Lymphangiogenesis is a precursor to lymphovascular invasion, and may therefore signal a higher risk of metastasis and mortality in primary cutaneous melanoma. This retrospective longitudinal study aimed to evaluate whether emergent lymphangiogenesis, as measured through co-expression of endothelial proteins with the proliferation marker Ki67, was associated with poorer prognosis in a cohort of patients with single primary cutaneous melanoma. We screened all patients with a single locally invasive primary cutaneous melanoma who received sentinel lymph node biopsy at a tertiary dermatology centre in Brisbane, Australia between 1994 and 2007. Primary melanoma sections were stained via Opal multiplex immunofluorescence, and categorized according to the presence of Ki67 within either CD31+ or D2-40+ endothelial cells. Multivariate Cox regression modelling was used to evaluate associations between endothelial Ki67 positivity and clinical outcomes, with adjustment for age, sex, Breslow depth, ulceration, and anatomical location. Overall, 264 patients were available for analysis, with a median follow-up duration of 7.1 years. The presence of D2-40+ /Ki67+ co-expression was associated with greater melanoma-specific mortality (adjusted hazard ratio [HR]: 2.03; 95% confidence interval [CI]: 1.33-3.10; p = 0.001) and recurrence (adjusted HR: 1.70; 95% CI: 1.33-3.10; p = 0.001) relative to absence. CD31+ /Ki67+ co-expression was not prognostic in this cohort. Lymphatic proliferation, as measured through D2-40+ /Ki67+ co-expression, predicted greater melanoma-specific mortality and recurrence in this cohort of primary cutaneous melanoma.

Cat-scratch disease masquerading as post-transplant lymphoproliferative disorder.

Lymphadenopathy in an immunosuppressed patient raises the quintessential diagnostic dilemma: infection or malignancy? We present the case of a transplant recipient on anti-rejection prophylaxis admitted with acute fever, malaise and a swollen right axillary node. The patient had pancytopenia and tested positive for Epstein-Barr virus; nodal core biopsy demonstrated atypical plasma cell infiltration, immediately raising suspicion for post-transplant lymphoproliferative disorder. However, excisional biopsy and Bartonella henselae serology clarified a final diagnosis of cat-scratch disease-a potentially fatal zoonosis requiring a disparate treatment regimen. Here, we explore this patient's investigations, hospital course and recovery, with an emphasis on recognizing and differentiating these diagnostic mimics in post-transplant practice.

Impact of the COVID-19 pandemic on delivery of prostate cancer care in Australia: An interrupted time series analysis.

The COVID-19 pandemic led to a major disruption to health services across the world. The aim of this population-based study was to assess the downstream effects of the pandemic on diagnostic tests and treatment activities related to prostate cancer (PC). The Australian Government Department of Health Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme databases were queried from January 2010 to June 2022. Two interrupted time series were performed Pre-COVID (January 2010 to February 2020) and peri-COVID (March 2020 to June 2022). Temporal modeling was performed to account for seasonal variation. Pre-COVID-19, monthly prostate-specific antigen (PSA) testing showed a declining trend and testing decreased by 81 tests per 100 000 annually. A single-month 38% drop in PSA testing was observed in April 2020; this corresponded to Australia's first wave. No change was observed in the rate of prostate biopsies. Peri-COVID-19 outbreaks, there was a slight shift toward the use of long-acting androgen deprivation therapy (ADT) at 4% with a predilection still for short-acting agents. with no registered change in the overall volume of radiotherapy or surgery. There were no deficits in the number of diagnostic and treatment activities for men with PC. Aside from a slight shift toward long-acting ADT use during the pandemic, no other patterns were observed. The longer-term impact such as missed diagnosis or late presentation affecting chances of survival due to COVID-19 is yet to be ascertained.

Filter and Wrapper Stacking Ensemble (FWSE): a robust approach for reliable biomarker discovery in high-dimensional omics data.

Selecting informative features, such as accurate biomarkers for disease diagnosis, prognosis and response to treatment, is an essential task in the field of bioinformatics. Medical data often contain thousands of features and identifying potential biomarkers is challenging due to small number of samples in the data, method dependence and non-reproducibility. This paper proposes a novel ensemble feature selection method, named Filter and Wrapper Stacking Ensemble (FWSE), to identify reproducible biomarkers from high-dimensional omics data. In FWSE, filter feature selection methods are run on numerous subsets of the data to eliminate irrelevant features, and then wrapper feature selection methods are applied to rank the top features. The method was validated on four high-dimensional medical datasets related to mental illnesses and cancer. The results indicate that the features selected by FWSE are stable and statistically more significant than the ones obtained by existing methods while also demonstrating biological relevance. Furthermore, FWSE is a generic method, applicable to various high-dimensional datasets in the fields of machine intelligence and bioinformatics.

pSTAT5 is associated with improved survival in patients with thick or ulcerated primary cutaneous melanoma.

Identifying prognostic biomarkers to predict clinical outcomes in stage I and II cutaneous melanomas could guide the clinical application of adjuvant and neoadjuvant therapies. We aimed to investigate the prognostic value of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) as a biomarker in early-stage melanoma. This study evaluated all initially staged Ib and II melanoma patients undergoing sentinel node biopsy at a tertiary centre in Brisbane, Australia between 1994 and 2007, with survival data collected from the Queensland Cancer Registry. Primary melanoma tissue from 189 patients was analysed for pSTAT5 level through immunohistochemistry. Cox regression modelling, with adjustment for sex, age, ulceration, anatomical location, and Breslow depth, was applied to determine the association between pSTAT5 detection and melanoma-specific survival. Median duration of follow-up was 7.4 years. High pSTAT5 detection was associated with ulceration and increased tumour thickness. However, multivariate analysis indicated that high pSTAT5 detection was associated with improved melanoma-specific survival (hazard ratio: 0.15, 95% confidence interval: 0.03-0.67) as compared to low pSTAT5 detection. This association persisted when pSTAT5 detection was limited to immune infiltrate or the vasculature, as well as when sentinel node positivity was accounted for. In this cohort, staining for high-pSTAT5 tumours identified a subset of melanoma patients with increased survival outcomes as compared to low-pSTAT5 tumours, despite the former having higher-risk clinicopathological characteristics at diagnosis. pSTAT5 is likely an indicator of local immune activation, and its detection could represent a useful tool to stratify the risk of melanoma progression.

Constrained neuro fuzzy inference methodology for explainable personalised modelling with applications on gene expression data.

Interpretable machine learning models for gene expression datasets are important for understanding the decision-making process of a classifier and gaining insights on the underlying molecular processes of genetic conditions. Interpretable models can potentially support early diagnosis before full disease manifestation. This is particularly important yet, challenging for mental health. We hypothesise this is due to extreme heterogeneity issues which may be overcome and explained by personalised modelling techniques. Thus far, most machine learning methods applied to gene expression datasets, including deep neural networks, lack personalised interpretability. This paper proposes a new methodology named personalised constrained neuro fuzzy inference (PCNFI) for learning personalised rules from high dimensional datasets which are structurally and semantically interpretable. Case studies on two mental health related datasets (schizophrenia and bipolar disorders) have shown that the relatively short and simple personalised fuzzy rules provided enhanced interpretability as well as better classification performance compared to other commonly used machine learning methods. Performance test on a cancer dataset also showed that PCNFI matches previous benchmarks. Insights from our approach also indicated the importance of two genes (ATRX and TSPAN2) as possible biomarkers for early differentiation of ultra-high risk, bipolar and healthy individuals. These genes are linked to cognitive ability and impulsive behaviour. Our findings suggest a significant starting point for further research into the biological role of cognitive and impulsivity-related differences. With potential applications across bio-medical research, the proposed PCNFI method is promising for diagnosis, prognosis, and the design of personalised treatment plans for better outcomes in the future.

Activation function 1 of progesterone receptor is required for progesterone antagonism of oestrogen action in the uterus.

BACKGROUND: Progesterone receptor (PGR) is a master regulator of uterine function through antagonistic and synergistic interplays with oestrogen receptors. PGR action is primarily mediated by activation functions AF1 and AF2, but their physiological significance is unknown. RESULTS: We report the first study of AF1 function in mice. The AF1 mutant mice are infertile with impaired implantation and decidualization. This is associated with a delay in the cessation of epithelial proliferation and in the initiation of stromal proliferation at preimplantation. Despite tissue selective effect on PGR target genes, AF1 mutations caused global loss of the antioestrogenic activity of progesterone in both pregnant and ovariectomized models. Importantly, the study provides evidence that PGR can exert an antioestrogenic effect by genomic inhibition of Esr1 and Greb1 expression. ChIP-Seq data mining reveals intermingled PGR and ESR1 binding on Esr1 and Greb1 gene enhancers. Chromatin conformation analysis shows reduced interactions in these genes' loci in the mutant, coinciding with their upregulations. CONCLUSION: AF1 mediates genomic inhibition of ESR1 action globally whilst it also has tissue-selective effect on PGR target genes.

State-Level Prevalence and Associates of Opioid Dependence in the USA.

Traditionally, opioid-related disease burden was primarily due to heroin use. However, increases in extra-medical (or non-medicinal use of prescription opioids; NMPOs) use has precipitated the current overdose epidemic in North America. We aim to examine the state-level prevalence of heroin and NMPO dependence and their associations with opioid-related mortality and state-level socio-demographic profiles. Data were pooled from the 2005-2014 National Survey on Drug Use and Health (NSDUH). We examine opioid-related mortality from CDC WONDER (Cause of Death database) by the past year prevalence of DSM-IV heroin and NMPO dependence, by age and sex, and their associations with state-level socio-demographic characteristics from census data. State-level rates of heroin dependence were associated with opioid-related death rates in young and mid-aged adults, while rates of NMPO dependence were associated with opioid-related death rates across all ages. The prevalence of heroin dependence was positively associated with state-level GDP/capita and urbanity. State-level NMPO dependence prevalence was associated with higher unemployment, lower GDP/capita, and a lower high-school completion rate. The prevalence of heroin and NMPO dependence are associated with a broad range of geographical and socio-demographic groups. Taking a wider view of populations affected by the opioid epidemic, inclusive interventions for all are needed to reduce opioid-related disease burden.

Multi-Excitation Raman Spectroscopy for Label-Free, Strain-Level Characterization of Bacterial Pathogens in Artificial Sputum Media.

The current methods for diagnosis of acute and chronic infections are complex and skill-intensive. For complex clinical biofilm infections, it can take days from collecting and processing a patient's sample to achieving a result. These aspects place a significant burden on healthcare providers, delay treatment, and can lead to adverse patient outcomes. We report the development and application of a novel multi-excitation Raman spectroscopy-based methodology for the label-free and non-invasive detection of microbial pathogens that can be used with unprocessed clinical samples directly and provide rapid data to inform diagnosis by a medical professional. The method relies on the differential excitation of non-resonant and resonant molecular components in bacterial cells to enhance the molecular finger-printing capability to obtain strain-level distinction in bacterial species. Here, we use this strategy to detect and characterize the respiratory pathogens Pseudomonas aeruginosa and Staphylococcus aureus as typical infectious agents associated with cystic fibrosis. Planktonic specimens were analyzed both in isolation and in artificial sputum media. The resonance Raman components, excited at different wavelengths, were characterized as carotenoids and porphyrins. By combining the more informative multi-excitation Raman spectra with multivariate analysis (support vector machine) the accuracy was found to be 99.75% for both species (across all strains), including 100% accuracy for drug-sensitive and drug-resistant S. aureus. The results demonstrate that our methodology based on multi-excitation Raman spectroscopy can underpin the development of a powerful platform for the rapid and reagentless detection of clinical pathogens to support diagnosis by a medical expert, in this case relevant to cystic fibrosis. Such a platform could provide translatable diagnostic solutions in a variety of disease areas and also be utilized for the rapid detection of anti-microbial resistance.

A critical decision point: Short- and long-term outcomes of older surgical patients admitted to a Queensland intensive care unit.

OBJECTIVES: Critical care admission is a pivotal juncture for older patients undergoing surgery. We aimed to identify the in-hospital and postdischarge outcomes of older postsurgical patients (≥65 years) admitted to the intensive care unit (ICU). METHODS: We collected clinical, morbidity and survival data on all patients aged ≥65 years postsurgically admitted to a tertiary metropolitan ICU between 2014 and 2019. RESULTS: Within this older cohort (n = 370), the oldest patients (≥85 years) had the highest 1-year mortality (RR: 4.00; P < 0.001). Major surgery (RR: 5.67; P < 0.001), emergency surgery (RR: 2.89; P < 0.001) and APACHE III score ≥50 (RR: 2.63; P < 0.001) were associated with reduced 1-year survival. CONCLUSIONS: APACHE III score and surgery subtype are strong predictors of post-ICU mortality and may be useful to preoperatively stratify whether surgery and subsequent ICU admission are in patients' best interests. These data may also inform prospective discussions regarding end-of-life care and advanced care planning.

Exploring Symptom Fluctuations and Triggers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Novel Patient-Centred N-of-1 Observational Designs: A Protocol for a Feasibility and Acceptability Study.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition of unknown aetiology associated with a range of disabling symptoms, including post-exertional malaise, chronic fatigue, musculoskeletal pain, orthostatic intolerance, unrefreshing sleep, and cognitive dysfunction. ME/CFS is a heterogeneous disorder, with significant variation in symptom type and severity between individuals, as well as within individuals over time. The diversity of ME/CFS symptom presentation makes management challenging; treatments supported by data from randomised controlled trials may not work for all individuals due to the variability in experienced symptoms. Studies using quantitative N-of-1 observational designs involve repeated outcome measurements in an individual over time and can generate rigorous individual-specific conclusions about symptom patterns and triggers in individuals with ME/CFS. This study aims to explore the feasibility and acceptability of using novel patient-centred N-of-1 observational designs to explore symptom fluctuations and triggers in ME/CFS at the individual level. METHODS AND ANALYSIS: Individuals with a medical diagnosis of ME/CFS will be recruited through ME/CFS patient organisations to participate in a series of patient-centred N-of-1 observational studies. Using a wrist-worn electronic diary, participants will complete ecological momentary assessments of fatigue, stress, mood, and cognitive demand, three times per day for a period of 6-12 weeks. Personally relevant symptoms and triggers will also be incorporated into the questionnaire design. Physical activity will be objectively measured via an integrated accelerometer. Feasibility and acceptability outcomes will be assessed including the percentage of diary entries completed, as well as recruitment and retention rate, feasibility of analysing and interpreting the data collected, and participant views about participation elicited via a post-study semi-structured interview. DISCUSSION: This study will assess the feasibility and acceptability of patient-centred N-of-1 observational studies to assess diseases with complex presentations such as ME/CFS, as well as provide individual-level evidence about fluctuations and triggers of ME/CFS symptoms that may aid self-management. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12618001898246. Registered on 22 November 2018.

A delicate balance: Psychotropic polypharmacy and anti-cholinergic use are correlated with fall incidence in Australian inpatients with dementia.

BACKGROUND: Persons with dementia commonly experience a range of behavioural and psychological symptoms, including agitation, aggression, perceptual disturbances, and depression. While psychotropic medications are regularly prescribed to mitigate these symptoms, these agents also carry a broad adverse effect profile. This study aimed to characterize psychotropic medication use in patients with dementia, as well as identify prescribing factors associated with falls in this cohort. METHODS: This retrospective study collected longitudinal demographic and medication data from all patients admitted to a neuro-cognitive unit at an Australian metropolitan hospital over a 2-year period. Psychotropic polypharmacy and psychotropic agent use per patient-fortnight were investigated for their association with inpatient falls. RESULTS: All patients (n = 147) were prescribed at least one psychotropic medication, with 96% receiving anti-psychotic medications and 90% receiving benzodiazepines. Patient fall rate was significantly associated with anticholinergic drug use (Incidence rate ratio: 2.2; P < .001), as well as concomitant use of ≥5 daily psychotropic agents (Incidence rate ratio: 3.1; P = .001). CONCLUSIONS: Patients with dementia are routinely prescribed a wide variety of psychotropic medications. Use of anticholinergic drugs and psychotropic polypharmacy are correlated with fall incidence in persons with dementia.

Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review.

Lung cancer is the leading cause of cancer related deaths in Canada with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Tumor characterization can identify cancer-driving mutations as treatment targets. One of the most successful examples of cancer targeted therapy is inhibition of mutated epidermal growth factor receptor (EGFR), which occurs in ~10-30% of NSCLC patients. While this treatment has benefited many patients with activating EGFR mutations, almost all who initially benefited will eventually acquire resistance. Approximately 50% of cases of acquired resistance (AR) are due to a secondary T790M mutation in exon 20 of the EGFR gene; however, many of the remaining mechanisms of resistance are still unknown. Much work has been done to elucidate the remaining mechanisms of resistance. This review aims to highlight both the mechanisms of resistance that have already been identified in patients and potential novel mechanisms identified in preclinical models which have yet to be validated in the patient settings.

Mechanical behavior of human mesenchymal stem cells during adipogenic and osteogenic differentiation.

Human mesenchymal stem cells (hMSCs) have gained widespread attention in the field of tissue engineering but not much is known about the changes of mechanical properties during the process of cell lineage commitment and the mechanisms of these behaviors. It is believed that exploring the inter-relations between stem cells mechanical properties and lineage commitment will shed light on the mechanobiology aspect of differentiation. hMSCs were cultured in adipogenic and osteogenic mediums and the elastic moduli were monitored using micropipette aspiration. It was found that hMSCs undergoing osteogenesis have an instantaneous Young's modulus of 890 +/- 219 Pa and an equilibrium Young's modulus of 224 +/- 40 Pa, each is about 2-fold higher than the control group. Interestingly, cells cultured in adipogenic medium exhibited a slight increase in the cellular modulus followed by a decrease relative to that of the control group. Gene expression study was employed to gain insights into this phenomenon. Concomitant up regulation of actin binding filamin A (FLNa) and gamma-Tubulin with the cellular elastic modulus indicated their important role in mechanical regulation during hMSCs differentiation. Statistical results showed that cell shape and cell area changed with cellular mechanical properties, which means that cell morphology has a close relation with cell elastic modulus in the initial stage of differentiation. Collectively, these results provide a quantitative description of hMSCs mechanical behavior during the process of differentiation as well as the possible accompanying mechanism at the biomolecular level.

Viscoelastic behaviour of human mesenchymal stem cells.

BACKGROUND: In this study, we have investigated the viscoelastic behaviour of individual human adult bone marrow-derived mesenchymal stem cells (hMSCs) and the role of F-actin filaments in maintaining these properties, using micropipette aspiration technique together with a standard linear viscoelastic solid model. RESULTS: Under a room temperature of 20 degrees C, the instantaneous and equilibrium Young's modulus, E0 and Einfinity, were found to be 886 +/- 289 Pa and 372 +/- 125 Pa, respectively, while the apparent viscosity, mu, was 2710 +/- 1630 Pa.s. hMSCs treated with cytochalasin D up to 20 microM at 20 degrees C registered significant drop of up to 84% in stiffness and increase of up to 255% in viscosity. At the physiological temperature of 37 degrees C, E0 and Einfinity have decreased by 42-66% whereas mu has increased by 95%, compared to the control. Majority of the hMSCs behave as viscoelastic solid with a rapid initial increase in aspiration length and it gradually levels out with time. Three other types of non-typical viscoelastic behavior of hMSCs were also seen. CONCLUSION: hMSCs behave as viscoelastic solid. Its viscoelstic behaviour are dependent on the structural integrity of the F-actin filaments and temperature.