Alfred Hospital

In summary, this chapter presents the history of how adverse events led to the introduction of the rapid response systems in Australia and New Zealand (ANZ). It also discusses the epidemiology of patients in deterioration in ANZ and the evidence for effectiveness of a tiered approach to escalation and response, highlighting the different approaches in afferent limb escalation. The chapter further reviews the importance of centralised governance, such as commissions and national standards. Finally, the chapter summarises the recommendations of the first Safety and Quality Conference on rapid response teams and the joint position statements of the College of Intensive Care Medicine and Australian and New Zealand Intensive Care Society.

Physician-led rapid response teams (RRTs) are also described as medical emergency teams (METs). The principles and underlying causes of physician-led RRTs are similar to all RRT calls. All medical emergency teams are multidisciplinary, though the composition and the specialty of the team leader of the MET vary depending on the hospital setup. Intensive care unit (ICU) staff are often involved in METs when there is an ICU in the hospital. Physicians bring additional skill sets to medical emergencies in addition to providing a prompt second opinion on the deteriorating patient. The main aim of physician-led RRTs is to triage the patient in the early phases of deterioration and facilitate resuscitative interventions when needed. Implementation of limitations of medical therapy is commonly performed by the MET. RRT implementation is associated with reduced cardiopulmonary arrest rates outside the intensive care unit and reduced in-hospital mortality rates. Evidence is lacking that physician-led RRTs lead to better outcomes compared to nurse-led teams.

Care pathways incorporating Hospital in the Home (HITH) programs are available for people following low-trauma (osteoporotic) hip fracture (LTHF) as a strategy to reduce total length of stay (LOS), but there is no published evidence supporting the development of key components of such programs for this specific population. As a precursor to program implementation, a multidisciplinary team devised criteria for HITH eligibility and considerations for readiness for HITH transfer. This study aimed to describe the rates and timing of suitability for HITH when these criteria and considerations were applied prospectively to adults admitted with LTHF who underwent surgical fixation. Prospective, 5-month audit of patients admitted to a single facility following LTHF. Criteria for HITH inclusion/exclusion and 3 time-based safety considerations for readiness for HITH transfer (time [post-operative day, POD] to first complication, time to medical stability, time to mobilization threshold) were applied to patient-level data routinely available in the medical record. Eligibility: Of 114 patients screened, 61 (54%) were initially eligible with 41 (36%) remaining eligible over the episode-of-care. Transfer considerations: 75% of those who experienced a complication did so by POD4; 75% achieved medical stability by POD5; 75% achieved the mobility criterion by POD7; and, 75% of patients met all criteria by POD7. Using data-informed criteria and considerations, we estimate that one-third of LTHF patients will be eligible for HITH with most ready for transfer within a week post-surgery. A HITH program using safety-focused criteria may help reduce LOS for patients with LTHF.

Background The Markers in Neuropsychiatric Disorders Study (The MiND Study) is investigating the diagnostic and wider utility of blood based biomarkers such as neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p‐tau), as well as other markers, to improve timely and accurate diagnosis of dementia and distinction from non‐neurodegenerative and primary psychiatric disorder (PPD). This in‐progress study has expanded significantly, becoming a robust platform for Australian and international collaborations. Methods Participants have been recruited and blood samples collected across Australia. Longitudinal clinical/diagnostic, questionnaire, cognitive, and health utilisation data is collected. Second timepoint bloods (24 months) are now underway. Samples have been been analysed for NfL, GFAP, p‐tau217, p‐tau181, amyloid beta, and genetics. Results As of January 2024, over 1500 referrals have been received, and over 1000 participants recruited from diverse specialist and community settings. Partnering with public and private pathology services, blood sample collection and storage processes have been developed across most of Australia. Approximately 2/3 of participants have volunteered to participate in the second timepoint blood samples. Findings thus far include plasma NfL reference ranges, strong diagnostic utility of blood and cerebrospinal fluid NfL to distinguish dementia from PPD, and GFAP and ptau217 to distinguish Alzheimer from non‐Alzheimer disease with very high accuracy, and high value placed on NfL testing by participants. Numerous collaborations and sub‐studies have developed, investigating cognitive and neuroimaging markers. Conclusions The MiND Study is large biobank and platform supporting collaborations, pioneering research to lead to clinical translation, with particular focus on clinical translation in to broad clinical settings, younger onset dementia, primary care settings, and non‐AD and neurodegenerative mimics such as primary psychiatric disorders.

Background Plasma and cerebrospinal (CSF) biomarkers are promising candidates for detecting neuropathology. While CSF biomarkers directly reflect pathophysiological processes within the central nervous system, their requirement for a lumbar puncture is a barrier to their widespread scalability in practice. Therefore, we examined cross‐sectional associations of plasma biomarkers of amyloid (Aβ42/Aβ40 and pTau‐181), neurodegeneration (Neurofilament Light, NfL), and neuroinflammation (Glial Fibrillary Acidic Protein, GFAP) with brain volume, cognition, and their corresponding CSF levels. Method This was a cross‐sectional dementia‐free community‐based cohort of participants aged ≥55 years. All participants underwent neuropsychological testing comprising mini‐mental state examinations (MMSE), clinical dementia rating sum‐of‐boxes (CDR‐SB), and domain‐specific tests (episodic memory, visual memory, language, and executive function, expressed as Z‐scores). SIMOA‐measured® paired CSF and plasma p‐Tau181, GFAP, Aβ42/Aβ40 ratio, and NfL were obtained, as were brain MRI scans. Multivariable linear regression adjusting for age, sex, and education was employed to evaluate associations of log10‐transformed plasma biomarker levels with cognitive performance and cortical thickness (adjusted for total intracranial volume). Pearson’s correlations and Bland‐Altman plots were employed to evaluate correlations and agreement between paired levels of CSF and plasma biomarkers. Result Of 147 dementia‐free participants (mean age 66.7±7.7 years, 93% Caucasian), 34% were male. Lower plasma Aβ42/40 was significantly associated with poorer CDR‐SB (β‐6.62, (95%C.I. ‐11.97, ‐1.27), p=0.016). Higher plasma GFAP levels were associated with lower MMSE (β‐1.70, (95%C.I.‐3.22, ‐0.18) p=0.029)). Higher plasma GFAP and NfL were significantly associated with poorer visual and episodic memory Z‐scores (all p<0.05). Lower plasma NfL levels were associated with greater cortical thickness (β‐3.43, 95%C.I. ‐6.18, ‐0.67, p=0.015), with significant interactions observed with age (p‐interaction=0.014, Figure 1). Of 47 participants with CSF biomarkers, paired levels of plasma and CSF pTau‐181 (R:0.61, p<0.0001), Aβ42/40 (R:0.53, p=0.0001), GFAP (R:0.66, p<0.0001) and NfL (R:0.56, p<0.0001) were significantly correlated (Figure 2). Using Bland‐Altman analysis, greater dispersion was observed between paired CSF and plasma p‐Tau181 and Aβ42/40 levels (Figure 3). Conclusion Plasma biomarkers of neurodegenerative, neuroinflammation and amyloid pathology related closely with cognitive performance, neuroimaging indices, and their paired CSF levels. These may serve as promising candidates for detecting early neuropathology even in a dementia‐free community‐based population.

Background Moral distress is reported to be a critical force contributing to intensifying rates of anxiety, depression and burnout experienced by healthcare workers. In this paper, we examine the moral dilemmas and ensuing distress personally and collectively experienced by healthcare workers while caring for patients during the pandemic. Methods Data are drawn from free-text responses from a cross-sectional national online survey of Australian healthcare workers about the patient care challenges they faced. Results Three themes were derived from qualitative content analysis that illuminated the ways in which moral dilemmas and distress were relationally experienced by healthcare workers: (1) the moral ambiguity of how to care well for patients amid a rapidly changing work environment; (2) the distress of witnessing suffering shared between healthcare workers and patients; and (3) the distress of performing new forms of invisible work in the absence of institutional recognition. These findings reveal that moral distress was a strongly shared experience. Conclusions Findings advance understandings of moral distress as a relational experience, collectively felt, constituted, and experienced by healthcare workers. Considering how to harness collective solidarity in effectively responding to moral distress experienced across the frontline healthcare workforce is critical.

Purpose: Non-obstructive azoospermia (NOA) is a common, but complex problem, with multiple therapeutic options and a lack of clear guidelines. Hence, there is considerable controversy and marked variation in the management of NOA. This survey evaluates contemporary global practices related to medical and surgical management for patients with NOA. Materials and methods: A 56-question online survey covering various aspects of the evaluation and management of NOA was sent to specialists around the globe. This paper analyzes the results of the second half of the survey dealing with the management of NOA. Results have been compared to current guidelines, and expert recommendations have been provided using a Delphi process. Results: Participants from 49 countries submitted 336 valid responses. Hormonal therapy for 3 to 6 months was suggested before surgical sperm retrieval (SSR) by 29.6% and 23.6% of participants for normogonadotropic hypogonadism and hypergonadotropic hypogonadism respectively. The SSR rate was reported as 50.0% by 26.0% to 50.0% of participants. Interestingly, 46.0% reported successful SSR in <10% of men with Klinefelter syndrome and 41.3% routinely recommended preimplantation genetic testing. Varicocele repair prior to SSR is recommended by 57.7%. Half of the respondents (57.4%) reported using ultrasound to identify the most vascularized areas in the testis for SSR. One-third proceed directly to microdissection testicular sperm extraction (mTESE) in every case of NOA while others use a staged approach. After a failed conventional TESE, 23.8% wait for 3 months, while 33.1% wait for 6 months before proceeding to mTESE. The cut-off of follicle-stimulating hormone for positive SSR was reported to be 12-19 IU/mL by 22.5% of participants and 20-40 IU/mL by 27.8%, while 31.8% reported no upper limit. Conclusions: This is the largest survey to date on the real-world medical and surgical management of NOA by reproductive experts. It demonstrates a diverse practice pattern and highlights the need for evidence-based international consensus guidelines.

Background: There are no approved oral disease-modifying treatments for Alzheimer's disease (AD). Objectives: The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement. Design: ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial. Setting: Multicenter - 52 medical research centers/hospitals in 5 countries. Intervention: 508 participants with early AD (Stage 3) were randomized to receive either blarcamesine (n = 338) in medium dose group 30 mg or in high dose group 50 mg or placebo (n = 170) oral capsules once daily for 48 weeks. Participants in these groups were offered to enroll into the open-label-extension study ATTENTION-AD, which completed June 2024, ClinicalTrials.gov Identifier NCT04314934. Measurements: The co-primary cognitive and functional outcomes were assessed as change in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB and biomarkers from the A/T/N spectrum, plasma Aβ42/40-ratio and global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), plasma biomarker measurements were analyzed by Welch's t-test, and volumetric MRI scans were analyzed by general linear model. Results: Among 462 randomized participants in the intent-to-treat population (mean age, 73.7 years; 225 [48.7%] women), 338 (73.2%) completed the trial. The co-primary outcome was met under the multiplicity control rule, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the prespecified blarcamesine and placebo groups for ADAS-Cog13 was significant at a level of P < 0.025 and for CDR-SB was significant at a level of P < 0.025, while ADCS-ADL did not reach significance at Week 48 (ADAS-Cog13 difference of -2.027 [95% CI -3.522 to -0.533]; P = 0.008; CDR-SB difference of -0.483 [95% CI -0.853 to -0.114]; P = 0.010; ADCS-ADL difference of 0.775 [95%CI -0.874 to 2.423]; P = 0.357). Plasma Aβ42/40-ratio increased significantly with blarcamesine group vs. placebo, (P = 0.048) and whole brain volume loss was significantly decreased (P = 0.002). Participants in the full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine and 17 (10.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. One death in the blarcamesine group and 1 in the placebo group were both not considered treatment related. Conclusions: Blarcamesine, demonstrating a safety profile with no associated neuroimaging adverse events, significantly slowed clinical progression by 36.3% at 48 weeks with blarcamesine group as well as the individual 30 mg (by 34.6%) and 50 mg (by 38.5%) blarcamesine groups vs. placebo on the prespecified primary cognitive endpoint ADAS-Cog13. The prespecified secondary endpoint CDR-SB, which is used as the sole primary endpoint in recent successful AD drug submissions, is significantly improved at Week 48 with blarcamesine relative to placebo. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of whole brain atrophy. Additionally, the prespecified SIGMAR1 gene variant subgroup analysis confirmed beneficial clinical effect of blarcamesine group through upstream SIGMAR1 activation - subjects with the common SIGMAR1 wild-type gene (excluding carriers of the mutated SIGMAR1 rs1800866 variant) experienced an even greater significant clinical benefit with slowed clinical progression by 49.8% at 48 weeks on the prespecified primary cognitive endpoint ADAS-Cog13. Oral once daily blarcamesine could represent a novel treatment in early AD and be complementary or alternative to anti-beta amyloid drugs.

Introduction: Although there are several models of integrated architecture, we still lack models and theories about the integration process of health system responses to HIV/AIDS and NCDs. Objective: The overall purpose of this study is to design an action model, a systematic approach, for the integration of health system responses to HIV/AIDS and NCDs in developing countries. Methods: An iterative and progressive approach of model development using inductive qualitative evidence synthesis techniques was applied. As evidence about integration is spread across different fields, synthesis of evidence from a broad range of disciplines was conducted. Results: An action model of integration having 5 underlying principles, 4 action fields, and a 9-step action cycle is developed. The INTEGRATE model is an acronym of the 9 steps of the integration process: 1) Interrelate the magnitude and distribution of the problems, 2) Navigate the linkage between the problems, 3) Testify individual level co-occurrence of the problems, 4) Examine the similarities and understand the differences between the response functions, 5) Glance over the health system’s environment for integration, 6) Repackage and share evidence in a useable form, 7) Ascertain the plan for integration, 8) Translate the plan in to action, 9) Evaluate and Monitor the integration. Conclusion: Our model provides a basis for integration of health system responses to HIV/AIDS and NCDs in the context of developing countries. We propose that future empirical work is needed to refine the validity and applicability of the model.

Objective The 5xFAD mouse model of Alzheimer disease (AD) recapitulates amyloid‐beta (Aβ) deposition and pronounced seizure susceptibility observed in patients with AD. Forty‐hertz audiovisual stimulation is a noninvasive technique that entrains gamma neural oscillations and can reduce Aβ pathology and modulate glial expression in AD models. We hypothesized that 40‐Hz sensory stimulation would improve seizure susceptibility in 5xFAD mice and this would be associated with reduction of plaques and modulation of glial phenotypes. Methods 5xFAD mice and wild‐type (WT) littermates received 1 h/day 40‐Hz audiovisual stimulation or sham (n = 7–11/group), beginning 2 weeks before and continuing throughout amygdala kindling epileptogenesis. Postmortem analyses included Aβ pathology and morphology of astrocytes and microglia. Results 5xFAD mice exhibited enhanced susceptibility to seizures compared to WT, evidenced by fewer stimulations to reach kindling endpoint (incidence rate ratio [IRR] = 1.46, p < .0001) and a trend to higher seizure severity (odds ratio [OR] = .34, p = .059). Forty‐hertz stimulation reduced the behavioral severity of the first seizure (OR = 4.04, p = .02) and delayed epileptogenesis, increasing the number of stimulations required to reach kindling endpoint (IRR = .82, p = .01) compared to sham, regardless of genotype. 5xFAD mice receiving sensory stimulation exhibited ~50% reduction in amyloid pathology compared to sham. Furthermore, markers of astrocytes and microglia were upregulated in both genotypes receiving 40‐Hz stimulation. Significance Forty‐hertz sensory entrainment slows epileptogenesis in the mouse amygdala kindling model. Although this intervention improves Aβ pathology in 5xFAD mice, the observed antiepileptogenic effect may also relate to effects on glia, because mice without Aβ plaques (i.e., WT) also experienced antiepileptogenic effects of the intervention.

Background Despite widespread use of standardized classification systems, risk stratification of thyroid nodules is nuanced and often requires diagnostic surgery. Genomic sequencing is available for this dilemma however, costs and access restricts global applicability. Artificial intelligence (AI) has the potential to overcome this issue nevertheless, the need for black‐box interpretability is pertinent. We aimed to create an ultrasonographic segmentation and classification model that offers explainability and risk accountability. Methodology Four hundred and fourteen ultrasonography images were collected from 105 patients undergoing thyroidectomy, divided into training and testing groups. Classification ground truth used is exclusively surgical histopathology. Relevant nodules were manually annotated by a dedicated study radiologist and surgeon. Three AI architectures with and without block attention modules were trained to identify the relevant nodule and the best performing was selected for the subsequent task in classifying identified nodules into benign or malignant. Gradient‐Weighted Class Activation Map is used to provide saliency mapping for visual interpretability. Findings Superior performance was recorded by the block attention model which stratified thyroid nodules into benign versus malignant with an accuracy of 93% versus 90%, F‐score 90% versus 89%, sensitivity 93% versus 91% and specificity 92% versus 91% on a training dataset versus a testing dataset respectively. GradCAM Visual interpretability maps demonstrate salient areas for a benign nodule diagnosis overlaps spongiform areas and malignant diagnosis salient areas overlap solid components of a partially cystic‐solid nodule and microcalcifications within nodules. These findings are consistent with established diagnostic criteria for benign and malignant nodules. Conclusion We developed an image segmentation and classification model for the risk stratification of thyroid nodules benchmarking surgical histopathology as ground truth and providing visual interpretability.

The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as the fraction unbound of PIP (fUNB_PIP). This has led to a plethora of subgroup-specific models, increasing the risk of misusing published models when optimising dosing regimens. In this study, we aimed to develop a single model to simultaneously describe the PK of PIP/TAZ in diverse patient populations and evaluate the current dosing recommendations by predicting the PK/pharmacodynamics (PD) target attainment throughout life. Population PK models were separately built for PIP and TAZ based on data from 13 studies in various patient populations. In the development of those single-drug models, postnatal age (PNA), postmenstrual age (PMA), total body weight (TBW), height, and serum creatinine (SCR) were tested as covariates. Subsequently, a combined population PK model was established and the correlations between the PK of PIP and TAZ were tested. Monte Carlo simulations were performed based on the final combined model to evaluate the current dosing recommendations. The final combined model for PIP/TAZ consisted of four compartments (two for each drug), with covariates including TBW, PMA, and SCR. For a 70-kg, 35-year-old patient with SCR of 0.83 mg L−1, the PIP values for V1, CL, V2 and Q2 were 10.4 L, 10.6 L h−1, 11.6 L and 15.2 L h−1, respectively, and the TAZ values were 10.5 L, 9.58 L h−1, 13.7 L and 16.8 L h−1, respectively. The CL for both drugs show maturation in early life, reaching 50% at 54.2 weeks PMA. With advancing age, CL of TAZ declines to 50% at 61.6 years PMA, whereas CL of PIP declines more slowly, reaching 50% at 89.1 years PMA. The fUNB_PIP was estimated as 64.5% and non-linear elimination was not supported by our data. The simulation results indicated considerable differences in PK/PD target attainment for different patient populations under current recommended dosing regimens. We developed a combined population PK model for PIP/TAZ across a broad range of patients covering the extremes of patient characteristics. This model can be used as a robust a priori model for Bayesian forecasting to achieve individualised dosing. The simulations indicate that adjustments based on the allometric theory as well as maturation and decline of CL of PIP may help the current dosing recommendations to provide consistent target attainment across patient populations.

Aims: Clustering algorithms have been widely applied to tumor DNA methylation datasets to define methylation-based cancer subtypes. This study aimed to evaluate the agreement between subtypes obtained from common clustering strategies. Materials & methods: We used tumor DNA methylation data from 409 women with breast cancer from the Melbourne Collaborative Cohort Study (MCCS) and 781 breast tumors from The Cancer Genome Atlas (TCGA). Agreement was assessed using the adjusted Rand index for various combinations of number of CpGs, number of clusters and clustering algorithms (hierarchical, K-means, partitioning around medoids, and recursively partitioned mixture models). Results: Inconsistent agreement patterns were observed for between-algorithm and within-algorithm comparisons, with generally poor to moderate agreement (ARI <0.7). Results were qualitatively similar in the MCCS and TCGA, showing better agreement for moderate number of CpGs and fewer clusters (K = 2). Restricting the analysis to CpGs that were differentially-methylated between tumor and normal tissue did not result in higher agreement. Conclusion: Our study highlights that common clustering strategies involving an arbitrary choice of algorithm, number of clusters and number of methylation sites are likely to identify different DNA methylation-based breast tumor subtypes.