Managing falls onsite in residential aged care homes reduced hospitalisation: Mixed methods results from the Falls Outreach and Residential Mobile Assessment Team (FORMAT) pilot study.

OBJECTIVE: Falls are the leading cause of hospital transfer from residential aged care homes (RACHs). However, many falls do not result in significant injury, and ageing patients are exposed to complications while hospitalised. Inreach services are designed to reduce hospital transfer by providing care, support and assessment to residents at the RACH. This study evaluated a pilot inreach program targeting ageing patients following a fall. METHODS: We conducted a prospective, mixed methods evaluation of a 5-month (May-September 2022) pilot implementation across 108 government-funded RACHs within a single health-care network in Melbourne, Australia. RESULTS: A total of 123 residents (median [interquartile range] age: 88 [82, 94] years, female: 49%) were included in the intervention. The majority (n = 116, 94%) of residents were managed onsite and required no further investigation (n = 80, 69%) or treatment (n = 63, 54%). Among the seven residents referred to the emergency department (ED), two received hospital admission and five were transferred back to residential care. In the 7 days following referral to the intervention, four additional residents were referred to the ED and one received hospital admission. Qualitative feedback (n = 40) included specific comments relating to themes of general satisfaction (n = 20, 50%), compliments for staff (n = 16, 40%) and acknowledgement of comprehensiveness (n = 9, 23%). CONCLUSIONS: Implementation of a specialised fall assessment team to complement an existing geriatric-led RACH assessment service meant that a high rate of eligible residents were managed onsite, with very low need for subsequent hospitalisation. Residents, family members and caregivers expressed high rates of satisfaction with the service.

N-95/P2 respirator compliance with fit testing recommendations and respirator satisfaction amongst hospital staff.

BACKGROUND: Filtering Facepiece Respirators (FFRs) are an important and readily scalable infection control measure; however their effectiveness is ultimately determined by compliance. We aimed to examine staff compliance and satisfaction with wearing the N95/P2 FFRs assigned to them via the standardised fit testing protocol implemented in a single large healthcare network in Victoria, Australia. METHODS: In this cross-sectional survey, employees from five hospital campuses who participated in the health networks N95/P2 FFR fit testing process were invited in person to participate in the study. Data were analysed descriptively, after which chi-squared analysis was performed to determine differences between respirator types, gender, and age groups. RESULTS: Amongst the 258 staff members surveyed, 28% had either never or only sometimes worn an FFR to which they had been successfully fit tested, and 11% had experienced facial changes that potentially rendered their most recent fit test invalid. More than half (53%) of those surveyed had experienced side effects, the most common being skin irritation and pressure sores. A majority (87%) of staff felt that wearing an FFR had some impact on their ability to perform their duties. Pooled mean self-reported satisfaction ratings were highest for three-panel flat-fold and duckbill models. CONCLUSION: 28% of HCWs surveyed described not wearing N-95/P2 FFRs for which they had successfully been fit tested. Reasons for non-compliance remain unclear, but rates of side effects and interference with duties were high. Further research is required to determine and address potential causative factors and ascertain ongoing optimal organisation-level fit test strategies.

Hypomethylating agent decitabine sensitizes diffuse large B-cell lymphoma to venetoclax.

Despite recent advances in the therapy of diffuse large B-cell lymphoma (DLBCL), many patients are still not cured. Therefore, new therapeutic strategies are needed. The anti-apoptotic B-cell lymphoma 2 (BCL2) gene is commonly dysregulated in DLBCL due to various mechanisms such as chromosomal translocation t(14;18)(q32;q21) and copy number alterations; however, targeting BCL-2 with the selective inhibitor, venetoclax, led to response in only a minority of patients. Thus, we sought to identify a rational combination partner of venetoclax to improve its activity against DLBCL cells. Utilizing a functional assay, dynamic BH3 profiling, we found that the DNA hypomethylating agent decitabine increased mitochondrial apoptotic priming and BCL-2 dependence in DLBCL cells. RNA-sequencing analysis revealed that decitabine suppressed the pro-survival PI3K-AKT pathway and altered the mitochondria membrane composition in DLBCL cell lines. Additionally, it induced a DNA damage response and increased BAX and BAK activities. The combination of decitabine and venetoclax synergistically suppressed proliferation of DLBCL cells both in vitro and in vivo in a DLBCL cell line-derived xenograft mouse model. Our study suggests that decitabine plus venetoclax is a promising combination to explore clinically in DLBCL.

Striving to be the fittest: quantitative P2/N95 respirator fit test results among hospital staff during the COVID-19 pandemic.

Objective: To provide fit rates for specific P2/N95 respirators and compare these results by age, sex, clean-shaven status, and fit tester experience. Design: Exploratory audit involving secondary analysis of existing quantitative fit testing data. Setting: In response to the COVID-19 pandemic, healthcare services across Australia implemented respiratory protection protocols. This study details healthcare workers' (HCWs) fit testing results from a large Victorian public health service. Participants: Fit-tested employees of a large tertiary public health network. Methods: Fit rates for ten individual P2/N95 respirators were calculated, and the effect of age, sex, clean-shaven status, and fit tester experience was examined via logistic regression. Results: 4593 employees were included, with 97.98% successfully fitting at least one respirator. Males were found to have significantly increased odds of achieving fit success compared to females (OR 11.61 95%CI 1.60-84.10). Fit rates dropped by 4% with each 1-year age increase (OR 0.96 95%CI 0.94-0.98). Clean-shaven individuals were also more likely to achieve a fit compared to non-clean-shaved individuals (OR 79.23 95%CI 10.21-614.62). More experienced fit testers also yielded significantly higher fit rates (OR 3.95, 95%CI 2.34-6.67). Conclusions: 98% of staff achieved a successful fitting of at least one respirator, with three-panel flat fold models (Industree Trident, 3M Aura 9320A+, and 3M Aura 1870+) performing the most consistently. An individual's ability to achieve a successful fit was associated with; male sex, younger age, clean-shaven status, and fit tester experience.

Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies.

The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.

Systematic characterization of therapeutic vulnerabilities in Multiple Myeloma with Amp1q reveals increased sensitivity to the combination of MCL1 and PI3K inhibitors.

The development of targeted therapy for patients with Multiple Myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chr1q (Amp1q) is the most frequent arm-level copy number gain in patients with MM, and it is associated with higher risk of progression and death despite recent advances in therapeutics. Thus, developing targeted therapy for patients with MM and Amp1q stands to benefit a large portion of patients in need of more effective management. Here, we employed large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with Amp1q and showed increased sensitivity to the combination of MCL1 and PI3K inhibitors. Using single-cell RNA sequencing, we compared subclones with and without Amp1q within the same patient tumors and showed that Amp1q is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number for part of the chr1q arm, we showed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with Amp1q.

Medical student deployment to a single metropolitan hospital during the COVID-19 pandemic: A mixed methods analysis.

OBJECTIVES: To explore student and staff satisfaction with the use of medical students as a surge workforce during the COVID-19 pandemic. METHOD: We conducted a mixed methods analysis of staff and student experiences with the medical student workforce at a single metropolitan ED over an 8-month period between December 2021 and July 2022, using an online survey tool. Students were invited to complete the survey fortnightly, whereas senior medical and nursing staff were invited weekly. RESULTS: There was a 32% response rate for surveys sent to medical student assistants (MSAs) and 18% and 15% for medical and nursing staff, respectively. Most students felt well prepared and supported in the role and would recommend it to other students. They reported that the role allowed them to gain experience and confidence within the ED, especially after much of their learning had moved online throughout the pandemic. Senior nurses and doctors found MSAs to be useful members of the team, largely through their assistance with task completion. Both staff and students recommended a more comprehensive orientation, changes to the supervision model and increased clarity in the students' scope of practice. CONCLUSIONS: The results of the present study provide insight into the use of medical students as an emergency surge workforce. Responses from medical students and staff suggested that the project was beneficial for both groups as well as for overall departmental performance. These findings are likely to be translatable beyond the COVID-19 pandemic setting.

A phase 1b study of ibrutinib in combination with obinutuzumab in patients with relapsed or refractory chronic lymphocytic leukemia.

This study investigated ibrutinib plus obinutuzumab in relapsed/refractory CLL, evaluating tolerability of 3 sequencing regimens as well as overall safety and efficacy. Fifty-two patients were initially randomized 1:1:1 to receive either obinutuzumab 1 month before ibrutinib initiation, ibrutinib 1 month prior to obinutuzumab initiation, or to start both drugs concomitantly. Higher rates of infusion-related reactions were observed with the first sequence, and only the latter 2 cohorts were expanded. Grade 4 hematologic toxicity was uncommon, and notable all-grade non-hematologic toxicities included bruising (58%), hypertension (46%), arthralgia (38%), diarrhea (37%), transaminitis (35%), atrial fibrillation (21%), and serious infection (17%). Best overall response rate was 96% (including 40% CR and 56% PR). Best rates of undetectable minimal residual disease in peripheral blood and bone marrow were 27% and 19%, respectively. With a median follow-up of 41.5 months, four-year progression-free and overall survival rates are 74% and 93%, respectively. Correlative studies demonstrated that serum CCL4 and CXCL13 levels were associated with clinical response, and BH3 profiling revealed increased BCL-2 and BCL-xL dependence in CLL cells from patients on treatment. Overall, ibrutinib plus obinutuzumab was highly active, with a manageable safety profile, supporting further investigation of this type of approach in relapsed/refractory CLL.

Negative predictive value of the FebriDx host response point-of-care test in patients presenting to a single Australian emergency department with suspected COVID-19: an observational diagnostic accuracy study.

OBJECTIVES: To determine the negative predictive value (NPV) of the FebriDx point-of-care host response device in patients presenting with symptoms suggestive of COVID-19 infection in a mostly immunised Australian emergency department (ED) population during the late 2021 phase of the COVID-19 pandemic. DESIGN: Observational diagnostic accuracy study comparing FebriDx point-of-care test to SARS-CoV-2 PCR. SETTING: An ED in Melbourne, Australia, with 63 000 annual presentations in 2021. PARTICIPANTS: Patients aged 16 and over who met the Victorian Department of Health case definition for suspected COVID-19 infection PCR testing. Patients meeting any of the following criteria were excluded: <16 years of age; acute respiratory symptom(s) with onset>14 days prior to testing; current immunosuppressive or interferon therapy; live immunisation within the last 30 days; fever lasting>7 days; antibiotic or antiviral use in the preceding 14 days; experience of major trauma, major surgical intervention or severe burns within the last 30 days. PRIMARY AND SECONDARY OUTCOME MEASURES: COVID-19 PCR results (detected, not detected) and FebriDx results (bacterial positive, viral negative, viral positive). RESULTS: 94 participants were enrolled (female: 46; male: 48), 34% of participants (tested positive for COVID-19 according to PCR results, with a background incidence among all adult ED attenders of 2.5%. The sensitivity of FebriDx for detection of COVID-19 was 56% (95% CI 40% to 100%) and specificity was 92% (95% CI 84% to 100%). For the population tested, this resulted in an NPV of 80% (95% CI 71% to 100%) and a positive predictive value of 78% (95% CI 60% to 100%). CONCLUSIONS: In the context of a population with low COVID-19 infection rates, an evolved variant of COVID-19 and a very high community COVID-19 vaccination rate, FebriDx demonstrated reduced sensitivity and NPV relative to results from earlier international tests. These contextual factors should be considered during any attempt to generalise the current results. TRIAL REGISTRATION NUMBER: ACTRN12620001029987 (Australian Clinical Trials).

Impact of the Canadian CT head rule supplemented by the original published minimum inclusion criteria to assist emergency department clinicians' assessment of patients presenting post fall from residential aged care: a retrospective audit.

BACKGROUND: A large number of CT brain (CTB) scans are ordered in the ED for older patients with a confirmed or possible head strike but no ongoing symptoms of a head injury. This study aimed to evaluate the effect of the Canadian CT head rule supplemented by the original published minimum inclusion criteria to assist clinician assessment of the need for CTB following minimal trauma fall in patients presenting from residential aged care facilities to a major metropolitan emergency department (ED). METHODS: This study was conducted as a pre- and post-intervention retrospective audit. The intervention involved implementation of a decision support tool to help clinicians assess patients presenting to the ED following a fall. The tool integrated the Canadian CT Head Rule (CCHR) in conjunction with a simplified set of inclusion criteria to help clinicians define a minimum threshold for a "minor head injury". Outcome data pertaining to CT brain ordering practices and results were compared over symmetrical 3-month time periods pre- and post-intervention in 2 consecutive years. RESULTS: The study included 233 patients in the pre-intervention arm and 241 in the post-intervention arm. Baseline demographics and clinical characteristics were similar in both groups. There was a 20% reduction in the total number of CTB scans ordered following tool implementation, with 134 (57.0%) scans in the pre-intervention group and 90 (37.3%) in the post-intervention group (p <  0.01). The diagnostic yield in the pre- and post-intervention groups was 3.7 and 5.6% respectively (p = 0.52). No variation was observed in medical management between groups, and no patients in either group underwent neurosurgical intervention. CONCLUSIONS: Use of the CCHR supplemented by the original published minimum inclusion criteria appeared to safely reduce the number of CTB scans performed in residential aged care facility residents presenting to an ED after a fall, with no associated adverse outcomes. A larger study across multiple centres is required to determine widespread efficacy and safety of this tool.

Validation of the ECHS non trauma cranial CT rule in Australia: A prospective cohort study.

INTRODUCTION: Computed tomography (CT) is a commonly used imaging modality in Emergency Departments (EDs), however its use is questionable in many low yield settings. The Emergency CT Head score (ECHS) is a recently published clinical tool that assists in stratifying the need for CT brain (CTB) for patients presenting without a history of trauma. We sought to validate this tool in an Australian ED setting. METHODS: We prospectively evaluated 412 patients who received CTB without a history of trauma at a large Australian ED. We assessed them for the 4 main ECHS data points: focal neurological deficit on physical examination, new acute onset headache, transient neurological deficit, and a combination of new onset seizures with an altered conscious state. We examined their association with acute and chronic CTB findings. We then applied the ECHS to our data, calculating its sensitivity and its appropriateness at this single site via the calculation of a receiver operating curve (ROC). RESULTS: 10.2% of all CTB performed were positive for an acute or chronic abnormality. Only sex (male) and focal motor deficit were independent predictors of positive CTB at univariate analysis. The ECHS did not perform as anticipated in our population, with a ROC area under the curve of 0.498. An ECHS score of >0, which has been proposed as the threshold to not require imaging, had sensitivity of only 83.3% in our population. CONCLUSIONS: Further research and validation is required in order to safely implement the ECHS clinical score in the Australian ED setting.

Outcomes for emergency department patients with suspected and confirmed COVID-19: An analysis of the Australian experience in 2020 (COVED-5).

OBJECTIVE: The aim of the present study was to describe the characteristics and outcomes of patients presenting to Australian EDs with suspected and confirmed COVID-19 during 2020, and to determine the predictors of in-hospital death for SARS-CoV-2 positive patients. METHODS: This analysis from the COVED Project presents data from 12 sites across four Australian states for the period from 1 April to 30 November 2020. All adult patients who met local criteria for suspected COVID-19 and underwent testing for SARS-CoV-2 in the ED were eligible for inclusion. Study outcomes were mechanical ventilation and in-hospital mortality. RESULTS: Among 24 405 eligible ED presentations over the whole study period, 423 tested positive for SARS-CoV-2. During the 'second wave' from 1 July to 30 September 2020, 26 (6%) of 406 SARS-CoV-2 patients received invasive mechanical ventilation, compared to 175 (2%) of the 9024 SARS-CoV-2 negative patients (odds ratio [OR] 3.5; 95% confidence interval [CI] 2.3-5.2, P < 0.001), and 41 (10%) SARS-CoV-2 positive patients died in hospital compared to 312 (3%) SARS-CoV-2 negative patients (OR 3.2; 95% CI 2.2-4.4, P = 0.001). For SARS-CoV-2 positive patients, the strongest independent predictors of hospital death were age (OR 1.1; 95% CI 1.1-1.1, P < 0.001), higher triage category (OR 3.5; 95% CI 1.3-9.4, P = 0.012), obesity (OR 4.2; 95% CI 1.2-14.3, P = 0.024) and receiving immunosuppressive treatment (OR 8.2; 95% CI 1.8-36.7, P = 0.006). CONCLUSIONS: ED patients who tested positive for SARS-CoV-2 had higher odds of mechanical ventilation and death in hospital. The strongest predictors of death were age, a higher triage category, obesity and receiving immunosuppressive treatment.

BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia.

Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alemtuzumab, have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and T-cell receptor pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL.

Experiences of adolescent witnesses to peer victimization: The bystander effect.

Many anti-bullying programs now emphasize the role of bystanders - youth who witness peer victimization. Using a large sample of adolescents (aged 12-18) from the United Kingdom who completed an online survey, the present study examined the types of bystander interventions, their outcomes, and reasons for intervening and not intervening. No significant group differences by any demographic group were found in intervening or not. Results showed that those who had a negative affective reaction when they witnessed bullying were more likely to intervene. Two intervening behaviors (telling the bully to stop and telling an adult) were the strongest predictors of positive results. The most frequently selected reason for not intervening was not knowing what to do, and for intervening, having prosocial and altruistic motives was most common. These and other results are discussed for theoretical and practical implications.