Invasive fungal infection following venetoclax and posaconazole co-administration.

The co-administration of venetoclax, a BCL-2 inhibitor, with a mould-active azole, such a posaconazole, has potential to both prevent invasive fungal infection (IFI) and reduce the required treatment dose, and cost, of venetoclax. Posaconazole drug-level monitoring is critical to ensuring adequate mould prophylaxis. A retrospective audit of 99 patients at a tertiary cancer centre, with myeloid malignancies co-prescribed venetoclax and posaconazole between January 2018 and April 2022, was undertaken to evaluate the adequacy of posaconazole prescribing and the rate of breakthrough IFI. Seventy-six patients (77%) had at least one posaconazole level measured in the study period, with 37% requiring a dose adjustment based on steady-state trough levels. Breakthrough IFI occurred in 4% of patients, typically within 1 month of commencing anti-mould prophylaxis. Close monitoring of posaconazole levels in venetoclax-treated patients, particularly in the early, outpatient setting, is critical.

Vaccine schedule recommendations and updates for patients with hematologic malignancy post-hematopoietic cell transplant or CAR T-cell therapy.

Revaccination after receipt of a hematopoietic cell transplant (HCT) or cellular therapies is a pillar of patient supportive care, with the potential to reduce morbidity and mortality linked to vaccine-preventable infections. This review synthesizes national, international, and expert consensus vaccination schedules post-HCT and presents evidence regarding the efficacy of newer vaccine formulations for pneumococcus, recombinant zoster vaccine, and coronavirus disease 2019 in patients with hematological malignancy. Revaccination post-cellular therapies are less well defined. This review highlights important considerations around poor vaccine response, seroprevalence preservation after cellular therapies, and the optimal timing of revaccination. Future research should assess the immunogenicity and real-world effectiveness of new vaccine formulations and/or vaccine schedules in patients post-HCT and cellular therapy, including analysis of vaccine response that relates to the target of cellular therapies.

Executive summary of consensus clinical practice guidelines for the prevention of infection in patients with multiple myeloma.

Infection remains a significant contributor to morbidity and mortality in patients with myeloma. This guideline was developed by a multidisciplinary group of clinicians who specialise in the management of patients with myeloma and infection from the medical and scientific advisory group from Myeloma Australia and the National Centre for Infections in Cancer. In addition to summarising the current epidemiology and risk factors for infection in patients with myeloma, this guideline provides recommendations that address three key areas in the prevention of infection: screening for latent infection, use of antimicrobial prophylaxis and immunoglobulin replacement and vaccination against leading respiratory infections (severe acute respiratory syndrome coronavirus 2, influenza and Streptococcus pneumoniae) and other preventable infections. This guideline provides a practical approach to the prevention of infection in patients with myeloma and harmonises the clinical approach to screening for infection, use of prophylaxis and vaccination to prevent infectious complications.

Penicillin versus anti-staphylococcal beta-lactams for penicillin-susceptible Staphylococcus aureus blood stream infections: a retrospective cohort study.

The objective of the study is to assess the efficacy and tolerability of penicillins compared to anti-staphylococcal beta-lactams for treatment of penicillin-susceptible Staphylococcus aureus bloodstream infections (PSSA BSI). A retrospective cohort study was conducted of 140 sequential PSSA BSI presenting to a local health district (90 cases included). Penicillin susceptibility was confirmed by disc diffusion, Vitek® and Nitrocefin beta-lactamase methods. Clinical information regarding comorbidities and infection complexity was recorded. Antibiotic choice, dosage and duration were reviewed. Outcomes were compared according to the definitive treatment with either penicillin or ASBLs. The primary outcome was 30-day mortality. Secondary outcomes included renal injury, microbiological relapse and treatment tolerability. Ninety patients met inclusion criteria and were included in subsequent analysis. Of PSSA BSI, 69% were community acquired. Eighty-two percent had complex PSSA infections. The average duration of bacteraemia was 2.8 days (SD = 1.8 days). Sixty-six patients received definitive penicillin treatment, with a mean of 3.5 days of empiric antibiotics prior to penicillin. Twenty-four patients received definitive ASBL treatment (11 cefazolin, 13 flucloxacillin). There was no difference in 30-day mortality between groups (p = 1). There was no difference in renal injury (p > 0.5), hospital length of stay (p = 0.59) or microbiological relapse within 1 year (p = 0.17). Penicillin treatment was well tolerated. Our data supports penicillin as a suitable and well-tolerated alternative to ASBL in managing complex PSSA BSI.

Latent infection screening and prevalence in cancer patients born outside of Australia: a universal versus risk-based approach?

PURPOSE: Contention surrounds how best to screen patients for latent and undiagnosed infection prior to cancer treatment. Early treatment and prophylaxis against reactivation may improve infection-associated morbidity. This study sought to examine rates of screening and prevalence of latent infection in overseas-born patients receiving cancer therapies. METHODS: A single-centre retrospective audit of 952 overseas-born patients receiving chemotherapy, targeted agents and immunotherapy between January 1 and December 31 2019 was undertaken at Peter MacCallum Cancer Centre. Pre-treatment screening for hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), latent tuberculosis (LTBI), toxoplasmosis and strongyloidiasis was audited. RESULTS: Approximately half of our overseas-born patients were screened for HBV (58.9%) and HCV (50.7%). Fewer patients were screened for HIV (30.5%), LTBI (18.3%), strongyloidiasis (8.6%) or toxoplasmosis (8.1%). Although 59.7% of our patients were born in countries with high epidemiological risk for latent infection, according to World Health Organization data, 35% were not screened for any infection prior to commencement of therapy. CONCLUSION: The prevalence of latent infections amongst overseas-born patients with cancer, and complexities associated with risk-based screening, likely supports universal latent infection screening amongst this higher-risk cohort.

Consensus guidelines for the diagnosis and management of invasive fungal disease due to moulds other than Aspergillus in the haematology/oncology setting, 2021.

Invasive fungal disease (IFD) due to moulds other than Aspergillus is a significant cause of mortality in patients with malignancies or post haemopoietic stem cell transplantation. The current guidelines focus on the diagnosis and management of the common non-Aspergillus moulds (NAM), such as Mucorales, Scedosporium species (spp.), Lomentospora prolificans and Fusarium spp. Rare but emerging NAM including Paecilomyces variotii, Purpureocillium lilacinum and Scopulariopsis spp. are also reviewed. Culture and histological examination of tissue biopsy specimens remain the mainstay of diagnosis, but molecular methods are increasingly being used. As NAM frequently disseminate, blood cultures and skin examination with biopsy of any suspicious lesions are critically important. Treatment requires a multidisciplinary approach with surgical debridement as a central component. Other management strategies include control of the underlying disease/predisposing factors, augmentation of the host response and the reduction of immunosuppression. Carefully selected antifungal therapy, guided by susceptibility testing, is critical to cure. We also outline novel antifungal agents still in clinical trial which offer substantial potential for improved outcomes in the future. Paediatric recommendations follow those of adults. Ongoing epidemiological research, improvement in diagnostics and the development of new antifungal agents will continue to improve the poor outcomes that have been traditionally associated with IFD due to NAM.

Children's sleepiness facilitates the effect of vicarious learning on the development of fear.

A substantial body of research demonstrates the importance of sleep for emotional processing and learning as well as the association between sleep problems and heightened anxiety. However, there is currently no research exploring the impact of sleepiness on vicariously learned fear responses. Experiment 1 (N = 38) first demonstrated no effect of trait or state sleepiness on children's (7-11 years of age) subjective ratings of fear. Experiment 2 (N = 42) and Experiment 3 (N = 46) used an established vicarious learning paradigm to demonstrate that trait sleepiness facilitated vicariously acquired avoidance preferences for animals paired with fearful faces (fear-paired animals), whereas state sleepiness facilitated children's fear cognitions and attentional bias toward fear-paired animals. This study is the first to demonstrate the role of state and trait sleepiness in moderating vicarious fear learning in children.

TNF alpha inhibitors in Alzheimer's disease: A systematic review.

OBJECTIVES: The objective of this study was to evaluate the effect of tumour necrosis factor-alpha inhibitors (TNF-αI) on Alzheimer's disease-associated pathology. DESIGN: A literature search of PubMed, Embase, PsychINFO, Web of Science, Scopus, and the Cochrane Library databases for human and animal studies that evaluated the use of TNF-αI was performed on 26 October 2016. RESULTS: The main outcomes assessed were cognition and behaviour, reduction in brain tissue mass, presence of plaques and tangles, and synaptic function. Risk of bias was assessed regarding blinding, statistical model, outcome reporting, and other biases. Sixteen studies were included, 13 of which were animal studies and 3 of which were human. All animal studies found that treatment with TNF-αI leads to an improvement in cognition and behaviour. None of the studies measured change in brain tissue mass. The majority of studies documented a beneficial effect in other areas, including the presence of plaques and tangles and synaptic function. The amount of data from human studies was limited. Two out of 3 studies concluded that TNF-αI are beneficial in Alzheimer's disease patients, with one being an observational study and the latter being a small pilot study, with a high risk of bias. CONCLUSION: It was concluded that a large-scale randomized controlled trial assessing the effectiveness of TNF-αI on humans is warranted.

Reductions in Children's Vicariously Learnt Avoidance and Heart Rate Responses Using Positive Modeling.

Recent research has indicated that vicarious learning can lead to increases in children's fear beliefs and avoidance preferences for stimuli and that these fear responses can subsequently be reversed using positive modeling (counterconditioning). The current study investigated children's vicariously acquired avoidance behavior, physiological responses (heart rate), and attentional bias for stimuli and whether these could also be reduced via counterconditioning. Ninety-six (49 boys, 47 girls) 7- to 11-year-olds received vicarious fear learning for novel stimuli and were then randomly assigned to a counterconditioning, extinction, or control group. Fear beliefs and avoidance preferences were measured pre- and post-learning, whereas avoidance behavior, heart rate, and attentional bias were all measured post-learning. Control group children showed increases in fear beliefs and avoidance preferences for animals seen in vicarious fear learning trials. In addition, significantly greater avoidance behavior, heart rate responding, and attentional bias were observed for these animals compared to a control animal. In contrast, vicariously acquired avoidance preferences of children in the counterconditioning group were significantly reduced post-positive modeling, and these children also did not show the heightened heart rate responding to fear-paired animals. Children in the extinction group demonstrated comparable responses to the control group; thus the extinction procedure showed no effect on any fear measures. The findings suggest that counterconditioning with positive modelling can be used as an effective early intervention to reduce the behavioral and physiological effects of vicarious fear learning in childhood.

A comparison of positive vicarious learning and verbal information for reducing vicariously learned fear.

Research with children has demonstrated that both positive vicarious learning (modelling) and positive verbal information can reduce children's acquired fear responses for a particular stimulus. However, this fear reduction appears to be more effective when the intervention pathway matches the initial fear learning pathway. That is, positive verbal information is a more effective intervention than positive modelling when fear is originally acquired via negative verbal information. Research has yet to explore whether fear reduction pathways are also important for fears acquired via vicarious learning. To test this, an experiment compared the effectiveness of positive verbal information and positive vicarious learning interventions for reducing vicariously acquired fears in children (7-9 years). Both vicarious and informational fear reduction interventions were found to be equally effective at reducing vicariously acquired fears, suggesting that acquisition and intervention pathways do not need to match for successful fear reduction. This has significant implications for parents and those working with children because it suggests that providing children with positive information or positive vicarious learning immediately after a negative modelling event may prevent more serious fears developing.

Learning to fear a second-order stimulus following vicarious learning.

Vicarious fear learning refers to the acquisition of fear via observation of the fearful responses of others. The present study aims to extend current knowledge by exploring whether second-order vicarious fear learning can be demonstrated in children. That is, whether vicariously learnt fear responses for one stimulus can be elicited in a second stimulus associated with that initial stimulus. Results demonstrated that children's (5-11 years) fear responses for marsupials and caterpillars increased when they were seen with fearful faces compared to no faces. Additionally, the results indicated a second-order effect in which fear-related learning occurred for other animals seen together with the fear-paired animal, even though the animals were never observed with fearful faces themselves. Overall, the findings indicate that for children in this age group vicariously learnt fear-related responses for one stimulus can subsequently be observed for a second stimulus without it being experienced in a fear-related vicarious learning event. These findings may help to explain why some individuals do not recall involvement of a traumatic learning episode in the development of their fear of a specific stimulus.

Low-risk penicillin allergy delabeling: a scoping review of direct oral challenge practice, implementation, and multi-disciplinary approaches.

INTRODUCTION: Penicillin allergy is common, and there is increased clinician interest in direct oral challenge (DOC) as a testing strategy for low-risk penicillin allergy. To aid wider implementation of DOC, consensus definitions of low-risk penicillin allergy phenotypes, and standardized approaches to assessment, DOC procedures, and evaluation, are required. AREAS COVERED: This review systematically reviews studies that have utilized penicillin DOC in healthcare settings to identify heterogeneity in implementation approaches and synthesize low-risk definitions, procedures, and evaluation. EXPERT OPINION: Opportunity exists to standardize penicillin DOC procedures in patients with a low-risk penicillin allergy to optimize antimicrobial prescribing and reduce the burden of penicillin allergy. Standardizing the definitions of 'low-risk' and 'positive challenge,' and improving the evaluation of patient safety, alongside the development of a unified approach to the structure of undertaking an oral challenge, is likely to increase uptake and confidence among non-allergist clinicians.

Disseminated Invasive Mucormycosis Infection Following Autologous Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma.

Invasive fungal infections (IFI) are challenging to predict, diagnose and treat, and are associated with a particularly high mortality among patients with hematological malignancies. They are relatively uncommon in patients with lymphoma, compared with those with acute leukemia or undergoing allogeneic transplantation. We present a patient, autografted for recurrent lymphoma, with fever and refractory diarrhea persisting post engraftment, eventually attributable to disseminated mucor infection. This case illustrates the challenge of timely diagnosis and initiation of treatment for IFI in lymphoma patients, who do not routinely receive antifungal prophylaxis, and the importance of aggressive investigation and symptom-directed tissue sampling for evidence of IFI in febrile immunocompromised hosts not responding to broad-spectrum antibiotics.

Recommendations on prevention of infections in patients with T-cell lymphomas: a narrative review and synthesis.

T/Natural killer (NK) cell lymphomas (TCL) represent a heterogenous subgroup of non-Hodgkin lymphoma, associated with poorer prognosis and higher treatment toxicity. A cohesive synthesis of infection outcomes among TCL patients is lacking. International guidelines offer no specific recommendations regarding prophylaxis or supportive infection care for TCL patients. This systematic narrative review highlights infection outcomes in TCL patients treated with conventional, and novel therapies. Recommendations for infection screening, antimicrobial prophylaxis and vaccination strategies are outined.

Predicting infections in patients with haematological malignancies treated with chimeric antigen receptor T-cell therapies: A systematic scoping review and narrative synthesis.

BACKGROUND: Chimeric antigen receptor T cells (CAR-T cells) are increasingly used to treat haematological malignancies. Strategies for preventing infections in CAR-T-treated patients rely on expert opinions and consensus guidelines. OBJECTIVES: This scoping review aimed to identify risk factors for infections in CAR-T-treated patients with haematological malignancies. DATA SOURCES: A literature search utilized MEDLINE, EMBASE and Cochrane to identify relevant studies from conception until 30 September 2022. STUDY ELIGIBILITY CRITERIA: Trials and observational studies were eligible. PARTICIPANTS: Studies required ≥10 patients treated for haematological malignancy to report infection events (as defined by the study), and either (a) a descriptive, univariate or multivariate analysis of the relationship between infections event and a risk factors for infections, or (b) diagnostic performance of a biochemical/immunological marker in CAR-T-treated patients with infection. METHODS: A scoping review was conducted in accordance with PRISMA guidelines. DATA SOURCES: A literature search utilised MEDLINE, EMBASE and Cochrane to identify relevant studies from conception until September 30, 2022. Eligibility/Participants/Intervention: Trials and observational studies were eligible. Studies required ≥ 10 patients treated for haematological malignancy, to report infection events (as defined by the study), and either A) a descriptive, univariate or multivariate analysis of the relationship between infections event and a risk-factors for infections, or B) diagnostic performance of a biochemical/immunological marker in CAR-T treated patients with infection. ASSESSMENT OF RISK OF BIAS: Bias assessment was undertaken according to Joanna Brigg's Institute criteria for observational studies. METHODS OF DATA SYNTHESIS: Data were synthesized descriptively because of the heterogeneity of reporting. RESULTS: A total of 1522 patients across 15 studies were identified. All-cause infections across haematological malignancies were associated with lines of prior therapy, steroid administration, immune-effector cell-associated neurotoxicity and treatment-emergent neutropenia. Procalcitonin, C-reactive protein and cytokine profiles did not reliably predict infections. Predictors of viral, bacterial and fungal infections were poorly canvassed. DISCUSSION: Meta-analysis of the current literature is not possible because of significant heterogeneity in definitions of infections and risk factors, and small, underpowered cohort studies. Radical revision of how we approach reporting infections for novel therapies is required to promptly identify infection signals and associated risks in patients receiving novel therapies. Prior therapies, neutropenia, steroid administration and immune-effector cell-associated neurotoxicity remain the most associated with infections in CAR-T-treated patients.

Infections in haematology patients treated with CAR-T therapies: A systematic review and meta-analysis.

A registered (PROSPERO - CRD42022346462) systematic review and meta-analysis was conducted of all-grade infections amongst adult patients receiving CAR-T therapy for haematological malignancy. Meta-analysis of pooled incidence, using random effects model, was conducted. Cochran's Q test examined heterogeneity. 2678 patients across 33 studies were included in the primary outcome. Forty-percent of patients (95% CI: 0.33 - 0.48) experienced an infection of any grade. Twenty-five percent of infection events (95% CI: 0.16 - 0.34) were severe. Late infections were as common as early infections (IRR = 0.86, 95% CI: 0.38 - 1.98). All-grade infections, bacterial and viral infections were highest in myeloma patients at 57%, 37% and 28% respectively. Patients with NHL more commonly experienced late infections. Pooled rate of invasive candidiasis/yeast infections was 2% in studies utilizing anti-yeast prophylaxis. This review identified a high rate of all-grade infections, moderate rate of severe infections, and myeloma as a high-risk haematological group.

Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis.

Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein-coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.

COVID-19 infection among patients with cancer in Australia from 2020 to 2022: a national multicentre cohort study.

Background: The global COVID-19 pandemic disproportionately affected certain populations and its management differed between countries. This national study describes characteristics and outcomes of COVID-19 in patients with cancer in Australia. Methods: We performed a multicentre cohort study of patients with cancer and COVID-19 from March 2020 to April 2022. Data were analysed to determine varying characteristics between cancer types and changes in outcomes over time. Multivariable analysis was performed to determine risk factors associated with oxygen requirement. Findings: 620 patients with cancer from 15 hospitals had confirmed COVID-19. There were 314/620 (50.6%) male patients, median age 63.5 years (IQR 50-72) and majority had solid organ tumours (392/620, 63.2%). The rate of COVID-19 vaccination (≥1 dose) was 73.4% (455/620). Time from symptom onset to diagnosis was median 1 day (IQR 0-3), patients with haematological malignancy had a longer duration of test positivity. Over the study period, there was a significant decline in COVID-19 severity. Risk factors associated with oxygen requirement included male sex (OR 2.34, 95% CI 1.30-4.20, p = 0.004), age (OR 1.03, 95% CI 1.01-1.06, p = 0.005); not receiving early outpatient therapy (OR 2.78, 95% CI 1.41-5.50, p = 0.003). Diagnosis during the omicron wave was associated with lower odds of oxygen requirement (OR 0.24, 95% CI 0.13-0.43, p < 0.0001). Interpretation: Outcomes from COVID-19 in patients with cancer in Australia over the pandemic have improved, potentially related to changing viral strain and outpatient therapies. Funding: This study was supported by research funding from MSD.

Opioid Use Stigma: An Examination of Student Attitudes on Harm Reduction Strategies.

Understanding how the public views harm reduction strategies may help inform researchers on how to reduce related stigma and barriers to help-seeking. The current study explored whether stigma towards those who use opioids was affected by gender and type of harm reduction strategy used. Undergraduate students (N = 328) were randomly assigned to read one of six vignettes varying by gender and the type of harm reduction strategy: no harm reduction, opioid agonist therapy (OAT), or safe consumption sites (SCSs). Results demonstrated that participants were less stigmatizing towards the character who engaged in OAT compared to the character with no harm reduction. There was also a pattern demonstrating that SCSs may be perceived more negatively than OAT, although these differences only met conventional significance, not adjusted/corrected alphas. There were no significant effects for gender. Qualitative results revealed that participants held misconceptions about harm reduction. Implications and future directions are discussed.