Big Multiple Sclerosis Data network: an international registry research network.

BACKGROUND: The Big Multiple Sclerosis Data (BMSD) network ( https://bigmsdata.org ) was initiated in 2014 and includes the national multiple sclerosis (MS) registries of the Czech Republic, Denmark, France, Italy, and Sweden as well as the international MSBase registry. BMSD has addressed the ethical, legal, technical, and governance-related challenges for data sharing and so far, published three scientific papers on pooled datasets as proof of concept for its collaborative design. DATA COLLECTION: Although BMSD registries operate independently on different platforms, similarities in variables, definitions and data structure allow joint analysis of data. Certain coordinated modifications in how the registries collect adverse event data have been implemented after BMSD consensus decisions, showing the ability to develop together. DATA MANAGEMENT: Scientific projects can be proposed by external sponsors via the coordinating centre and each registry decides independently on participation, respecting its governance structure. Research datasets are established in a project-to-project fashion and a project-specific data model is developed, based on a unifying core data model. To overcome challenges in data sharing, BMSD has developed procedures for federated data analysis. FUTURE PERSPECTIVES: Presently, BMSD is seeking a qualification opinion from the European Medicines Agency (EMA) to conduct post-authorization safety studies (PASS) and aims to pursue a qualification opinion also for post-authorization effectiveness studies (PAES). BMSD aspires to promote the advancement of real-world evidence research in the MS field.

Comparative Effectiveness of Natalizumab, Fingolimod, and Injectable Therapies in Pediatric-Onset Multiple Sclerosis: A Registry-Based Study.

BACKGROUND AND OBJECTIVES: Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. METHODS: This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. RESULTS: A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. DISCUSSION: Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

Predictive Tool Use and Willingness for Surgery in Patients With Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Despite the increasing number of tools available to predict the outcomes of total knee arthroplasty (TKA), the effect of these predictive tools on patient decision-making remains uncertain. Objective: To assess the effect of an online predictive tool on patient-reported willingness to undergo TKA. Design, Setting, and Participants: This parallel, double-masked, 2-arm randomized clinical trial compared predictive tool use with treatment as usual (TAU). The study was conducted between June 30, 2022, and July 31, 2023. Participants were followed up for 6 months after enrollment. Participants were recruited from a major Australian private health insurance company and from the surgical waiting list for publicly funded TKA at a tertiary hospital. Eligible participants had unilateral knee osteoarthritis, were contemplating TKA, and had previously tried nonsurgical interventions, such as lifestyle modifications, physiotherapy, and pain medications. Intervention: The intervention group was provided access to an online predictive tool at the beginning of the study. This tool offered information regarding the likelihood of improvement in quality of life if patients chose to undergo TKA. The predictions were based on the patient's age, sex, and baseline symptoms. Conversely, the control group received TAU without access to the predictive tool. Main Outcomes and Measures: The primary outcome measure was the reduction in participants' willingness to undergo surgery at 6 months after tool use as measured by binomial logistic regression. Secondary outcome measures included participant treatment preference and the quality of their decision-making process as measured by the Knee Decision Quality Instrument. Results: Of 211 randomized participants (mean [SD] age, 65.8 [8.3] years; 118 female [55.9%]), 105 were allocated to the predictive tool group and 106 to the TAU group. After adjusting for baseline differences in willingness for surgery, the predictive tool did not significantly reduce the primary outcome of willingness for surgery at 6 months (adjusted odds ratio, 0.85; 95% CI, 0.42-1.71; P = .64). Conclusions and Relevance: Despite the absence of treatment effect on willingness for TKA, predictive tools might still enhance health outcomes of patients with knee osteoarthritis. Additional research is needed to optimize the design and implementation of predictive tools, address limitations, and fully understand their effect on the decision-making process in TKA. Trial Registration: ANZCTR.org.au Identifier: ACTRN12622000072718.

Long-term clinical outcomes in patients with multiple sclerosis who are initiating disease-modifying therapy with natalizumab compared with BRACETD first-line therapies.

Background: Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) is of clinical relevance. Objectives: Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizumab or a BRACETD therapy (interferon beta, glatiramer acetate, teriflunomide, or dimethyl fumarate). Design: This retrospective analysis utilized data from MSBase to create a matched population allowing comparison of first-line natalizumab to first-line BRACETD. Methods: This study included patients who initiated treatment either with natalizumab or a BRACETD DMT within 1 year of MS diagnosis and continued treatment for ⩾6 months, after which patients could switch DMTs or discontinue treatment. Patients had a minimum follow-up time of ⩾60 months from initiation. A subgroup analysis compared the natalizumab group to patients in the BRACETD group who escalated therapy after 6 months. Outcomes included unadjusted annualized relapse rates (ARRs), time-to-first relapse, time-to-first confirmed disability improvement (CDI), and time-to-first confirmed disability worsening (CDW). Results: After 1:1 propensity score matching, 355 BRACETD patients were matched to 355 natalizumab patients. Patients initiating natalizumab were less likely to experience a relapse over the duration of follow-up, with ARRs [95% confidence interval (CI)] of 0.080 (0.070-0.092) for natalizumab patients and 0.191 (0.178-0.205) for BRACETD patients (p < 0.0001). A Cox regression model of time-to-first relapse showed a reduced risk of relapse for natalizumab patients [hazard ratio (95% CI) of 0.52 (0.42-0.65); p < 0.001] and a more favorable time-to-first CDI. The risk of CDW was similar between groups. The subgroup analysis showed an increased relapse risk as well as a significantly higher risk of CDW for BRACETD patients. Conclusion: Early initiation of natalizumab produced long-term benefits in relapse outcomes in comparison with BRACETD, regardless of a subsequent escalation in therapy.

Fluorine-18-labelled Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography or Magnetic Resonance Imaging to Diagnose and Localise Prostate Cancer. A Prospective Single-arm Paired Comparison (PEDAL).

BACKGROUND AND OBJECTIVE: Multiparametric magnetic resonance imaging (mpMRI) of the prostate is used for prostate cancer diagnosis. However, mpMRI has lower sensitivity for small tumours. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) offers increased sensitivity over conventional imaging. This study aims to determine whether the diagnostic accuracy of 18F-DCFPyL PSMA-PET/CT was superior to that of mpMRI for detecting prostate cancer (PCa) at biopsy. METHODS: Between 2020 and 2021, a prospective multicentre single-arm phase 3 imaging trial enrolled patients with clinical suspicion for PCa to have both mpMRI and PSMA-PET/CT (thorax to thigh), with reviewers blinded to the results of other imaging. Multiparametric MRI was considered positive for Prostate Imaging Reporting and Data System (PIRADS) 3-5. PSMA-PET/CT was assessed quantitatively (positive maximum standardised uptake value [SUVmax] >7) and qualitatively (five-point lexicon of certainty). Patients underwent targeted and systematic biopsy, with the technique at the discretion of the treating urologist. Clinically significant PCa (csPCa) was defined as International Society of Urological Pathology grade group (GG) ≥2. The primary outcome was the diagnostic accuracy for detecting PCa, reported as sensitivity, specificity, negative predictive value (NPV), and area under the curve (AUC) of the receiver operating curve. The secondary endpoints included a comparison of the diagnostic accuracy for detecting csPCa, assessing gains in combining PMSA-PET/CT with mpMRI to mpMRI alone. KEY FINDINGS AND LIMITATIONS: Of the 236 patients completing both mpMRI and PSMA-PET/CT, 184 (76.7%) had biopsy. Biopsy histology was benign (n = 73), GG 1 (n = 27), and GG ≥2 (n = 84). The diagnostic accuracy of mpMRI for detecting PCa (AUC 0.76; 95% confidence interval [CI] 0.69, 0.82) was higher than that of PSMA-PET/CT (AUC 0.63; 95% CI 0.56, 0.70, p = 0.03). The diagnostic accuracy of mpMRI for detecting csPCa (AUC 0.72; 95% CI 0.67, 0.78) was higher than that of PSMA-PET/CT (AUC 0.62; 95% CI 0.55, 0.69) but not statistically significant (p = 0.27). A combination of PSMA-PET/CT and mpMRI showed excellent sensitivity (98.8%, 95% CI 93.5%, 100%) and NPV (96%, 95% CI 79.6%, 99.9%) over mpMRI alone (86.9% and 80.7%, respectively, p = 0.01). Thirty-two patients (13.6%) had metastatic disease. They tended to be older (68.4 vs 65.1 yr, p = 0.023), and have higher prostate-specific antigen (PSA; median PSA 9.6 vs 6.2ng/ml, p < 0.001) and abnormal prostate on digital rectal examination (78.2% vs 44.1%, p < 0.001). CONCLUSIONS AND CLINICAL IMPLICATIONS: Multiparametric MRI had superior diagnostic accuracy to PSMA-PET/CT for detecting PCa, though the difference is not significant in case of csPCa detection. A combination of mpMRI and PSMA-PET/CT showed improved sensitivity and NPV. PSMA-PET/CT could be considered for diagnostic use in patients unable to have mpMRI or those with concerning clinical features but negative mpMRI. PATIENT SUMMARY: In this trial, we compared the ability of 18F-labelled prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) with that of multiparametric magnetic resonance imaging (mpMRI) to diagnose prostate cancer by biopsy in a prostate-specific antigen screening population. We found that MRI was superior to PSMA to diagnose prostate cancer, though there was no difference in ability to diagnose clinically significant prostate cancer. PSMA-PET/CT could be considered for diagnostic use in patients unable to have mpMRI or those with concerning clinical features but negative mpMRI. Combining MRI with PSMA-PET increases the negative predictive value over MRI alone and may help men avoid invasive prostate biopsy.

Changes in incidence of hepatitis C virus reinfection and access to direct-acting antiviral therapies in people with HIV from six countries, 2010-19: an analysis of data from a consortium of prospective cohort studies.

BACKGROUND: Reinfection after successful treatment with direct-acting antivirals is hypothesised to undermine efforts to eliminate hepatitis C virus (HCV) infection among people with HIV. We aimed to assess changes in incidence of HCV reinfection among people with HIV following the introduction of direct-acting antivirals, and the proportion of all incident cases attributable to reinfection. METHODS: We pooled individual-level data on HCV reinfection in people with HIV after spontaneous or treatment-induced clearance of HCV from six cohorts contributing data to the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC) in Australia, Canada, France, the Netherlands, Spain, and Switzerland between Jan 1, 2010, and Dec 31, 2019. Participants were eligible if they had evidence of an HCV infection (HCV antibody or RNA positive test) followed by spontaneous clearance or treatment-induced clearance, with at least one HCV RNA test after clearance enabling measurement of reinfection. We assessed differences in first reinfection incidence between direct-acting antiviral access periods (pre-direct-acting antiviral, limited access [access restricted to people with moderate or severe liver disease and other priority groups], and broad access [access for all patients with chronic HCV]) using Poisson regression. We estimated changes in combined HCV incidence (primary and reinfection) and the relative contribution of infection type by calendar year. FINDINGS: Overall, 6144 people with HIV who were at risk of HCV reinfection (median age 49 years [IQR 42-54]; 4989 [81%] male; 2836 [46%] men who have sex with men; 2360 [38%] people who inject drugs) were followed up for 17 303 person-years and were included in this analysis. The incidence of first HCV reinfection was stable during the period before the introduction of direct-acting antivirals (pre-introduction period; 4·1 cases per 100 person-years, 95% CI 2·8-6·0). Compared with the pre-introduction period, the average incidence of reinfection was 4% lower during the period of limited access (incidence rate ratio [IRR] 0·96, 95% CI 0·78-1·19), and 28% lower during the period of broad access (0·72, 0·60-0·86). Between 2015 and 2019, the proportion of incident HCV infections due to reinfection increased, but combined incidence declined by 34%, from 1·02 cases per 100 person-years (95% CI 0·96-1·07) in 2015 to 0·67 cases per 100 person-years (95% CI 0·59-0·75) in 2019. INTERPRETATION: HCV reinfection incidence and combined incidence declined in people with HIV following direct-acting antiviral introduction, suggesting reinfection has not affected elimination efforts among people with HIV in InCHEHC countries. The proportion of incident HCV cases due to reinfection was highest during periods of broad access to direct-acting antivirals, highlighting the importance of reducing ongoing risks and continuing testing in people at risk. FUNDING: Australian National Health and Medical Research Council.

Costs associated with invasive Scedosporium and Lomentospora prolificans infections: a case-control study.

BACKGROUND: Little is known about the short- and long-term healthcare costs of invasive Scedosporium/Lomentospora prolificans infections, particularly in patient groups without haematological malignancy. This study investigated excess index hospitalization costs and cumulative costs of these infections. The predictors of excess cost and length of stay (LOS) of index hospitalization were determined. These estimates serve as valuable inputs for cost-effectiveness models of novel antifungal agents. METHODS: A retrospective case-control study was conducted at six Australian hospitals. Cases of proven/probable invasive Scedosporium/L. prolificans infections between 2011 and 2021 (n = 34) were matched with controls (n = 66) by predefined criteria. Cost data were retrieved from activity-based costing systems and analysis was performed from the Australian public hospital perspective. All costs were presented in 2022 Australian dollars (AUD). Median regression analysis was used to adjust excess costs of index hospitalization whereas cumulative costs up to 1.5 years follow-up were estimated using interval-partitioned survival probabilities. RESULTS: Invasive Scedosporium/L. prolificans infections were independently associated with an adjusted median excess cost of AUD36 422 (P = 0.003) and LOS of 16.27 days (P < 0.001) during index hospitalization. Inpatient stay was the major cost driver (42.7%), followed by pharmacy cost, of which antifungal agents comprised 23.8% of the total cost. Allogeneic haematopoietic stem cell transplant increased the excess cost (P = 0.013) and prolonged LOS (P < 0.001) whereas inpatient death within ≤28 days reduced both cost (P = 0.001) and LOS (P < 0.001). The median cumulative cost increased substantially to AUD203 292 over 1.5 years in cases with Scedosporium/L. prolificans infections. CONCLUSIONS: The economic burden associated with invasive Scedosporium/L. prolificans infections is substantial.

Prognostic models for clinical outcomes in patients with venous leg ulcers: A systematic review.

OBJECTIVE: The purpose of this review was to identify prognostic models for clinical application in patients with venous leg ulcers (VLUs). METHODS: Literature searches were conducted in Embase, Medline, Cochrane, and CINAHL databases from inception to December 22, 2021. Eligible studies reported prognostic models aimed at developing, validating, and adjusting multivariable prognostic models that include multiple prognostic factors combined, and that predicted clinical outcomes. Methodological quality was assessed using the CHARMS checklist and PROBAST short form questionnaire. RESULTS: Thirteen studies were identified, of which three were validation studies of previously published models, four reported derivation and validation of models, and the remainder reported derivation models only. There was substantial heterogeneity in the model characteristics, including 11 studies focused on wound healing outcomes reporting 91 different predictors. Three studies shared similar predicted outcomes, follow-up timepoint and used a Cox proportional hazards model. However, these models reported different predictor selection methods and different predictors and it was therefore not feasible to summarize performance, such as discriminative ability. CONCLUSIONS: There are no standout risk prediction models in the literature with promising clinical application for patients with VLUs. Future research should focus on developing and validating high-performing models in wider VLU populations.

Trial of Vancomycin and Cefazolin as Surgical Prophylaxis in Arthroplasty.

BACKGROUND: The addition of vancomycin to beta-lactam prophylaxis in arthroplasty may reduce surgical-site infections; however, the efficacy and safety are unclear. METHODS: In this multicenter, double-blind, superiority, placebo-controlled trial, we randomly assigned adult patients without known methicillin-resistant Staphylococcus aureus (MRSA) colonization who were undergoing arthroplasty to receive 1.5 g of vancomycin or normal saline placebo, in addition to cefazolin prophylaxis. The primary outcome was surgical-site infection within 90 days after surgery. RESULTS: A total of 4239 patients underwent randomization. Among 4113 patients in the modified intention-to-treat population (2233 undergoing knee arthroplasty, 1850 undergoing hip arthroplasty, and 30 undergoing shoulder arthroplasty), surgical-site infections occurred in 91 of 2044 patients (4.5%) in the vancomycin group and in 72 of 2069 patients (3.5%) in the placebo group (relative risk, 1.28; 95% confidence interval [CI], 0.94 to 1.73; P = 0.11). Among patients undergoing knee arthroplasty, surgical-site infections occurred in 63 of 1109 patients (5.7%) in the vancomyin group and in 42 of 1124 patients (3.7%) in the placebo group (relative risk, 1.52; 95% CI, 1.04 to 2.23). Among patients undergoing hip arthroplasty, surgical-site infections occurred in 28 of 920 patients (3.0%) in the vancomyin group and in 29 of 930 patients (3.1%) in the placebo group (relative risk, 0.98; 95% CI, 0.59 to 1.63). Adverse events occurred in 35 of 2010 patients (1.7%) in the vancomycin group and in 35 of 2030 patients (1.7%) in the placebo group, including hypersensitivity reactions in 24 of 2010 patients (1.2%) and 11 of 2030 patients (0.5%), respectively (relative risk, 2.20; 95% CI, 1.08 to 4.49), and acute kidney injury in 42 of 2010 patients (2.1%) and 74 of 2030 patients (3.6%), respectively (relative risk, 0.57; 95% CI, 0.39 to 0.83). CONCLUSIONS: The addition of vancomycin to cefazolin prophylaxis was not superior to placebo for the prevention of surgical-site infections in arthroplasty among patients without known MRSA colonization. (Funded by the Australian National Health and Medical Research Council; Australian New Zealand Clinical Trials Registry number, ACTRN12618000642280.).

The impact of healthcare systems on the clinical diagnosis and disease-modifying treatment usage in relapse-onset multiple sclerosis: a real-world perspective in five registries across Europe.

Introduction: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing-remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS (SPMS) diagnoses, allows examination of the impact of health system characteristics on the stated clinical diagnosis and treatment access. Methods: We analysed registry data from six cohorts in five countries (Czech Republic, Denmark, Germany, Sweden and United Kingdom) on patients with an initial diagnosis of RRMS. We standardised our approach utilising a pre-existing algorithm (DecisionTree, DT) to determine patient diagnoses of RRMS or secondary progressive MS (SPMS). We identified five global drivers of DMT prescribing: Provision, Availability, Funding, Monitoring and Audit, data were analysed against these concepts using meta-analysis and univariate meta-regression. Results: In 64,235 patients, we found variations in DMT use between countries, with higher usage in RRMS and lower usage in SPMS, with correspondingly lower usage in the UK compared to other registers. Factors such as female gender (p = 0.041), increasing disability via Expanded Disability Status Scale (EDSS) score (p = 0.004), and the presence of monitoring (p = 0.029) in SPMS influenced the likelihood of receiving DMTs. Standardising the diagnosis revealed differences in reclassification rates from clinical RRMS to DT-SPMS, with Sweden having the lowest rate Sweden (Sweden 0.009, range: Denmark 0.103 - UK portal 0.311). Those with higher EDSS at index (p < 0.03) and female gender (p < 0.049) were more likely to be reclassified from RRMS to DT-SPMS. The study also explored the impact of diagnosis on DMT usage in clinical SPMS, finding that the prescribing environment and auditing practices affected access to treatment. Discussion: This highlights the importance of a healthcare system's approach to verifying the clinical label of MS course in facilitating appropriate prescribing, with some flexibility allowed in uncertain cases to ensure continued access to treatment.

Patients' Views on AI for Risk Prediction in Shared Decision-Making for Knee Replacement Surgery: Qualitative Interview Study.

BACKGROUND: The use of artificial intelligence (AI) in decision-making around knee replacement surgery is increasing, and this technology holds promise to improve the prediction of patient outcomes. Ambiguity surrounds the definition of AI, and there are mixed views on its application in clinical settings. OBJECTIVE: In this study, we aimed to explore the understanding and attitudes of patients who underwent knee replacement surgery regarding AI in the context of risk prediction for shared clinical decision-making. METHODS: This qualitative study involved patients who underwent knee replacement surgery at a tertiary referral center for joint replacement surgery. The participants were selected based on their age and sex. Semistructured interviews explored the participants' understanding of AI and their opinions on its use in shared clinical decision-making. Data collection and reflexive thematic analyses were conducted concurrently. Recruitment continued until thematic saturation was achieved. RESULTS: Thematic saturation was achieved with 19 interviews and confirmed with 1 additional interview, resulting in 20 participants being interviewed (female participants: n=11, 55%; male participants: n=9, 45%; median age: 66 years). A total of 11 (55%) participants had a substantial postoperative complication. Three themes captured the participants' understanding of AI and their perceptions of its use in shared clinical decision-making. The theme Expectations captured the participants' views of themselves as individuals with the right to self-determination as they sought therapeutic solutions tailored to their circumstances, needs, and desires, including whether to use AI at all. The theme Empowerment highlighted the potential of AI to enable patients to develop realistic expectations and equip them with personalized risk information to discuss in shared decision-making conversations with the surgeon. The theme Partnership captured the importance of symbiosis between AI and clinicians because AI has varied levels of interpretability and understanding of human emotions and empathy. CONCLUSIONS: Patients who underwent knee replacement surgery in this study had varied levels of familiarity with AI and diverse conceptualizations of its definitions and capabilities. Educating patients about AI through nontechnical explanations and illustrative scenarios could help inform their decision to use it for risk prediction in the shared decision-making process with their surgeon. These findings could be used in the process of developing a questionnaire to ascertain the views of patients undergoing knee replacement surgery on the acceptability of AI in shared clinical decision-making. Future work could investigate the accuracy of this patient group's understanding of AI, beyond their familiarity with it, and how this influences their acceptance of its use. Surgeons may play a key role in finding a place for AI in the clinical setting as the uptake of this technology in health care continues to grow.

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.

Evaluation of Managing Cancer and Living Meaningfully (CALM) in people with advanced non-small cell lung cancer treated with immunotherapies or targeted therapies: protocol for a single-arm, mixed-methods pilot study.

INTRODUCTION: People with advanced non-small cell lung cancer (NSCLC) treated with immunotherapies (IT) or targeted therapies (TT) may have improved outcomes in a subset of people who respond, raising unique psychological concerns requiring specific attention. These include the need for people with prolonged survival to reframe their life plans and tolerate uncertainty related to treatment duration and prognosis. A brief intervention for people with advanced cancer, Managing Cancer and Living Meaningfully (CALM), could help people treated with IT or TT address these concerns. However, CALM has not been specifically evaluated in this population. This study aims to evaluate the acceptability and feasibility of CALM in people with advanced NSCLC treated with IT or TT and obtain preliminary evidence regarding its effectiveness in this population. METHODS AND ANALYSIS: Twenty people with advanced NSCLC treated with IT or TT will be recruited from Peter MacCallum Cancer Centre, Melbourne, Australia. Participants will complete three to six sessions of CALM delivered over 3-6 months. A prospective, single-arm, mixed-methods pilot study will be conducted. Participants will complete outcome measures at baseline, post-intervention, 3 months and 6 months, including Patient Health Questionnaire, Death and Dying Distress Scale, Functional Assessment of Cancer Therapy General and Clinician Evaluation Questionnaire. The acceptability of CALM will be assessed using patient experiences surveys and qualitative interviews. Feasibility will be assessed by analysis of recruitment rates, treatment adherence and intervention delivery time. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/82047/PMCC). Participants with cancer will complete a signed consent form prior to participation, and carers and therapists will complete verbal consent. Results will be made available to funders, broader clinicians and researchers through conference presentations and publications. If CALM is found to be acceptable in this cohort, this will inform a potential phase 3 trial.

A plain language summary on the effectiveness of cladribine tablets compared with other oral treatments for multiple sclerosis: results from the MSBase registry.

WHAT IS THIS SUMMARY ABOUT?: Patient registries contain anonymous data from people who share the same medical condition. The MSBase registry contains information from over 80,000 people living with multiple sclerosis (MS) across 41 countries. Using information from the MSBase registry, the GLIMPSE (Generating Learnings In MultiPle SclErosis) study looked at real-life outcomes in 3475 people living with MS who were treated with cladribine tablets (Mavenclad®) compared with other oral treatments. WHAT WERE THE RESULTS?: Results showed that people treated with cladribine tablets stayed on treatment for longer than other treatments given by mouth. They also had fewer relapses (also called flare ups of symptoms) than people who received a different oral treatment for their MS. WHAT DO THE RESULTS MEAN?: The results provide evidence that, compared with other oral treatments for MS, cladribine tablets are an effective medicine for people living with MS.

Does initial high efficacy therapy in multiple sclerosis surpass escalation treatment strategy? A comparison of patients with relapsing-remitting multiple sclerosis in the Czech and Swedish national multiple sclerosis registries.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS) the most common treatment strategy has been to start with low-moderate efficacy disease modifying therapy (LE-DMT) and to escalate to more efficacious treatments in cases of breakthrough disease activity. However, recent evidence suggests a better outcome in patients commencing with moderate-high efficacy DMT (HE-DMT) immediately after clinical onset. OBJECTIVE: The aim of this study is to compare disease activity and disability outcomes in patients treated with the two alternative strategies using the Swedish and Czech national multiple sclerosis registries, taking advantage of the fact that the relative frequency of each strategy differs markedly between these two countries. METHODS: Adult RRMS patients who initiated their first-ever DMT between 2013 and 2016 and were included in the Swedish MS register were compared with a similar cohort from the MS register of the Czech Republic using propensity score overlap weighting as a balancing method. The main outcomes of interest were time to confirmed disability worsening (CDW), time to achieve an expanded disability status scale (EDSS) value of 4, time to relapse, and time to confirmed disability improvement (CDI). To support the results, a sensitivity analysis focusing solely on patients from Sweden starting with HE-DMT and patients from the Czech Republic starting with LE-DMT was performed. RESULTS: In the Swedish cohort, 42% of patients received HE-DMT as initial therapy compared to 3.8% of patients in the Czech cohort. The time to CDW was not significantly different between the Swedish and Czech cohorts (p-value 0.2764), with hazard ratio (HR) of 0.89 and a 95% confidence interval (CI) of 0.77-1.03. Patients from the Swedish cohort exhibited better outcomes for all remaining variables. The risk of reaching EDSS 4 was reduced by 26% (HR 0.74, 95%CI 0.6-0.91, p-value 0.0327), the risk of relapse was reduced by 66% (HR 0.34, 95%CI 0.3-0.39, p-value <0.001), and the probability of CDI was three times higher (HR 3.04, 95%CI 2.37-3.9, p-value <0.001). CONCLUSION: The analysis of the Czech and the Swedish RRMS cohorts confirmed a better prognosis for patients in Sweden, where a significant proportion of patients received HE-DMT as initial treatment.

Time-to-hepatitis C treatment initiation among people who inject drugs in Melbourne, Australia.

This study aims to understand the time-to-treatment initiation pre and post DAA access to inform strategies to improve HCV care. The data for our study were derived from the SuperMIX cohort study of people who inject drugs in Melbourne, Australia. Time-to-event analysis using Weibull accelerated failure time was performed for data collected between 2009 and 2021, among a cohort of HCV-positive participants. Among 223 participants who tested positive for active hepatitis C infection, 102 people (45.7%) reported treatment initiation, with a median time-to-treatment of 7 years. However, the median time-to-treatment reduced to 2.3 years for those tested positive after 2016. The study found that treatment with Opioid Agonist Therapy (TR 0.7, 95% CI 0.6-0.9), engagement with health or social services (TR 0.7, 95% CI 0.6-0.9), and having a first positive HCV RNA test after March 2016 (TR 0.3, 95% CI 0.2-0.3) were associated with a reduced time-to-treatment initiation. The study highlights the need for strategies to improve engagement with health services, including drug treatment services into routine HCV care to achieve timely treatment.

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.

Childhood trauma is prevalent and associated with co-occurring depression, anxiety, mania and psychosis in young people attending Australian youth mental health services.

OBJECTIVES: Childhood trauma is common and associated with mental ill health. While high rates of trauma are observed across individual disorders, there is evidence that trauma is associated with an admixture of affective, anxiety and psychotic symptoms in adults. Given that early onset of mental disorder and trauma exposure herald poor outcomes, it is important to examine trauma prevalence rates in youth mental health services and to determine whether this trauma-related clustering is present in help-seeking young people. METHODS: We used data from the Transitions Study, a longitudinal investigation of young people attending headspace youth mental health services in Australia between January 2011 and August 2012. Participants were 775 young people aged 12-25. Childhood trauma was assessed using the Childhood Trauma Questionnaire. Multinomial regression was used to assess whether reported childhood trauma was more strongly associated with the co-occurrence of depression, anxiety, mania and psychosis symptoms than with any one in isolation. RESULTS: Approximately 84% of participants reported some form of abuse (emotional: 68%; physical: 32%; sexual: 22%) or neglect (emotional: 65%; physical: 46%). Exposure to multiple trauma types was common. Childhood trauma was significantly associated with each symptom domain. More severe childhood trauma was more strongly associated with the co-occurrence of symptoms than with any one symptom domain in isolation, such that more severely trauma-exposed young people were more likely to experience increased symptom clustering. CONCLUSIONS: Childhood trauma is pervasive in youth mental health services and associated with a symptom profile that cuts across traditional diagnostic boundaries.

Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand.

BACKGROUND: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete. METHODS: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included. RESULTS: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89). CONCLUSIONS: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV.

Predicting 30-day readmission following total knee arthroplasty using machine learning and clinical expertise applied to clinical administrative and research registry data in an Australian cohort.

BACKGROUND: Thirty-day readmission is an increasingly important problem for total knee arthroplasty (TKA) patients. The aim of this study was to develop a risk prediction model using machine learning and clinical insight for 30-day readmission in primary TKA patients. METHOD: Data used to train and internally validate a multivariable predictive model were obtained from a single tertiary referral centre for TKA located in Victoria, Australia. Hospital administrative data and clinical registry data were utilised, and predictors were selected through systematic review and subsequent consultation with clinicians caring for TKA patients. Logistic regression and random forest models were compared to one another. Calibration was evaluated by visual inspection of calibration curves and calculation of the integrated calibration index (ICI). Discriminative performance was evaluated using the area under the receiver operating characteristic curve (AUC-ROC). RESULTS: The models developed in this study demonstrated adequate calibration for use in the clinical setting, despite having poor discriminative performance. The best-calibrated readmission prediction model was a logistic regression model trained on administrative data using risk factors identified from systematic review and meta-analysis, which are available at the initial consultation (ICI = 0.012, AUC-ROC = 0.589). Models developed to predict complications associated with readmission also had reasonable calibration (ICI = 0.012, AUC-ROC = 0.658). CONCLUSION: Discriminative performance of the prediction models was poor, although machine learning provided a slight improvement. The models were reasonably well calibrated, meaning they provide accurate patient-specific probabilities of these outcomes. This information can be used in shared clinical decision-making for discharge planning and post-discharge follow up.