Immune-related adverse events are associated with therapeutic efficacy of immunotherapy in patients with melanoma brain metastases.

Immunotherapy with T-cell checkpoint inhibitors have changed the treatment landscape for patients with melanoma brain metastases (MBMs), offering increased survival compared with historical outcomes. We sought to identify clinical features associated with intracranial tumour responses or progression-free survival (PFS) in patients with MBMs treated with immunotherapy. Patients with MBMs treated with immunotherapy from August 2013 to March 2020 were identified through local databases. Melanoma disease burdens and immune-related adverse events (irAEs) were assessed retrospectively by review of patient medical records. Efficacy was evaluated by determining objective response rates (ORRs) in brain metastases using immune-Response Evaluation Criteria in Solid Tumours criteria, MBM-specific survival and overall PFS. Twenty-six patients were identified as eligible for this study. The presence and volume of extracranial metastases (ECM) were associated with a non-significant trend of reduced intracranial ORRs and PFS. Patients with irAEs, on the other hand, had significantly increased intracranial ORRs and PFS compared to those without irAEs. Severe, grade ≥3 irAEs and co-occurrence of ≥2 irAEs were also significantly associated with longer PFS. The presence and volume of ECM correlated inversely with development and severity of irAEs. We report a strong association between the development of irAEs and favourable melanoma-specific outcomes in patients with MBMs receiving immunotherapy. Contrary to previous studies, we found that co-occurrence of ECM in these patients was associated with fewer irAEs and reduced treatment efficacy.

Escalating Mean Arterial Pressure in Severe Traumatic Brain Injury: A Prospective, Observational Study.

To investigate cerebral autoregulatory status in patients with severe traumatic brain injury (TBI), guidelines now suggest active manipulation of mean arterial pressure (MAP). There is a paucity of data, however, describing the effect on intracranial pressure (ICP) when MAP is raised. Consecutive patients with TBI requiring ICP monitoring were enrolled from November 2019 to April 2020. The MAP and ICP were recorded continuously, and clinical annotations were made whenever intravenous vasopressors were commenced or adjusted to defend cerebral perfusion pressure (CPP) targets. A significant change in MAP burden was defined as MAP >100min.mm Hg over 15 min. The primary outcome was the change in ICP burden over the same 15-min period. Bedside and clinical parameters were then compared between these groups. Twenty-eight patients were enrolled, providing 212 clinical events, of which 60 were deemed significant. Over the first 15 min, 65% were associated with a net negative ICP burden. A greater reduction in ICP burden was observed with events occurring in patients without a history of hypotension at scene (p = 0.016), after three days post-injury (p = 0.0018), and where the pressure-reactivity index (PRx) was <0.25 (p = 0.0005) or the ICP amplitude to CPP correlation coefficient (RAC) was <-0.10 (p = 0.0036) at the initiation of vasopressor changes. The ICP burden in the first 15 min was highly correlated with the next 15-min period. In patients with severe TBI requiring ICP monitoring, increasing MAP to pursue a CPP target was followed by a net negative ICP burden in approximately two-thirds of events. These data suggest a MAP challenge may be a useful adjunct in managing intracranial hypertension.

Blood Biomarkers of Glioma in Response Assessment Including Pseudoprogression and Other Treatment Effects: A Systematic Review.

Imaging-based monitoring of disease burden in glioma patients is frequently confounded by treatment effects. Circulating biomarkers could theoretically augment imaging-based response monitoring. This systematic review aimed to present and evaluate evidence for differential expression and diagnostic accuracy of circulating biomarkers with respect to outcomes of tumor response, progression, stable disease, and treatment effects (pseudoprogression, radionecrosis, pseudoresponse, and pseudolesions) in patients undergoing treatment for World Health Organization grades II-IV diffuse astrocytic and oligodendroglial tumors. MEDLINE, EMBASE, Web Of Science, and SCOPUS databases were searched until August 18, 2019, for observational or diagnostic studies on multiple circulating biomarker types: extracellular vesicles, circulating nucleic acids, circulating tumor cells, circulating proteins, and metabolites, angiogenesis related cells, immune cells, and other cell lines. Methodological quality of included studies was assessed using an adapted Quality Assessment of Diagnostic Accuracy Studies-2 tool, and level of evidence (IA-IVD) for individual biomarkers was evaluated using an adapted framework from the National Comprehensive Cancer Network guidelines on evaluating tumor marker utility. Of 13,202 unique records, 58 studies met the inclusion criteria. One hundred thirty-three distinct biomarkers were identified in a total of 1,853 patients across various treatment modalities. Fifteen markers for response, progression, or stable disease and five markers for pseudoprogression or radionecrosis reached level IB. No biomarkers reached level IA. Only five studies contained data for diagnostic accuracy measures. Overall methodological quality of included studies was low. While extensive data on biomarker dysregulation in varying response categories were reported, no biomarkers ready for clinical application were identified. Further assay refinement and evaluation in larger cohorts with diagnostic accuracy study designs are required. PROSPERO Registration: CRD42018110658.

Surveillance Systems from Public Health Institutions and Scientific Societies for Antimicrobial Resistance and Healthcare-Associated Infections in Europe (SUSPIRE): protocol for a systematic review.

INTRODUCTION: The worldwide spread of antimicrobial resistance is now recognised as a global public health threat. Owing to the geographical heterogeneity, complexity and continuously evolving dynamics of resistant organisms and genes, surveillance is a key tool for understanding, measuring and informing actions in the fight against this problem. To date there is no harmonisation of key indicators or of methodologies used to obtain them. METHODS AND ANALYSIS: The main objective of this project is to systematically review and analyse the current publicly available surveillance activities on antimicrobial resistance and healthcare-associated infections in Europe. Eligible activities are those endorsed by regional, national or transnational health organisations and scientific societies providing data on a periodic basis. Grey and peer-reviewed literature will be searched with no language restrictions. Three independent reviewers will perform a two-step selection process using a previously piloted, tailored electronic data extraction form. Descriptive summaries and tables of all relevant findings will be performed and reported according to PRISMA guidelines. ETHICS AND DISSEMINATION: We did not seek ethical approval for this study because the data to be collected are not linked to individuals. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: CRD42016033867.

EpideMiology and control measures of outBreaks due to Antibiotic-Resistant orGanisms in EurOpe (EMBARGO): a systematic review protocol.

INTRODUCTION: Improving our understanding of outbreaks due to antibiotic-resistant bacteria (ARB) and their control is critical in the current public health scenario. The threat of outbreaks due to ARB requires multifaceted efforts. However, a global overview of epidemiological characteristics of outbreaks due to ARB and effective infection control measures is missing. In this paper, we describe the protocol of a systematic review aimed at mapping and characterising the epidemiological aspects of outbreaks due to ARB and infection control measures in European countries. METHODS AND ANALYSIS: The databases MEDLINE, Web of Knowledge and Cochrane library will be searched using a 3-step search strategy. Selection of articles for inclusion will be performed by 2 reviewers using predefined eligibility criteria. All study designs will be included if they report an outbreak and define the microbiological methods used for microorganism identification. The target bacteria will be methicillin-resistant and vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, ceftazidime-resistant and carbapenem-resistant Acinetobacter baumannii, ceftazidime-resistant and carbapenem-resistant Pseudomonas aeruginosa, ciprofloxacin-resistant Escherichia coli, extended-spectrum ß-lactamase-producing E. coli and Klebsiella pneumoniae, carbapenem-resistant and carbapenamase-producing Enterobacteriaceae. Data will be extracted using a tailored pilot tested form and the quality of reporting will be assessed using the ORION (Outbreak Reports and Intervention Studies Of Nosocomial infections) tool. Data will be synthesised and reported by the type of ARB, setting and country. Infection control measures and bundles of measures will be described. The effectiveness will be reported as defined by the authors. Regression analysis will be used to define independent factors associated with outbreaks' control. Heterogeneity between studies will be assessed by forest plots and I² statistics. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study. Findings will be disseminated through journal publication and conference presentations and talks.

Developing a model to assess community-level risk of oral diseases for planning public dental services in Australia.

BACKGROUND: Poor oral health is a chronic condition that can be extremely costly to manage. In Australia, publicly funded dental services are provided to community members deemed to be eligible-those who are socio-economically disadvantaged or determined to be at higher risk of dental disease. Historically public dental services have nominally been allocated based on the size of the eligible population in a geographic area. This approach has been largely inadequate for reducing disparities in dental disease, primarily because the approach is treatment-focused, and oral health is influenced by a variety of interacting factors. This paper describes the developmental process of a multi-dimensional community-level risk assessment model, to profile a community's risk of poor oral health. METHODS: A search of the evidence base was conducted to identify robust frameworks for conceptualisation of risk factors and associated performance indicators. Government and other agency websites were also searched to identify publicly available data assets with items relevant to oral diseases. Data quality and analysis considerations were assessed for the use of mixed data sources. RESULTS: Several frameworks and associated indicator sets (twelve national and eight state-wide data collections with relevant indicators) were identified. Determination of the system inputs for the Model were primarily informed by the World Health Organisation's (WHO) operational model for an Integrated Oral Health-Chronic Disease Prevention System, and Australia's National Oral Health Plan 2004-2013. Data quality and access informed the final selection of indicators. CONCLUSIONS: Despite limitations in the quality and regularity of data collections, there are numerous data sources available that provide the required data inputs for community-level risk assessment for oral health. Assessing risk in this way will enhance our ability to deliver appropriate public oral health care services and address the uneven distribution of oral disease across the social gradient.