Association between frailty and clinical outcomes in hospitalised patients requiring Code Blue activation.

BACKGROUND: Code Blues allow a rapid, hospital wide response to acutely deteriorating patients. The concept of frailty is being increasingly recognised as an important element in determining outcomes of critically ill patients. We hypothesised that increasing frailty would be associated with worse outcomes following a Code Blue. AIMS: To investigate the association between increasing frailty and outcomes of Code Blues. METHODS: Single-centre retrospective design of patients admitted to Frankston Hospital in Australia between 1 January 2013 and 31 December 2017 who triggered a Code Blue. Frailty evaluation was made based on electronic medical records as were the details and the outcomes of the Code Blue. The primary outcome measure was a composite of hospital mortality or Cerebral Performance Categories scale ≥3. Secondary outcomes included the immediate outcome of the Code Blue and hospital mortality. RESULTS: One hundred and forty-eight of 911 screened patients were included in the final analysis. Seventy-three were deemed 'frail' and the remainder deemed 'fit'. Seventy-eight percent of frail patients reached the primary outcome, compared with 41% of fit patients (P < 0.001). Multivariable analysis demonstrated frailty to be associated with primary outcome (odds ratio = 2.87; 95% confidence interval (CI) 1.28-6.44; P = 0.01). A cardiac aetiology for the Code Blue was also associated with an increased odds of primary outcome (OR = 3.52; 95% CI 1.51-8.05; P = 0.004). CONCLUSIONS: Frailty is independently associated with the composite outcome of hospital mortality or severe disability following a Code Blue. Frailty is an important tool in prognostication for these patients and might aid in discussions regarding treatment limitations.

A composite biomarker of neutrophil-lymphocyte ratio and hemoglobin level correlates with clinical response to PD-1 and PD-L1 inhibitors in advanced non-small cell lung cancers.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been incorporated into various clinical oncology guidelines for systemic treatment of advanced non-small cell lung cancers (aNSCLC). However, less than 50% (and 20%) of the patients responded to the therapy as a first (or second) line of therapy. PD-L1 immunohistochemistry (IHC) is an extensively studied biomarker of response to ICI, but results from this test have equivocal predictive power. In order to identify other biomarkers that support clinical decision-making around whether to treat with ICIs or not, we performed a retrospective study of patients with aNSCLC who underwent ICI-based therapy in the Mount Sinai Health System between 2014 and 2019. METHODS: We analyzed data from standard laboratory tests performed in patients as a part of the routine clinical workup during treatment, including complete blood counts (CBC) and a comprehensive metabolic panel (CMP), to correlate test results with clinical response and survival. RESULTS: Of 11,138 NSCLC patients identified, 249 had been treated with ICIs. We found associations between high neutrophil-to-lymphocyte ratio (NLR ≥ 5) and poor survival in ICI-treated NSCLC. We further observed that sustained high NLR after initiation of treatment had a more profound impact on survival than baseline NLR, regardless of PD-L1 status. Hazard ratios when comparing patients with NLR ≥ 5 vs. NLR < 5 are 1.7 (p = 0.02), 3.4 (p = 4.2 × 10- 8), and 3.9 (p = 1.4 × 10- 6) at baseline, 2-8 weeks, and 8-14 weeks after treatment start, respectively. Mild anemia, defined as hemoglobin (HGB) less than 12 g/dL was correlated with survival independently of NLR. Finally, we developed a composite NLR and HGB biomarker. Patients with pretreatment NLR ≥ 5 and HGB < 12 g/dL had a median overall survival (OS) of 8.0 months (95% CI 4.5-11.5) compared to the rest of the cohort with a median OS not reached (95% CI 15.9-NE, p = 1.8 × 10- 5), and a hazard ratio of 2.6 (95% CI 1.7-4.1, p = 3.5 × 10- 5). CONCLUSIONS: We developed a novel composite biomarker for ICI-based therapy in NSCLC based on routine CBC tests, which may provide meaningful clinical utility to guide treatment decision. The results suggest that treatment of anemia to elevate HGB before initiation of ICI therapy may improve patient outcomes or the use of alternative non-chemotherapy containing regimens.

Defining futile and potentially avoidable interhospital trauma transfers.

PURPOSE: Interhospital transfer of critically injured patients to a major trauma service reduces preventable death in major trauma. Yet some of those transferred die without intervention. These 'futile' interhospital trauma transfers (IHTs), and other potentially avoidable IHTs place enormous stress on families of trauma victims, can delay care, and incur great cost to public health resources. This study sought to characterise these IHTs using current state guidelines for interhospital transfer. METHODS: A retrospective cohort study was conducted using our institution's trauma registry from January 2016-December 2020. All adult patients transferred to our major trauma service were analysed. Futile IHTs were defined as death or transfer to hospice care without surgical, endoscopic, or radiological intervention, and without ICU admission, within 72 h of admission. Potentially avoidable IHTs were defined as all patients discharged alive without intervention or ICU care, and secondary over-triage patients are a subset of these patients who were discharged within 72 h of admission. Patient demographics, injuries, and treatments were categorised from electronic records and analysed. RESULTS: Of 2,837 IHTs, seven (0.2 %) met criteria for futility. The majority were female, median age of 80 (IQR 85-75) and had a median Injury Severity Score (ISS) of 16 (IQR 25.5-11.5). By contrast, 1391 patients (49 %) were classified as potentially avoidable and 513 (18 %) were considered secondary over-triage. The majority were male, median age of 43 (IQR 62-28), and had a median ISS of 9 (IQR 13-4). Of these potentially avoidable IHTs, 984 (70.7 %) were discharged directly home. CONCLUSION: Futile IHTs were infrequent, however over half of all trauma patients transferred from other hospitals were discharged without tertiary-level intervention. Trauma services should consider developing systems such as telehealth to support regional general and orthopaedic surgeons to co-manage lower risk trauma, particularly minor head and minor spinal trauma patients. This could be an integral part of safely reducing potentially avoidable IHTs and their associated costs while maintaining a low rate of preventable mortality in trauma.

Humeral metastases: an unusual presentation of pancreatic cancer.

In patients presenting with symptomatic bone metastases, the usual primary malignancies are breast, prostate, thyroid, lung and kidney. Pancreatic cancers are an uncommon cause of bone metastasis and, when they are, it is typically to the axial skeleton. We present the case of a 77-year-old woman who presented to our emergency department with right arm pain. Investigation demonstrated a metastatic lesion with impending pathological fracture. Further investigation found a necrotic pancreatic mass in the tail of the pancreas. Histopathology from the humeral metastasis was consistent with metastatic adenosquamous carcinoma of pancreatic origin. The humerus metastasis was successfully managed with an intramedullary nail. This case highlights an unusual presentation of pancreatic adenocarcinoma with humeral bone metastasis.

Case report of Brunner's gland hyperplasia: A rare "mimic" of malignant pathology.

INTRODUCTION: Brunner's gland hyperplasia is a rare, benign lesion of the duodenum. The symptomology can range from asymptomatic (as an incidental finding on endoscopy) to gastrointestinal obstruction or haemorrhage. CASE PRESENTATION: We report a case of a 60-year-old man presenting with post-prandial vomiting and weight loss. Inpatient evaluation led to the likely diagnosis of a duodenal malignancy for which the patient underwent a laparotomy and proximal duodenectomy. CLINICAL DISCUSSION: Brunner's gland hyperplasia is a rare, benign condition that can be overtreated due to the difficulty in obtaining an accurate pre-operative diagnosis. The literature has been reviewed to discuss the approach to diagnosis. CONCLUSION: This case highlights the potential for Brunner's gland hyperplasia mimicking a malignancy.

Activating Notch1 mutations are an early event in T-cell malignancy of Ikaros point mutant Plastic/+ mice.

Ikaros and Notch1 genes are critical to T-cell differentiation through transcriptional activation of target genes and interaction with chromatin remodeling complexes. An Ikaros (Plastic) point mutation inhibits activity of normal Ikaros and Ikaros family members, and leads to T-cell lymphoma in heterozygotes (Plstc/+). Analysis revealed Notch1 activating mutations in 12 of 17 Plstc/+ lymphomas (70%), analogous to those in human T-ALL. Mice acquired Notch1 mutations in lymph nodes as early as 7 weeks. Thus, combined Notch1 and Ikaros dysfunction can be a significant early event in T-cell proliferation and tumorigenesis.

Oral cavities of healthy infants harbour high proportions of Streptococcus salivarius strains with phenotypic and genotypic resistance to multiple classes of antibiotics.

Emerging antibiotic resistance in the oropharyngeal microbiota, of which Streptococcus salivarius is a prominent species, represents a challenge for treating paediatric populations. In this study, we investigated the role of Streptococcussalivarius as a reservoir for antibiotic resistance genes (ARG) in the oral microbiota by analysing 95 Streptococcussalivarius isolates from 22 healthy infants (2-16 months of age). MICs of penicillin G, amoxicillin, erythromycin, tetracycline, doxycycline and streptomycin were determined. ARG profiles were assessed in a subset of 21 strains by next-generation sequencing of genomes, followed by searches of assembled reads against the Comprehensive Antibiotic Resistance Database. Strains resistant to erythromycin, penicillins and tetracyclines were isolated from 83.3, 33.3 and 16.6 %, respectively, of infants aged 2 to 8 months with no prior antibiotic treatment. These percentages were100.0, 66.6 and 50.0 %, by 13 to 16 months of age. ARG or polymorphisms associated with antibiotic resistance were the most prevalent and involved genes for macrolide efflux (mel, mefA/E and macB), ribosomal protection [erm(B), tet(M) and tet(O)] and ß-lactamase-like proteins. Phylogenetically related strains showing multidrug-resistant phenotypes harboured multidrug efflux ARG. Polymorphic genes associated with antibiotic resistance to drugs affecting DNA replication, folate synthesis, RNA/protein synthesis and regulators of antibiotic stress responses were detected. These data imply that Streptococcussalivarius strains established during maturation of the oral microbiota harbour a diverse array of functional ARG, even in the absence of antibiotic selective pressures, highlighting a potential role for this species in shaping antibiotic susceptibility profiles of oropharyngeal communities.

The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function.

PI3KC2α is a broadly expressed lipid kinase with critical functions during embryonic development but poorly defined roles in adult physiology. Here we utilize multiple mouse genetic models to uncover a role for PI3KC2α in regulating the internal membrane reserve structure of megakaryocytes (demarcation membrane system) and platelets (open canalicular system) that results in dysregulated platelet adhesion under haemodynamic shear stress. Structural alterations in the platelet internal membrane lead to enhanced membrane tether formation that is associated with accelerated, yet highly unstable, thrombus formation in vitro and in vivo. Notably, agonist-induced 3-phosphorylated phosphoinositide production and cellular activation are normal in PI3KC2α-deficient platelets. These findings demonstrate an important role for PI3KC2α in regulating shear-dependent platelet adhesion via regulation of membrane structure, rather than acute signalling. These studies provide a link between the open canalicular system and platelet adhesive function that has relevance to the primary haemostatic and prothrombotic function of platelets.

Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer.

Enterobacteria, especially Escherichia coli, are abundant in patients with inflammatory bowel disease or colorectal cancer (CRC). However, it is unclear whether cancer is promoted by inflammation-induced expansion of E. coli and/or changes in expression of specific microbial genes. Here we use longitudinal (2, 12 and 20 weeks) 16S rRNA sequencing of luminal microbiota from ex-germ-free mice to show that inflamed Il10(-/-) mice maintain a higher abundance of Enterobacteriaceae than healthy wild-type mice. Experiments with mono-colonized Il10(-/-) mice reveal that host inflammation is necessary for E. coli cancer-promoting activity. RNA-sequence analysis indicates significant changes in E. coli gene catalogue in Il10(-/-) mice, with changes mostly driven by adaptation to the intestinal environment. Expression of specific genes present in the tumour-promoting E. coli pks island are modulated by inflammation/CRC development. Thus, progression of inflammation in Il10(-/-) mice supports Enterobacteriaceae and alters a small subset of microbial genes important for tumour development.

Stochastic changes over time and not founder effects drive cage effects in microbial community assembly in a mouse model.

Maternal transmission and cage effects are powerful confounding factors in microbiome studies. To assess the consequences of cage microenvironment on the mouse gut microbiome, two groups of germ-free (GF) wild-type (WT) mice, one gavaged with a microbiota harvested from adult WT mice and another allowed to acquire the microbiome from the cage microenvironment, were monitored using Illumina 16S rRNA sequencing over a period of 8 weeks. Our results revealed that cage effects in WT mice moved from GF to specific pathogen free (SPF) conditions take several weeks to develop and are not eliminated by the initial gavage treatment. Initial gavage influenced, but did not eliminate a successional pattern in which Proteobacteria became less abundant over time. An analysis in which 16S rRNA sequences are mapped to the closest sequenced whole genome suggests that the functional potential of microbial genomes changes significantly over time shifting from an emphasis on pathogenesis and motility early in community assembly to metabolic processes at later time points. Functionally, mice allowed to naturally acquire a microbial community from their cage, but not mice gavaged with a common biome, exhibit a cage effect in Dextran Sulfate Sodium-induced inflammation. Our results argue that while there are long-term effects of the founding community, these effects are mitigated by cage microenvironment and successional community assembly over time, which must both be explicitly considered in the interpretation of microbiome mouse experiments.

Peak Studio: a tool for the visualization and analysis of fragment analysis files.

While emerging technologies such as next-generation sequencing are increasingly important tools for the analysis of metagenomic communities, molecular fingerprinting techniques such as automated ribosomal intergenic spacer analysis (ARISA) and terminal restriction fragment length polymorphisms (T-RFLP) remain in use due to their rapid speed and low cost. Peak Studio is a java-based graphical user interface (GUI) designed for the visualization and analysis of fragment analysis (FSA) files generated by the Applied Biosystems capillary electrophoresis instrument. Specifically designed for ARISA and T-RFLP experiments, Peak Studio provides the user the ability to freely adjust the parameters of a peak-calling algorithm and immediately see the implications for downstream clustering by principal component analysis. Peak Studio is fully open-source and, unlike proprietary solutions, can be deployed on any computer running Windows, OS X or Linux. Peak Studio allows data to be saved in multiple formats and can serve as a pre-processing suite that prepares data for statistical analysis in programs such as SAS or R.