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Background: Coagulase-negative staphylococci (CoNS) are often considered contaminants when isolated from blood cultures. While criteria exist to distinguish true bacteremia from contamination (Table 1), clinical judgement is often necessary. Clinical microbiology laboratories have traditionally identified CoNS to the species level only if present in multiple cultures. There have been concerns that blood cultures positive for rare or less familiar CoNS species might be misinterpreted as true bacteremia. Tufts Medical Center (TMC) clinical microbiology laboratory started reporting all CoNS to the species level in January 2023. We studied the impact of species-level identification of CoNS on clinically relevant outcomes following this change. Methods: The study evaluated inpatients at TMC aged ≥ 18 years with CoNS isolated from blood cultures between July 2022 and June 2023. The primary outcome was the difference in anti-staphylococcal antibiotic utilization between the pre- and post-intervention groups. Secondary outcomes included differences in true bacteremia diagnosis, length of hospital stay, and mortality between the two groups. We also compared the performance of Souvenir’s criteria with clinical judgement at distinguishing contamination from true bacteremia. A total of 100 patients were included in the pre- and post-intervention groups to detect an estimated effect size of 15% with a power of 81%. Results: Most patients were male, White, and English speaking (Table 2). No differences were found between the two groups in terms of infectious disease consultation frequency, blood culture collection department, or the presence of central venous catheters (Table 2). Staphylococcus epidermidis was the predominant CoNS in the post-intervention group. Blood cultures were repeated before and after starting antibiotics in 24% and 74% (pre-intervention) and 18% and 84% (post-intervention) of cases, respectively. Anti-staphylococcus antibiotic use was the same in both groups (82%). The median antibiotic therapy duration was 4.5 days pre- vs 3 days post-intervention (p =0.39). There were no differences in hospital length of stay or mortality between the two groups (Table 3). The clinical diagnosis of true bacteremia was established in 28% of cases in the pre- vs 25% in the post-intervention group (p= 0.63). Compared to clinical judgement, Souvenir’s true bacteremia criteria demonstrated a sensitivity of 80.3%, negative PV of 91.9%, and positive PV of 55.2%. Conclusions: Species-level identification of CoNS positive blood cultures did not impact antibiotic utilization, diagnosis of true bacteremia, length of hospital stay, or mortality. Further studies with larger cohorts and prospective designs are needed to validate these findings and assess the long-term implications in patients.

Abstract Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. However, the determination of TM-interconnectivity in individual tumors is challenging and the impact on patient survival unresolved. Here, we establish a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells using a dye uptake methodology, and validate it with recording of cellular calcium epochs and clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, TM-network connectivity correlates with the mesenchymal subtype and dismal patient survival. CHI3L1 gene expression serves as a robust molecular marker of connectivity and functionally influences TM networks. The connectivity signature allows insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.

Lung cancer persists as a significant global health dilemma, characterized by elevated incidence and mortality rates worldwide. Despite recent strides in diagnostic methodologies, screening approaches, and therapeutic modalities, lung cancer retains its status as the foremost cause of cancer-related fatalities internationally. The disease is predominantly categorized into two primary forms: small-cell carcinomas and the notably more prevalent non-small-cell carcinomas, constituting approximately 85% of cases. While smoking stands as the primary risk factor for lung cancer, accounting for 80-90% of related deaths, other factors such as dietary habits, air pollution, genetic predisposition, and prior lung conditions play substantial roles. Diagnostic procedures encompass a range of techniques, including radiography, sputum cytology, bronchoscopy, biomarker analysis, among others. The imperative for progress and refinement in diagnostic tools, especially for early detection and monitoring in high-risk demographics, underscores the urgency. Continual research and enhancement of surgical, systemic, and localized treatments are indispensable in the battle against lung cancer. Despite advancements, challenges persist in achieving timely diagnoses, particularly in high-risk groups, and augmenting overall survival rates. This comprehensive review delves into current research advancements in lung cancer, with specific focus on classification, patient well-being, risk factors, diagnostic methodologies, and treatment options.

Vascular malformations are congenital vascular anomalies resulting from a disruption in the vasculogenesis process. (1) They are congenital changes that enlarge as the child develops and do not undergo spontaneous involution. They can be classified based on the type of vessels involved (capillary, arterial, venous, lymphatic, mixed) and the nature of the vascular flow (low-flow and high-flow). The clinical presentation of vascular malformations is highly diverse, and despite being congenital, they can remain asymptomatic for a long time, complicating the diagnostic process. (1,3) The presence of malformations carries the risk of health-threatening complications. One such complication is Kasabach-Merritt syndrome, characterized by thrombocytopenia, microangiopathic hemolytic anemia, and consumptive coagulopathy in the presence of a rapidly enlarging vascular tumor. (4,5) Another threat is a coagulopathy limited to the vascular anomaly (LIC). It is characterized by elevated D-dimers and fibrin degradation products, low levels of fibrinogen, FV, FVIII, FXIII, and antithrombin, and sometimes mild to moderate thrombocytopenia. (6,7) Early implementation of anticoagulant therapy allows for the avoidance of health-threatening conditions and the development of disseminated intravascular coagulation syndrome (DIC). (8)

Abstract We analyzed single nucleotide polymorphisms (SNPs) in PKNOX1 (rs2839629) and in the intergenic region between PKNOX1 and CBS (rs915854) by Sanger sequencing in 88 patients with multiple myeloma treated with bortezomib. All patients (n = 13) harboring a homozygous mutation in PKNOX1 (rs2839629) also had a homozygous mutated rs915854 genotype. Homozygous mutated genotypes of rs2839629 and rs915854 were significantly enriched in patients with painful peripheral neuropathy (PNP) (P

Hepatocellular carcinoma (HCC) stands as a pressing global health concern. It is the predominant form of liver cancer and ranks among the leading causes of cancer-related death globally. Hepatitis B virus infection and hepatitis C infection remain the primary risk factors for the development of HCC. However, recently other factors such as cirrhosis due to chronic alcohol intake and non-alcoholic steatohepatitis have been becoming an increasingly common risk factor. The advancement and refinement of diagnostic methods play a crucial role in early diagnosis and surveillance, especially in high-risk populations. Patients diagnosed with hepatocellular carcinoma face a challenging prognosis, despite advancements in surgical techniques and other therapeutic interventions. This underscores the importance of sustained attention to this issue. Continuous research into systemic therapies and refining diagnostic strategies is imperative to address the dynamic landscape of HCC. Efforts to reduce risk factors, coupled with improved surveillance, may contribute to a decline in HCC incidence in the future. This comprehensive review delves into current research on HCC, focusing on risk factors, symptoms, diagnosis, and treatment options.

Abstract This proof of concept describes the use of evoked electromyographic (EMG) activation of the facial nerve for intraoperative monitoring of the electrode insertion during cochlear implantation (CI). Intraoperative EMG measurements from the facial nerve were conducted in nine patients undergoing CI implantation. Electric current pulses were emitted from contacts on the CI array during and immediately after electrode insertion. For control, the results of EMG measurements were compared to postoperative flat panel volume computed tomography scans with secondary reconstruction (fpVCTSECO). During insertion, the EMG response evoked by the electrical stimulation from the CI was growing with the stimulating contact approaching the facial nerve and declined with increasing distance. After full insertion, contacts on the apical half of the CI array stimulated higher EMG responses compared with those on the basal half. Comparison with postoperative imaging demonstrated that electrode contacts stimulating high EMG responses had the shortest distances to the facial nerve. It could be demonstrated that electrically evoked EMG activation of the facial nerve can be used to monitor the progress during CI electrode insertion and to control the intracochlear electrode position after full insertion.

Abstract Background The ability to view the posterior segment in keratoprosthesis (Kpro) implanted patients is limited. The purpose of this retrospective, observational study was to investigate the use of ultra-wide field (UWF) scanning laser ophthalmoscopy imaging and its utility for serial evaluation of the retina and optic nerve in patients with either a Boston type I or II Kpro. Methods A retrospective chart review was performed for patients with a Boston type I or II Kpro seen at The Ohio State University Wexner Medical Center. Images were graded for quality by two masked observers on a defined four-point scale (“Poor”, “Fair”, “Good”, or “Very good”) and assessed for visible posterior segment anatomy. Interobserver agreement was described using the Kappa statistic coefficient (κ) with 95% confidence intervals. Results A total of 19 eyes from 17 patients were included in this study. Eighteen eyes had a type I Kpro, while one eye had a type II Kpro. UWF imaging from 41 patient visits were reviewed by two observers. Interobserver agreement between the two graders was fair for image quality (κ = 0.36), moderate for visibility of the macula with discernible details (κ = 0.59), moderate for visibility of the anterior retina with discernable details (κ = 0.60), and perfect agreement for visibility of the optic nerve with discernible details (κ = 1.0). In 6 eyes, UWF imaging was performed longitudinally (range 3–9 individual visits), allowing for long-term follow-up (range 3–46 months) of posterior segment clinical pathology. Conclusions UWF imaging provides adequate and reliable visualization of the posterior segment in Kpro implanted patients. This imaging modality allowed for noninvasive longitudinal monitoring of retinal and optic nerve disease in this selected patient population.

IntroductionIn patients with peripheral neuropathies (PNP), neuropathic pain is present in 50% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation.MethodsTo test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls.ResultsWhile we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction.ConclusionIn patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies.

We are rapidly approaching a future in which cancer patient digital twins will reach their potential to predict cancer prevention, diagnosis, and treatment in individual patients. This will be realized based on advances in high performance computing, computational modeling, and an expanding repertoire of observational data across multiple scales and modalities. In 2020, the US National Cancer Institute, and the US Department of Energy, through a trans-disciplinary research community at the intersection of advanced computing and cancer research, initiated team science collaborative projects to explore the development and implementation of predictive Cancer Patient Digital Twins. Several diverse pilot projects were launched to provide key insights into important features of this emerging landscape and to determine the requirements for the development and adoption of cancer patient digital twins. Projects included exploring approaches to using a large cohort of digital twins to perform deep phenotyping and plan treatments at the individual level, prototyping self-learning digital twin platforms, using adaptive digital twin approaches to monitor treatment response and resistance, developing methods to integrate and fuse data and observations across multiple scales, and personalizing treatment based on cancer type. Collectively these efforts have yielded increased insights into the opportunities and challenges facing cancer patient digital twin approaches and helped define a path forward. Given the rapidly growing interest in patient digital twins, this manuscript provides a valuable early progress report of several CPDT pilot projects commenced in common, their overall aims, early progress, lessons learned and future directions that will increasingly involve the broader research community.

IntroductionApproximately 40% of patients with uveal melanoma (UM) will develop metastatic disease. Tumors measuring at least 12mm in basal diameter with a class 2 signature, as defined by a widely used gene expression-profiling test, are associated with significantly higher risk of metastasis, with a median time to recurrence of 32 months. No therapy has been shown to reduce this risk.Materials and MethodsThis was a single-arm, multicenter study in patients with high-risk UM who received definitive treatment of primary disease and had no evidence of metastasis. Patients were consecutively enrolled to receive 12 four-week cycles of adjuvant crizotinib at a starting dose of 250mg twice daily and were subsequently monitored for 36 months. The primary outcome of this study was to assess recurrence-free survival (RFS) of patients with high-risk UM who received adjuvant crizotinib.Results34 patients enrolled and received at least one dose of crizotinib. Two patients were unevaluable due to early withdrawal and loss to follow-up, leaving 32 patients evaluable for efficacy. Eight patients (25%) did not complete the planned 48-week course of treatment due to disease recurrence (n=5) or toxicity (n=3). All patients experienced at least one adverse event (AE), with 11/34 (32%) experiencing a Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 AE. After a median duration of follow up of 47.1 months, 21 patients developed distant recurrent disease. The median RFS was 34.9 months (95% CI (Confidence Interval), 23-55 months), with a 32-month recurrence rate of 50% (95% CI, 33-67%). Analysis of protein contents from peripheral blood extracellular vesicles in a subset of patient samples from baseline, on-treatment, and off-treatment, revealed a change in protein content associated with crizotinib exposure, however without a clear association with disease outcome.ConclusionsThe use of adjuvant crizotinib in patients with high-risk UM did not result in improved RFS when compared to historical controls. Analysis of blood extracellular vesicles revealed changes in protein content associated with treatment, raising the possibility of future use as a biomarker. Further investigation of adjuvant treatment options are necessary for this challenging disease.

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.