Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts.

Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors. SIGNIFICANCE: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC.

Deconvolution of the X-ray absorption spectrum of trans-1,3-butadiene with resonant Auger spectroscopy.

High-resolution carbon K-edge X-ray photoelectron, X-ray absorption, non-resonant and resonant Auger spectra are presented of gas phase trans-1,3-butadiene alongside a detailed theoretical analysis utilising nuclear ensemble approaches and vibronic models to simulate the spectroscopic observables. The resonant Auger spectra recorded across the first pre-edge band reveal a complex evolution of different electronic states which remain relatively well-localised on the edge or central carbon sites. The results demonstrate the sensitivity of the resonant Auger observables to the weighted contributions from multiple electronic states. The gradually evolving spectral features can be accurately and feasibly simulated within nuclear ensemble methods and interpreted with the population analysis.

Methotrexate-based PROTACs as DHFR-specific chemical probes.

Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular retention and target specificity. Mechanisms of MTX resistance in cancers include a decrease in MTX poly-γ-glutamylation and an upregulation of DHFR. Here, we report a series of potent MTX-based proteolysis targeting chimeras (PROTACs) to investigate DHFR degradation pharmacology and one-carbon biochemistry. These on-target, cell-active PROTACs show proteasome- and E3 ligase-dependent activity, and selective degradation of DHFR in multiple cancer cell lines. By comparison, treatment with MTX increases cellular DHFR protein expression. Importantly, these PROTACs produced distinct, less-lethal phenotypes compared to MTX. The chemical probe set described here should complement conventional DHFR inhibitors and serve as useful tools for studying one-carbon biochemistry and dissecting complex polypharmacology of MTX and related drugs. Such compounds may also serve as leads for potential autoimmune and antineoplastic therapeutics.

Evaluating Stacked Methylation Markers for Blood-Based Multicancer Detection.

The ability to detect several types of cancer using a non-invasive, blood-based test holds the potential to revolutionize oncology screening. We mined tumor methylation array data from the Cancer Genome Atlas (TCGA) covering 14 cancer types and identified two novel, broadly-occurring methylation markers at TLX1 and GALR1. To evaluate their performance as a generalized blood-based screening approach, along with our previously reported methylation biomarker, ZNF154, we rigorously assessed each marker individually or combined. Utilizing TCGA methylation data and applying logistic regression models within each individual cancer type, we found that the three-marker combination significantly increased the average area under the ROC curve (AUC) across the 14 tumor types compared to single markers (p = 1.158 × 10-10; Friedman test). Furthermore, we simulated dilutions of tumor DNA into healthy blood cell DNA and demonstrated increased AUC of combined markers across all dilution levels. Finally, we evaluated assay performance in bisulfite sequenced DNA from patient tumors and plasma, including early-stage samples. When combining all three markers, the assay correctly identified nine out of nine lung cancer plasma samples. In patient plasma from hepatocellular carcinoma, ZNF154 alone yielded the highest combined sensitivity and specificity values averaging 68% and 72%, whereas multiple markers could achieve higher sensitivity or specificity, but not both. Altogether, this study presents a comprehensive pipeline for the identification, testing, and validation of multi-cancer methylation biomarkers with a considerable potential for detecting a broad range of cancer types in patient blood samples.

Inhibition of NAD+-Dependent Metabolic Processes Induces Cellular Necrosis and Tumor Regression in Rhabdomyosarcoma Models.

PURPOSE: Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. NAMPT is necessary for efficient NAD+ production and may be exploited in cells with increased metabolic demands. We have identified NAMPT as a dependency in rhabdomyosarcoma (RMS), a malignancy for which novel therapies are critically needed. Here we describe the effect of NAMPT inhibition on RMS proliferation and metabolism in vitro and in vivo. EXPERIMENTAL DESIGN: Assays of proliferation and cell death were used to determine the effects of pharmacologic NAMPT inhibition in a panel of ten molecularly diverse RMS cell lines. Mechanism of the clinical NAMPTi OT-82 was determined using measures of NAD+ and downstream NAD+-dependent functions, including energy metabolism. We used orthotopic xenograft models to examine tolerability, efficacy, and drug mechanism in vivo. RESULTS: Across all ten RMS cell lines, OT-82 depleted NAD+ and inhibited cell growth at concentrations ≤1 nmol/L. Significant impairment of glycolysis was a universal finding, with some cell lines also exhibiting diminished oxidative phosphorylation. Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions with OT-82 treatment delivered on the clinical schedule. CONCLUSIONS: RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy.

Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma.

Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC. Furthermore, a combination screen with a wide variety of targets revealed multiple synergistic combinations that may pave the way for novel therapeutical strategies against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic assays established increased brain penetrance with intra-arterial (IA) delivery over intra-venous (IV) delivery and demonstrated a higher CNS penetrance for the combination melphalan/elimusertib. The mechanisms of synergistic activity for melphalan/elimusertib were assessed through transcriptome analyses and showed dysregulation of key oncogenic pathways (e.g. MYC, mammalian target of rapamycin mTOR, p53) and activation of critical biological processes (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC.

High-throughput approaches to uncover synergistic drug combinations in leukemia.

We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.

Evaluation and comparison of four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy.

BACKGROUND: Semi-quantitative and quantitative immunoassays are the most commonly used methodology to evaluate immunity post immunization. OBJECTIVES: To compare four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy. STUDY DESIGN: 210 serological samples from COVID-19 infection and vaccination cohorts were used to create a serological sample repository. Serological methods from four manufacturers, namely Euroimmun, Roche, Abbott, and DiaSorin, were evaluated for quantitative, semi-quantitative, and qualitative antibody measurements. All four methods measure IgG antibodies against the SARS-CoV-2 spike receptor-binding domain and report the results in Binding Antibody Unit/mL (BAU/mL). A Total Error Allowable (TEa) of ±25% was chosen as the criteria to determine whether two methods are clinically equivalent quantitatively. Semi-quantitative results (titers) were derived using numeric antibody concentration divided by the cut-off value for each method. RESULTS: All paired quantitative comparisons demonstrated unacceptable performance. With ±25% as TEa, the best agreement was 74 (35.2% out of 210 samples) between Euroimmun and DiaSorin, whereas the lowest agreement was 11 (5.2% out of 210 samples) between Euroimmun and Roche. Antibody titers amongst all four methods were significantly different (p < 0.001). The highest titer difference from the same sample is between Roche and DiaSorin with a 1392-fold difference. On qualitative comparison, none of the paired comparison showed acceptable comparison (p < 0.001). CONCLUSIONS: Poor correlation exists between four evaluated assays, quantitatively, semi-quantitatively, and qualitatively. Further harmonization of assays is required to achieve comparable measurements.

Effect of Digital Medication Event Reminder and Monitor-Observed Therapy vs Standard Directly Observed Therapy on Health-Related Quality of Life and Catastrophic Costs in Patients With Tuberculosis: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Little is known about whether digital adherence technologies are economical for patients with tuberculosis (TB) in resource-constrained settings. Objective: To test the hypothesis that for patients with TB, a digital medication event reminder monitor (MERM)-observed therapy provides higher health-related quality of life (HRQoL) and lower catastrophic costs compared with standard directly observed therapy (DOT). Design, Setting, and Participants: This study was a secondary analysis of a randomized, 2-arm, open-label trial conducted in 10 health care facilities in Ethiopia. Eligible participants were adults with new or previously treated, bacteriologically confirmed, drug-sensitive pulmonary TB who were eligible to start first-line anti-TB therapy. Participants were enrolled between June 2, 2020, and June 15, 2021, with the last participant completing follow-up on August 15, 2021. Interventions: Participants were randomly assigned (1:1) to receive a 15-day TB medication supply dispensed with a MERM device to self-administer and return every 15 days (intervention arm) or the standard in-person DOT (control arm). Both groups were observed throughout the standard 2-month intensive treatment phase. Main Outcomes and Measures: Prespecified secondary end points of the original trial were HRQoL using the EuroQoL 5-dimension 5-level (EQ-5D-5L) tool and catastrophic costs, direct (out-of-pocket) and indirect (guardian and coping) costs from the individual patient perspective using the World Health Organization's Tool to Estimate Patient Costs, and common factors associated with lower HRQoL and higher catastrophic costs. Results: Among 337 patients screened for eligibility, 114 were randomly assigned, and 109 were included in the final complete-case intention-to-treat analysis (57 control and 52 intervention participants). The mean (SD) age was 33.1 (11.1) years; 72 participants (66.1%) were men, and 15 (13.9%) had HIV coinfection. EQ-5D-5L overall median (IQR) index value was 0.964 (0.907-1). The median (IQR) value was significantly higher in intervention (1 [0.974-1]) vs control (.908 [0.891-0.964]) (P < .001). EQ-5D-5L minimum and maximum health state utility values in intervention were 0.906 and 1 vs 0.832 and 1 in control. Patients' overall median (IQR) postdiagnosis cost was Ethiopian birr (ETB) 80 (ETB 16-ETB 480) (US $1.53). The median cost was significantly lower in intervention (ETB 24 [ETB 16-ETB 48]) vs control (ETB 432 [ETB 210-ETB 1980]) (P < .001), with median possible cost savings of ETB 336 (ETB 156-ETB 1339) (US $6.44) vs the control arm. Overall, 42 participants (38.5%; 95% CI, 29.4%-48.3%) faced catastrophic costs, and this was significantly lower in the intervention group (11 participants [21.2%]; 95% CI, 11.1%-34.7%) vs control (31 participants [54.4%]; 95% CI, 40.7%-67.6%) (P < .001). Trial arm was the single most important factor in low HRQoL (adjusted risk ratio [ARR], 1.49; 95% CI, 1.35-1.65; P < .001), while trial arm (ARR, 2.55; 95% CI, 1.58-4.13; P < .001), occupation (ARR, 2.58; 95% CI, 1.68-3.97; P < .001), number of cohabitants (ARR, 0.64; 95% CI, 0.43-0.95; P = .03), and smoking (ARR, 2.71; 95% CI, 1.01-7.28; P = .048) were the most important factors in catastrophic cost. Conclusions and Relevance: In patients with TB, MERM-observed therapy was associated with higher HRQoL and lower catastrophic costs compared with standard DOT. Patient-centered digital health technologies could have the potential overcoming structural barriers to anti-TB therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT04216420.

Spontaneous coronary artery dissection, fibromuscular dysplasia, and biventricular stress cardiomyopathy: a case report.

Background: Spontaneous coronary artery dissection (SCAD) is an important cause of acute coronary syndrome and is associated with fibromuscular dysplasia (FMD). The diagnosis of stress cardiomyopathy in patients with SCAD and FMD is uncommon, though an important consideration given the shared risk profile. Complications of severe left ventricular (LV) dysfunction associated with stress cardiomyopathy, such as LV thrombus, complicate the management of SCAD where anticoagulation is controversial in the context of SCAD-associated intramural haematoma. Case summary: A 65-year-old female presented with non-ST elevation myocardial infarction with a recent diagnosis of hypertension but no other traditional cardiovascular risk factors. There was, however, a family history of early cardiac death from myocardial infarction affecting her mother. Echocardiography demonstrated severe biventricular dysfunction with circumferential akinesis of the mid to apical segments. Coronary angiography demonstrated type 2A SCAD involving the first diagonal artery. Cardiac magnetic resonance imaging (MRI) confirmed a diagnosis of stress cardiomyopathy with biventricular involvement, complicated by LV apical thrombus and a focal region of myocardial infarction. Vascular imaging confirmed the presence of FMD. Guideline-directed heart failure therapy in addition to clopidogrel and rivaroxaban was prescribed. Follow-up contrast echocardiography at six-weeks confirmed resolution of LV dysfunction and resolution of the LV thrombus with no adverse events. Discussion: The dual diagnosis of SCAD and stress cardiomyopathy is uncommon. Cardiac MRI was useful for confirming the diagnosis of stress cardiomyopathy and the presence of LV thrombus, where anticoagulation may complicate the management of intramural haematoma in patients with concomitant SCAD and FMD.

Characterization and clustering of kinase isoform expression in metastatic melanoma.

Mutations to the human kinome are known to play causal roles in cancer. The kinome regulates numerous cell processes including growth, proliferation, differentiation, and apoptosis. In addition to aberrant expression, aberrant alternative splicing of cancer-driver genes is receiving increased attention as it could lead to loss or gain of functional domains, altering a kinase's downstream impact. The present study quantifies changes in gene expression and isoform ratios in the kinome of metastatic melanoma cells relative to primary tumors. We contrast 538 total kinases and 3,040 known kinase isoforms between 103 primary tumor and 367 metastatic samples from The Cancer Genome Atlas (TCGA). We find strong evidence of differential expression (DE) at the gene level in 123 kinases (23%). Additionally, of the 468 kinases with alternative isoforms, 60 (13%) had significant difference in isoform ratios (DIR). Notably, DE and DIR have little correlation; for instance, although DE highlights enrichment in receptor tyrosine kinases (RTKs), DIR identifies altered splicing in non-receptor tyrosine kinases (nRTKs). Using exon junction mapping, we identify five examples of splicing events favored in metastatic samples. We demonstrate differential apoptosis and protein localization between SLK isoforms in metastatic melanoma. We cluster isoform expression data and identify subgroups that correlate with genomic subtypes and anatomic tumor locations. Notably, distinct DE and DIR patterns separate samples with BRAF hotspot mutations and (N/K/H)RAS hotspot mutations, the latter of which lacks effective kinase inhibitor treatments. DE in RAS mutants concentrates in CMGC kinases (a group including cell cycle and splicing regulators) rather than RTKs as in BRAF mutants. Furthermore, isoforms in the RAS kinase subgroup show enrichment for cancer-related processes such as angiogenesis and cell migration. Our results reveal a new approach to therapeutic target identification and demonstrate how different mutational subtypes may respond differently to treatments highlighting possible new driver events in cancer.

Clinical characteristics and outcome of infective endocarditis due to Abiotrophia and Granulicatella compared to Viridans group streptococci.

OBJECTIVE: To describe the clinical characteristics and outcome of Abiotrophia and Granulicatella infective endocarditis and compare them with Viridans group streptococci infective endocarditis. METHODS: All patients in the International Collaboration on Endocarditis (ICE) - prospective cohort study (PCS) and the ICE-PLUS cohort were included (n = 8112). Data from patients with definitive or possible IE due to Abiotrophia species, Granulicatella species and Viridans group streptococci was analyzed. A propensity score (PS) analysis comparing the ABI/GRA-IE and VGS-IE groups according to a 1:2 ratio was performed. RESULTS: Forty-eight (0.64%) cases of ABI/GRA-IE and 1,292 (17.2%) VGS-IE were included in the analysis. The median age of patients with ABI/GRA-IE was lower than VGS-IE (48.1 years vs. 57.9 years; p = 0.001). Clinical features and the rate of in-hospital surgery was similar between ABI/GRA-IE and VGS-IE (52.1% vs. 45.4%; p = 0.366). Unadjusted in-hospital death was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 8.8%; p = 0.003), and cumulative six-month mortality was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 11.9%; p<0.001). After PS analysis, in-hospital mortality was similar in both groups, but six-month mortality was lower in the ABI/GRA IE group (2.1% vs. 10.4%; p = 0.029). CONCLUSIONS: Patients with ABI/GRA-IE were younger, had similar clinical features and rates of surgery and better prognosis than VGS-IE.

Mechanism of Thimerosal-Induced Structural Destabilization of a Recombinant Rotavirus P[4] Protein Antigen Formulated as a Multi-Dose Vaccine.

In a companion paper, a two-step developability assessment is presented to rapidly evaluate low-cost formulations (multi-dose, aluminum-adjuvanted) for new subunit vaccine candidates. As a case study, a non-replicating rotavirus (NRRV) recombinant protein antigen P[4] was found to be destabilized by the vaccine preservative thimerosal, and this effect was mitigated by modification of the free cysteine (C173S). In this work, the mechanism(s) of thimerosal-P[4] protein interactions, along with subsequent effects on the P[4] protein's structural integrity, are determined. Reversible complexation of ethylmercury, a thimerosal degradation byproduct, with the single cysteine residue of P[4] protein is demonstrated by intact protein mass analysis and biophysical studies. A working mechanism involving a reversible S-Hg coordinate bond is presented based on the literature. This reaction increased the local backbone flexibility of P[4] within the helical region surrounding the cysteine residue and then caused more global destabilization, both as detected by HX-MS. These effects correlate with changes in antibody-P[4] binding parameters and alterations in P[4] conformational stability due to C173S modification. Epitope mapping by HX-MS demonstrated involvement of the same cysteine-containing helical region of P[4] in antibody-antigen binding. Future formulation challenges to develop low-cost, multi-dose formulations for new recombinant protein vaccine candidates are discussed.

Preventing COVID-19 Outbreaks in Long-Term Care Facilities Through Preemptive Testing of Residents and Staff Members - Fulton County, Georgia, March-May 2020.

Long-term care facility (LTCF) residents are at particularly high risk for morbidity and mortality associated with infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), given their age and high prevalence of chronic medical conditions, combined with functional impairment that often requires frequent, close contact with health care providers, who might inadvertently spread the virus to residents (1,2). During March-May 2020 in Fulton County, Georgia, >50% of COVID-19-associated deaths occurred among LTCF residents, although these persons represented <1% of the population (3,4). Mass testing for SARS-CoV-2 has been an effective strategy for identifying asymptomatic and presymptomatic infections in LTCFs (5). This analysis sought to evaluate the timing at which mass testing took place in relation to the known presence of a COVID-19 infection and the resulting number of infections that occurred. In 15 LTCFs that performed facility-wide testing in response to an identified case, high prevalences of additional cases in residents and staff members were found at initial testing (28.0% and 7.4%, respectively), suggesting spread of infection had already occurred by the time the first case was identified. Prevalence was also high during follow-up, with a total of 42.4% of residents and 11.8% of staff members infected overall in the response facilities. In comparison, 13 LTCFs conducted testing as a preventive strategy before a case was identified. Although the majority of these LTCFs identified at least one COVID-19 case, the prevalence was significantly lower at initial testing in both residents and staff members (0.5% and 1.0%, respectively) and overall after follow-up (1.5% and 1.7%, respectively). These findings indicate that early awareness of infections might help facilities prevent potential outbreaks by prioritizing and adhering more strictly to infection prevention and control (IPC) recommendations, resulting in fewer infections than would occur when relying on symptom-based screening (6,7).

Epidemiology, Management, and Outcomes of Large and Small Native Joint Septic Arthritis in Adults.

BACKGROUND: Native joint septic arthritis (NJSA) is poorly studied. We describe the epidemiology, treatment, and outcomes of large joint NJSA (LNJSA) and small joint NJSA (SNJSA) in adults at Middlemore Hospital, Auckland, New Zealand. METHODS: This was a coding-based retrospective study of patients ≥16 years old admitted between 2009 and 2014. Prosthetic joint infections were excluded. RESULTS: Five hundred forty-three NJSA episodes were included (302 LNJSA, 250 SNJSA). Only 40% had positive synovial fluid culture. Compared to SNJSA, LNJSA has higher incidence (13 vs 8/100 000 person-years [PY]), occurs in older, more comorbid patients, and is associated with greater rates of treatment failure (23% vs 12%) and mortality, despite longer antibiotic treatment. Total incidence is higher than previously reported (21/100 000 PY), with marked interethnic variation. Incidence rises with age (LNJSA only) and socioeconomic deprivation (LNJSA and SNJSA). Tobacco smokers and males are overrepresented. The most commonly involved joints were knee (21%) and hand interphalangeal (20%). Staphylococcus aureus was the most common pathogen (53%). Mean antibiotic duration was 25 days for SNJSA and 40 days for LNJSA, and the mean number of surgical procedures was 1.5 and 1.6, respectively. Treatment failure was independently associated with LNJSA, age, intra-articular nonarthroplasty prosthesis, and number of surgical procedures. CONCLUSIONS: This is the largest contemporary series of adult NJSA. SNJSA has better outcomes than LNJSA and may be able to be safely treated with shorter antimicrobial courses. Incidence is high, with significant ethnic and socioeconomic variation. Microbiological NJSA case ascertainment underestimates case numbers as it frequently excludes SNJSA.

Infective Endocarditis: A Contemporary Study of Microbiology, Echocardiography and Associated Clinical Outcomes at a Major Tertiary Referral Centre.

BACKGROUND: The epidemiology of infective endocarditis (IE) continues to evolve, with antimicrobial resistance and clinical outcomes largely dependent on the environment of acquisition. This study aimed to provide a contemporary review of the microbiology and antimicrobial management of IE and report echocardiographic findings and predictors of adverse outcomes in community-acquired and health care-associated IE. METHODS: Consecutive presentations of IE to a major Australian tertiary referral centre between January 2011 and April 2016 were examined. Culprit organisms and resistance patterns were recorded, as was transthoracic and transoesophageal echocardiography. Real-world antimicrobial prescription and use of an outpatient parenteral antimicrobial therapy (OPAT) service were also assessed, and clinical outcomes analysed. RESULTS: Of 204 consecutive cases, 30% were associated with health care, a group with a higher burden of comorbidities and more prone to complications. Health care-associated cases had lower rates of surgical intervention but higher mortality. A history of intravenous drug use (IVDU) conferred risk for recurrent IE whereas multivalvular involvement predicted heart failure hospitalisation. Staphylococcus aureus was isolated in 45%. Whilst methicillin resistance remains low, the prevalence of S. aureus IE is increasing. Single antimicrobial agents were commonly used (83%) and therapy via OPAT was safe and significantly reduced length of hospital stay. Not undergoing transoesophageal echocardiography (TOE) or definitive surgical management conferred poorer prognosis. CONCLUSIONS: The epidemiology of IE is evolving and there is need for updated epidemiological data and associated clinical outcomes. Environment of acquisition remains important in the face of increasing health care provision and the changing predominance of culprit microorganisms.

QuantiFERON-TB Gold Versus Tuberculin Screening and Care Retention Among Persons Experiencing Homelessness: Georgia, 2015-2017.

Objectives. To characterize the cascade of care for latent tuberculosis infection (LTBI) in persons experiencing homelessness (PEH) and evaluate the effect of screening by QuantiFERON-TB Gold (QFT) versus tuberculin skin test (TST). Methods. We performed a retrospective cohort study of all PEH screened for LTBI by QFT and TST from May 2015 to April 2017 in Fulton County, Georgia. Results. There were 3504 PEH screened by QFT and 5509 by TST, with 2925 TSTs administered on site at community shelters and 2584 at the health department. More valid test results were obtained in those screened by QFT (99.0% vs 69.0%; P < .001) because of low return rates for reading in both TST arms. For tests administered on site, testing by QFT versus TST improved retention in care with significantly more estimated LTBI cases following up for a medical examination (67.8% vs 51.0%; P < .001) and starting LTBI treatment (58.4% vs 39.8%; P < .001). Conclusions. A QFT-based screening strategy in PEH improved diagnosis and retention in care for new LTBI cases compared with TST and may be an effective strategy to limit progression to active tuberculosis.

Comparison of the new and traditional CKD-EPI GFR estimation equations with urinary inulin clearance: A study of equation performance.

BACKGROUND: Diagnosis, prognostication and treatment in chronic kidney disease is often informed by an estimate of the glomerular filtration rate (GFR). Commonly used GFR estimation (eGFR) equations are based on serum creatinine (Cr) concentrations and display suboptimal precision and accuracy. Newer equations incorporating additional endogenous markers such as ß-Trace Protein (BTP), ß2-Microglobulin (B2M) and cystatin C (cysC) have been developed but require validation. METHODS: This prospective cohort study evaluated the performance of 6 eGFR equations developed by the chronic kidney disease - epidemiology collaboration group (CKD-EPI) against urinary inulin clearance GFR in patients recruited from outpatient nephrology clinics. RESULTS: Mean biases were negligible and similar between equations. The eGFR-EPI Cr/cysC had the best precision and accuracy of all the equations and the best agreement with inulin mGFR when classifying participants into GFR categories. The BTP and B2M equations displayed the worst precisions and accuracies and showed the least consistent performance across levels of GFR. Thus, the eGFR-EPI Cr/cysC is the least biased, most precise and has the highest accuracy as compared to other eGFR-EPI equations. CONCLUSIONS: The BTP and B2M equations are the worst performing of the eGFR-EPI equations, and no benefit is observed with the addition of BTP or B2M to Cr/cysC.

Impact of radiology reports on timely tuberculosis diagnosis.

PURPOSE: As tuberculosis becomes less common in higher income countries, clinician familiarity with the disease is declining. Little is known about how chest radiograph interpretations affect tuberculosis care. We sought to determine how tuberculosis-related terminology in an initial chest radiograph reading impacted patient care. STUDY DESIGN: We examined a retrospective cohort of patients with pulmonary tuberculosis in North Carolina from 1 January 2011 to 31 December 2014. Tuberculosis-related terminology was categorised into four mutually exclusive categories. The primary outcomes of interest were the time from the chest radiograph to (1) obtaining the first sputum specimen for acid-fast smear and mycobacterial culture, and (2) initiation of antituberculous treatment. RESULTS: Of 550 available chest radiograph reports, 175 (31.8%) contained the word 'tuberculosis', 30 (5.5%) contained the word 'mycobacteria' or 'granulomatous', 43 (7.8%) contained the word 'cavity', and 301 (54.7%) had none of the above terms mentioned. Patients with the word 'tuberculosis' in the radiology report had a significantly shorter time to collection of the initial sputum specimen for acid-fast smear and mycobacterial culture (median 2 days) and to the start of antituberculous treatment (median 4 days) than patients with none of the keywords. Use of the term 'cavity' in the report was associated with a shorter time to initiation of antituberculous treatment (median 4 days) than if none of the keywords were used. CONCLUSION: Chest radiograph reports that contained keywords for pulmonary tuberculosis, such as 'tuberculosis' or 'cavity', were associated with less time to collection of sputum and antituberculous treatment.