Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set

BACKGROUND: A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. PATIENTS AND METHODS: This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. RESULTS: Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). CONCLUSION: In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. CLINICAL TRIAL NUMBER: NCT02889978

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

A finite strain fibre-reinforced viscoelasto-viscoplastic model of plant cell wall growth

A finite strain fibre-reinforced viscoelasto-viscoplastic model implemented in a finite element (FE) analysis is presented to study the expansive growth of plant cell walls. Three components of the deformation of growing cell wall, i.e. elasticity, viscoelasticity and viscoplasticity-like growth, are modelled within a consistent framework aiming to present an integrative growth model. The two aspects of growth—turgor-driven creep and new material deposition—and the interplay between them are considered by presenting a yield function, flow rule and hardening law. A fibre-reinforcement formulation is used to account for the role of cellulose microfibrils in the anisotropic growth. Mechanisms in in vivo growth are taken into account to represent the corresponding biologycontrolled behaviour of a cell wall. A viscoelastic formulation is proposed to capture the viscoelastic response in the cell wall. The proposed constitutive model provides a unique framework for modelling both the in vivo growth of cell wall dominated by viscoplasticity-like behaviour and in vitro deformation dominated by elastic or viscoelastic responses. A numerical scheme is devised, and FE case studies are reported and compared with experimental data

Clinician-facilitated physical activity intervention versus pulmonary rehabilitation for improving physical activity in COPD: a feasibility study

Pulmonary rehabilitation (PR) may not suit all individuals with chronic obstructive pulmonary disease (COPD) and may not result in increased physical activity. Higher levels of physical activity are associated with reduced mortality and morbidity. The aim of this study was to assess the feasibility of conducting a trial to investigate the effectiveness of a clinician-facilitated physical activity intervention (PAI) versus PR in improving physical activity in patients with COPD referred to PR. In this randomised controlled mixed methods feasibility study, all patients referred to PR who were eligible and willing were assessed at baseline and then randomised to the PAI or to PR. The assessments were repeated post-intervention and at 3-month follow-up. The main outcome was step count measured by Actigraph. Semi-structured interviews were conducted post-intervention. The N = 50 patients; mean (SD) age, 64.1(8.6) years, 24M were recruited and randomised; N = 23 (PAI) and n = 26 (PR): one patient was excluded from the analysis as that person did not meet the GOLD diagnostic criteria. Key feasibility criteria were met; recruitment was 11%, dropouts in PAI were 26% (n = 6) and 50% (n = 13/26) PR. Participants in both groups experienced a range of health benefits from their respective programmes. The PAI appears to be effective in increasing step counts in people with COPD: mean change (standard deviation) [confidence interval] for the PAI group was 972.0(3230.3)[–1080.3 to 3024.4], n = 12 and 4.3(662.7)[-440.9 to 449.5], n = 11 for the PR group. The PAI met all domains of fidelity. This study provides key information to inform a future-randomised controlled trial in physical activity

Immunolocalization of cell wall polymers in grapevine (Vitis vinifera) internodes under nitrogen, phosphorus or sulfur deficiency

Abstract The impact on cell wall (CW) of the deficiency in nitrogen (–N), phosphorus (–P) or sulphur (–S), known to impair essential metabolic pathways, was investigated in the economically important fruit species Vitis vinifera L. Using cuttings as an experimental model a reduction in total internode number and altered xylem shape was observed. Under –N an increased internode length was also seen. CW composition, visualised after staining with calcofluor white, Toluidine blue and ruthenium red, showed decreased cellulose in all stresses and increased pectin content in recently formed internodes under –N compared to the control. Using CW-epitope specific monoclonal antibodies (mAbs), lower amounts of extensins incorporated in the wall were also observed under –N and –P conditions. Conversely, increased pectins with a low degree of methyl-esterification and richer in long linear 1,5-arabinan rhamnogalacturonan-I (RG-I) side chains were observed under –N and –P in mature internodes which, in the former condition, were able to form dimeric association through calcium ions. –N was the only condition in which 1,5-arabinan branched RG- content was not altered, as –P and –S older internodes showed, respectively, lower and higher amounts of this polymer. Higher xyloglucan content in older internodes was also observed under –N. The results suggest that impairments of specific CW components led to changes in the deposition of other polymers to promote stiffening of the CW. The unchanged extensin amount observed under –S may contribute to attenuating the effects on the CW integrity caused by this stress. Our work showed that, in organized V. vinifera tissues, modifications in a given CW component can be compensated by synthesis of different polymers and/or alternative linking between polymers. The results also pinpoint different strategies at the CW level to overcome mineral stress depending on how essential they are to cell growth and plant development

Recognition of vitamin B metabolites by mucosal-associated invariant T cells

The mucosal-associated invariant T-cell antigen receptor (MAIT TCR) recognizes MR1 presenting vitamin B metabolites. Here we describe the structures of a human MAIT TCR in complex with human MR1 presenting a non-stimulatory ligand derived from folic acid and an agonist ligand derived from a riboflavin metabolite. For both vitamin B antigens, the MAIT TCR docks in a conserved manner above MR1, thus acting as an innate-like pattern recognition receptor. The invariant MAIT TCR a-chain usage is attributable to MR1-mediated interactions that prise open the MR1 cleft to allow contact with the vitamin B metabolite. Although the non-stimulatory antigen does not contact the MAIT TCR, the stimulatory antigen does. This results in a higher affinity of the MAIT TCR for a stimulatory antigen in comparison with a non-stimulatory antigen. We formally demonstrate a structural basis for MAIT TCR recognition of vitamin B metabolites, while illuminating how TCRs recognize microbial metabolic signatures

Role of previous hospitalization in clinically-significant MRSA infection among HIV-infected inpatients: results of a case-control study

<p>Abstract</p> <p>Background</p> <p>HIV-infected subjects have high incidence rates of <it>Staphylococcus aureus </it>infections, with both methicillin-susceptible and methicillin-resistant (MRSA) strains. Possible explanations could include the high burden of colonization, the behavioral risk factors, and the frequent exposures to health care facilities of HIV-infected patients. The purpose of the study was to assess the risk factors for clinically- significant methicillin-resistant <it>Staphylococcus aureus </it>(CS-MRSA) infections in HIV-infected patients admitted to Infectious Diseases Units.</p> <p>Methods</p> <p>From January 1, 2002 to December 31, 2005, we conducted a retrospective case-control (1:2) study. We identified all the cases of CS-MRSA infections in HIV-infected patients admitted to the National Institute for Infectious Diseases (INMI) "Lazzaro Spallanzani" in the 4-year study period. A conditional logistic regression model was used to identify risk factors for CS-MRSA infection.</p> <p>Results</p> <p>We found 27 CS-MRSA infections, i.e. 0.9 CS-MRSA infections per 100 HIV-infected individuals cared for in our Institute. At multivariate analysis, independent predictors of CS-MRSA infection were cumulative hospital stay, invasive procedures in the previous year, and low CD4 cell count. Particularly, the risk for CS-MRSA increased by 14% per an increase of 5 days hospitalization in the previous year. Finally, we identified a low frequency of community-acquired MRSA infections (only 1 of 27; 3.7%) among HIV-infected patients.</p> <p>Conclusion</p> <p>Clinicians should be aware of the risk for CS-MRSA infection in the clinical management of HIV-infected patients, especially in those patients with a low CD4 cell count, longer previous hospital stay, and previous invasive procedures.</p

Developmental features of cotton fibre middle lamellae in relation to cell adhesion and cell detachment in cultivars with distinct fibre qualities.

Background: Cotton fibre quality traits such as fibre length, strength, and degree of maturation are determined by genotype and environment during the sequential phases of cotton fibre development (cell elongation, transition to secondary cell wall construction and cellulose deposition). The cotton fibre middle lamella (CFML) is crucial for both cell adhesion and detachment processes occurring during fibre development. To explore the relationship between fibre quality and the pace at which cotton fibres develop, a structural and compositional analysis of the CFML was carried out in several cultivars with different fibre properties belonging to four commercial species: Gossypium hirsutum, G. barbadense, G. herbaceum and G. arboreum. Results: Cotton fibre cell adhesion, through the cotton fibre middle lamella (CFML), is a developmentally regulated process determined by genotype. The CFML is composed of de-esterified homogalacturonan, xyloglucan and arabinan in all four fibre-producing cotton species: G. hirsutum, G. barbadense, G. herbaceum and G. arboreum. Conspicuous paired cell wall bulges are a feature of the CFML of two G. hirsutum cultivars from the onset of fibre cell wall detachment to the start of secondary cell wall deposition. Xyloglucan is abundant in the cell wall bulges and in later stages pectic arabinan is absent from these regions. Conclusions: The CFML of cotton fibres is re-structured during the transition phase. Paired cell wall bulges, rich in xyloglucan, are significantly more evident in the G. hirsutum cultivars than in other cotton species

The epidemiology of hematogenous vertebral osteomyelitis: a cohort study in a tertiary care hospital

<p>Abstract</p> <p>Background</p> <p>Vertebral osteomyelitis is a common manifestation of osteomyelitis in adults and associated with considerable morbidity. Limited data exist regarding hematogenous vertebral osteomyelitis. Our objective was to describe the epidemiology and management of hematogenous vertebral osteomyelitis.</p> <p>Methods</p> <p>We performed a 2-year retrospective cohort study of adult patients with hematogenous vertebral osteomyelitis at a tertiary care hospital.</p> <p>Results</p> <p>Seventy patients with hematogenous vertebral osteomyelitis were identified. The mean age was 59.7 years (±15.0) and 38 (54%) were male. Common comorbidities included diabetes (43%) and renal insufficiency (24%). Predisposing factors in the 30 days prior to admission included bacteremia (19%), skin/soft tissue infection (17%), and having an indwelling catheter (30%). Back pain was the most common symptom (87%). Seven (10%) patients presented with paraplegia. Among the 46 (66%) patients with a microbiological diagnosis, the most common organisms were methicillin-susceptible <it>S. aureus </it>[15 (33%) cases], and methicillin-resistant <it>S. aureus </it>[10 (22%)]. Among the 44 (63%) patients who had a diagnostic biopsy, open biopsy was more likely to result in pathogen recovery [14 (93%) of 15 with open biopsy vs. 14 (48%) of 29 with needle biopsy; p = 0.003]. Sixteen (23%) patients required surgical intervention for therapeutic purposes during admission.</p> <p>Conclusions</p> <p>This is one of the largest series of hematogenous vertebral osteomyelitis. A microbiological diagnosis was made in only approximately two-thirds of cases. <it>S. aureus </it>was the most common causative organism, of which almost half the isolates were methicillin-resistant.</p