Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The ...impact of classspecific mutations on this rate of mutation replacement is uncertain. Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and Säo Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model. Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval CI, 14.7-408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log 10 copies/mL; 95% CI, .90-3.25 log 10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001). Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The longterm persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study.
The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, ...Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality.
From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained.
In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval CI, 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings.
After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.)
The goal of the Response Evaluation in Neurofibromatosis and Schwannomatosis Visual Outcomes Committee is to define the best functional outcome measures for future neurofibromatosis type 1 ...(NF1)-associated optic pathway glioma (OPG) clinical trials.
The committee considered the components of vision, other ophthalmologic parameters affected by OPG, potential biomarkers of visual function, and quality of life measures to arrive at consensus-based, evidence-driven recommendations for objective and measurable functional endpoints for OPG trials.
Visual acuity (VA) assessments using consistent quantitative testing methods are recommended as the main functional outcome measure for NF1-OPG clinical trials. Teller acuity cards are recommended for use as the primary VA endpoint, and HOTV as a secondary endpoint once subjects are old enough to complete it. The optic disc should be assessed for pallor, as this appears to be a contributory variable that may affect the interpretation of VA change over time. Given the importance of capturing patient-reported outcomes in clinical trials, evaluating visual quality of life using the Children's Visual Function Questionnaire as a secondary endpoint is also proposed.
The use of these key functional endpoints will be essential for evaluating the efficacy of future OPG clinical trials.
The hallmark of N-linked protein glycosylation is the generation of diverse glycan structures in the secretory pathway. Dynamic, non-template-driven processes of N-glycan remodeling in the ...endoplasmic reticulum and the Golgi provide the cellular setting for structural diversity. We applied newly developed mass spectrometry-based analytics to quantify site-specific N-glycan remodeling of the model protein Pdi1p expressed in insect cells. Molecular dynamics simulation, mutational analysis, kinetic studies of in vitro processing events and glycan flux analysis supported the defining role of the protein in N-glycan processing.
Ebola virus disease (EVD) plagues low-resource and difficult-to-access settings. Machine learning prognostic models and mHealth tools could improve the understanding and use of evidence-based care ...guidelines in such settings. However, data incompleteness and lack of interoperability limit model generalizability. This study harmonizes diverse datasets from the 2014-16 EVD epidemic and generates several prognostic models incorporated into the novel
app that provides informed access to recommended evidence-based guidelines.
Multivariate logistic regression was applied to investigate survival outcomes in 470 patients admitted to five Ebola treatment units in Liberia and Sierra Leone at various timepoints during 2014-16. We generated a parsimonious model (viral load, age, temperature, bleeding, jaundice, dyspnea, dysphagia, and time-to-presentation) and several fallback models for when these variables are unavailable. All were externally validated against two independent datasets and compared to further models including expert observational wellness assessments. Models were incorporated into an app highlighting the signs/symptoms with the largest contribution to prognosis.
The parsimonious model approached the predictive power of observational assessments by experienced clinicians (Area-Under-the-Curve, AUC = 0.70-0.79, accuracy = 0.64-0.74) and maintained its performance across subcohorts with different healthcare seeking behaviors. Age and viral load contributed > 5-fold the weighting of other features and including them in a minimal model had a similar AUC, albeit at the cost of specificity.
Clinically guided prognostic models can recapitulate clinical expertise and be useful when such expertise is unavailable. Incorporating these models into mHealth tools may facilitate their interpretation and provide informed access to comprehensive clinical guidelines.
Howard Hughes Medical Institute, US National Institutes of Health, Bill & Melinda Gates Foundation, International Medical Corps, UK Department for International Development, and GOAL Global.
The recent Ebola epidemic exemplified the importance of understanding and controlling emerging infections. Despite the importance of T cells in clearing virus during acute infection, little is known ...about Ebola-specific CD8⁺ T cell responses. We investigated immune responses of individuals infected with Ebola virus (EBOV) during the 2013–2016 West Africa epidemic in Sierra Leone, where the majority of the >28,000 EBOV disease (EVD) cases occurred. We examined T cell memory responses to seven of the eight Ebola proteins (GP, sGP, NP, VP24, VP30, VP35, and VP40) and associated HLA expression in survivors. Of the 30 subjects included in our analysis, CD8⁺ T cells from 26 survivors responded to at least one EBOV antigen. A minority, 10 of 26 responders (38%), made CD8⁺ T cell responses to the viral GP or sGP. In contrast, 25 of the 26 responders (96%) made response to viral NP, 77% to VP24 (20 of 26), 69% to VP40 (18 of 26), 42% (11 of 26) to VP35, with no response to VP30. Individuals making CD8⁺ T cells to EBOV VP24, VP35, and VP40 also made CD8⁺ T cells to NP, but rarely to GP. We identified 34 CD8⁺ T cell epitopes for Ebola. Our data indicate the immunodominance of the EBOV NP-specific T cell response and suggest that its inclusion in a vaccine along with the EBOV GP would best mimic survivor responses and help boost cell-mediated immunity during vaccination.
Emerging technologies show promise for enhanced characterization of Parkinson's Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the ...conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS).
We evaluated 176 PD subjects (mean age 65, 65% male, 66% H&Y stage 2) during routine clinic visits using the motor MDS-UPDRS and a 10-min motor protocol with a body-fixed sensor (DynaPort MT, McRoberts BV), including the 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed. Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS.
Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p < 0.05) and motor subtype (6 of 12 measures, p < 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for a 1.5- or 1.9-fold increased variance in either cognition or physical functioning disability, respectively. Among minimally-impaired subjects in the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity.
Clinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity.
•Wearable device measures were associated with the motor MDS-UPDRS and PD subtype.•Measures explained increased variance in cognition and disability beyond the UPDRS.•Wearables detect motor heterogeneity in minimally-impaired subjects with normal gait.
Background
This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV ...melanoma.
Methods
After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156).
Results
Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18;
p
= 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053;
p
= 0.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882;
p
= 0.260). Positive DTH skin testing correlated with increased survival.
Discussion
In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.
Mammalian protein O‐mannosylation, initiated by attachment of α‐mannopyranose to Ser or Thr residues, comprise a group of post‐translational modifications (PTMs) involved in muscle and brain ...development. Recent advances in glycoproteomics methodology and the “SimpleCell” strategy have enabled rapid identification of glycoproteins and specific glycosylation sites. Despite the enormous progress made, the biological impact of the mammalian O‐mannosyl glycoproteome remains largely unknown to date. Tools are still needed to investigate the structure, role, and abundance of O‐mannosyl glycans. Although O‐mannosyl branching has been shown to be of relevance in integrin‐dependent cell migration, and also plays a role in demyelinating diseases, such as multiple sclerosis, a broader understanding of the biological roles of branched O‐mannosyl glycans is lacking in part due to the paucity of detection tools. In this work, a glycopeptide vaccine construct was synthesized and used to generate antibodies against branched O‐mannosyl glycans. Glycopeptide microarray screening revealed high selectivity of the induced antibodies for branched glycan core structures presented on different peptide backbones, with no cross‐reactivity observed with related linear glycans. For comparison, microarray screening of the mannose‐binding lectin concanavalin A (ConA), which is commonly used in glycoproteomics workflows to enrich tryptic O‐mannosyl peptides, showed that the ConA lectin did not recognize branched O‐mannosyl glycans. The binding preference of ConA for short linear O‐mannosyl glycans was rationalized in terms of molecular structure using crystallographic data augmented by molecular modeling. The contrast between the ConA binding specificity and that of the new antibodies indicates a novel role for the antibodies in studies of protein O‐mannosylation.
Glycan detection: Antibodies were generated for detection of core m2 O‐mannosyl glycans, a class of protein modifications of importance in tumor progression and brain biology. The binding specificities of the induced antibodies were evaluated on glycopeptide microarrays and the binding recognition was compared with the lectin ConA. The observed binding data was further rationalized by molecular modelling. The obtained antibodies were highly selective for core m2‐modified glycopeptides and contrasted the binding specificity of ConA.
Objective
To evaluate the clinical and radiographic predictors of the need for partial or circumferential resection of the inferior vena cava (IVC) requiring complex vascular reconstruction during ...venous tumour thrombectomy for renal cell carcinoma (RCC).
Patients and Methods
Data were collected on 172 patients with RCC and IVC (levels I–IV) venous tumour thrombus who underwent radical nephrectomy with tumour thrombectomy at the Mayo Clinic between 2000 and 2010. Preoperative imaging was re‐reviewed by one of two radiologists blinded to details of the patient's surgical procedure. Univariable and multivariable associations of clinical and radiographic features with IVC resection were evaluated by logistic regression. A secondary analysis was used to assess the ability of the model to predict histological invasion of the IVC by the tumour thrombus.
Results
Of the 172 patients, 38 (22%) underwent IVC resection procedures during nephrectomy. Optimum radiographic thresholds were determined to predict the need for IVC resection based on preoperative imaging included a renal vein diameter at the renal vein ostium (RVo) of 15.5 mm, maximum anterior–posterior (AP) diameter of the IVC of 34.0 mm and AP and coronal diameters of the IVC at the RVo of 24 and 19 mm, respectively. On multivariable analysis, the presence of a right‐sided tumour (odds ratio 3.3; P = 0.017), an AP diameter of the IVC at the RVo of ≥24.0 mm (odds ratio 4.4; P = 0.017), and radiographic identification of complete occlusion of the IVC at the RVo (odds ratio 4.9; P < 0.001) were associated with a significantly increased risk of IVC resection. The c‐index for the model was 0.81.
Conclusions
We present a multivariable model of the radiographic features associated with the need for IVC resection during tumour thrombectomy. Pending external validation, this model may be used for preoperative planning, patient counselling and planned involvement of vascular surgical colleagues in anticipation of the need for complex vascular repair.
PDF
