Homo naledi is a previously-unknown species of extinct hominin discovered within the Dinaledi Chamber of the Rising Star cave system, Cradle of Humankind, South Africa. This species is characterized ...by body mass and stature similar to small-bodied human populations but a small endocranial volume similar to australopiths. Cranial morphology of H. naledi is unique, but most similar to early Homo species including Homo erectus, Homo habilis or Homo rudolfensis. While primitive, the dentition is generally small and simple in occlusal morphology. H. naledi has humanlike manipulatory adaptations of the hand and wrist. It also exhibits a humanlike foot and lower limb. These humanlike aspects are contrasted in the postcrania with a more primitive or australopith-like trunk, shoulder, pelvis and proximal femur. Representing at least 15 individuals with most skeletal elements repeated multiple times, this is the largest assemblage of a single species of hominins yet discovered in Africa.
The mechanisms by which eosinophilic inflammation damages the epithelium and contributes to recurrent acute exacerbations in chronic rhinosinusitis (CRS) have not been fully elucidated.
We tested the ...hypotheses that eosinophils deposit toxic major basic protein (MBP) in the mucus and that MBP reaches concentrations able to damage the sinonasal epithelium.
Tissue specimens with mucus attached to the tissue were carefully collected from 22 patients with CRS and examined by using immunofluorescence staining for MBP. This immunofluorescence was digitally analyzed to determine the area covered by MBP and the intensity of the staining (estimating MBP concentration). Levels of MBP in extracts from nasal mucus were quantitated by means of RIA.
Heterogeneous eosinophilia was evident within tissue and mucus specimens. All tissue specimens showed intact eosinophils, but diffuse extracellular MBP deposition, as a marker of eosinophil degranulation, was rare. In contrast, all mucus specimens showed diffuse MBP throughout and abundant diffuse extracellular MBP deposition within clusters of eosinophils. Digitized analyses of MBP immunofluorescence revealed increased area coverage (
P < .0001) in mucus compared with that seen in tissue. Estimated concentrations of MBP within the clusters suggested toxic levels. MBP concentrations in mucus extract reached 11.7 μg/mL; MBP was not detectable in healthy control subjects.
In patients with CRS, eosinophils form clusters in the mucus where they release MBP, which is diffusely deposited on the epithelium, a process not observed in the tissue. Estimated MBP levels far exceed those needed to damage epithelium from the luminal side and could predispose patients with CRS to secondary bacterial infections.
Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by ...the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (TRegs; P = .0006). Monoclonal antibody (mAb)–mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted TRegs (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased TRegs (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti–IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced TReg frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated TReg depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti–IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.
We present an economic evaluation of a recently completed cohort study in which 2054 seniors were screened for atrial fibrillation (AF) in 22 Canadian family practices. Using a Markov model, trial ...and literature data were used to project long-term outcomes and costs associated with 4 AF screening strategies for individuals aged 65 years or older: no screening, screen with 30-second radial manual pulse check (pulse check), screen with a blood pressure machine with AF detection (BP-AF), and screen with a single-lead electrocardiogram (SL-ECG). Costs and outcomes were discounted at 1.5% and the model used a lifetime horizon from a public payer perspective. Compared with no screening, screening for AF in Canadian family practice offices using pulse check or screen with a blood pressure machine with AF detection is the dominant strategy whereas screening with SL-ECG is a highly cost-effective strategy with an incremental cost per quality-adjusted life-year (QALY) gained of CAD$4788. When different screening strategies were compared, screening with pulse check had the lowest expected costs ($202) and screening with SL-ECG had the highest expected costs ($222). The no-screening arm resulted in the lowest number of QALYs (8.74195) whereas pulse check and SL-ECG resulted in the highest expected QALYs (8.74362). Probabilistic analysis confirmed that pulse check had the highest probability of being cost-effective (63%) assuming a willingness to pay of $50,000 per QALY gained. Screening for AF in seniors during routine appointments with Canadian family physicians is a cost-effective strategy compared with no screening. Screening with a pulse check is likely to be the most cost-effective strategy.
Nous présentons une évaluation économique d’une étude de cohorte récemment effectuée dans laquelle 2054 personnes âgées ont passé un examen de dépistage de la fibrillation auriculaire (FA) dans 22 cabinets de médecine familiale canadiens. À l’aide d’un modèle de Markov, nous avons utilisé les données des essais cliniques et de la littérature médicale pour faire des projections à long terme des résultats et des coûts de quatre stratégies de dépistage de la FA chez les personnes âgées de 65 ans et plus : aucun dépistage, dépistage par vérification manuelle du pouls pendant 30 secondes (vérification du pouls), dépistage à l’aide d’un tensiomètre permettant de détecter la FA, et dépistage par électrocardiogramme à dérivation unique (ECG-DU). Les coûts et les résultats ont été actualisés de 1,5 %, et l’horizon temporel utilisé par le modèle était celui de la vie entière du point de vue d’un payeur public. Comparativement à l’absence de dépistage, le dépistage de la FA dans les cabinets de médecine familiale canadiens par vérification du pouls ou à l’aide d’un tensiomètre permettant de détecter la FA est la stratégie prépondérante, tandis que le dépistage par ECG-DU présente un rapport coût-efficacité avantageux avec un coût supplémentaire de l'année de vie ajustée en fonction de la qualité (AVAQ) gagnée de 4788 CAD. La comparaison des différentes stratégies de dépistage a permis de conclure que la vérification du pouls était associée au coût probable le moins élevé (202 $), tandis que l’ECG-DU avait le coût probable le plus élevé (222 $). C’est dans le groupe sans dépistage que le nombre de AVAQ a été le moins élevé (8,74195), tandis que la vérification du pouls et l’ECG-DU ont produit le nombre probable de AVAQ le plus élevé (8,74362). L’analyse probabiliste a confirmé que la vérification du pouls était la stratégie présentant la plus forte probabilité de rapport coût-efficacité élevé (63 %) en supposant que le payeur est disposé à débourser 50 000 $ par AVAQ gagnée. Le dépistage de la FA chez les personnes âgées à l’occasion d’une consultation de routine dans un cabinet de médecine familiale canadien est une stratégie présentant un meilleur rapport coût-efficacité que l’absence de dépistage. Le dépistage par vérification du pouls est probablement la stratégie présentant le meilleur rapport coût-efficacité.
Detection of undiagnosed or undertreated ("actionable") atrial fibrillation could increase the use of appropriate oral anticoagulant therapy and reduce the risk of stroke. We sought to compare newer ...screening technologies with a pulse-check for the detection of atrial fibrillation and to determine whether the detection of actionable atrial fibrillation increases the use of oral anticoagulant agents.
This prospective multicentre cohort study involved 22 primary care clinics. We recruited participants aged 65 years and older who were attending routine appointments. Each participant underwent 3 methods of screening: a 30-second radial pulse-check; single-lead electrocardiogram; and screening by blood pressure machine with atrial fibrillation detection algorithms. Participants who received a positive result on 1 or more test underwent 12-lead electrocardiogram with or withour 24-hour Holter. Screening tests were compared using the McNemar test. Participants with confirmed atrial fibrillation received follow-up at 90 days.
The mean age of participants was 73.7 (± 6.9) years, and 53.4% of participants were female. Of 2171 patients, we had data from all 3 screening tests for 2054 patients. Both single-lead electrocardiogram and the blood pressure device showed superior specificity compared with pulse-check (
< 0.001 for each). Fifty-six patients (2.7%) had confirmed atrial fibrillation: 12 patients had newly detected atrial fibrillation (none of the patients were using anticoagulation agents), and 44 patients had previously diagnosed atrial fibrillation (42 patients were receiving anticoagulant therapy, 2 were not). Thus, 14 patients had actionable atrial fibrillation (0.7%). By 90 days, 77% of patients with actionable atrial fibrillation had started anticoagulant therapy.
Newer screening technologies showed superior specificity compared with a pulse-check. Screening detected undiagnosed or undertreated atrial fibrillation in 0.7% of participants, and 77% started appropriate anticoagulant therapy.
ClinicalTrials.gov, no. NCT02262351.
We hereby report the design and implementation of an Autonomous Microbial Cell Culture and Classification (AMC(3)) system for rapid detection of food pathogens. Traditional food testing methods ...require multistep procedures and long incubation period, and are thus prone to human error. AMC(3) introduces a "one click approach" to the detection and classification of pathogenic bacteria. Once the cultured materials are prepared, all operations are automatic. AMC(3) is an integrated sensor array platform in a microbial fuel cell system composed of a multi-potentiostat, an automated data collection system (Python program, Yocto Maxi-coupler electromechanical relay module) and a powerful classification program. The classification scheme consists of Probabilistic Neural Network (PNN), Support Vector Machines (SVM) and General Regression Neural Network (GRNN) oracle-based system. Differential Pulse Voltammetry (DPV) is performed on standard samples or unknown samples. Then, using preset feature extractions and quality control, accepted data are analyzed by the intelligent classification system. In a typical use, thirty-two extracted features were analyzed to correctly classify the following pathogens: Escherichia coli ATCC#25922, Escherichia coli ATCC#11775, and Staphylococcus epidermidis ATCC#12228. 85.4% accuracy range was recorded for unknown samples, and within a shorter time period than the industry standard of 24 hours.
Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor ...(IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells.
To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses.
A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ).
Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study.
ClinicalTrials.gov NCT00626015.
After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and ...injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.
We have developed GAMMI, an approach to the inference of cis-regulatory modules that employs an evolutionary search to identify modules conserved across a set of DNA sequences from different species. ...This paper describes the motivation and system design for GAMMI, and presents the results of initial tests of the system using artificial sequences with implanted artificial modules. Based on these preliminary tests, GAMMI appears to be a promising approach to the module inference problem.
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