3,845 research outputs found
Population pharmacokinetics and pharmacodynamics of investigational regimens' drugs in the TB-PRACTECAL clinical trial (the PRACTECAL-PKPD study): a prospective nested study protocol in a randomised controlled trial
Introduction Drug-resistant
tuberculosis (TB) remains
a global health threat, with little over 50% of patients
successfully treated. Novel regimens like the ones being
studied in the TB-PRACTECAL
trial are urgently needed.
Understanding anti-TB
drug exposures could explain the
success or failure of these trial regimens. We aim to study
the relationship between the patients’ exposure to anti-TB
drugs in TB-PRACTECAL
investigational regimens and their
treatment outcomes.
Methods and analysis Adults with multidrug-resistant
TB randomised to investigational regimens in TB-PRACTECAL
will be recruited to a nested pharmacokinetic-pharmacodynamic
(PKPD) study. Venous blood samples
will be collected at 0, 2 and 23 hours postdose on day
1 and 0, 6.5 and 23 hours postdose during week 8 to
quantify drug concentrations in plasma. Trough samples
will be collected during week 12, 16, 20 and 24 visits.
Opportunistic samples will be collected during weeks
32 and 72. Drug concentrations will be quantified using
liquid chromatography-tandem
mass spectrometry.
Sputum samples will be collected at baseline, monthly to
week 24 and then every 2 months to week 108 for MICs
and bacillary load quantification. Full blood count, urea
and electrolytes, liver function tests, lipase, ECGs and
ophthalmology examinations will be conducted at least
monthly during treatment.
PK and PKPD models will be developed for each drug with
nonlinear mixed effects methods. Optimal dosing will be
investigated using Monte-Carlo
simulations.
Ethics and dissemination The study has been approved
by the Médecins sans Frontières (MSF) Ethics Review
Board, the LSHTM Ethics Committee, the Belarus RSPCPT
ethics committee and PharmaEthics and the University of
Witwatersrand Human Research ethics committee in South
Africa. Written informed consent will be obtained from all
participants. The study results will be shared with public
health authorities, presented at scientific conferences and
published in a peer-reviewed
journal.
Trial registration number NCT04081077; Pre-results
Tailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms.
Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4+ cells into cytotoxic effectors required the presence of CD8+ cells. Serial exposures to DART led to the exponential expansion of CD4 + and CD8 + cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma
Discovery (theoretical prediction and experimental observation) of a large-gap topological-insulator class with spin-polarized single-Dirac-cone on the surface
Recent theories and experiments have suggested that strong spin-orbit
coupling effects in certain band insulators can give rise to a new phase of
quantum matter, the so-called topological insulator, which can show macroscopic
entanglement effects. Such systems feature two-dimensional surface states whose
electrodynamic properties are described not by the conventional Maxwell
equations but rather by an attached axion field, originally proposed to
describe strongly interacting particles. It has been proposed that a
topological insulator with a single spin-textured Dirac cone interfaced with a
superconductor can form the most elementary unit for performing fault-tolerant
quantum computation. Here we present an angle-resolved photoemission
spectroscopy study and first-principle theoretical calculation-predictions that
reveal the first observation of such a topological state of matter featuring a
single-surface-Dirac-cone realized in the naturally occurring BiSe
class of materials. Our results, supported by our theoretical predictions and
calculations, demonstrate that undoped compound of this class of materials can
serve as the parent matrix compound for the long-sought topological device
where in-plane surface carrier transport would have a purely quantum
topological origin. Our study further suggests that the undoped compound
reached via n-to-p doping should show topological transport phenomena even at
room temperature.Comment: 3 Figures, 18 pages, Submitted to NATURE PHYSICS in December 200
Fertility Desire and Intention of People Living with HIV/AIDS in Tanzania: A call for Restructuring Care and Treatment Services.
Scaling up of antiretroviral therapy (ART) is currently underway in sub-Saharan Africa including, Tanzania, increasing survival of people living with HIV/AIDS (PLWHA). Programmes pay little attention to PLWHA's reproductive health needs. Information on fertility desire and intention would assist in the integration of sexual and reproductive health in routine care and treatment clinics. A cross-sectional study of all PLWHA aged 15--49 residing in Kahe ward in rural Kilimanjaro Tanzania was conducted. Participants were recruited from the community and a local counselling centre located in the ward. Data on socio-demographic, medical and reproductive characteristics were collected through face-to-face interviews. Data were entered and analysed using STATA statistical software. A total of 410 PLWHA with a mean age of 34.2 and constituting 264 (64.4%) females participated. Fifty-one per cent reported to be married/cohabiting, 73.9% lived with their partners and 60.5% were sexually active. The rate of unprotected sex was 69.0% with 12.5% of women reporting to be pregnant at the time of the survey. Further biological children were desired by 37.1% of the participants and lifetime fertility intention was 2.4 children. Increased fertility desire was associated with living and having sex with a partner, HIV disclosure, good perceived health status and CD4 count >=200 cells for both sexes. Reduced desire was associated with havingmore than 2 children among females, divorce or separation, and having a child with the current partner among both males and females. Fertility desire and intention of PLWHA was substantially high though lower than that of the general population in Tanzania. Practice of unprotected sexual intercourse with higher pregnancy rate was observed. Fertility desire was determined by individual perceived health and socio-family related factors. With increasing ART coverage and subsequent improved quality of life of PLWHA, these findings underscore the importance of integrating reproductive health services in the routine care and treatment of HIV/AIDS worldwide. The results also highlight a group of PLWHA with potentially high desire for children who need to be targeted during care
Tuning of Human Modulation Filters Is Carrier-Frequency Dependent
Licensed under the Creative Commons Attribution License
Aharonov-Bohm interference in topological insulator nanoribbons
Topological insulators represent novel phases of quantum matter with an
insulating bulk gap and gapless edges or surface states. The two-dimensional
topological insulator phase was predicted in HgTe quantum wells and confirmed
by transport measurements. Recently, Bi2Se3 and related materials have been
proposed as three-dimensional topological insulators with a single Dirac cone
on the surface and verified by angle-resolved photoemission spectroscopy
experiments. Here, we show unambiguous transport evidence of topological
surface states through periodic quantum interference effects in layered
single-crystalline Bi2Se3 nanoribbons. Pronounced Aharonov-Bohm oscillations in
the magnetoresistance clearly demonstrate the coverage of two-dimensional
electrons on the entire surface, as expected from the topological nature of the
surface states. The dominance of the primary h/e oscillation and its
temperature dependence demonstrate the robustness of these electronic states.
Our results suggest that topological insulator nanoribbons afford novel
promising materials for future spintronic devices at room temperature.Comment: 5 pages, 4 figures, RevTex forma
Examining the effect of Libet clock stimulus parameters on temporal binding
Temporal binding refers to the subjective temporal compression between actions and their outcomes. It is widely used as an implicit measure of sense of agency, that is, the experience of controlling our actions and their consequences. One of the most common measures of temporal binding is the paradigm developed by Haggard, Clark and Kalogeras (2002) based on the Libet clock stimulus. Although widely used, it is not clear how sensitive the temporal binding effect is to the parameters of the clock stimulus. Here, we present five experiments examining the effects of clock speed, number of clock markings and length of the clock hand on binding. Our results show that the magnitude of temporal binding increases with faster clock speeds, whereas clock markings and clock hand length do not significantly influence temporal binding. We discuss the implications of these results
Detecting and predicting neutralization of alemtuzumab responses in MS
Objective: To test the hypothesis that anti-drug antibodies against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance. Methods: Recombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding anti-drug antibodies. Alemtuzumab IgG Alexa-Fluor 488 conjugate was used in a competitive-binding cell based assay to detect neutralizing anti-drug antibodies. The assays were used to retrospectively screen, blinded, banked-serum samples from people with multiple sclerosis (n=32) who had received three or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month post-infusion. Results: The number of individuals showing limited depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for future disease activity. Anti-drug antibody responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred prior to the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Pre-infusion, anti-drug antibody levels predicted limited, post-infusion lymphocyte depletion. Conclusions: Although anti-drug antibodies to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of, lymphocyte depletion and the anti-drug response may be of practical value in patients requiring additional cycles of alemtuzumab. Anti-drug antibody detection may help to inform on re-treatment or switching to another treatment
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