The majority of low field Magnetic Resonance (MR) analyses rely on T
lifetime measurements. Modification of the T
measurement to include a T
dimension has made the T
-T
measurement a very powerful ...analytical technique. The T
-T
measurement is uniquely well suited to characterization of different spin populations in porous materials, such as fluid bearing reservoir rocks, and in soft biopolymer materials, for example foods. However, the T
-T
measurement is challenging or impossible if the T
relaxation lifetime, or a component lifetime, is short-lived and the signal unobservable in an echo measurement. This occurs in many important classes of materials. A short lifetime T
will not however, in general, preclude observation of a free induction decay with signal decay governed by T
*. As outlined in this paper a T
-T
* measurement is a useful analog to the T
-T
experiment. T
-T
* measurement enables one to differentiate species as a function of T
* in one dimension and T
in the other dimension. Monitoring changes of the T
-T
* coordinate, and associated signal intensity changes, has the potential to reveal structural changes in materials evolving in time. These methods may also be employed to discriminate and identify solid-like species present in static samples. The T
-T
* measurement is very general in application, but in this paper we focus on cement-based mortars to develop and illustrate the essential ideas. T
-T
* results show a multi-modal behaviour of the MR signal lifetimes, T
and T
*, in mortar samples under study, indicating at least two different water populations. The short T
* lifetime was assigned to interlayer water (water between C-S-H layers) where the associated T
is also short lived. The longer T
* lifetime was assigned to water in the pore space, where T
is also longer lived. In addition to mortar samples we also show application of the method to a crystalline organic species, o-phenylenediamine, which features Sinc Gaussian and exponential decays of transverse magnetization.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly transmissible human pathogen. Infection is often misdiagnosed, in part because of poor availability of data in disease-endemic areas. We ...sampled 150 apparently healthy ruminants throughout Nigeria for virus seropositivity and detected virus-specific IgG in cattle (24%) and goats (2%), highlighting the need for further investigations.
Idecabtagene vicleucel (ide-cel) is an autologous B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy approved for relapsed/refractory multiple myeloma (RRMM) on the basis of ...the phase II pivotal KarMMa trial, which demonstrated best overall and ≥ complete response rates of 73% and 33%, respectively. We report clinical outcomes with standard-of-care (SOC) ide-cel under the commercial Food and Drug Administration label.
Data were retrospectively collected from patients with RRMM who underwent leukapheresis as of February 28, 2022, at 11 US institutions with intent to receive SOC ide-cel. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines and managed according to each institution's policies. Responses were graded on the basis of the International Myeloma Working Group response criteria.
One hundred fifty-nine of 196 leukapheresed patients received ide-cel by data cutoff. One hundred twenty (75%) infused patients would have been ineligible for participation in the KarMMa clinical trial because of comorbidities at the time of leukapheresis. Any grade and grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 82/3% and 18/6%, respectively. Best overall and ≥ complete response rates were 84% and 42%, respectively. At a median follow-up of 6.1 months from chimeric antigen receptor T infusion, the median progression-free survival was 8.5 months (95% CI, 6.5 to not reached) and the median overall survival was 12.5 months (95% CI, 11.3 to not reached). Patients with previous exposure to B-cell maturation antigen-targeted therapy, high-risk cytogenetics, Eastern Cooperative Oncology Group performance status ≥ 2 at lymphodepletion, and younger age had inferior progression-free survival on multivariable analysis.
The safety and efficacy of ide-cel in patients with RRMM in the SOC setting were comparable with those in the phase II pivotal KarMMa trial despite most patients (75%) not meeting trial eligibility criteria.
In 2015, the laboratory at the Ebola treatment center in Coyah, Guinea, confirmed Ebola virus disease (EVD) in 286 patients. The cycle threshold (Ct) of an Ebola virus-specific reverse ...transcription-polymerase chain reaction assay and 13 blood chemistry parameters were measured on admission and during hospitalization. Favipiravir treatment was offered to patients with EVD on a compassionate-use basis.
To reduce biases in the raw field data, we carefully selected 163 of 286 patients with EVD for a retrospective study to assess associations between potential risk factors, alterations in blood chemistry findings, favipiravir treatment, and outcome.
The case-fatality rate in favipiravir-treated patients was lower than in untreated patients (42.5% 31 of 73 vs 57.8% 52 of 90; P = .053 by univariate analysis). In multivariate regression analysis, a higher Ct and a younger age were associated with survival (P < .001), while favipiravir treatment showed no statistically significant effect (P = .11). However, Kaplan-Meier analysis indicated a longer survival time in the favipiravir-treated group (P = .015). The study also showed characteristic changes in blood chemistry findings in patients who died, compared with survivors.
Consistent with the JIKI trial, this retrospective study revealed a trend toward improved survival in favipiravir- treated patients; however, the effect of treatment was not statistically significant, except for its influence on survival time.
The Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths. Genome sequencing in viral outbreaks is desirable to ...characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 × 10(-3) and 1.42 × 10(-3) mutations per site per year. This is equivalent to 16-27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic. Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions. Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities. To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15-60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.
Abstract
Background
The largest West African monkeypox outbreak began September 2017, in Nigeria. Four individuals traveling from Nigeria to the United Kingdom (n = 2), Israel (n = 1), and Singapore ...(n = 1) became the first human monkeypox cases exported from Africa, and a related nosocomial transmission event in the United Kingdom became the first confirmed human-to-human monkeypox transmission event outside of Africa.
Methods
Epidemiological and molecular data for exported and Nigerian cases were analyzed jointly to better understand the exportations in the temporal and geographic context of the outbreak.
Results
Isolates from all travelers and a Bayelsa case shared a most recent common ancestor and traveled to Bayelsa, Delta, or Rivers states. Genetic variation for this cluster was lower than would be expected from a random sampling of genomes from this outbreak, but data did not support direct links between travelers.
Conclusions
Monophyly of exportation cases and the Bayelsa sample, along with the intermediate levels of genetic variation, suggest a small pool of related isolates is the likely source for the exported infections. This may be the result of the level of genetic variation present in monkeypox isolates circulating within the contiguous region of Bayelsa, Delta, and Rivers states, or another more restricted, yet unidentified source pool.
Molecular and epidemiological data from multiple human monkeypox exportations from Nigeria show no direct linkage between travelers; however, limited genetic variation among sequenced viruses point to a possible common source pool or independently acquired infections within a small geographic area.
In the event of an unpredictable viral outbreak requiring high/maximum biosafety containment facilities (i.e. BSL3 and BSL4), X-ray irradiation has the potential to relieve pressures on conventional ...diagnostic bottlenecks and expediate work at lower containment. Guided by Monte Carlo modelling and in vitro 1-log
decimal-reduction value (D-value) predictions, the X-ray photon energies required for the effective inactivation of zoonotic viruses belonging to the medically important families of Flaviviridae, Nairoviridae, Phenuiviridae and Togaviridae are demonstrated. Specifically, it is shown that an optimized irradiation approach is attractive for use in a multitude of downstream detection and functional assays, as it preserves key biochemical and immunological properties. This study provides evidence that X-ray irradiation can support emergency preparedness, outbreak response and front-line diagnostics in a safe, reproducible and scalable manner pertinent to operations that are otherwise restricted to higher containment BSL3 or BSL4 laboratories.
Betaine is a bioactive peptide whose beneficial effects on diabetes complications have been considered, previously. The present study aimed to investigate the possible protective effects of betaine ...against hyperglycemia-induced steroidogenesis impairment and apoptosis in mice granulosa cells. Ovarian granulosa cells were isolated from C57/BL6 mice and cultured in steroidogenesis medium (SM) containing 30 ng/ml FSH and 0.5 µM testosterone. The cells were cultured in SM containing low (5 mM) or high (30 mM) glucose concentrations for 24 h in the presence or absence of betaine (5 mM). At the end of the experiment, estradiol and progesterone were measured by ELISA in the culture medium. Expression of apoptosis and steroidogenesis associated genes and caspase-3 activity were determined by qRT-PCR and colorimetric assays, respectively. Exposure of mice granulosa cells to high glucose concentration inhibited the steroidogenesis by decreasing estradiol and progesterone secretion and downregulation of steroidogenesis-related genes including 3βHSD, Cyp11a1, Cyp19a1, and StAR. Betaine treatment could ameliorate the steroidogenesis impairment at molecular and biochemical levels. High glucose concentration also enhanced apoptosis in mice granulosa cells that were characterized by elevation of caspase-3 activity, upregulation of bax gene and downregulation of bcl2 gene. Betaine treatment could attenuate the apoptotic-related changes induced by high glucose concentration in granulosa cells. According to the results of the present study, betaine could ameliorate the adverse effects of hyperglycemia on the physiological function of ovarian granulosa cells. The results highlight the potential role of betaine for the intervention of ovarian dysfunction in diabetic patients.
Abbreviations: AABA: Betaine-α-aminobutyric acid; AGEs: Advanced glycation end products; bax: bcl2 Associated X; bcl2: B-cell lymphoma 2; AMPK: AMP-activated protein kinase; BHMT: Betaine homocysteine methyltransferase; C/EBP: CCAAT-enhancer-binding proteins; Cyp11a1: Cholesterol side-chain cleavage cytochrome P450; Cyp19a1: Cytochrome P450 aromatase; DM: Diabetes mellitus; E2: Estradiol; ERS: Endoplasmic reticulum stress; GCs: Granulosa cells; GLUT: Glucose transporter; FSH: Follicle-stimulating hormone; 3βHSD: 3β-hydroxysteroid dehydrogenase; IL-1β: interleukin-1ß; LH: Luteinizing hormone; MDCK: Madin-Darby Canine Kidney cell; MT: Methionine synthase, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NLRP3: NLR Family Pyrin Domain Containing 3; NF-κB: Nuclear factor κB; P4: Progesterone; ROS: Reactive oxygen species; SGLT: Sodium dependent glucose transporter; SLC7A6: Solute Carrier Family 7 Member 6; StAR: Steroidogenic acute regulatory protein; STZ: Streptozotocin; Tumor necrosis factor α: TNF-α; TXNIP: Thioredoxin interacting protein.
We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell ...therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.
Background. Patients with unilateral breast cancer carrying pathogenic variants in BRCA1/2 have the option to undergo contralateral prophylactic mastectomy (CPM). However, differences in CPM use and ...survival outcomes following CPM are poorly understood in this high-risk population, in part due to a lack of data from contemporary clinical cohorts. The objective of this study was to evaluate post-CPM overall survival (OS) and related racial/ethnic differences in a contemporary clinical cohort. Methods. We retrospectively reviewed the medical records of women with a personal history of unilateral breast cancer carrying pathogenic variants in BRCA1/2 who were diagnosed between 1996 and 2012. Genetic test results, self-reported demographic characteristics, and clinical factors were abstracted from electronic medical records. Results. Of 144 BRCA-positive patients, the majority were White (79.2%, n = 114). Overall, 56.1% (n = 81) of all BRCA1/2 carriers chose to undergo CPM, with no racial/ethnic difference in CPM election (p = 0.78). Of 81 patients who underwent CPM, there is strong evidence of a difference in survival between the racial/ethnic groups, with White patients having the highest OS compared to non-White patients (p = 0.001). Of the 63 patients who did not undergo CPM, there is no racial/ethnic difference in overall survival (p = 0.61). In multivariable cox regression, adjusted for demographic and clinical characteristics, OS was significantly lower among non-Whites than in Whites (HR = 0.39, p = 0.04). Conclusions. Evaluation of a contemporary clinical cohort of BRCA-positive women with unilateral breast cancer showed no racial/ethnic difference in CPM use, but there was a significant difference in post-CPM overall survival.
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