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An ultrasonic sonar-based ranging technique is introduced for measuring full-field railroad crosstie (sleeper) deflections. Tie deflection measurements have numerous applications, such as detecting degrading ballast support conditions and evaluating sleeper or track stiffness. The proposed technique utilizes an array of air-coupled ultrasonic transducers oriented parallel to the tie, capable of “in-motion” contactless inspections. The transducers are used in pulse-echo mode, and the distance between the transducer and the tie surface is computed by tracking the time-of-flight of the reflected waveforms from the tie surface. An adaptive, reference-based cross-correlation operation is used to compute the relative tie deflections. Multiple measurements along the width of the tie allow the measurement of twisting deformations and longitudinal deflections (3D deflections). Computer vision-based image classification techniques are also utilized for demarcating tie boundaries and tracking the spatial location of measurements along the direction of train movement. Results from field tests, conducted at walking speed at a BNSF train yard in San Diego, CA, with a loaded train car are presented. The tie deflection accuracy and repeatability analyses indicate the potential of the technique to extract full-field tie deflections in a non-contact manner. Further developments are needed to enable measurements at higher speeds.

To address limitations of the currently used reduced-intensity/myeloablative conditioning (RIC/MAC) classification scheme we aimed to develop a tool that can capture more standardized the conditioning intensity of allogeneic hematopoietic cell transplantation (HCT). We assigned intensity weight scores for frequently used conditioning regimen components and used their sum to generate the transplant conditioning intensity (TCI) score. We retrospectively tested the impact of TCI on 8255 adult (45–65 years) acute myeloid leukemia patients who underwent HCT in first complete remission. A Cox model for early nonrelapse mortality (NRM) yielded a 3-group TCI risk scheme (low, intermediate, high) with respective TCI scores of [1–2], [2.5–3.5] and [4–6]. On multivariate modeling, TCI grouping was highly and better predictive for early (day 100 and 180) NRM, 2-year NRM and relapse (REL) as compared with the RIC/MAC classification. Validation was done on 200 bootstrap samples. Moreover, TCI scoring enabled the identification of a distinct subgroup of RIC and MAC conditioning regimens with an intermediate TCI [2.5–3.5] score that had identical outcomes and which are frequently referred as “reduced toxicity conditioning”. TCI scheme provides an improvement of the RIC/MAC classification. We propose TCI as a new tool to define and measure the conditioning regimen intensity.

General methods to prepare chiral pyridine derivatives are greatly sought after due to their significance in medicinal chemistry. Here, we report highly enantioselective catalytic transformations of poorly reactive β-substituted alkenyl pyridines to access a wide range of alkylated chiral pyridines. The simple methodology involves reactivity enhancement via Lewis acid (LA) activation, the use of readily available and highly reactive Grignard reagents, and a copper-chiral diphosphine ligand catalyst. Apart from allowing the introduction of different linear, branched, cyclic, and functionalised alkyl chains at the β-position of alkenyl pyridines, the catalytic system also shows high functional group tolerance. Chiral pyridines are valuable building blocks in medicinal chemistry applications. Here, the authors report the copper-catalysed Lewis acid-assisted asymmetric alkylation of β-substituted alkenyl pyridines with Grignard reagents affording chiral pyridines with excellent enantioselectivity.

Toxic tumour syndrome (TTS) is a particularly aggressive form of secondary vasculopathy occurring after radiation therapy of uveal melanoma due to the persistence of the necrotic tumour mass inside the eye. The development of TTS confers a particularly unfavourable functional and anatomical ocular prognosis, ultimately requiring enucleation in most cases if untreated. Vitreoretinal (VR) surgery has been successfully applied for treatment and prevention of TTS using both resecting and non-resecting techniques. In this systematic review, we aim to define characteristics of uveal melanomas benefiting the most from secondary VR surgery and to outline the optimal type and timing of VR intervention in such cases. Analysis of the literature reveals that endoresection should be performed within 3 months after radiotherapy to tumours thicker than 7 mm and with a largest basal diameter between 8 mm and 15 mm with post-equatorial location, especially after proton beam treatment. Alternatively, endodrainage remains a valid therapeutic option in eyes with macula-off retinal detachment, tumour diameter larger than 15 mm or ciliary body involvement. VR surgery can be successful in the management of TTS following radiotherapy for uveal melanoma when timing and indication are appropriately evaluated.

This paper discusses a non-destructive evaluation (NDE) technique for the detection of damage in composite aircraft structures following high energy wide area blunt impact (HEWABI) from ground service equipment (GSE), such as heavy cargo loaders and other heavy equipment. The test structures typically include skin, co-cured stringers, and C-frames that are bolt-connected onto the skin with shear ties. The inspection exploits the waveguide geometry of these structures by utilizing ultrasonic guided waves and a line scan approach. Both a contact prototype and a non-contact prototype were developed and tested on realistic test panels subjected to impact in the laboratory. The results are presented in terms of receiver operating characteristic curves that show excellent probability of detection with low false alarm rates for defects located in the panel skin and stringers.

Upfront high-dose therapy with melphalan (HDM) followed by autologous stem cell transplantation (ASCT) has established itself as a core treatment for newly diagnosed multiple myeloma (NDMM) patients in the past 30 years. Induction therapy, HDM-ASCT, and subsequent consolidation and maintenance therapy comprise the current fundamental framework for MM treatment. The introduction of anti-CD38 monoclonal antibodies such as daratumumab and isatuximab has changed the treatment paradigm for transplant-eligible NDMM patients in that quadruplets have become the new standard induction therapy. The treatment landscape of MM is undergoing a transformative shift with the introduction of potent new immunotherapies, such as chimeric antigen receptor (CAR)-T cells and bispecific antibodies (BsAbs), which are currently used in the relapsed/refractory setting (RRMM) and are already being tested in the NDMM. This review will focus on the incorporation of immunotherapy in the treatment scenario of NDMM patients eligible for ASCT.

Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma.

Age-related hearing loss (ARHL) and dementia are two highly prevalent conditions in the adult population. Recent studies have suggested that hearing loss is independently associated with poorer cognitive functioning. The aim of this study was to evaluate the prevalence of ARHL and cognitive impairment in a large sample of subjects older than 65 years and to correlate hearing function with cognitive function. A total of 488 subjects older than 65 years (mean age 72.8 years) participating in the Great Age Study underwent a complete audiological, neurological and neuropsychological evaluation as part of a multidisciplinary assessment. The prevalence of a hearing loss greater than 25 dB HL was 64.1%, of Central Auditory Processing Disorder (CAPD) was 14.3 and 25.3% of the subjects reported a hearing handicap as reported on the Hearing Handicap Inventory for the Elderly Screening Version questionnaire. Multiple logistic regression analysis corrected for gender, age and education duration showed that mild cognitive impairment (MCI) was significantly associated with hearing impairment (CAPD and hearing threshold; odds ratio 1.6, p = 0.05) and that Alzheimer's disease (AD) was significantly associated with CAPD (odds ratio 4.2, p = 0.05). Given that up to 80% of patients affected by MCI convert to AD, adding auditory tests to a screening cognitive battery might have value in the early diagnosis of cognitive decline.

Ravulizumab is a second-generation C5i engineered from eculizumab to achieve immediate, complete, and sustained inhibition of terminal complement activity in PNH. The REACTION observational cohort study describes the effectiveness and tolerability of ravulizumab in Italian patients who were previously treated with eculizumab. Eighty-one PNH patients were enrolled in this study. The primary endpoint was the percentage change in lactate dehydrogenase (LDH) from baseline to the end of observation (52 weeks follow-up). Among secondary endpoints, transfusion avoidance, breakthrough hemolysis (BTH) and patients’ quality of life (QoL) were evaluated. The median (25–75 percentiles) percentage change in LDH at 52 weeks follow-up was -2.6 (-11.5–13.4) U/L, with 92.3% of the patients presenting LDH within or < 1.5 × upper limit of normal (ULN). Overall, 20 (25.0%) patients required transfusion during the eculizumab period and 15 (18.8%) during the ravulizumab. Seven BTH events were observed, 5 during eculizumab period and 2 (triggered by other medical conditions) during ravulizumab, suggesting the reduction of pharmacokinetic BTH during ravulizumab treatment. EORTC-QLQ-C30 and FACIT-Fatigue scores were similar to the general population, and patients’ preference indicated ravulizumab as the favorite treatment. The REACTION study confirmed the effectiveness of ravulizumab in maintaining stable disease and hemolysis control in the real-world setting. Clinical trial registration. NCT05274633, 02-Mar-2022.

Background The role of autologous hematopoietic stem cell transplantation (AHSCT) in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-ALL) remains controversial. The aim of this retrospective study was to analyze results of AHSCT and to identify prognostic factors. Methods Overall, 700 patients transplanted in first complete remission between the years 1999-2020 were included. Median patient age was 31.9 years (68% male). B-cell precursor ALL (BCP-ALL) and T-cell precursor ALL (TCP-ALL) was diagnosed in 35% and 65%, respectively. Among 190 patients with available data, negative minimal residual disease (MRD) status was reported in 167 (88%) cases. Results The probabilities of overall survival (OS) and leukemia-free survival (LFS) at 2 years were 67% and 56%; relapse incidence (RI) and non-relapse mortality (NRM) were 39% and 5%, respectively. TCP-ALL was associated with lower RI (41% vs. 56%, p= 0.001), higher LFS (52% vs. 38%, p= 0.002) and OS (58% vs 45%, p= 0.001) at 5 years when compared to BCP-ALL. In the multivariate analysis, TCP-ALL and longer interval from diagnosis do AHSCT were associated with reduced risk of relapse (HR 0.7, p= 0.006 and HR=0.95, p= 0.018), better LFS (HR=0.76, p= 0.02 and HR=0.95, p= 0.01) and OS (HR=0.75, p= 0.024 and HR=0.94, p= 0.013, respectively). Increasing patient age was associated with higher NRM (HR=1.49, p <0.0001), worse LFS (HR=1.1, p= 0.01) and OS (HR=1.17, p= 0.0001). Conclusions Autologous hematopoietic stem cell transplantation is relatively safe option of late treatment intensification in adults with Ph- ALL. It may be a valuable option especially in patients with TCP-ALL, however it should be proved in prospective clinical trials.