Miracle-dz/UniFAR-FTUs huggingface dataset:
Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy.

Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease-negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials. gov as #NCT01865617.
Visualizing the iron atom exchange front in the Fe(II)-catalyzed recrystallization of goethite by atom probe tomography

Significance The bioavailability of iron in the environment, and coupled metals, nutrients, and contaminants, depends on the stability of common Fe(III) minerals such as goethite (FeOOH) and hematite (Fe2O3). At redox boundaries, iron isotopic tracer studies suggest that interaction with aqueous Fe(II) creates dynamic conditions of atom exchange (AE). However, mechanistic models have not advanced beyond speculation, because of the challenges of mapping AE fronts recorded in isotopic distributions in individual nanoscale crystallites. Here we demonstrate successful use of 3D atom probe tomography for this purpose. The penetration depth, spatial heterogeneity, and ties to mineral defects are visualized, helping constrain mechanistic models and setting a precedent for detailed interrogation of iron redox cycling in the environment. The autocatalytic redox interaction between aqueous Fe(II) and Fe(III)-(oxyhydr)oxide minerals such as goethite and hematite leads to rapid recrystallization marked, in principle, by an atom exchange (AE) front, according to bulk iron isotopic tracer studies. However, direct evidence for this AE front has been elusive given the analytical challenges of mass-resolved imaging at the nanoscale on individual crystallites. We report successful isolation and characterization of the AE front in goethite microrods by 3D atom probe tomography (APT). The microrods were reacted with Fe(II) enriched in tracer 57Fe at conditions consistent with prior bulk studies. APT analyses and 3D reconstructions on cross-sections of the microrods reveal an AE front that is spatially heterogeneous, at times penetrating several nanometers into the lattice, in a manner consistent with defect-accelerated exchange. Evidence for exchange along microstructural domain boundaries was also found, suggesting another important link between exchange extent and initial defect content. The findings provide an unprecedented view into the spatial and temporal characteristics of Fe(II)-catalyzed recrystallization at the atomic scale, and substantiate speculation regarding the role of defects controlling the dynamics of electron transfer and AE interaction at this important redox interface.
Effects of antiarrhythmics on the electrical restitution in perfused guinea‐pig heart are critically determined by the applied cardiac pacing protocol

What is the central question of this study? Are modifications in the restitution of ventricular action potential duration induced by antiarrhythmic drugs the same when assessed with premature extrastimulus application at variable coupling intervals (the standard stimulation protocol) and with steady state pacing at variable rates (the dynamic stimulation protocol)? What is the main finding and its importance? With class I and class III antiarrhythmics, the effects on electrical restitution determined with the standard stimulation protocol dissociate from those obtained during dynamic pacing. These findings indicate a limited value of the electrical restitution assessments based on extrasystolic stimulations alone, as performed in the clinical studies, in estimating the outcomes of antiarrhythmic drug therapies.
Anterior Intraparietal Area: A Hub in the Observed Manipulative Action Network

Abstract Current knowledge regarding the processing of observed manipulative actions (OMAs) (e.g., grasping, dragging, or dropping) is limited to grasping and underlying neural circuitry remains controversial. Here, we addressed these issues by combining chronic neuronal recordings along the anteroposterior extent of monkeys’ anterior intraparietal (AIP) area with tracer injections into the recorded sites. We found robust neural selectivity for 7 distinct OMAs, particularly in the posterior part of AIP (pAIP), where it was associated with motor coding of grip type and own-hand visual feedback. This cluster of functional properties appears to be specifically grounded in stronger direct connections of pAIP with the temporal regions of the ventral visual stream and the prefrontal cortex, as connections with skeletomotor related areas and regions of the dorsal visual stream exhibited opposite or no rostrocaudal gradients. Temporal and prefrontal areas may provide visual and contextual information relevant for manipulative action processing. These results revise existing models of the action observation network, suggesting that pAIP constitutes a parietal hub for routing information about OMA identity to the other nodes of the network.
Comparison of retention and stability of implant-retained overdentures based upon implant number and distribution.

PURPOSE The purpose of this investigation was to evaluate the effects of number and distribution of implants upon in vitro dislodging forces to a simulated implant-supported overdenture and to examine differences between several different attachment systems. MATERIALS AND METHODS An experiment was undertaken utilizing a model simulating a mandibular edentulous ridge with dental implants in positions on the model approximating tooth positions in the natural dentition. A cobalt-chromium-cast testing framework was used to measure the peak load required to disconnect an attachment. Four different types of commercially available attachments were used in various positions on the model in sequence to evaluate the effects of retention and stability of overdentures based on implant number and distribution: (1) ERA, (2) O-Ring, (3) Locator, and (4) Ball. For each group, 10 measurements were made of peak dislodging forces. Means were calculated and differences among the systems, directions, and groups were identified using a repeated measured analysis of variance (α = .05). RESULTS The interactions between the attachment system, direction of force, and implant number and distribution were statistically significant. Vertical dislodging forces of the simulated overdenture prosthesis increased with additional widely spaced implants. Oblique dislodging forces of the simulated prosthesis increased with additional widely spaced implants except in the two-implant model with all attachments, and in the four-implant groups with Locator attachments. Anteroposterior dislodging forces of a simulated overdenture prosthesis increased with additional widely spaced implants except in the four-implant groups with Ball and Locator attachments. Ball attachments reported the highest levels of retention and stability followed by Locator, O-Ring, and ERA. CONCLUSIONS Within the limitations of this study, retention and stability of an implant overdenture prosthesis are significantly affected by implant number, implant distribution, and abutment type.
Low‐dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD‐FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience

Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. The fludarabine, cyclophosphamide, and rituximab (FCR) regimen is considered the treatment of choice for young fit patients with CLL; however, this combination is toxic for older patients. At the time this study was first planned and initiated, there was no standard chemo‐immunotherapy regimen regarded as standard therapy for the less fit elderly patient with CLL. Here, we conducted a single‐arm, phase II trial to examine the efficacy and safety of lower‐dose fludarabine and cyclophosphamide combined with a standard dose of rituximab (LD‐FCR) in elderly patients with previously untreated CLL. Forty patients received LD‐FCR and were included in the efficacy analysis. Two patients treated with FC alone were only included in the safety analysis. The median age was 72.7 years (range, 65.0 to 85.0). The overall response and complete response rates were 67.5% and 42.5%, respectively. Median progression‐free survival (PFS) was 35.5 months (95% CI, 29.27‐41.67). Two patients (4.8%) died during the study period. Hematological toxicities and infections were the most common complications encountered; grade 3 to 4 treatment‐related neutropenia occurred in 20 (47.6%) patients. During the entire study follow‐up, 26 patients (61.9%) had all grades of infection including six (14.3%) with neutropenic fever and eight (19%) with grade 3 to 4 non‐neutropenic infections. In conclusion, LD‐FCR is an effective and relatively safe regimen for previously untreated patients with CLL. It has the advantage of being both “time and cost limited” and, even in the era of novel agents, can still be considered when planning treatment for elderly patients without high‐risk biomarkers. However, recent results in fit elderly patients using the combination of bendamustine and rituximab which have achieved longer PFS with good safety profile must be taken into consideration in this regard.
Magnesium but not nicotinamide prevents vascular calcification in experimental uraemia.

Background Optimal phosphate control is an unmet need in chronic kidney disease (CKD). High serum phosphate increases calcification burden and is associated with mortality and cardiovascular disease in CKD. Nicotinamide (NA) alone or in combination with calcium-free phosphate binders might be a strategy to reduce phosphate levels and calcification and thus impact cardiovascular disease in CKD. Methods We studied the effect of NA alone and in combination with magnesium carbonate (MgCO3) as a potential novel treatment strategy. CKD was induced in dilute brown non-agouti/2 mice by subtotal nephrectomy followed by a high-phosphate diet (HP) and 7 weeks of treatment with NA, MgCO3 or their combination. Control mice underwent subtotal nephrectomy and received an HP or underwent sham surgery and received standard chow plus NA. Results CKD mice showed increased serum fibroblast growth factor 23 and calcium-phosphate product that was normalized by all treatment regimes. NA alone increased soft tissue and vascular calcification, whereas any treatment with MgCO3 significantly reduced calcification severity in CKD. While MgCO3 supplementation alone resulted in decreased calcification severity, it resulted in increased intestinal expression of the phosphate transporters type II sodium-dependent phosphate transporter 1 (Pit-1). Combined therapy of MgCO3 and NA reduced tissue calcification and normalized expression levels of intestinal phosphate transporter proteins. Conclusions In conclusion, the data indicate that NA increases while MgCO3 reduces ectopic calcification severity. Augmented expression of intestinal phosphate transporters by MgCO3 treatment was abolished by the addition of NA. However, the clinical relevance of the latter remains to be explored. Importantly, the data suggest no benefit of NA regarding treatment of calcification in addition to MgCO3.
Coding sequences of sarcoplasmic reticulum calcium ATPase regulatory peptides and expression of calcium regulatory genes in recurrent exertional rhabdomyolysis

Background Sarcolipin (SLN), myoregulin (MRLN), and dwarf open reading frame (DWORF) are transmembrane regulators of the sarcoplasmic reticulum calcium transporting ATPase (SERCA) that we hypothesized played a role in recurrent exertional rhabdomyolysis (RER). Objectives Compare coding sequences of SLN, MRLN, DWORF across species and between RER and control horses. Compare expression of muscle Ca2+ regulatory genes between RER and control horses. Animals Twenty Thoroughbreds (TB), 5 Standardbreds (STD), 6 Quarter Horses (QH) with RER and 39 breed‐matched controls. Methods Sanger sequencing of SERCA regulatory genes with comparison of amino acid (AA) sequences among control, RER horses, human, mouse, and rabbit reference genomes. In RER and control gluteal muscle, quantitative real‐time polymerase chain reaction of SERCA regulatory peptides, the calcium release channel (RYR1), and its accessory proteins calsequestrin (CASQ1), and calstabin (FKBP1A). Results The SLN gene was the highest expressed horse SERCA regulatory gene with a uniquely truncated AA sequence (29 versus 31) versus other species. Coding sequences of SLN, MRLN, and DWORF were identical in RER and control horses. A sex‐by‐phenotype effect occurred with lower CASQ1 expression in RER males versus control males (P < .001) and RER females (P = .05) and higher FKBP1A (P = .01) expression in RER males versus control males. Conclusions and Clinical Importance The SLN gene encodes a uniquely truncated peptide in the horse versus other species. Variants in the coding sequence of SLN, MLRN, or DWORF were not associated with RER. Males with RER have differential gene expression that could reflect adaptations to stabilize RYR1.
Depressive symptoms in inflammatory bowel disease: an extraintestinal manifestation of inflammation?

Depressive symptoms are reported by more than 20% of people with inflammatory bowel disease (IBD), while sleep difficulties and fatigue are even more common. Co‐morbid depressive symptoms predict a poor IBD course, including increased risk of relapse and surgery, which is inconsistently improved by psychological treatments. Rather than being distinct systems, there is compelling evidence for bidirectional communication between gut and brain, driven by neural, metabolic, endocrine and inflammatory mediators. An emerging concept is that depressive symptoms may be mechanistically linked to excess inflammation and dysregulation of the gut–brain axis. Given the close link between the intestinal microbiota and host immune responses, patients prone to shifts in their intestinal microbiome, including smokers, those with poor diet and early life stress, may be exposed to exaggerated immune responses. Excess inflammation is associated with brain changes (depressive symptoms, fatigue, sleep difficulties) and worsening gastrointestinal symptoms, which are exacerbated by psychological distress. Equally, treatments both for depressive symptoms and IBD provide opportunities to break this cycle by reducing the causes and effects of inflammation. As well as addressing potential risk factors such as smoking and diet, treatments to alter the microbiome may reduce depressive symptoms. Observational evidence suggests that anti‐inflammatory treatments for IBD may improve co‐morbid depressive symptoms correlating with reduction in inflammation. With a growing range of treatments targeting inflammation centrally, peripherally and in the gut, IBD provides a unique model to understand the interplay between brain and gut in the pathogenesis of depressive symptoms, both in IBD and in the whole population.
Proposal of a new way to evaluate the external sphincter function prior male sling surgey

ABSTRACT Objective: To propose a new way to objectively evaluate the external sphincter function prior to male sling surgery. Materials and Methods: We evaluated the pre-operative sphincter function throughout sphincter pressure at rest (SPAR) and sphincter pressure under contraction (SPUC) obtained throughout urethral profilometry profile (UPP) of 10 consecutive patients (age range, 54-79 years) treated with the retrourethral transobturator sling (RTS) for stress urinary incontinence (SUI) because of prostate surgery. The primary endpoint for surgery success rate was post-operative pad weight test. This was correlated to pre-operative pad test, RT, SPAR and SPUC. Post-operatively patients were classified as continent (no pad use) and those who still were incontinent. Results: Mean SPUC in the continent and incontinent group was respectively 188 + 8.8 (median 185.1, range 181 to 201) and 96.9 + 49.4 (median 109.9, range 35.6 to 163.6) (P = 0.008). Mean 24-hour pad test was 151 + 84.2gm (median 140, range 80 to 245) and 973 + 337.1gm (median 1940, range 550 to 1200) in post-operative continent and incontinent groups respectively (P = 0.008). The repositioning test (RT) was positive in all continent patients except one. The RT was also positive in three incontinence patients (false positive). In all post-operative continent patients SPUC was higher than 180cmH2O and pre-operative pad test was less than 245gm. Conclusions: SPUC seems to be a way for optimizing the sphincter evaluation as well to become a useful tool for patient selection prior to RTS surgery.
A systematic review and meta-analysis on the effect of reminiscence therapy for people with dementia

ABSTRACT Background: The main objective of this study was to conduct a meta-analysis to identify the effects of reminiscence therapy in people with dementia (PWD). Methods: A systematic search of randomized controlled trials (RCTs) was conducted using bibliographic databases. A total of 157 original published studies were identified in the search, and 24 complete articles were included in the final review to check for the level of evidence. Two of the study authors independently assessed the quality of the included studies using the “Risk of Bias” (ROB) tool developed by the Cochrane Collaboration. Depression, quality of life, and behavioral and psychological symptoms of dementia (BPSD) were selected to measure the effect of reminiscence therapy. To determine the effects of reminiscence therapy on these variables, each individual study was analyzed using Comprehensive Meta-Analysis Software® (Biostat, Englewood, NJ, USA). Results: The overall effect size was presented using standardized mean differences (SMDs) and 95% confidence intervals. Cohen’s d effect size for depression was −0.541 (95% CI: −0.847 to −0.234, Z = −3.730, p<0.001), indicating that depression was significantly reduced in the reminiscence group compared to the control group. Increased quality of life and decreased BPSD were also found in the reminiscence group compared to the control group. Conclusion: Reminiscence therapy has a moderate effect on depression and can be broadly used to decrease depression as an alternative to antipsychotics, which can have harmful side effects and high cost.
L-carnitine does not ameliorate asparaginase-associated hepatotoxicity in a C57BL6 mouse model

Asparaginase-associated hepatotoxicity (AAH) is common in patients treated for acute lymphoblastic leukemia (ALL), usually manifested as hyperbilirubinemia, transaminitis, and steatosis, and prolonged prothrombin time [1]. It represents a significant cause of treatment delay and interruption, and limits the use of asparaginase in adults despite its benefit on treatment outcome [2,3]. Currently, there are no standard guidelines for the management of AAH in ALL patients. In the past several years, the potential of L-carnitine as a solution for AAH has begun to emerge in literature, with over twenty reported cases attributing the resolution of AAH to its administration [4–9]. L-carnitine is an endogenous quaternary ammonium compound which transports fatty acids into mitochondria under the catalyzation of carnitine palmitoyltransferases for b-oxidation, and has proved effective in the context of hepatotoxicity induced by valproate and anti-tuberculosis medications [10,11]. However, the mechanism underlying the pathogenesis of AAH remains unclear, although the involvement of oxidative stress has been proposed [12]. Preclinical data on asparaginase hepatotoxicity and the effect of L-carnitine in wellestablished animal models are scarce. In the study, we used mid-aged (31–35 week old) female C57BL6 mice (Jackson Lab) as a model to elucidate what effects L-carnitine (Carnitor, Leadiant Biosciences) has on liver damage caused by intense treatment with pegaspargase (Oncaspar, Baxalta US Inc.), the most common formulation of asparaginase used in US and European ALL regimens. Mice were assigned to one of four treatment groups: control, carnitine, asparaginase, and asparaginaseþ carnitine (Figure 1). Dosages of pegaspargase and L-carnitine were 1200U/kg twice a week and 500mg/kg daily respectively, based on those used in previous publications [13,14], and are clinically relevant. Mice were sacrificed and tissues collected after overnight fasting at the end of the 2 week regimens. Consistent with murine data [13] and ultrasound observations in patients [1], hepatic steatosis was induced by pegaspargase treatment alone (p1⁄4 5.9 10 ) (Figure 2(A,B)). One of the most common clinical signs of hepatotoxicity, hyperbilirubinemia, was also induced by pegaspargase treatment, indicated by both total bilirubin and direct bilirubin levels (p1⁄4 .0076 for total bilirubin, and p1⁄4 .0088 for direct bilirubin) (Figure 2(C,D)). When given alone, L-carnitine did not have any impact on liver fat accumulation (p1⁄4 .21) (Figure 2(A,B)) or serum bilirubin levels (p1⁄4 .94 for total bilirubin, and p1⁄4 .40 for direct bilirubin) (Figure 2(C,D)). However, the addition of L-carnitine to the pegaspargase regimen worsened steatosis by over 60% (p1⁄4 .0015) (Figure 2(A,B)), and had no impact on bilirubin levels (p1⁄4 .35 for total bilirubin, and p1⁄4 .96 for direct bilirubin) (Figure 2(C,D)). In line with clinical observations [15], we also saw lower albumin and higher triglyceride levels in serum from pegaspargase-treated mice (p1⁄4 . 0054 for