Lymphodepleting chemotherapy practices and effect on safety and efficacy outcomes in patients with solid tumours undergoing T cell receptor-engineered T cell (TCR-T) Therapy: a systematic review and meta-analysis.

BACKGROUND: T cell receptor-engineered T cell (TCR-T) therapy has shown promising efficacy in advanced solid tumours. Lymphodepleting (LD) chemotherapy improves TCR-T cell therapy efficacy but is associated with significant toxicities. Evidence is sparse regarding the optimum LD regimen for TCR-T cell therapy in solid tumours. METHODS: A systematic review was conducted of interventional, prospective clinical trials describing LD practices prior to TCR-T cell therapy in patients with advanced solid tumours. The objective was to define LD regimens administered prior to TCR-T cell therapy and their effects on specific safety and efficacy outcomes in this patient population. RESULTS: Searches returned 484 studies, 19 (231 patients) met the eligibility criteria. Cyclophosphamide (cyclo) 60 mg/kg daily (2 days), plus fludarabine (fludara) 25 mg/m2 daily (5 days) was the most common LD regimen (38% of studies). Higher dose LD regimens were associated with increased pooled incidence rates of febrile neutropaenia compared to low dose (0.64, [95% Confidence interval (CI): 0.50-0.78], vs. 0.39 [95% CI: 0.25-0.53], respectively) but were not significantly associated with higher objective responses (odds ratio: 1.05, 95%CI: 0.60-1.82, p = 0.86). A major shortfall in safety data reporting was identified; determination of LD regimen effects on many safety outcomes was not possible. CONCLUSION: Standard consensus guidelines for the design and reporting of adoptive cell therapy (ACT) studies would facilitate accurate risk-benefit analysis for optimising LD regimens in patients with advanced solid tumours.

Impact of a pharmacist-led tacrolimus management protocol in the outpatient setting.

BACKGROUND: Clinical pharmacists are often used to make recommendations regarding tacrolimus therapy in the post transplant setting.Therapeutic drug monitoring (TDM) of tacrolimus after transplant is based on trough levels in the setting of predetermined institutional immunosuppression goals. To evaluate time within therapeutic range (TTR) of tacrolimus the Rosendaal method can be utilized. OBJECTIVE: Our study aimed to compare objective therapeutic drug monitoring outcomes after the implementation of a pharmacist driven tacrolimus management protocol (postprotocol initiation) with previous management by providers (preprotocol initiation). PRACTICE DESCRIPTION: The Ohio State University Wexner Medical Center (OSUWMC) is a 700-bed academic medical center in Columbus, OH. On average, OSUWMC completes more than 300 kidney transplants each year. There are 6 abdominal transplant pharmacists (including one postgraduate year 2 transplant pharmacy resident) that rotate through the inpatient and outpatient setting. PRACTICE INNOVATION: A pharmacist-led tacrolimus management protocol in kidney transplant recipients was initiated in October 2018 at our institution, which enabled pharmacists to dose and adjust tacrolimus in the outpatient setting in accordance with prespecified goals. EVALUATION METHODS: This single-center retrospective analysis included adult kidney transplant recipients on de novo tacrolimus. Patient's tacrolimus levels were evaluated for 6 months after transplant. The mean tacrolimus percent TTR and the median coefficient of variation (CV) were calculated and compared in postprotocol initiation group (n = 85) with preprotocol initiation group (n = 39). TTR was calculated using the Rosendaal method. RESULTS: There was no statistically significant difference between the preprotocol initiation and postprotocol initiation group mean TTR (59.6% vs. 60.5%, P = 0.723), mean CV from 0-3 months after transplant (36.3 vs. 36.0, P = 0.900), and mean CV from at least 3-6 months after transplant (24.5 vs. 22.7, P = 0.351). Rejection rates, development of donor-specific antibodies, and renal function were similar between groups. CONCLUSION: Based on our findings, transplant pharmacists were equally as effective at maintaining tacrolimus percent TTR and CV in the designated kidney transplant recipients included in the management protocol compared with primary management by other transplant providers. The delegation of tacrolimus management to clinical pharmacists is a viable alternative to primary management by outpatient practitioners.

Safety of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients With Preexisting Renal Dysfunction.

BACKGROUND: Although intravenous (IV) bisphosphonates are first-line medications for the management of hypercalcemia, studies examining their use in patients with preexisting renal dysfunction are limited. OBJECTIVE: The objective of this study is to describe the safety and efficacy of pamidronate and zoledronic acid in the treatment of hypercalcemia in patients with baseline renal dysfunction. METHODS: A retrospective analysis was conducted of IV pamidronate and zoledronic acid in adult patients with hypercalcemia and creatinine clearance (CrCl) <60 mL/min. The primary endpoint was incidence of all-grade serum creatinine (SCr) elevations. Secondary endpoints included refractory hypercalcemia, hypocalcemia, osteonecrosis of the jaw (ONJ), corrected serum calcium (CSC) decrease ≥1.0 mg/dL by day 7 of bisphosphonate administration, and normalization of CSC ≤10.5 mg/dL by days 10 and 30. RESULTS: A total of 113 patients were included (n = 55 pamidronate, n = 58 zoledronic acid). The primary endpoint of all-grade SCr elevation occurred in 28 (24.8%) patients. Grades 3/4 SCr elevations occurred in 10.9% of patients treated with pamidronate and 1.7% of patients receiving zoledronic acid. Approximately 16% and 14% of patients developed grades 1 and 2 hypocalcemia, respectively, and there were no cases of ONJ. Overall, 64.6% of patients achieved normalization of CSC by day 10, and there were no statistical differences between bisphosphonate type and renal function. CONCLUSIONS AND RELEVANCE: The analysis suggests an association between IV bisphosphonates and increased rates of SCr elevations among patients with preexisting renal dysfunction. Future prospective studies are necessary to elucidate these findings.

Can a robot teach me that? Children's ability to imitate robots.

Commensurate with constant technological advances, social robots are increasingly anticipated to enter homes and classrooms; however, little is known about the efficacy of social robots as teaching tools. To investigate children's learning from robots, 1- to 3-year-olds observed either a human or a robot demonstrate two goal-directed object manipulation tasks and were then given the opportunity to act on the objects. Children exhibited less imitation from robotic models that varied with task complexity and age, a phenomenon we term the "robot deficit." In addition, the more children engaged with the robot prior to administration of the imitation task, the more likely they were to replicate the robot's actions. These findings document how children are able to learn from robots but that ongoing design of robotic platforms needs to be oriented to developing more socially engaging means of interacting.

A call to incorporate systems theory and human factors into the existing investigation of harm in clinical research involving healthcare products.

This is a joint statement from individual pharmacology and pharmaceutical professionals acting in their own capacity, including members of the Alliance for Clinical Research Excellence and Safety (ACRES) and the International Society of Pharmacovigilance (ISoP). By building on the extensive pharmacological and regulatory investigations that already take place, we are calling for a fuller and more robust systems-based approach to the independent investigation of clinical research when serious incidents of harm occur, starting with first-in-human clinical trials. To complement existing activities and regulations, we propose an additional approach blending evidence derived from both pharmacological and organizational science, which addresses human factors and transparency, to enhance organizational learning and continuous improvement. As happens with investigations in other sectors of society, such as the chemical and aviation sector, this systems approach should be seen as an additional way to understand how problems occur and how they might be prevented in the future. We believe that repetition of potentially preventable and adverse outcomes during clinical research, by failing to identify and act upon all systematic vulnerabilities, is a situation that needs urgent change. As we will discuss further on, approaches based on applying systems theory and human factors are much more likely to improve objectivity and transparency, leading to better system design.

Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4): functional differences of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding.

Degradation of the cartilage proteoglycan aggrecan is an early event in the development of osteoarthritis, and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are considered to be the major aggrecan-degrading enzymes. We have recently found that ADAMTS-5 is rapidly endocytosed via low density lipoprotein receptor-related protein 1 (LRP1) and degraded by chondrocytes. Here we report that this regulatory mechanism also applies to ADAMTS-4, although its rate of endocytosis is slower than that of ADAMTS-5. Domain deletion mutagenesis of ADAMTS-4 identified that the cysteine-rich and spacer domains are responsible for binding to LRP1, whereas the thrombospondin 1 and spacer domains are responsible in ADAMTS-5. The estimated t½ value of ADAMTS-4 endocytosis was about 220 min, whereas that of ADAMTS-5 was 100 min. The difference in half-lives between the two enzymes is explained by the 13-fold lower affinity of ADAMTS-4 for LRP1 compared with that of ADAMTS-5. Studies using soluble ligand binding clusters of LRP1 showed that ADAMTS-4 binds to clusters II and IV with similar KD,app values of 98 and 73 nm, respectively, whereas ADAMTS-5 binds to cluster II, III, and IV with KD,app values of 3.5, 41, and 9 nm, respectively. Thus, ADAMTS-5 competitively inhibits ADAMTS-4 endocytosis but not vice versa. This study highlights that the affinity between a ligand and LRP1 dictates the rate of internalization and suggests that LRP1 is a major traffic controller of the two aggrecanases, especially under inflammatory conditions, where the protein levels of ADAMTS-4 increase, but those of ADAMTS-5 do not.

Low-Field Magnetic Resonance Imaging Findings of the Fetlock Region of Nonracehorses.

Low-field, magnetic resonance imaging (MRI) is an advanced imaging modality widely used to diagnose distal limb pathology in horses, but there are limited data regarding lesion distribution within the metacarpo/metatarsophalangeal joint (MCP/MTPJ) region in lame nonracehorses. The aim of this study was to describe the low-field MRI findings and lesion distribution in nonracehorses with MCP/MTPJ region pain. Clinical records from horses undergoing MRI of the MCP/MTPJ region between July 2016 and March 2023 were reviewed. Horses were included if pain causing lameness was localized to this region and conventional imaging failed to provide a definitive diagnosis. Eighty-four horses met the inclusion criteria. Soft tissues were affected in 76 (90.5%) horses, with suspensory ligament branch injuries being the most frequent (60.7%) soft tissue pathology identified. Osseous pathology was diagnosed in 51 horses. The subchondral bone (SCB) of the distal third metacarpal/metatarsal bone (MC3/MT3) was the osseous structure most frequently affected (40.5%), with 79.4% of these horses having lesions on the dorsal aspect of the bone. Osteoarthritis was present in 48 (57.1%) horses. The main limitations of the study were the lack of a standardized diagnostic analgesia pattern due to varying veterinary surgeon involvement, and the absence of bilateral magnetic resonance (MR) sequences in all limbs. MRI is a useful diagnostic tool to assess soft tissue structures in the MCP/MTP region, especially in horses with thick skin, which may make ultrasonographic imaging unreliable.

Current Advances in Graft-versus-host Disease After Intestinal Transplantation.

Graft-versus-host disease (GvHD) remains a potentially fatal complication following intestinal transplant (ITx). Over the past decade, advances in the understanding of the pathophysiology of this complex immunological phenomenon have led to the reassessment of the host systemic immune response and have created a gateway for novel preventive and therapeutic strategies. Although sufficient evidence dictates the use of corticosteroids as a first-line option, the treatment for refractory disease remains contentious and lacks a standardized therapeutic approach. Timely diagnosis remains crucial, and the advent of chimerism detection and immunological biomarkers have transformed the identification, prognostication, and potential for survival after GvHD in ITx. The objectives of the following review aim to discuss the clinical and diagnostic features, pathophysiology, advances in immune biomarkers, as well as therapeutic opportunities in the prevention and treatment of GvHD in ITx.

Investigating Temporal Features of Carotid Intima-Media Thickness from Ultrasound Imaging with Recurrent Neural Networks.

Measuring carotid intima-media thickness (cIMT) of the Common Carotid Artery (CCA) via B-mode ultrasound imaging is a non-invasive yet effective way to monitor and assess cardiovascular risk. Recent studies using Convolutional Neural Networks (CNNs) to automate the process have mainly focused on the detection of regions of interest (ROI) in single frame images collected at fixed time points and have not exploited the temporal information captured in ultrasound imaging. This paper presents a novel framework to investigate the temporal features of cIMT, in which Recurrent Neural Networks (RNN) were deployed for ROI detection using consecutive frames from ultrasound imaging. The cIMT time series can be formed from estimates of cIMT in each frame of an ultrasound scan, from which additional information (such as min, max, mean, and frequency) on cIMT time series can be extracted. Results from evaluation show the best performance for ROI detection improved 4.75% by RNN compared to CNN-based methods. Furthermore, the heart rate estimated from the cIMT time series for seven patients was highly correlated with the patient's clinical records, which suggests the potential application of the cIMT time series and related features for clinical studies in the future.Clinical relevance- The temporal features extracted from cIMT time series provide additional information that can be potentially beneficial for clinical studies.

The Effect of Needle Reuse on Piglet Skin Puncture Force.

The study investigated whether the repeat use of needles used to inject piglets with iron, influences the force required to puncture into piglet cadaver skin. Pig units (n = 31) were surveyed on needle reuse and injection practices, and these findings informed subsequent laboratory-based experiments on needle puncture force into piglet cadaver tissues. A 21 G 5/8" needle was reported as the most used needle type (67.7%), with 80.6% reporting needle reuse; 38.7% changed the needle between litters or earlier if damaged, 16.1% every three litters and 22.5% when it felt blunt or damaged, after each injection session or when changing the bottle of iron solution. There was a significant difference in puncture force between the 1st and 36th use (p < 0.05), and between the 1st and 100th use (p = 0.0015), but not between the 1st and 12th or 36th use (p > 0.999 and p = 0.8313, respectively). Scanning electron microscopy (SEM) imaging showed appreciable damage to the needle tip after 12 uses. The repeat use of needles in piglet cadavers increased the force of needle puncture compared to first-time use. When extrapolated to live animals, the use of blunt needles has the potential to cause pain and distress.