Miracle-dz/UniFAR-FTUs huggingface dataset:
Therapeutic Drug Monitoring of Orally Administered Letermovir Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

With balanced safety-efficacy profile, letermovir anti-cytomegalovirus (CMV) prophylaxis is used in hematopoietic stem cell transplant recipients (HSCTR). We assessed feasibility and usefulness of letermovir therapeutic drug monitoring (TDM) in HSCTR. ABSTRACT With balanced safety-efficacy profile, letermovir anti-cytomegalovirus (CMV) prophylaxis is used in hematopoietic stem cell transplant recipients (HSCTR). We assessed feasibility and usefulness of letermovir therapeutic drug monitoring (TDM) in HSCTR. We performed a prospective observational study on letermovir-TDM including 40 consecutive adult CMV-seropositive allogeneic-HSCTR who received orally (PO) administered letermovir. Minimal blood concentrations of letermovir (Ctrough) were measured on days 3 and 7 postletermovir initiation and weekly thereafter. Letermovir-Ctrough remained stable during the first 70 days post-HSCT at a median of 286 μg/L (interquartile range, 131 to 591 μg/L), with large interpatient/intrapatient variability. No associations between breakthrough clinically significant CMV infection or detectable CMV DNAemia and letermovir-Ctrough were observed. Patients with letermovir-associated adverse events had higher letermovir-Ctrough than patients without (400 versus 266 μg/L, P = 0.02). Letermovir-Ctrough was similar in patients with or without gastrointestinal symptoms (280 versus 300 μg/L, P = 0.49). Acute grade ≥2 GvHD was associated with higher letermovir-Ctrough (479 versus 248 μg/L, P = 0.001), including gastrointestinal GvHD (499 versus 263 μg/L, P = 0.004). Concomitantly administered posaconazole and cyclosporine were associated with higher letermovir-Ctrough (707 versus 259 μg/L, P < 0.001 and 437 versus 248 μg/L, P = 0.01, respectively). In multivariable analysis, both posaconazole (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4 to 9.7; P < 0.0001) and cyclosporine-adjusted letermovir dose at 240 mg daily (OR, 3.5; 95% CI, 1.4 to 9.0; P = 0.01) were independently associated with higher letermovir-Ctrough. In conclusion, administration of PO letermovir led to measurable and relatively stable letermovir-Ctrough, without noticeable associations with clinical efficacy. Letermovir exposure was not affected by gastrointestinal symptoms, but with posaconazole and cyclosporine administration. Associations between letermovir and concomitantly administered agents and adverse events warrant additional clinical studies.
Application of finite element analysis to tissue differentiation and bone remodelling approaches and their use in design optimization of orthopaedic implants: A review

Post‐operative bone growth and long‐term bone adaptation around the orthopaedic implants are simulated using the mechanoregulation based tissue‐differentiation and adaptive bone remodelling algorithms, respectively. The primary objective of these algorithms was to assess biomechanical feasibility and reliability of orthopaedic implants. This article aims to offer a comprehensive review of the developments in mathematical models of tissue‐differentiation and bone adaptation and their applications in studies involving design optimization of orthopaedic implants over three decades. Despite the different mechanoregulatory models developed, existing literature confirm that none of the models can be highly regarded or completely disregarded over each other. Not much development in mathematical formulations has been observed from the current state of knowledge due to the lack of in vivo studies involving clinically relevant animal models, which further retarded the development of such models to use in translational research at a fast pace. Future investigations involving artificial intelligence (AI), soft‐computing techniques and combined tissue‐differentiation and bone‐adaptation studies involving animal subjects for model verification are needed to formulate more sophisticated mathematical models to enhance the accuracy of pre‐clinical testing of orthopaedic implants.
Streptococcus mutans PrsA mediates AtlA secretion contributing to extracellular DNA release and biofilm formation in the pathogenesis of infective endocarditis

ABSTRACT The role of secretion chaperone-regulated virulence proteins in the pathogenesis of infective endocarditis (IE) induced by viridans streptococci such as Streptococcus mutans is unclear. In this study, we investigated the contribution of the foldase protein PrsA, a putative parvulin-type peptidyl-prolyl isomerase, to the pathogenesis of S. mutans-induced IE. We found that a prsA-deficient strain had reduced virulence in terms of formation of vegetation on damaged heart valves, as well as reduced autolysis activity, eDNA release and biofilm formation capacity. The secretion and surface exposure of AtlA in vitro was reduced in the prsA-deficient mutant strain, and complementation of recombinant AtlA in the culture medium restored a wild type biofilm phenotype of the prsA-deficient mutant strain. This result suggests that secretion and surface localization of AtlA is regulated by PrsA during biofilm formation. Together, these results demonstrate that S. mutans PrsA could regulate AtlA-mediated eDNA release to contribute to biofilm formation in the pathogenesis of IE.
Astragalus polysaccharides and astragaloside IV alleviate inflammation in bovine mammary epithelial cells by regulating Wnt/β-catenin signaling pathway

The Wnt/β-catenin signaling regulates cell renewal and repair and is closely associated with inflammation. Astragalus polysaccharides (APS) and astragaloside IV (AS-IV), which are the main active substances extracted from Radix Astragali, protect cells by regulating Wnt signaling in cells, exerting antiinflammatory, antioxidant, and antistress effects. However, the mechanisms by which APS and AS-IV interact with Wnt signaling to achieve their therapeutic effects in bovine mammary epithelial cells (BMECs) are not understood. In this study, we used lipopolysaccharide (LPS)-stimulated BMECs as an in vitro model of inflammation to investigate the effects of APS and AS-IV on Wnt signaling in inflamed BMECs. Drug concentrations were screened using the CCK-8 method, the effect on protein expression was analyzed using immunoblotting, the effect on inflammatory factors using enzyme-linked immunosorbent assay, and the effect on oxidative factors using enzyme labeling and flow cytometry. LPS activated the expression of inflammatory and oxidative factors in cells and inhibited Wnt/β-catenin signaling. APS and AS-IV antagonized the inhibitory effect of LPS, protecting BMECs. They inhibited the expression of the IL-6, IL-8, and TNF-α inflammatory factors, and that of the MDA oxidative factor, and activated Wnt signaling in LPS-stimulated BMECs. Silencing of β-catenin abolished the protective effect of APS and AS-IV against LPS-stimulated BMECs. Thus, APS and AS-IV mediate protective effects in inflammatory BMECs model through activation of the Wnt signaling pathway. Wnt signaling pathway is one of the targets of the inhibitory effects of APS and AS-IV on inflammation.
Lymph Node Fibroblastic Reticular Cells Attenuate Immune Responses Through Induction of Tolerogenic Macrophages at Early Stage of Transplantation

Background. Fibroblastic reticular cells (FRCs) are a type of stromal cells located in the T zone in secondary lymphoid organs. Previous studies showed that FRCs possess the potential to promote myeloid differentiation. We aim to investigate whether FRCs in lymph nodes (LNs) could induce tolerogenic macrophage generation and further influence T-cell immunity at an early stage of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods. LNs were assayed to confirm the existence of proliferating macrophages after allo-HSCT. Ex vivo—expanded FRCs and bone marrow cells were cocultured to verify the generation of macrophages. Real-time quantitative PCR and ELISA assays were performed to observe the cytokines expressed by FRC. Transcriptome sequencing was performed to compare the difference between FRC-induced macrophages (FMs) and conventional macrophages. Mixed lymphocyte reaction and the utilization of FMs in acute graft-versus-host disease (aGVHD) mice were used to test the inhibitory function of FMs in T-cell immunity in vitro and in vivo. Results. We found a large number of proliferating macrophages near FRCs in LNs with tolerogenic phenotype under allo-HSCT conditions. Neutralizing anti–macrophage colony-stimulating factor receptor antibody abolished FMs generation in vitro. Phenotypic analysis and transcriptome sequencing suggested FMs possessed immunoinhibitory function. Mixed lymphocyte reaction proved that FMs could inhibit T-cell activation and differentiation toward Th1/Tc1 cells. Injection of FMs in aGVHD mice effectively attenuated aGVHD severity and mortality. Conclusions. This study has revealed a novel mechanism of immune regulation through the generation of FRC-induced tolerogenic macrophages in LNs at an early stage of allo-HSCT.
The link between Industry 4.0 and lean manufacturing: mapping current research and establishing a research agenda

In recent years, Industry 4.0 has emerged as one of the most discussed concepts and has gained significant popularity in both academia and the industrial sector. Both Industry 4.0 and lean manufacturing utilise decentralised control and aim to increase productivity and flexibility. However, there have been few studies investigating the link between these two domains. This article explores this novel area and maps the current literature. This is achieved through a systematic literature review methodology, investigating literature published up to and including August 2017. This article identifies four main research streams concerning the link between Industry 4.0 and lean manufacturing, and a research agenda for future studies is proposed.
Batch Calibration: Rethinking Calibration for In-Context Learning and Prompt Engineering

Prompting and in-context learning (ICL) have become efficient learning paradigms for large language models (LLMs). However, LLMs suffer from prompt brittleness and various bias factors in the prompt, including but not limited to the formatting, the choice verbalizers, and the ICL examples. To address this problem that results in unexpected performance degradation, calibration methods have been developed to mitigate the effects of these biases while recovering LLM performance. In this work, we first conduct a systematic analysis of the existing calibration methods, where we both provide a unified view and reveal the failure cases. Inspired by these analyses, we propose Batch Calibration (BC), a simple yet intuitive method that controls the contextual bias from the batched input, unifies various prior approaches, and effectively addresses the aforementioned issues. BC is zero-shot, inference-only, and incurs negligible additional costs. In the few-shot setup, we further extend BC to allow it to learn the contextual bias from labeled data. We validate the effectiveness of BC with PaLM 2-(S, M, L) and CLIP models and demonstrate state-of-the-art performance over previous calibration baselines across more than 10 natural language understanding and image classification tasks.
Targeted SARS-CoV-2 treatment is associated with decreased mortality in immunocompromised patients with COVID-19

Abstract Background Little is known about targeted (antiviral or monoclonal antibody) anti-SARS-CoV-2 treatment in immunocompromised patients with COVID-19. Objectives To assess the real-life efficacy and tolerance of targeted treatment of COVID-19 in immunocompromised patients. Patients and methods Single-centre retrospective case series of immunocompromised patients with COVID-19 between December 2021 and March 2022. We recorded all cases of COVID-19 among immunocompromised patients treatment between 20 December 2021 and 15 March 2022. Choice of treatment was left to the physician’s decision, according to internal treatment protocol, treatment availability and circulating variants. Main outcome was death from COVID-19 after no treatment or targeted treatment. Results Sixty-seven immunocompromised patients [38 male; median (IQR) age, 53 (43–63) years], with a median (IQR) follow-up of 60 (47–80) days. Ten patients did not receive any targeted treatment. Targeted treatment consisted of IV curative remdesivir (n = 22), sotrovimab (n = 16), tixagevimab/cilgavimab (n = 13) and casirivimab/imdevimab (n = 1). Ten patients (15%) presented severe COVID-19 and 2 (3%) died from Omicron COVID-19. Comparing patients who received targeted anti-SARS-CoV-2 treatment and no prophylaxis, (n = 42; 81%) with those who did not (n = 10; 19%), death rate was significantly lower in treated patients [n = 0 (0%) versus n = 2 (20%); P = 0.034]. No severe adverse events were reported among treated patients. Among 15 patients who received tixagevimab/cilgavimab as pre-exposure prophylaxis, 6 received an additional curative treatment and none died from COVID-19. Conclusions Our results suggest that targeted COVID-19 treatment, including direct antivirals or monoclonal antibodies, is safe and efficient and could be proposed in high-risk immunocompromised patients.
Counteracting heart failure with diabetes drugs: a review into the pharmacokinetic and pharmacodynamic properties

ABSTRACT Introduction Heart failure (HF) is becoming a huge public health burden. New diabetes drugs for type 2 diabetes (T2D), sodium-glucose cotransporter type 2 inhibitors (SGLT2is), reduce the rate of hospitalization for HF in placebo-controlled trials. Areas covered Pharmacokinetics of dapagliflozin and empagliflozin (in presence of renal impairment and hepatic dysfunction, two comorbidities frequently associated with HF) and pharmacodynamic studies in patients with HF. Main HF outcomes in T2D patients with cardiovascular risk and in patients with reduced (HFrEF) or preserved (HFpEF) ejection fraction, with or without T2D, from DAPA-HF, EMPEROR-Reduced and EMPEROR-Preserved original findings and post hoc analyses. Expert opinion No clinically relevant changes are expected concerning SGLT2i pharmacokinetics in patients with HF while pharmacodynamic studies reported improvements in myocardium/vascular parameters, biomarkers, and functional status. All SGLT2is showed a remarkable reduction in hospitalization for HF in patients with T2D and high cardiovascular risk. Furthermore, both dapagliflozin and empagliflozin improved the prognosis of patients with HFrEF, independently of the presence of T2D. Similar results were reported with empagliflozin in patients with HFpEF, to be confirmed with dapagliflozin in an ongoing trial (DELIVER). Thus, SGLT2is offer a new opportunity for the prevention and management of HF in patients with or without T2D.
Hand size estimates of fibromyalgia patients are associated with clinical and experimental pain

Introduction Simply inspecting one’s own body can reduce clinical pain and magnification of body parts can increase analgesia. Thus, body perceptions seem to play an important role for analgesia. Conversely, pain may also affect bodily perceptions. Therefore, we evaluated the effects of clinical and/or experimental pain on perceived hand size in fibromyalgia patients (FM) and healthy controls (HC). Methods To investigate the effects of chronic and/or acute pain on size perception we compared hand size estimates of 35 HC and 32 FM patients at baseline and during tonic mechanical pain stimuli applied to one ear lobe. Mechanical stimuli were adjusted for each individual pain sensitivity to achieve a rating of 4 ± 1 VAS (0–10) units. Photographs of each subject’s hands were digitally manipulated to produce a monotonic series of 5 images larger and 6 smaller than actual size which were then presented to the participants in ascending and descending order (total number of images: 12). Results FM and HC participants’ clinical pain ratings at baseline were 3.3 (3.1) and . 3 (.8) VAS units, respectively. At baseline, FM participants selected significantly smaller hand images than HC as representative of their actual size (p < .02). During application of tonic experimental pain, the image size chosen to represent their actual hand size decreased significantly in FM participants and HC (p < .001) but this decrease was not different between groups (p > .05). Hand size estimates of FM participants correlated negatively with their clinical pain ratings (p < .04). Conclusion The decreased hand size perception of FM patients and HC was associated with their clinical and/or experimental pain, supporting the hypothesis that pain can result in visual body distortions.
Safe Non-Stochastic Control of Control-Affine Systems: An Online Convex Optimization Approach

We study how to safely control nonlinear control-affine systems that are corrupted with bounded non-stochastic noise, i.e., noise that is unknown a priori and that is not necessarily governed by a stochastic model. We focus on safety constraints that take the form of time-varying convex constraints such as collision-avoidance and control-effort constraints. We provide an algorithm with bounded dynamic regret, i.e., bounded suboptimality against an optimal clairvoyant controller that knows the realization of the noise a priori. We are motivated by the future of autonomy where robots will autonomously perform complex tasks despite real-world unpredictable disturbances such as wind gusts. To develop the algorithm, we capture our problem as a sequential game between a controller and an adversary, where the controller plays first, choosing the control input, whereas the adversary plays second, choosing the noise's realization. The controller aims to minimize its cumulative tracking error despite being unable to know the noise's realization a priori. We validate our algorithm in simulated scenarios of (i) an inverted pendulum aiming to stay upright, and (ii) a quadrotor aiming to fly to a goal location through an unknown cluttered environment.
Self-Defense and Police Reporting of Intimate Partner Violent Victimization: A Comparison of White, Black, and Hispanic Women Victims

Although the use of self-defense is common in incidents of intimate partner violence (IPV), correlates of self-protective behaviors in IPV are less known. Furthermore, while research has examined the unintended consequence of dual arrest as a result of using self-defense in IPV incidents, research has not examined whether self-defense is associated with the likelihood of reporting the victimization to the police. The purpose of this study is to first examine the racial differences in the use of self-defense in incidents of IPV. Second, this study examines the relationship between the use of physical self-defense and formal help-seeking (i.e., calling the police) and whether those relationships vary across race/ethnicity for White, Black, and Hispanic women. Using a large nationally representative sample of IPV incidents in the United States, this study found that incidents with Black female victims were more likely to feature physical self-defense compared to incidents with White female victims. Furthermore, incidents with Black female victims were more likely to be reported to the police. There was a positive relationship between physical self-defense and reporting to the police for Black women and an inverse relationship between physical self-defense and reporting to the police for Hispanic women.
Humanoid walking pattern generation based on model predictive control approximated with basis functions

ABSTRACT This paper proposes a real-time walking pattern generator (WPG) based on model predictive control (MPC). Since reducing the calculation time is a crucial problem in real-time WPG, we consider introducing basis functions to reduce the number of control input. The control inputs in the MPC are described by a series of basis functions. Compared with the standard discrete-time MPC formulation, the approach with basis functions requires fewer optimization variables at the cost of decreasing precision. In order to find an appropriate trade-off, two basis functions named Laguerre functions and Haar functions, are tested in this paper. MPC with Laguerre functions decreases more computational load while MPC with Haar functions offers a more accurate solution. The approach is not restricted to Laguerre functions or Haar functions, users can select their own basis functions for different applications and preferences. GRAPHICAL ABSTRACT
Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial

Abstract Background STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival. Methods Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression). Results Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity. Conclusions There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases.
A Year at the Forefront of Engineering Photosynthesis

ABSTRACT Multiple proof-of-principle experiments and successful field trials have demonstrated that engineering photosynthesis is a viable strategy for improving crop yields. Advances to engineering technologies have accelerated efforts to improve photosynthesis, generating a large volume of published literature: this Review therefore aims to highlight the most promising results from the period February 2021 to January 2022. Recent research has demonstrated the importance of understanding the impact of changing climates on photosynthesis to ensure that proposed engineering strategies are resilient to climate change. Encouragingly, there have been several reports of strategies that have benefits at temperatures higher than current ambient conditions. There has also been success in engineering synthetic bypass pathways, providing support for the feasibility of a synthetic biology approach. Continued developments in all areas of engineering photosynthesis will be necessary for sustainably securing sufficient crop yields for the future. This article has an associated First Person interview with the first author of the paper.