Miracle-dz/UniFAR-FTUs huggingface dataset:
Leukocyte-Rich versus Leukocyte-Poor Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis: A Double-Blind Randomized Trial

Background: Platelet-rich plasma (PRP) is gaining large interest in clinical practice as a minimally invasive injective treatment for knee osteoarthritis (OA). Different preparation methods are available, and the presence of leukocytes, deemed detrimental in some preclinical studies, is one of the most debated aspects regarding PRP efficacy. Purpose: To compare the safety and effectiveness of leukocyte-rich PRP (LR-PRP) and leukocyte-poor PRP (LP-PRP) for the treatment of knee OA. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 192 patients with symptomatic knee OA (Kellgren-Lawrence grade 1-3) were randomly allocated to 3 weekly injections of LR-PRP or LP-PRP. LP-PRP was obtained with a filter for leukodepletion. LR-PRP and LP-PRP were divided into aliquots of 5 mL, with a mean platelet concentration of 1146.8 × 109/L and 1074.9 × 109/L and a mean leukocyte concentration of 7991.4 × 106/L and 0.1 × 106/L, respectively. Patients were evaluated at baseline and thereafter at 2, 6, and 12 months for the primary outcome, the International Knee Documentation Committee (IKDC) subjective score; and for secondary outcomes, the Knee injury and Osteoarthritis Outcome Score (KOOS) subscales, EuroQol–visual analog scale (EQ-VAS), and Tegner score. Results: No differences between groups were observed in terms of absolute values or improvement of the clinical scores across all follow-up intervals. The mean IKDC subjective score at baseline and 12 months improved from 45.6 to 60.7 in the LR-PRP group as compared with 46.8 to 62.9 in the LP-PRP group (P = .626). No severe adverse events were described in either group, although 15 mild adverse events (knee pain or swelling) were reported: 12.2% for LR-PRP and 4.7% for LP-PRP (P = .101). No statistically significant difference was also found between LR-PRP and LP-PRP in terms of failures (7.8% vs 3.5%, P = .331). Conclusion: This double-blind randomized trial showed that 3 intra-articular LR-PRP or LP-PRP injections produced similar clinical improvement in the 12 months of follow-up in patients with symptomatic knee OA. Both treatment groups reported a low number of adverse events, without intergroup differences. The presence of leukocytes did not significantly affect the clinical results of PRP injections. Registration: NCT02923700 (ClinicalTrials.gov identifier).
GSTM1 and GSTT1 polymorphisms in healthy volunteers – a worldwide systematic review

Abstract The GSTM1 and GSTT1 genes encode homonymous enzymes, which are responsible for the detoxification of several substances potentially harmful to the human body, such as air pollution, drugs, pesticides, and tobacco. However, some individuals may present a complete deletion of these genes and, consequently, an enzyme deficiency leading to an inadequate metabolism and, therefore, a higher susceptibility to some clinical conditions. Interethnic variations have also been described for both genes, making necessary the study of the deletion frequencies of GSTM1 and GSTT1 in different populations around the world. So, the aim of this study was to enable the synthesis and discussion of the main population differences of GSTM1 and GSTT1 polymorphisms in healthy volunteers. Searches were performed in the PubMed database, including 533 articles and 178,566 individuals in the analyses. We found an overrepresentation of European individuals and studies, and an underrepresentation of non-European ethnicities. Moreover, there are significant frequency differences among distinct ethnic groups: East Asians present the highest frequencies worldwide for GSTM1 and GSTT1 deletions, which could suggest higher disorders risk for this population; in contrast, Sub-Saharan Africans presented the lowest frequency of GSTM1 worldwide, corroborating evolution inferences performed previously for other genes codifying metabolism enzymes. Also, admixture is a relevant component when analyzing frequency values for both genes, but further studies focusing on this subject are warranted.
Wogonin and its analogs for the prevention and treatment of cancer: A systematic review

The medicinal plant Scutellaria baicalensis, commonly known as Chinese skullcap or Huang‐Qin, has been used as a traditional medicine for several thousand years. The roots of this plant contain bioactive compounds, such as wogonin (WOG), wogonoside, baicalein, and baicalin. The aim of this article is to evaluate the therapeutic potential and mechanisms of action of WOG against different cancers. Numerous in vitro and in vivo studies have revealed that WOG exerts immense therapeutic potential against bladder cancer, breast cancer, cholangiocarcinoma, cervical cancer, colorectal cancer, gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hepatic cancer, leukemia, lung cancer, lymphoma, melanoma, multiple myeloma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cancer by regulating various cell signaling pathways. WOG, in combination with established chemotherapeutic drugs, improves the efficacy of treatment and lowers toxicity. Nevertheless, human trials are warranted to validate these findings. Numerous preclinical studies, combined with an extensive margin of safety and no severe side effects, underscore WOG's therapeutic potential as an anticancer drug. These studies propound the use of WOG as a potential anticancer candidate; however, further high‐quality studies are required to firmly establish the clinical efficacy of WOG for the prevention and treatment of human malignancies.
Validation of p16 immunocytochemical staining on alcohol‐fixed aspirate smears: A single‐institutional study with review of the literature

Determining human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma can have a significant impact on treatment and clinical outcomes. Because fine‐needle aspiration (FNA) is typically an initial diagnostic modality in a patient workup for primary or suspected metastatic disease, immunostaining for p16 on FNA material is a promising option to determine HPV tumor status, possibly avoiding biopsies or excisions. In this study, the authors investigated the possibility of using alcohol‐fixed smears as a reliable alternative for reporting p16 status.
Oral step-down therapy in patients with uncomplicated Staphylococcus aureus primary bacteremia and catheter-related bloodstream infections

Abstract Patients with uncomplicated Staphylococcus aureus primary bacteremia and catheter-related bloodstream infection (CRBSI) should be treated for at least 14 days. However, evidence for oral step-down therapy is lacking in these patients. A retrospective cohort was identified from 2013 to 2018 in a 1,950-bed tertiary hospital. An oral antimicrobial therapy (OAT) group was defined as patients treated with oral antibiotics following less than 10 days of intravenous antimicrobial therapy (IAT). Treatment failure was defined as any case of recurrence or death within 90 days. A total of 103 patients were included in the analysis, including 32 patients treated with OAT. Rates of treatment failure were 3.2% and 12.7% in the OAT and IAT groups (P = 0.113). The length of hospital stay was shorter in the OAT group. OAT was not an independent risk factor for treatment failure. OAT may reduce the duration of hospitalization without adverse effects in these patients.
Hypertension-mediated organ damage in masked hypertension

Objectives: Masked hypertension – a blood pressure (BP) phenotype characterized by a clinic BP in the normal range but elevated BP outside the office – is associated with early hypertension-mediated organ damage. This study examined early target organ manifestations of masked hypertension diagnosed by home (HBPM) and ambulatory (ABPM) BP monitoring. Methods: Left ventricular (LV) structure and diastolic function measured by echocardiography, microalbuminuria, and coronary artery calcification were evaluated in 420 patients with high clinic BP (SBP 120–150 mmHg or DBP 80–95 mmHg). Evidence of hypertension-mediated organ damage was compared in patients with sustained normotension, masked hypertension, and sustained hypertension based on measurements by HBPM, daytime ABPM, and 24-h ABPM. Results: The 420 participants averaged 48 (12) [mean (SD)] years of age; the average clinic BP was 130 (13)/81 (8) mmHg. In individuals with masked hypertension diagnosed by HBPM, indexed LV mass, relative wall thickness, and e′ and E/e′ (indices of LV relaxation), were generally intermediate between values observed in normotensives and sustained hypertensive patients, and were significantly greater in masked hypertension than normotensives. Similar trends were observed when masked hypertension was diagnosed by ABPM but a diagnosis of masked hypertension was not as reliably associated with LV remodeling or impaired LV relaxation in comparison to normotensives. There were trends towards greater likelihoods of detectable urinary microalbumin and coronary calcification in masked hypertension than in normotensives. Conclusion: These results support previous studies demonstrating early hypertension-mediated organ damage in patients with masked hypertension, and suggest that HBPM may be superior to ABPM in identifying patients with masked hypertension who have early LV remodeling and diastolic LV dysfunction.
High-speed atomic force microscopy reveals a three-state elevator mechanism in the citrate transporter CitS

Significance As cellular membranes are impermeable to most molecules, transporter proteins are typically present in the membrane to transport small molecules in or out of the cell. Due to the small, nanometer size of these transporters, it is challenging to study their transport mechanism. Here, we use advanced microscopy approaches to study in real time and at the single-molecule level the mode of action of the dimeric CitS tranpsorter. Using high-speed atomic force microscopy, we visualize the dynamic, elevator-like movement of the transporter, and we reveal that the two protomers move independently. We also discovered an intermediate state, reminiscent of another, unrelated transporter, indicating that independent evolutionary pathways have led to similar three-state elevator mechanisms. The secondary active transporter CitS shuttles citrate across the cytoplasmic membrane of gram-negative bacteria by coupling substrate translocation to the transport of two Na+ ions. Static crystal structures suggest an elevator type of transport mechanism with two states: up and down. However, no dynamic measurements have been performed to substantiate this assumption. Here, we use high-speed atomic force microscopy for real-time visualization of the transport cycle at the level of single transporters. Unexpectedly, instead of a bimodal height distribution for the up and down states, the experiments reveal movements between three distinguishable states, with protrusions of ∼0.5 nm, ∼1.0 nm, and ∼1.6 nm above the membrane, respectively. Furthermore, the real-time measurements show that the individual protomers of the CitS dimer move up and down independently. A three-state elevator model of independently operating protomers resembles the mechanism proposed for the aspartate transporter GltPh. Since CitS and GltPh are structurally unrelated, we conclude that the three-state elevators have evolved independently.
Efficacy of Repair for ACL Injury: A Meta‑analysis of Randomized Controlled Trials

Abstract We aim to compare the curative effect of primary repair for anterior cruciate ligament (ACL) injury with reconstruction and provide the reliable evidence for its clinical application. The literatures were searched in PubMed, EMBASE, Springer, and other medical literature databases published between January 1970 and June 2021. Basic characteristics, surgery technique, clinical outcome scores and physical examination results were recorded and evaluated. Seven randomized controlled trials (RCT) were eligible for inclusion. The results showed that there were no statistically significant differences between arthroscopic ACL repair and ACL reconstruction for Tegner, Lysholm, Lachman, KT-1000, range of motion (ROM), functional outcomes and reoperation rate (P>0.05), even the result of IKDC scores showed that arthroscopic repair was better than reconstruction (P=0.04). However, through the subgroup analysis, it was found that the short-term follow-up results of arthroscopic ACL repair were indeed better than those of open ACL repair. Therefore, we can assume that the arthroscopic ACL repair technique is an optional and promising surgical method to treat ACL injury.
Diagnosis and Management of Multiple Myeloma: A Review.

Importance Multiple myeloma is a hematologic malignancy characterized by presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year. Observations Among patients with multiple myeloma, approximately 73% have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at the time of presentation. Evaluation of patients with possible multiple myeloma includes measurement of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels; serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis; and full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging. The Revised International Staging System combines data from the serum biomarkers β2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization-t(4;14), del(17p), and t(14;16)-to assess estimated progression-free survival and overall survival. At diagnosis, 28% of patients are classified as having Revised International Staging stage I multiple myeloma, and these patients have a median 5-year survival of 82%. Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy. This induction therapy combined with autologous hematopoietic stem cell transplantation followed by maintenance lenalidomide is standard of care for eligible patients. Conclusions and Relevance Approximately 34 920 people in the US and 155 688 people worldwide are diagnosed with multiple myeloma each year. Induction therapy with an injectable proteasome inhibitor, an oral immunomodulatory agent and dexamethasone followed by treatment with autologous hematopoietic stem cell transplantation, and maintenance therapy with lenalidomide are among the treatments considered standard care for eligible patients.
Proteomics in uveal melanoma

Purpose of review This article reviews the latest proteomic research on uveal melanoma. Recent findings Proteomic analysis of uveal melanoma cell lines and tissue specimens has improved our understanding of the pathophysiology of uveal melanoma and helped identify potential prognostic biomarkers. Circulating proteins in patient serum may aid in the surveillance of metastatic disease. The proteomes of aqueous and vitreous biopsy specimens may provide safer biomarkers for metastatic risk and candidate therapeutic targets in uveal melanoma. Proteomic analysis has the potential to benefit patient outcomes by improving diagnosis, prognostication, surveillance, and treatment of uveal melanoma. Summary These recent findings demonstrate that proteomic analysis is an important area of research to better understand the pathophysiology of uveal melanoma and improve the personalized management of our patients.
Data-Driven Policy Iteration for Nonlinear Optimal Control Problems

The design of optimal control laws for nonlinear systems is tackled without knowledge of the underlying plant and of a functional description of the cost function. The proposed data-driven method is based only on real-time measurements of the state of the plant and of the (instantaneous) value of the reward signal and relies on a combination of ideas borrowed from the theories of optimal and adaptive control problems. As a result, the architecture implements a policy iteration strategy in which, hinging on the use of neural networks, the policy evaluation step and the computation of the relevant information instrumental for the policy improvement step are performed in a purely continuous-time fashion. Furthermore, the desirable features of the design method, including convergence rate and robustness properties, are discussed. Finally, the theory is validated via two benchmark numerical simulations.
The Prognostic Value of Albumin-Globulin Ratio and Eosinophil-Neutrophil Ratio in Patients with Advanced Tumors Undergoing Treatment with PD-1/PD-L1 Inhibitors

Abstract We investigated the prognostic value of peripheral serum biomarkers, including albumin-globulin ratio (AGR) and eosinophil-neutrophil ratio (ENR), in patients with advanced tumors treated with PD-1/PD-L1 inhibitors. We also retrospectively analyzed the clinical efficacy of PD-1/PD-L1 inhibition in 95 patients with advanced tumors treated at our center. The prognostic value of baseline AGR, baseline ENR, and baseline neutrophil-lymphocyte ratio (NLR) in the serum were evaluated. We also developed a risk scoring tool to stratify patients based on their prognosis. Univariate Cox regression analysis revealed that age, NLR, Eastern Cooperative Oncology Group (ECOG) performance status (PS), platelet-neutrophil ratio (PLR), ENR, AGR, lactate dehydrogenase levels, treatment line, and treatment type were correlated with progression-free survival (PFS). Multivariate Cox regression analysis showed that age, AGR, ENR, and treatment type were independent prognostic factors for PFS. Patients in the low-risk group had significantly longer PFS than those in the high-risk group. The nomogram concordance index (C-index) was 0.716. Patients with a decrease in AGR of over 20% after the first and second treatment cycles had significantly worse PFS than those without decreased AGR. These findings suggest that baseline AGR and ENR may be useful prognostic biomarkers for patients with advanced tumors treated with PD-1/PD-L1 inhibitors.
Differential impact of TGFβ/SMAD signaling activity elicited by Activin A and Nodal on endoderm differentiation of epiblast stem cells

Allocation of cells to an endodermal fate in the gastrulating embryo is driven by Nodal signaling and consequent activation of TGFβ pathway. In vitro methodologies striving to recapitulate the process of endoderm differentiation, however, use TGFβ family member Activin in place of Nodal. This is despite Activin not known to have an in vivo role in endoderm differentiation. In this study, five epiblast stem cell lines were subjected to directed differentiation using both Activin A and Nodal to induce endodermal fate. A reporter line harboring endoderm markers FoxA2 and Sox17 was further analyzed for TGFβ pathway activation and WNT response. We demonstrated that Activin A‐treated cells remain more primitive streak‐like when compared to Nodal‐treated cells that have a molecular profile suggestive of more advanced differentiation. Activin A elicited a robust TGFβ/SMAD activity, enhanced WNT signaling activity and promoted the generation of DE precursors. Nodal treatment resulted in lower TGFβ/SMAD activity, and a weaker, sustained WNT response, and ultimately failed to upregulate endoderm markers. This is despite signaling response resembling more closely the activity seen in vivo. These findings emphasize the importance of understanding the downstream activities of Activin A and Nodal signaling in directing in vitro endoderm differentiation of primed‐state epiblast stem cells.
Disease-Associated Multimolecular Signature in the Urine of Patients with Lyme Disease Detected Using Raman Spectroscopy and Chemometrics

A urine-based screening technique for Lyme disease (LD) was developed in this research. The screen is based on Raman spectroscopy, iterative smoothing-splines with root error adjustment (ISREA) spectral baselining, and chemometric analysis using Rametrix software. Raman spectra of urine from 30 patients with positive serologic tests (including the US Centers for Disease Control [CDC] two-tier standard) for LD were compared against subsets of our database of urine spectra from 235 healthy human volunteers, 362 end-stage kidney disease (ESKD) patients, and 17 patients with active or remissive bladder cancer (BCA). We found statistical differences (p < 0.001) between urine scans of healthy volunteers and LD-positive patients. We also found a unique LD molecular signature in urine involving 112 Raman shifts (31 major Raman shifts) with significant differences from urine of healthy individuals. We were able to distinguish the LD molecular signature as statistically different (p < 0.001) from the molecular signatures of ESKD and BCA. When comparing LD-positive patients against healthy volunteers, the Rametrix-based urine screen performed with 86.7% for overall accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. When considering patients with ESKD and BCA in the LD-negative group, these values were 88.7% (accuracy), 83.3% (sensitivity), 91.0% (specificity), 80.7% (PPV), and 92.4% (NPV). Additional advantages to the Raman-based urine screen include that it is rapid (minutes per analysis), is minimally invasive, requires no chemical labeling, uses a low-profile, off-the-shelf spectrometer, and is inexpensive relative to other available LD tests. Graphical Abstract
Associations between diabetes mellitus and the risk of hepatocellular carcinoma in Asian individuals with hepatitis B and C infection: systematic review and a meta-analysis of cohort studies

Supplemental Digital Content is available in the text. We aim to further analyze and compare associations between diabetes mellitus and the risk of hepatocellular carcinoma (HCC) in Asian individuals with hepatitis B or C virus infection by conducting an updated meta-analysis of cohort studies. Literature search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library from the beginning of indexing for each database to January 1, 2020. A total of 22 articles met the inclusion criteria, in which 18 were cohort studies and 4 were case-control studies. We identified eight cohort studies and three case-control studies that presented results on diabetes mellitus and the risk of HCC in Asian subjects with hepatitis B virus (HBV) infection: the cumulative relative risk (RR) with 95% confidence interval (CI) was 1.37 (95% CI: 1.24 to 1.51; I2 = 27.8%) for cohort studies and cumulative odds ratio (OR) with 95% CI was 1.99 (95% CI: 0.73 to 5.48; I2 = 88.4%) for case-control studies. Thirteen cohort studies and two case-control studies presented results on the association between diabetes mellitus and the risk of HCC in Asian subjects with hepatitis C virus (HCV) infection: the RR with 95% CI was 1.76 (95% CI: 1.42 to 2.17; I2 = 62.8%) for cohort studies and OR with 95% CI was 1.77 (95% CI: 1.18 to 2.64; I2 = 0.0%) for case-control studies. In summary, our meta-analysis strongly supports the association between coexistent HCV and diabetes with the increasing risk of HCC; although the results equally support diabetes mellitus being significantly associated with increased risk of HCC among patients with HBV infection, this correlation is weaker than the former.