Miracle-dz/UniFAR-FTUs huggingface dataset:
Cerebrospinal Fluid Penetration of Ceftolozane-Tazobactam in Critically Ill Patients with an Indwelling External Ventricular Drain

The aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. ABSTRACT The aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modeled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (interquartile range [IQR]) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19 to 128) h·mg/liter and 323 (183 to 414) h·mg/liter, respectively. For tazobactam, these values were 5.6 (2 to 24) h·mg/liter and 52 (36 to 80) h·mg/liter, respectively. Mean ± standard deviation (SD) CSF penetration ratios were 0.2 ± 0.2 and 0.2 ± 0.26 for ceftolozane and tazobactam, respectively. With the regimen of 3.0 g every 8 h, a probability of target attainment (PTA) of ≥0.9 for 40% fT>MIC in the CSF was possible only when MICs were ≤0.25 mg/liter. The CSF cumulative fractional response for Pseudomonas aeruginosa-susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT>1 mg/liter was 12%. The current maximal dose of ceftolozane-tazobactam (3.0 g every 8 h) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/liter).
Piglet production by non‐surgical transfer of vitrified embryos, transported to commercial swine farms and warmed on site

Abstract We investigated the feasibility of piglet production by non‐surgical embryo transfer (Ns‐ET) of vitrified porcine blastocysts and expanded blastocysts transported to commercial farms and warmed on site (V/T/W embryos). Ns‐ET was performed by depositing 11–20 vitrified and warmed embryos at a proximal site within the uterus via a catheter. In Experiment 1, the effect of donor–recipient estrous cycle asynchrony on the efficiency of Ns‐ET of vitrified and ordinary warmed embryos was investigated at the experimental facility. With a 1‐day delay recipients relative to that of donor, the farrowing rate was 50.0% and the survival rate to term was 21.1%. In Experiment 2, Ns‐ET using recipients with a 1‐day delay and vitrified embryos after one‐step warming and dilution was evaluated at the experimental facility. Although the resulting farrowing rate was 42.9%, the survival rate was 6.4%. In Experiment 3, Ns‐ET was conducted using V/T/W embryos at four commercial farms, where piglets derived from them were produced. When artificial insemination was conducted prior to Ns‐ET, the farrowing and survival rates obtained using V/T/W embryos were 75.0%, and 21.3%, respectively. These results show that Ns‐ET of V/T/W embryos using this protocol would be feasible for piglet production at farms.
Chronic opioid exposure differentially modulates oxycodone self‐administration in male and female rats

Withdrawal from opioid painkillers can produce short‐lived physical symptoms and protracted psychological symptoms including anxiety and depressive‐like states that often lead to opioid misuse and opioid use disorder (OUD). Studies testing the hypothesis that opioid withdrawal potentiates the reinforcing effects of opioid self‐administration (SA) are largely inconclusive and have focused on males. Although some clinical evidence indicates that women are more likely than men to misuse opioids to self‐medicate, preclinical studies in both sexes are lacking. Based on clinical reports, we hypothesized that withdrawal from escalating‐dose morphine injections that approximates a prescription painkiller regimen would lead to increased oxycodone SA to a greater extent in female compared to male rats. After escalating‐dose morphine (5–30 mg/kg or vehicle, twice/day for 12 days), rats underwent a 2‐week abstinence period during which withdrawal signs were measured. The impact of this treatment was assessed on oxycodone SA acquisition, maintenance, dose response, and progressive ratio responding, with additional analyses to compare sexes. We found that both sexes expressed somatic withdrawal, whereas only males demonstrated hyperalgesia in the warm water tail flick assay. During SA acquisition, males with prior morphine exposure took significantly more oxycodone than females. Finally, females with prior morphine exposure demonstrated the lowest motivation to SA oxycodone in the progressive ratio test. Contrary to our initial hypothesis, our findings suggest that prior opioid exposure increases vulnerability to initiate misuse more in males and decreases the reinforcing efficacy of oxycodone in females.
Assessment of Stem Volume on Plots Using Terrestrial Laser Scanner: A Precision Forestry Application

Timber volume is an important asset, not only as an ecological component, but also as a key source of present and future revenues, which requires precise estimates. We used the Trimble TX8 survey-grade terrestrial laser scanner (TLS) to create a detailed 3D point cloud for extracting total tree height and diameter at breast height (1.3 m; DBH). We compared two different methods to accurately estimate total tree heights: the first method was based on a modified version of the local maxima algorithm for treetop detection, “HTTD”, and for the second method we used the centers of stem cross-sections at stump height (30 cm), “HTSP”. DBH was estimated by a computationally robust algebraic circle-fitting algorithm through hierarchical cluster analysis (HCA). This study aimed to assess the accuracy of these descriptors for evaluating total stem volume by comparing the results with the reference tree measurements. The difference between the estimated total stem volume from HTTD and measured stems was 2.732 m3 for European oak and 2.971 m3 for Norway spruce; differences between the estimated volume from HTSP and measured stems was 1.228 m3 and 2.006 m3 for European oak and Norway spruce, respectively. The coefficient of determination indicated a strong relationship between the measured and estimated total stem volumes from both height estimation methods with an R2 = 0.89 for HTTD and R2 = 0.87 for HTSP for European oak, and R2 = 0.98 for both HTTD and HTSP for Norway spruce. Our study has demonstrated the feasibility of finer-resolution remote sensing data for semi-automatic stem volumetric modeling of small-scale studies with high accuracy as a potential advancement in precision forestry.
Ultrasound-guided subparaneural popliteal sciatic nerve block: there is more to it than meets the eyes

The popliteal sciatic nerve block is routinely used for anesthesia and analgesia during foot and ankle surgery. This article reviews our current understanding of the anatomy of the sciatic nerve and discusses how fascial tissue layers associated with the nerve may affect block outcomes . The anatomy of the sciatic nerve is more complex than previously described. The tibial and common peroneal nerves within the sciatic nerve trunk appear to be centrally separated by the Compton-Cruveilhier septum and encompassed by their own paraneural sheaths. This unique internal architecture of the sciatic nerve appears to promote proximal spread of local anesthetic to the internal aspect of the sciatic nerve trunk after a subparaneural injection at or below the divergence of the tibial and common peroneal nerves.
Relationship and Effects of Community Problems on Anxiety and Suicide

Abstract This study aimed to explore the relationship and the effects of community problems on anxiety and suicide. Data were from a case-control psychological autopsy study (392 suicides and 416 community living controls) carried out in 16 rural counties from three provinces in China. The World Health Organization Suicide Prevention–Multisite Intervention Study on Suicidal behaviors scale of community stress and problems and Spielberger State-Trait Anxiety Inventory were used to measure the community problems and trait anxiety. Spearman's correlation and multivariable regression methods were used to probe the effect of community problems on anxiety and suicide. There were 12 and 6 community problems correlated with anxiety (rs = 0.169, p < 0.001) and suicide (rs = 0.081, p = 0.022), respectively. Medical care, alcohol abuse, superstition, and job security were important community problems for anxiety and suicide. Community problems had stronger correlation with anxiety than suicide. It might be an effective method to reduce anxiety and suicide risk by solving different community problems.
Pulmonary and systemic toxicity in rats following inhalation exposure of 3-D printer emissions from acrylonitrile butadiene styrene (ABS) filament

Abstract Background Fused filament fabrication 3-D printing with acrylonitrile butadiene styrene (ABS) filament emits ultrafine particulates (UFPs) and volatile organic compounds (VOCs). However, the toxicological implications of the emissions generated during 3-D printing have not been fully elucidated. Aim and methods The goal of this study was to investigate the in vivo toxicity of ABS-emissions from a commercial desktop 3-D printer. Male Sprague Dawley rats were exposed to a single concentration of ABS-emissions or air for 4 hours/day, 4 days/week for five exposure durations (1, 4, 8, 15, and 30 days). At 24 hours after the last exposure, rats were assessed for pulmonary injury, inflammation, and oxidative stress as well as systemic toxicity. Results and discussion 3-D printing generated particulate with average particle mass concentration of 240 ± 90 µg/m³, with an average geometric mean particle mobility diameter of 85 nm (geometric standard deviation = 1.6). The number of macrophages increased significantly at day 15. In bronchoalveolar lavage, IFN-γ and IL-10 were significantly higher at days 1 and 4, with IL-10 levels reaching a peak at day 15 in ABS-exposed rats. Neither pulmonary oxidative stress responses nor histopathological changes of the lungs and nasal passages were found among the treatments. There was an increase in platelets and monocytes in the circulation at day 15. Several serum biomarkers of hepatic and kidney functions were significantly higher at day 1. Conclusions At the current experimental conditions applied, it was concluded that the emissions from ABS filament caused minimal transient pulmonary and systemic toxicity.
Investigating the trade-off between folding and function in a multidomain Y-family DNA polymerase

The way in which multidomain proteins fold has been a puzzling question for decades. Until now, the mechanisms and functions of domain interactions involved in multidomain protein folding have been obscure. Here, we develop structure-based models to investigate the folding and DNA-binding processes of the multidomain Y-family DNA polymerase IV (DPO4). We uncover shifts in the folding mechanism among ordered domain-wise folding, backtracking folding, and cooperative folding, modulated by interdomain interactions. These lead to ‘U-shaped’ DPO4 folding kinetics. We characterize the effects of interdomain flexibility on the promotion of DPO4–DNA (un)binding, which probably contributes to the ability of DPO4 to bypass DNA lesions, which is a known biological role of Y-family polymerases. We suggest that the native topology of DPO4 leads to a trade-off between fast, stable folding and tight functional DNA binding. Our approach provides an effective way to quantitatively correlate the roles of protein interactions in conformational dynamics at the multidomain level.
Detection of Borrelia burgdorferi Sensu Lato and Relapsing Fever Borrelia in Feeding Ixodes Ticks and Rodents in Sarawak, Malaysia: New Geographical Records of Borrelia yangtzensis and Borrelia miyamotoi

Members of the Borrelia burgdorferi sensu lato (Bbsl) complex are etiological agents of Lyme disease (LD), and Borrelia miyamotoi is one of the relapsing fever Borrelia (RFB). Despite the serological evidence of LD in Malaysia, there has been no report from Sarawak, Malaysian Borneo. Thus, this study aimed to detect and characterize Borrelia in rodents and Ixodes ticks from primary forests and an oil palm (OP) plantation in Sarawak. Borrelia yangtzensis (a member of the Bbsl complex) was detected in 43.8% (14/32) of Ixodes granulatus; most of the positive ticks were from the OP plantation (13/14). Out of 56 rodents, B. yangtzensis was detected in four Rattus spp. from the OP plantation and B. miyamotoi was detected in one rodent, Sundamys muelleri, from the primary forest. Further, the positive samples of B. yangtzensis were randomly selected for multilocus sequence analysis (MLSA). The MLSA results of successfully amplified tick samples revealed a clustering with the sequences isolated from Japan and China. This study is the first evidence of B. miyamotoi, a known human pathogen in Malaysia, and B. yangtzensis, which is circulating in ticks and rodents in Sarawak, Malaysian Borneo, and presenting a new geographical record of the Borrelia spp.
Epigenetic Aberrations in Multiple Myeloma

Simple Summary Multiple Myeloma (MM) is a blood cancer characterized by an uncontrolled growth of cells named plasma cells, within the bone marrow. Patients with MM may present with anemia, bone lesions and kidney impairment. Several studies have been performed in order to provide an explanation to how this tumor may develop. Among them, the so called “epigenetic modifications” certainly represent important players that have been shown to support MM development and disease progression. The present article aims to summarize the current knowledge in the specific are of “epigenetics” in MM. Abstract Multiple myeloma (MM) is a plasma cell dyscrasia characterized by proliferation of clonal plasma cells within the bone marrow. Several advances in defining key processes responsible for MM pathogenesis and disease progression have been made; and dysregulation of epigenetics, including DNA methylation and histone modification, has emerged as a crucial regulator of MM pathogenesis. In the present review article, we will focus on the role of epigenetic modifications within the specific context of MM.
Cancer‐associated mutations in the condensin II subunit CAPH2 cause genomic instability through telomere dysfunction and anaphase chromosome bridges

Genome instability in cancer drives tumor heterogeneity, undermines the success of therapies, and leads to metastasis and recurrence. Condensins are conserved chromatin‐binding proteins that promote genomic stability, mainly by ensuring proper condensation of chromatin and mitotic chromosome segregation. Condensin mutations are found in human tumors, but it is not known how or even if such mutations promote cancer progression. In this study, we focus on condensin II subunit CAPH2 and specific CAPH2 mutations reported to be enriched in human cancer patients, and we test how CAPH2 cancer‐specific mutations may lead to condensin II complex dysfunction and contribute to genome instability. We find that R551P, R551S, and S556F mutations in CAPH2 cause genomic instability by causing DNA damage, anaphase defects, micronuclei, and chromosomal instability. DNA damage and anaphase defects are caused primarily by ataxia telangiectasia and Rad3‐related‐dependent telomere dysfunction, as anaphase bridges are enriched for telomeric repeat sequences. We also show that these mutations decrease the binding of CAPH2 to the ATPase subunit SMC4 as well as the rest of the condensin II complex, and decrease the amount of CAPH2 protein bound to chromatin. Thus, in vivo the R551P, R551S, and S556F cancer‐specific CAPH2 mutant proteins are likely to impair condensin II complex formation, impede condensin II activity during mitosis and interphase, and promote genetic heterogeneity in cell populations that can lead to clonal outgrowth of cancer cells with highly diverse genotypes.
Immune activation of Bio-Germanium in a randomized, double-blind, placebo-controlled clinical trial with 130 human subjects: Therapeutic opportunities from new insights

Germanium has long been considered a therapeutic agent with anticancer, antitumor, antiaging, antiviral and anti-inflammatory effects. Numerous clinical studies have explored the promising therapeutic effects of organic germanium on cancer, arthritis and senile osteoporosis. The immune activation property of organic germanium is considered the foundation of its various therapeutic effects. However, previous human clinical studies investigating immune activation with organic germanium compounds have certain limitations, as some studies did not strictly follow a randomized, double-blind, placebo-controlled design. To build a more clinically substantiated foundation for the mechanism underlying its immunostimulation, we structured by far the most rigorous clinical study to-date with a group of 130 human subjects to examine changes in immune profiles following germanium supplementation. We used Bio-Germanium, an organic germanium compound naturally synthesized via a yeast fermentation process. An 8-week randomized, double-blind, placebo-controlled study was conducted with 130 subjects with leukocyte counts of 4–8 (×103/μL) divided into the Bio-Germanium group and the placebo group. Anthropometric measurements; blood collection; biochemical analysis; urinalysis; and natural killer cell activity, cytokine and immunoglobulin assays were conducted. Results showed the Bio-Germanium group exhibited NK cell activity increases at effector cell:target cell (E:T) ratios of 50:1, 10:1, 5:1 and 2.5:1 (12.60±32.91%, 10.19±23.88%, 9.28±16.49% and 7.27±15.28%, respectively), but the placebo group showed decreases (P<0.01). The difference in the IgG1 change from baseline to follow-up between the Bio-Germanium and placebo groups was significant (P = 0.044). Our results and earlier clinical study of Bio-Germanium confirm that Bio-Germanium acts as an effective immunostimulant by increasing the cytotoxicity of NK cells and activating immunoglobulin, B cells and tumor necrosis factor (TNF)-α (P<0.05). As we have added newly discovered clinical findings for germanium’s immunostimulation mechanism, we believe Bio-Germanium is a highly promising therapeutic agent and should certainly be further explored for potential development opportunities in immunotherapy. Registered clinical trial [NCT03677921]; www.clinicaltrials. gov [KCT0002726]; https://cris.nih. go.kr
Assessment of Statin Interactions With the Human NTCP Transporter Using a Novel Fluorescence Assay

Sodium taurocholate cotransporting polypeptide (NTCP), which is highly expressed in the sinusoidal membrane of hepatocytes, maintains bile acid homeostasis and participates in the hepatic disposition of a variety of endogenous substances as well as xenobiotics. Manifested by the involvement of organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) in the hepatic uptake of statin drugs, sinusoidal membrane transporters play an important role in the pharmacokinetics and pharmacodynamics of these agents. It has been speculated that NTCP may function as an alternative pathway for statin hepatic uptake, complementary to OATP1B1 and OATP1B3. In the current study, we produced stable NTCP-expressing human embryonic kidney 293 (HEK293) cells and developed a fluorescence-based assay using flow cytometry for measuring NTCP transport with chenodeoxycholyl-(Nε-7-nitrobenz-2-oxa-1,3-diazole)-lysine (CDCA-NBD) as the substrate. NTCP-mediated CDCA-NBD transport was time-dependent and exhibited typical Michaelis–Menten kinetics, with a K m of 6.12 µM. Compounds known to interact with NTCP, including chenodeoxycholic acid and taurocholic acid, displayed concentration-dependent inhibition of NTCP-mediated CDCA-NBD transport. We report here a systematic evaluation of the interaction between statins and the NTCP transporter. Utilizing this system, several statins were either found to inhibit NTCP-dependent transport or act as substrates. We find a good correlation between the reported lipophilicity of statins and their ability to inhibit NTCP. The objective was to develop a higher-throughput system to evaluate potential inhibitors such as the statins. The in vitro assays using CDCA-NBD as fluorescent substrate are convenient, rapid, and have utility in screening drug candidates for potential drug–NTCP interactions.
Diagnostic Test Accuracy of the 4AT for Delirium Detection: A Systematic Review and Meta-Analysis

Under-recognition of delirium is an international problem. For the early detection of delirium, a feasible and valid screening tool for healthcare professionals is needed. This study aimed to present a scientific reason for using the 4 ‘A’s Test (4AT) through a systematic review and meta-analysis of studies on the diagnostic test accuracy. We systematically searched articles in the EMBASE, MEDLINE, CINAHL, and PsycINFO databases and selected relevant articles on the basis of the predefined inclusion criteria. The quality of the included articles was evaluated using the Quality Assessment of the Diagnostic Accuracy Studies-2 tool. We estimated the pooled values of diagnostic test accuracy by employing the bivariate model and the hierarchical summary receiver operating characteristic (HSROC) model in data synthesis. A total of 3729 patients of 13 studies were included in the analysis. The pooled estimates of sensitivity and specificity of the 4AT were 81.5% (95% confidence interval: 70.7%, 89.0%) and 87.5% (79.5%, 92.7%), respectively. Given the 4AT’s evidence of accuracy and practicality, we suggest healthcare professionals to utilize this tool for routine screening of delirium. However, for detecting delirium in the dementia population, further work is required to evaluate the 4AT with other cut-off points or scoring methods in order for it to be more sensitive and specific.
How age and infection history shape the antigen‐specific CD8+ T‐cell repertoire: Implications for vaccination strategies in older adults

Older adults often show signs of impaired CD8+ T‐cell immunity, reflected by weaker responses against new infections and vaccinations, and decreased protection against reinfection. This immune impairment is in part thought to be the consequence of a decrease in both T‐cell numbers and repertoire diversity. If this is indeed the case, a strategy to prevent infectious diseases in older adults could be the induction of protective memory responses through vaccination at a younger age. However, this requires that the induced immune responses are maintained until old age. It is therefore important to obtain insights into the long‐term maintenance of the antigen‐specific T‐cell repertoire. Here, we review the literature on the maintenance of antigen‐experienced CD8+ T‐cell repertoires against acute and chronic infections. We describe the complex interactions that play a role in shaping the memory T‐cell repertoire, and the effects of age, infection history, and T‐cell avidity. We discuss the implications of these findings for the development of new vaccination strategies to protect older adults.