Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutational signatures in T‐lymphocytes of rats treated with N‐propyl‐N‐nitrosourea and procarbazine

We have used whole genome sequencing (WGS) to determine mutational signatures induced in the T‐cells of rats treated in vivo with N‐propyl‐N‐nitrosourea (PNU) or procarbazine (PCZ). The signatures from the treated rats were different from the signature of background mutations. The main component of the spontaneous T‐cell mutational signature was C➔T transition with all other single base substitutions evenly distributed. The PNU‐induced mutational signature showed relatively equal contributions from C➔T and T➔C transitions, and T➔A transversions. The PCZ‐induced signature was characterized by T➔C transitions, T➔A and, to a smaller extent, T➔G transversions. C➔G transversions were infrequent in either the PNU or PCZ signatures. WGS not only allowed mutational signature detection, but also measured quantitative responses to mutagen treatment: 10–40× increases in the number of mutations per clone were detected in T‐cell clones from treated rats. The overall strand specificity of induced mutations for annotated rat genes was comparable to the strand specificity of mutations determined previously for the endogenous X‐linked Pig‐a gene. Our results provide valuable reference data for future applications of WGS in safety research and risk assessment.
Vitamin A and Vitamin E: Will the Real Antioxidant Please Stand Up?

Vitamin A, acting through its metabolite, all-trans-retinoic acid, is a potent transcriptional regulator affecting expression levels of hundreds of genes through retinoic acid response elements present within these genes. However, the literature is replete with claims that consider vitamin A to be an antioxidant vitamin, like vitamins C and E. This apparent contradiction in the understanding of how vitamin A acts mechanistically within the body is a major focus of this review. Vitamin E, which is generally understood to act as a lipophilic antioxidant protecting polyunsaturated fatty acids present in membranes, is often proposed to be a transcriptional regulator. The evaluation of this claim is another focus of the review. We conclude that vitamin A is an indirect antioxidant, whose indirect function is to transcriptionally regulate a number of genes involved in mediating the body's canonical antioxidant responses. Vitamin E, in addition to being a direct antioxidant, enables the increase of peroxidized lipids that alter both metabolic pathways and gene expression profiles within tissues and cells. However, there is little compelling evidence that vitamin E has a direct transcriptional mechanism like that of vitamin A. Thus, we propose that the term antioxidant not be applied to vitamin A, and we discourage the use of the term transcriptional mediator when discussing vitamin E. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Treating insomnia symptoms with medicinal cannabis: a randomized, crossover trial of the efficacy of a cannabinoid medicine compared with placebo

Abstract Study Objectives This randomized, double-blind, placebo-controlled, crossover study was conducted to evaluate the safety and efficacy of 2 weeks of nightly sublingual cannabinoid extract (ZTL-101) in treating chronic insomnia (symptoms ≥3 months). Methods Co-primary study endpoints were safety of the medication based on adverse event reporting and global insomnia symptoms (Insomnia Severity Index [ISI]). Secondary endpoints included: self-reported (sleep diary), actigraphy-derived, and polysomnography measurements of sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), sleep efficiency (SE); and self-reported assessments of sleep quality (sSQ) and feeling rested upon waking. Adjusted mean differences between placebo and ZTL-101 were calculated. Results Twenty-three of 24 randomized participants (n = 20 female, mean age 53 ± 9 years) completed the protocol. No serious adverse events were reported. Forty mild, nonserious, adverse events were reported (36 during ZTL-101) with all but one resolving overnight or soon after waking. Compared to placebo, ZTL-101 decreased ISI (−5.07 units [95% CI: −7.28 to −2.86]; p = 0.0001) and self-reported SOL (−8.45 min [95% CI: −16.33 to −0.57]; p = 0.04) and increased self-reported TST (64.6 min [95% CI: 41.70 to 87.46]; p < 0.0001), sSQ (0.74 units [95% CI: 0.51 to 0.97]; p < 0.0001), and feeling of being rested on waking (0.51 units [95% CI: 0.24 to 0.78]; p = 0.0007). ZTL-101 also decreased actigraphy-derived WASO (−10.2 min [95% CI: −16.2 to −4.2]; p = 0.002), and increased actigraphy-derived TST (33.4 min [95% CI: 23.07 to 43.76]; p < 0.001) and SE (2.9% [95% CI: 2.0 to 3.8]; p = 0.005). Conclusions Two weeks of nightly sublingual administration of a cannabinoid extract (ZTL-101) is well tolerated and improves insomnia symptoms and sleep quality in individuals with chronic insomnia symptoms. Clinical Trial ANZCTR; anzctr.org. au; ACTRN12618000078257.
Identifying biophysical assays and in silico properties that enrich for slow clearance in clinical-stage therapeutic antibodies

ABSTRACT Understanding the pharmacokinetic (PK) properties of a drug, such as clearance, is a crucial step for evaluating efficacy. The PK of therapeutic antibodies can be complex and is influenced by interactions with the target, Fc-receptors, anti-drug antibodies, and antibody intrinsic factors. A growing body of literature has linked biophysical properties of antibodies, particularly nonspecific-binding propensity, hydrophobicity and charged regions to rapid clearance in preclinical species and selected human PK studies. A clear understanding of the connection between biophysical properties and their impact on PK would allow for early selection and optimization of antibodies and reduce costly attrition during clinical trials due to sub-optimal human clearance. Due to the difficulty in obtaining large and unbiased human PK data, previous studies have focused mostly on preclinical PK. For this study, we obtained and curated the most comprehensive clinical PK dataset to date and calculated accurate estimates of linear clearance for 64 monoclonal antibodies ranging from investigational candidates in Phase 2 trials to marketed products. This allows for the first time a deep analysis of the influence of biophysical and sequence-based in silico properties directly on human clearance. We use statistical analysis and a Random Forest classifier to identify properties that have the greatest influence in our dataset. Our findings indicate that in vitro poly-specificity assay and in silico estimated isoelectric point can discriminate fast and slow clearing antibodies, extending previous observations on preclinical clearance. This provides a simple yet powerful approach to select antibodies with desirable PK during early-stage screening.
Quantitative Susceptibility Mapping for Staging Acute Cerebral Hemorrhages: Comparing the Conventional and Multiecho Complex Total Field Inversion magnetic resonance imaging MR Methods

The perceived acuity of intracerebral hemorrhage (ICH) impacts the management of patients, both within emergent and outpatient/urgent settings. Morphology enabled dipole inversion (MEDI) quantitative susceptibility imaging (QSM) has improved characterization of ICH acuity, despite outstanding limitations in distinguishing blood products.
Employment as a Plastic Surgeon

Abstract Intrinsic to the field of plastic surgery, constant changes in health care policy, consumer demands, and medical technology necessitate periodic evaluation of trends in employment over time. In this article, we review the existing literature to report the current state of plastic surgery employment in the United States with regards to compensation, practice patterns, subspecialty trends, contract negotiation, representation of women in the field of plastic surgery, burnout and job satisfaction, and retirement. Understanding how the plastic surgery job market is changing not only serves as a valuable tool for the individual plastic surgeon regarding the navigation of his or her own career but also offers insight into the future of the field as a whole.
Patient Demographics and Clinic Type Are Associated With Patient Engagement Within a Remote Monitoring Program.

Background: Remote physiological monitoring (RPM) is accessible, convenient, relatively inexpensive, and can improve clinical outcomes. Yet, it is unclear in which clinical setting or target population RPM is maximally effective. Objective: To determine whether patients' demographic characteristics or clinical settings are associated with data transmission and engagement. Methods: This is a prospective cohort study of adults enrolled in a diabetes RPM program for a minimum of 12 months as of April 2020. We developed a multivariable logistic regression model for engagement with age, gender, race, income, and primary care clinic type as variables and a second model to include first-order interactions for all demographic variables by time. The participants included 549 adults (mean age 53 years, 63% female, 54% Black, and 75% very low income) with baseline hemoglobin A1c ≥8.0% and enrolled in a statewide diabetes RPM program. The main measure was the transmission engagement over time, where engagement is defined as a minimum of three distinct days per week in which remote data are transmitted. Results: Significant predictors of transmission engagement included increasing age, academic clinic type, higher annual household income, and shorter time-in-program (p < 0.001 for each). Self-identified race and gender were not significantly associated with transmission engagement (p = 0.729 and 0.237, respectively). Conclusions: RPM appears to be an accessible tool for minority racial groups and for the aging population, yet engagement is impacted by primary care location setting and socioeconomic status. These results should inform implementation of future RPM studies, guide advocacy efforts, and highlight the need to focus efforts on maintaining engagement over time.
Improving selective targeting to cancer-associated fibroblasts by modifying liposomes with arginine based materials

Abstract A library of arginine-like surface modifiers was tested to improve the targetability of DOPE:DOPC liposomes towards myofibroblasts in a tumour microenvironment. Liposomes were characterised using zeta potential and dynamic light scattering. Cell viability remained unchanged for all liposomes. Liposomes were encapsulated using doxorubicin (DOX) with an encapsulation efficiency >94%. The toxicity of DOX-loaded liposomes was calculated via half-maximal inhibitory concentration (IC50) for fibroblasts and myofibroblasts. These liposomes resulted in significantly lower IC50-values for myofibroblasts compared to fibroblasts, making them more toxic towards the myofibroblasts. Furthermore, a significant increase in cell internalisation was observed for myofibroblasts compared to fibroblasts, using fluorescein-loaded liposomes. Most importantly, a novel regression model was constructed to predict the IC50-values for different modifications using their physicochemical properties. Fourteen modifications (A–N) were used to train and validate this model; subsequently, this regression model predicted IC50-values for three new modifications (O, P and Q) for both fibroblasts and myofibroblasts. Predicted and measured IC50-values showed no significant difference for fibroblasts. For myofibroblasts, modification O showed no significant difference. This study demonstrates that the tested surface modifications can improve targeting to myofibroblasts in the presence of fibroblasts and hence are suitable drug delivery vehicles for myofibroblasts in a tumour microenvironment.
Medicaid Expansion Association With End‐Stage Liver Disease Mortality Depends on Leniency of Medicaid Hepatitis C Virus Coverage

The Affordable Care Act expanded Medicaid around the same time that direct‐acting antivirals became widely available for the treatment of hepatitis C virus (HCV). However, there is significant variation in Medicaid HCV treatment eligibility criteria between states. We explored the combined effects of Medicaid expansion and leniency of HCV coverage under Medicaid on liver outcomes. We assessed state‐level end‐stage liver disease (ESLD) mortality rates, listings for liver transplantation (LT), and listing‐to‐death ratios (LDRs) for adults aged 25 to 64 years using data from United Network for Organ Sharing and Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research. States were divided into 4 nonoverlapping groups based on expansion status on January 1, 2014 (expansion versus nonexpansion) and leniency of Medicaid HCV coverage (lenient versus restrictive coverage). Joinpoint regression analysis evaluated the significant changes in slope over time (joinpoints) during the pre‐expansion (2009‐2013) and postexpansion (2014‐2018) time periods. We found significant changes in the annual percent change for population‐adjusted ESLD deaths between 2014 and 2015 in all cohorts except for the nonexpansion/restrictive cohort, in which deaths increased at the same annual percent change from 2009 to 2018 (annual percent change of +2.5%; 95% confidence interval [CI], 1.8‐3.3]). In the expansion/lenient coverage cohort, deaths increased at an annual percent change of +2.6% (95% CI, 1.8‐3.5) until 2014 and then tended to decrease at an annual percent change of −0.4% (95% CI, −1.5 to 0.8). LT listings tended to decrease over time for all cohorts. For LDRs, only the expansion/lenient and expansion/restrictive cohorts had statistically significant joinpoints. Improvements in ESLD mortality and LDRs were associated with both Medicaid expansion and leniency of HCV coverage under Medicaid. These findings suggest the importance of implementing more lenient and widespread public health insurance to improve liver disease outcomes, including mortality.
Development of a risk prediction nomogram for disposition of acute toxic exposure patients to intensive care unit

Early risk stratification of acutely poisoned patients is essential to identify patients at high risk of intensive care unit (ICU) admission. We aimed to develop a prognostic model and risk‐stratification nomogram based on the readily accessible clinical and laboratory predictors on admission for the probability of ICU admission in acutely poisoned patients. This retrospective cohort study included adult patients with acute toxic exposure to a drug or a chemical substance. Patients' demographic, toxicologic, clinical and laboratory data were collected. Among the 1260 eligible patients, 180 (14.3%) were admitted to the ICU. We developed a generalized prognostic model for predicting ICU admission in patients with acute poisoning. The predictors included the Glasgow coma scale, oxygen saturation, diastolic blood pressure, respiratory rate and blood bicarbonate concentration. The model displayed excellent discrimination and calibration (optimistic‐adjusted area under the curve = 0.924 and optimistic‐adjusted Hosmer and Lemeshow test = 0.922, respectively) when internally validated. Additionally, we developed prognostic models that determine ICU admission in patients with specific poisonings. Furthermore, we constructed risk‐stratification nomograms that rank the probability of ICU admission in these patients. The developed risk‐stratification nomograms help decision‐making regarding ICU admission in acute poisonings. Future external validation in independent cohorts is necessary before clinical application.
Mild Neurological Signs in FMR1 Premutation Women in an Unselected Community‐Based Cohort

Premutation‐sized (55–200) CGG repeat expansions in the FMR1 gene cause fragile X‐associated tremor/ataxia syndrome (FXTAS). Most studies of premutation carriers utilized reverse ascertainment to identify patients, leading to a selection bias for larger repeats. As shorter CGG premutation repeats are common in the population, understanding their impact on health outcomes has a potentially large public health footprint.
Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging‐related Alzheimer's disease (AD)‐like pathology. However, concerns over adverse effects have slowed the transition of common CN‐inhibiting drugs to the clinic for the treatment of AD and AD‐related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN‐mediated dephosphorylation of a non‐NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild‐type mice (3–4 months old) infused with oligomeric Aβ peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild‐type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aβ plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging‐related disorders.
Isokinetic Muscular Strength and Aerobic Physical Fitness in Recreational Long-Distance Runners: A Cross-Sectional Study

Abstract Andrade, MS, Silva, WA, de Lira, CAB, Mascarin, NC, Vancini, RL, Nikolaidis, PT, and Knechtle, B. Isokinetic muscular strength and aerobic physical fitness in recreational long-distance runners: A cross-sectional study. J Strength Cond Res 36(3): e73–e80, 2022—Muscular strength, bilateral asymmetry, and imbalance between antagonist muscles have been considered as risk factors for knee injuries. Moreover, muscular strength has also been associated with aerobic performance. The aim of the study was to investigate bilateral muscular symmetry and muscular strength balance assessed by isokinetic dynamometry in recreational long-distance runners and to verify whether knee muscular strength would be associated with maximal oxygen uptake (V̇o2max), anaerobic threshold (AT), and running economy (RE). Thirty-nine runners (male [n = 24]: age, 30 ± 8 years; height, 176.0 ± 7.3 cm; body mass, 70.3 ± 8.0 kg; race pace below 4:30 min·km−1 and female [n = 15]: age, 31 ± 7 years; height, 163.0 ± 3.8 cm; body mass, 55.9 ± 4.7 kg; race pace below 5:00 min·km−1) participated in this study. Comparing the conventional knee balance ratio with the literature recommendation (60%), male runners presented significantly lower values for the nondominant side (55.5 ± 7.3%; p = 0.001; d = 0.85; confidence interval [CI] = 0.47 to 1.20) but not for the dominant side (58.1 ± 6.8%; p = 0.208; d = 0.37; CI = −0.12 to 0.86). Female runners presented lower values for both sides (52.1 ± 7.1%; p = 0.001; d = 1.55; CI = 0.86 to 2.20 and 50.7 ± 8.0%; p = 0.001; d = 1.62; CI = 0.90 to 2.30 for dominant and nondominant sides, respectively). Female and male runners presented nonfunctional ratio imbalance and asymmetry of bilateral strength. Strength outcomes were not associated with V̇o2max, AT, or RE. In conclusion, recreational runners were characterized by an imbalance in muscular strength between knee flexor and extensor muscles, which was more obvious in female runners, and by symmetrical thigh muscle strength values. Moreover, muscular isokinetic knee flexor and extensor muscle strength was not associated with aerobic fitness parameters.
Impact of spectral saturation on leaf area index and aboveground biomass estimation of winter wheat

ABSTRACT The saturation problem associated with the use of normalized difference vegetation index for crop variable estimation is well known. However, its physical mechanism is not systemically explored. The wavebands computing the vegetation indices also suffered saturation when the leaf area index and aboveground biomass reached to 2.5 and 1 kg m−2, respectively. We thought that the saturation might be not only referred to normalized difference vegetation index, but also to certain wavebands. Furthermore, the performances of seven different vegetation indices were assessed on overcoming the saturation. The findings will improve our understanding of the spectral saturation.
Vasodilatation by carbon dioxide and sodium nitroglycerin reduces compliance of the cerebral arteries in humans

What is the central question of this study? Vascular compliance importantly contributes to the regulation of cerebral perfusion and complex mechanisms are known to influence compliance of a vascular bed: while vasodilatation mediates changes in vascular resistance, does it also affect compliance, particularly in the cerebral vasculature? What is the main finding and its importance? Cerebral vasodilatation, elicited by hypercapnia and sodium nitroglycerin administration, reduced cerebrovascular compliance by approximately 26% from baseline. This study provides new insight into mechanisms mediating cerebrovascular compliance.
Assessment of mortality and performance status in critically ill cancer patients: A retrospective cohort study

Introduction Given clinicians’ frequent concerns about unfavourable outcomes, Intensive Care Unit (ICU) triage decisions in acutely ill cancer patients can be difficult, as clinicians may have doubts about the appropriateness of an ICU admission. To aid to this decision making, we studied the survival and performance status of cancer patients 2 years following an unplanned ICU admission. Materials and methods This was a retrospective cohort study in a large tertiary referral university hospital in the Netherlands. We categorized all adult patients with an unplanned ICU admission in 2017 into two groups: patients with or without an active malignancy. Descriptive statistics, Pearson’s Chi-square tests and the Mann-Whitney U tests were used to evaluate the primary objective 2-year mortality and performance status. A good performance status was defined as ECOG performance status 0 (fully active) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out light work). A multivariable binary logistic regression analysis was used to identify factors associated with 2-year mortality within cancer patients. Results Of the 1046 unplanned ICU admissions, 125 (12%) patients had cancer. The 2-year mortality in patients with cancer was significantly higher than in patients without cancer (72% and 42.5%, P <0.001). The median performance status at 2 years in cancer patients was 1 (IQR 0–2). Only an ECOG performance status of 2 (OR 8.94; 95% CI 1.21–65.89) was independently associated with 2-year mortality. Conclusions In our study, the majority of the survivors have a good performance status 2 years after ICU admission. However, at that point, three-quarter of these cancer patients had died, and mortality in cancer patients was significantly higher than in patients without cancer. ICU admission decisions in acutely ill cancer patients should be based on performance status, severity of illness and long-term prognosis, and this should be communicated in the shared decision making. An ICU admission decision should not solely be based on the presence of a malignancy.