Miracle-dz/UniFAR-FTUs huggingface dataset:
Population pharmacokinetics of letermovir following oral and intravenous administration in healthy participants and allogeneic hematopoietic cell transplantation recipients

Letermovir is indicated for prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Two‐stage population pharmacokinetic (PK) modeling of letermovir was conducted to support dose rationale and evaluate the impact of intrinsic/extrinsic factors. Data from healthy phase I study participants over a wide dose range were modeled to evaluate the effects of selected intrinsic factors, including pharmacogenomics; next, phase III HSCT‐recipient data at steady‐state following clinical doses were modeled. The model in HSCT recipients adequately described letermovir PK following both oral or i.v. administration, and was consistent with the healthy participant model at steady‐state clinical doses. Intrinsic factor effects were not clinically meaningful. These staged analyses indicate that letermovir PK in HSCT recipients and healthy participants differ only with respect to bioavailability and absorption rate. The HSCT recipient model was suitable for predicting exposure for exposure–response analysis supporting final dose selection.
Perspective: Weekly Iron and Folic Acid Supplementation (WIFAS): A Critical Review and Rationale for Inclusion in the Essential Medicines List to Accelerate Anemia and Neural Tube Defects Reduction

ABSTRACT Weekly iron and folic acid supplementation (WIFAS) is among the 8 key effective actions for improving adolescent nutrition included by the WHO in the 2018 guidelines. However, at present WIFAS in the WHO-recommended formulation is not included in the Model Essential Medicines List (MEML), limiting the potential for countries to import, produce, and prioritize this formulation as part of their national supply management and procurement plans for medicines. The WHO WIFAS guideline presents evidence that the formulation reduces anemia, but not that folic acid reduces neural tube defects (NTDs), because sufficient evidence was unavailable at the time of the last review. Recently, a 3-arm, parallel-group, randomized, double-blind, placebo-controlled folic acid efficacy trial on WIFAS was conducted to address this evidence gap. The study population included 331 women (18–45 y old), randomly assigned to 3 treatment groups, including a supplement with 60 mg Fe as ferrous fumarate and either 0 mg, 0.4 mg, or 2.8 mg of folic acid, to be consumed once weekly for 16 wk, followed by a 4-wk washout period. In this article we critically review how the outcomes of this folic acid efficacy trial, and how the evidence generated, could potentially be used to inform WHO WIFAS guidelines for the potential inclusion of this formulation on the MEML, and how this, in turn, may affect product availability. If the new evidence on weekly folic acid is assessed as adequately reducing the risk of NTDs, a guideline revision could be warranted and WIFAS could be presented to the MEML for the dual benefits of anemia reduction and NTD prevention. This inclusion could enable acceleration of implementing policies and programs to contribute to global anemia and NTD reduction efforts.
Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus

Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age‐related cognitive impairment. However, metformin's therapeutic use as an anti‐aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen‐month‐old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate‐activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain.
From Environmental to Possible Occupational Exposure to Risk Factors: What Role Do They Play in the Etiology of Endometriosis?

Endometriosis is a gynecological disorder characterized by the presence of endometrial stroma and glands outside the uterine cavity. A systematic review of the literature was conducted to clarify, starting from environmental exposure data, whether possible occupational risk factors may correlate with the onset of the disease. The guidelines for reporting systematic reviews of the “PRISMA” statement were followed and two databases, Scopus and PubMed, were used. Of the 422 studies selected with specific keywords, 32 publications were eligible, 28 of which referred to chemical agents and 4 related to night work. Conflicting data emerged among these studies. Although some compounds seemed to be more involved than others in the onset of endometriosis. Association with exposure to organochlorine compounds is the most supported by the epidemiological data, while other pesticide exposure did not show any clear correlation. Likewise, the hypothesis of a correlation with perfluoroalkyls exposure is not currently supported by data. The involvement of metals as risk factors has not been confirmed, while the role of night work, in the case of long service, seems to play an etiological role. In order to clarify the potential occupational risk of endometriosis development, well-designed studies are needed to evaluate the potential association between chemical compounds and disease etiology.
Detection of Hypoxanthine from Inosine and Unusual Hydrolysis of Immunosuppressive Drug Azathioprine through the Formation of a Diruthenium(III) System

Hypoxanthine (hpx) is an important molecule for both biochemistry research and biomedical applications. It is involved in several biological processes associated to energy and purine metabolism and has been proposed as a biomarker for a variety of disease states. Consequently, the discovery and development of systems suitable for the detection of hypoxanthine is pretty appealing in this research field. Thus, we have obtained a stable diruthenium (III) compound in its dehydrated and hydrated forms with formula [{Ru(µ-Cl)(µ-hpx)}2Cl4] (1a) and [{Ru(µ-Cl)(µ-hpx)}2Cl4]·2H2O (1b), respectively. This purine-based diruthenium(III) system was prepared from two very different starting materials, namely, inosine and azathioprine, the latter being an immunosuppressive drug. Remarkably, it was observed that an unusual azathioprine hydrolysis occurs in the presence of ruthenium, thus generating hypoxanthine instead of the expected 6-mercaptopurine antimetabolite, so that the hpx molecule is linked to two ruthenium(III) ions. 1a and 1b were characterized through IR, SEM, powder and single-crystal X-ray Diffraction and Cyclic Voltammetry (CV). The electrochemical studies allowed us to detect the hpx molecule when coordinated to ruthenium in the reported compound. The grade of sensitivity, repeatability and stability reached by this diruthenium system make it potentially useful and could provide a first step to develop new sensor devices suitable to detect hypoxanthine.
Bile Acid Sequestrant Therapy in Microscopic Colitis

Goals: There is an unmet need in investigating corticosteroid-sparing treatments for induction and maintenance of remission in microscopic colitis (MC). The authors’ aim was to evaluate the outcomes of patients with MC treated with bile acid sequestrants (BAS). Background: MC is a common chronic diarrheal illness. Budesonide is effective induction therapy, but relapses are high after cessation of treatment. Study: Our cohort consisted of patients enrolled in our institutional MC registry, a biorepository of histology-confirmed diagnoses of MC. Patients receiving BAS for the treatment of MC were reviewed at each clinical visit for efficacy or ability to decrease budesonide maintenance dosing. Results: The authors included 79 patients (29 collagenous colitis and 50 lymphocytic colitis) with a median follow-up period of 35 months (range, 1 to 120). Most patients were female individuals (78%) and the median age was 69 years (range, 29 to 87). BAS therapy was used in 21 patients who were budesonide-naive, with a response rate of 76% (16/21). In patients treated previously with budesonide, 46 patients were budesonide-dependent and given BAS as maintenance therapy. Of these patients, 23 (50%) were able to decrease their budesonide dosing and 9 (20%) were able to stop budesonide completely. Seven of 46 patients (15%) stopped BAS because of intolerance, perceived lack of benefit, or treatment of concomitant diarrhea illness. Conclusions: BAS may be an effective corticosteroid-sparing option in the treatment of MC and should be considered after budesonide induction. Larger controlled studies are needed to confirm the efficacy for long-term maintenance and tolerability of BAS in patients with MC.
A survey of ewe mortality on the Central Tablelands of New South Wales in 2010, a year of above-average rainfall.

BACKGROUND Sheep producers reported elevated ewe mortality following a wetter-than-average season on the tablelands of New South Wales in 2010. We conducted a survey of local producers to determine the extent and cause of ewe losses, as well as associated risk factors. METHODS A questionnaire was designed and posted to sheep producers running at least 1000 sheep. Data from questionnaires were analysed using linear mixed models to identify risk factors associated with ewe mortality. Data on the likely causes of deaths, particularly those associated with foot abscess, were analysed by ordinal generalised linear mixed models to determine the most prevalent causes of ewe death. RESULTS The mean annual ewe mortality was 5.4% (range 0.1%-28.6%). Higher mortality was associated with older ewes and lambing in paddocks with longer pastures. The two most important causes of ewe death reported by farmers were 'died during lambing' and 'foot abscess'. Mortality due to foot abscess was more commonly reported in adult ewes than maiden ewes (odds ratio and 95% confidence interval: 5.61; 3.52, 8.94), when lambing on pasture longer than 5 cm than ≤5 cm (2.96; 1.54, 5.70) and when lambing in spring than in autumn (4.87; 1.36, 17.41). CONCLUSIONS The level of ewe mortality observed was at the upper end of that reported previously in Australia. Risk factor analysis suggested that, in wet years, losses due to foot abscess could be reduced by lambing older heavier ewes in autumn on pasture swards less than 5 cm high.
A mechanistic model for long-term immunological outcomes in South African HIV-infected children and adults receiving ART

Long-term effects of the growing population of HIV-treated people in Southern Africa on individuals and the public health sector at large are not yet understood. This study proposes a novel ‘ratio’ model that relates CD4+ T-cell counts of HIV-infected individuals to the CD4+ count reference values from healthy populations. We use mixed-effects regression to fit the model to data from 1616 children (median age 4.3 years at ART initiation) and 14,542 adults (median age 36 years at ART initiation). We found that the scaled carrying capacity, maximum CD4+ count relative to an HIV-negative individual of similar age, and baseline scaled CD4+ counts were closer to healthy values in children than in adults. Post-ART initiation, CD4+ growth rate was inversely correlated with baseline CD4+ T-cell counts, and consequently higher in adults than children. Our results highlight the impacts of age on dynamics of the immune system of healthy and HIV-infected individuals.
Impact of cell harvesting methods on detection of cell surface proteins and apoptotic markers

Assays based on the flow cytometry technique allow a convenient analysis of multiple cellular parameters; however, their results should be interpreted cautiously due to a strong impact of confounding factors. Different techniques in cell culturing such as either enzymatic or mechanic detachment of adherent cells can heavily influence the structure of the cell membrane or presence of the surface antigens leading to strong false positive signals, and finally, substantial experimental bias. The aim of our study was to assess and compare the impact of cell harvesting methods (both enzymatic and non-enzymatic) on the apoptosis process and on the surface antigen cytometric analyses. We found significant differences in the quality of analysis in terms of the amount of detected surface markers determined by the detachment method. Our results demonstrated clearly how important it is to carefully choose the appropriate detachment method and may help to avoid mistakes in experiment planning. In conclusion, we recommend to adjust the detachment method to the type of analyzed markers (surface antigens or translocated phosphatidylserine).
Glenoid Component Loosening in Anatomic Total Shoulder Arthroplasty: Association between Radiological Predictors and Clinical Parameters—An Observational Study

The mechanisms of glenoid component loosening in anatomic total shoulder arthroplasty (aTSA) are still unclear, and it remains undetermined which specific radiographic features are associated with clinical outcomes. Patients with primary osteoarthritis who underwent aTSA with a stemless implant and a pegged glenoid between January 2011 and December 2016 were extracted from a local registry. Anteroposterior radiographs were evaluated at six, 12, 24 months, and five years post-TSA for lateral humeral offset (LHO), joint gap (JG), acromiohumeral distance (AHD), and radiolucency (modified Franklin score); 147 patients were included. Mixed-model linear regression was used. Both constant score (CS) and subjective shoulder value (SSV) markedly decreased at five years follow-up compared to one year (p < 0.001 for both). AHD, LHO, and JG all showed a consistent and statistically significant decline over time, with the joint gap decreasing by half. Consistently, smaller JG and AHD were correlated with lower SSV (p = 0.03 and p = 0.07, respectively). Massive loosening was associated with a 14.5 points lower SSV (p < 0.01). Finally, narrowing of the JG was significantly correlated with increased radiolucency (p < 0.001) and tended toward worse SSV (p = 0.06). In summary, radiographic parameters displaying medialization and cranialization after aTSA with a cemented pegged glenoid are useful predictors of impaired shoulder function.
Aging of human hematopoietic stem cells is linked to changes in Cdc42 activity

In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSC). We report increased frequencies of HSC, hematopoietic progenitor cells and lineage negative cells in the elderly but a decreased frequency of multi-lymphoid progenitors. Aged human HSC further exhibited a delay in initiating division ex vivo though without changes in their division kinetics. The activity of the small RhoGTPase Cdc42 was elevated in aged human hematopoietic cells and we identified a positive correlation between Cdc42 activity and the frequency of HSC upon aging. The frequency of human HSC polar for polarity proteins was, similar to the mouse, decreased upon aging, while inhibition of Cdc42 activity via the specific pharmacological inhibitor of Cdc42 activity, CASIN, resulted in re-polarization of aged human HSC with respect to Cdc42. Elevated activity of Cdc42 in aged HSC thus contributed to age-related changes in HSC. Xenotransplant, using NBSGW mice as recipients, showed elevated chimerism in recipients of aged compared to young HSC. Aged HSC treated with CASIN ex vivo displayed an engraftment profile similar to recipients of young HSC. Taken together, our work reveals strong evidence for a role of elevated Cdc42 activity in driving aging of human HSC, and similar to mice, this presents a likely possibility for attenuation of aging in human HSC.
Brief Psychosocial Intervention to Address Poststroke Depression May Also Benefit Fatigue and Sleep–Wake Disturbance

Abstract Purpose This study aimed to determine if brief psychosocial/behavioral therapy directed to reduce poststroke depression would decrease fatigue and improve sleep–wake disturbance. Design A preplanned secondary data analysis from a completed clinical trial was conducted. Methods One hundred participants received usual care, in-person intervention, or telephone intervention. Depression, fatigue, and sleep–wake disturbance were measured at entry, 8 weeks, 21 weeks, and 12 months following the intervention. Findings Fatigue (within: p = .042, between: p = .394), sleep disturbance (within: p = .024, between: p = .102), and wake disturbance (within: p = .004, between: p = .508) decreased over the 12 months in the intervention groups, but not in the control group. This difference was clinically meaningful for wake disturbance and approached the clinically important difference for fatigue. Conclusions/Clinical Relevance Reduction in wake disturbance was consistent with clinically meaningful difference standards for patient-reported outcomes, warranting further research in larger samples.
Effect of Microbial Short-Chain Fatty Acids on CYP3A4-Mediated Metabolic Activation of Human Pluripotent Stem Cell-Derived Liver Organoids

The early and accurate prediction of the hepatotoxicity of new drug targets during nonclinical drug development is important to avoid postmarketing drug withdrawals and late-stage failures. We previously established long-term expandable and functional human-induced pluripotent stem cell (iPSC)-derived liver organoids as an alternative source for primary human hepatocytes. However, PSC-derived organoids are known to present immature fetal characteristics. Here, we treated these liver organoids with microbial short-chain fatty acids (SCFAs) to improve metabolic maturation based on microenvironmental changes in the liver during postnatal development. The effects of the three main SCFA components (acetate, propionate, and butyrate) and their mixture on liver organoids were determined. Propionate (1 µM) significantly promoted the CYP3A4/CYP3A7 expression ratio, and acetate (1 µM), propionate (1 µM), and butyrate (1 µM) combination treatment, compared to no treatment (control), substantially increased CYP3A4 activity and albumin secretion, as well as gene expression. More importantly, mixed SCFA treatment accurately revealed troglitazone-induced hepatotoxicity, which was redeemed on a potent CYP3A4 inhibitor ketoconazole treatment. Overall, we determined, for the first time, that SCFA mixture treatment might contribute to the accurate evaluation of the CYP3A4-dependent drug toxicity by improving metabolic activation, including CYP3A4 expression, of liver organoids.
Characteristics of Aerobic Exercise as Determinants of Blood Pressure Control in Hypertensive Patients: A Systematic Review and Meta-Analysis.

PURPOSE The purpose of this study was to evaluate the effect on blood pressure (BP) and heart rate (HR) according to aerobic exercise characteristics in adults with hypertension using a systematic review and meta-analysis. METHODS The related researches were selected from PubMed, EMBASE, Cochrane library, CINAHL, PsycINFO, SPORTDiscus and 5 domestic databases up to September 4, 2019. To estimate the effect size, random effect models were used to derive weighted mean differences (WMD) and their 95% confidence intervals (CI) of aerobic exercise on BP and HR. RESULTS A total of 37 RCTs with 1,813 samples were included. Aerobic exercise was found to significantly reduce systolic BP (WMD, - 8.29 mmHg; 95% CI, - 10.12 to - 6.46), diastolic BP (WMD, - 5.19 mmHg; 95% CI, - 6.24 to - 4.14) and HR (WMD, - 4.22 beats/min; 95% CI, - 5.36 to -3.09). In detail, systolic BP and diastolic BP were significantly decreased in all groups of exercise types, frequency and duration. Systolic BP and diastolic BP were significantly decreased in the moderate and vigorous-intensity group. Exercise characteristics with the most dramatical change in systolic BP were water-based training, moderate-intensity, 3 times a week and 8 to 11 weeks of duration. In diastolic BP, the greatest effect size was over 24 weeks of exercise. CONCLUSION Moderate aerobic exercise, especially water-based exercise can be an important part of lifestyle modification for hypertensive patients. Also, it can be recommended in a variety of clinical settings for lowering BP and HR. However, there is insufficient evidence that low-intensity exercise is effective in lowering BP.
Cutting Edge: Heterogeneity in Cell Age Contributes to Functional Diversity of NK Cells

Key Points Homeostatic turnover generates heterogeneity in cell age among naive group 1 ILCs. Turnover of tissue-resident ILC1s is slower than that of circulating NK cells. Older NK cells mount more robust adaptive responses during CMV infection. Visual Abstract Heterogeneity among naive adaptive lymphocytes determines their individual functions and fate decisions during an immune response. NK cells are innate lymphocytes capable of generating “adaptive” responses during infectious challenges. However, the factors that govern various NK cell functions are not fully understood. In this study, we use a reporter mouse model to permanently “time stamp” NK cells and type 1 innate lymphoid cells (ILC1s) to characterize the dynamics of their homeostatic turnover. We found that the homeostatic turnover of tissue-resident ILC1s is much slower than that of circulating NK cells. NK cell homeostatic turnover is further accelerated without the transcription factor Eomes. Finally, heterogeneity in NK cell age diversifies NK cell function, with “older” NK cells exhibiting more potent IFN-γ production to activating stimuli and more robust adaptive responses during CMV infection. These results provide insight into how the functional response of an NK cell varies over its lifespan.
Defect‐Related Emissions and Magnetization Properties of ZnO Nanorods

A clear correlation between defect‐related emissions and the magnetization of ZnO nanorods synthesized by a one‐step aqueous chemical method is demonstrated. The relative contribution of the emission bands arising from various types of defects is determined and found to be linked with the size of the nanorods and annealing conditions. When the size of the nanorods and the annealing temperature are increased, the magnetization of pure ZnO nanorods decreases with the reduction of a defect‐related band originating from singly charged oxygen vacancies ($V_{\rm o}^ +$). With a sufficient increase of annealing temperature (at 900 °C), the nanorods show diamagnetic behavior. Combining with the electron paramagnetic resonance results, a direct link between the magnetization and the relative occupancy of the singly charged oxygen vacancies present on the surface of ZnO nanorods is established.