Miracle-dz/UniFAR-FTUs huggingface dataset:
Higher Dosing of Rifamycins Does Not Increase Activity against Mycobacterium tuberculosis in the Hollow-Fiber Infection Model

Improvements in the translational value of preclinical models can allow more-successful and more-focused research on shortening the duration of tuberculosis treatment. Although the hollow-fiber infection model (HFIM) is considered a valuable addition to the drug development pipeline, its exact role has not been fully determined yet. ABSTRACT Improvements in the translational value of preclinical models can allow more-successful and more-focused research on shortening the duration of tuberculosis treatment. Although the hollow-fiber infection model (HFIM) is considered a valuable addition to the drug development pipeline, its exact role has not been fully determined yet. Since the strategy of increasing the dose of rifamycins is being evaluated for its treatment-shortening potential, additional in vitro modeling is important. Therefore, we assessed increased dosing of rifampin and rifapentine in our HFIM in order to gain more insight into the place of the HFIM in the drug development pipeline. Total and free-fraction concentrations corresponding to daily dosing of 2.7, 10, and 50 mg of rifampin/kg of body weight, as well as 600 mg and 1,500 mg rifapentine, were assessed in our HFIM using the Mycobacterium tuberculosis H37Rv strain. Drug activity and the emergence of drug resistance were assessed by CFU counting and subsequent mathematical modeling over 14 days, and pharmacokinetic exposures were checked. We found that increasing rifampin exposure above what is expected with the standard dose did not result in higher antimycobacterial activity. For rifapentine, only the highest concentration showed increased activity, but the clinical relevance of this observation is questionable. Moreover, for both drugs, the emergence of resistance was unrelated to exposure. In conclusion, in the simplest experimental setup, the results of the HFIM did not fully correspond to preexisting clinical data. The inclusion of additional parameters and readouts in this preclinical model could be of interest for proper assessment of the translational value of the HFIM.
Drug Combination in Cancer Treatment—From Cocktails to Conjugated Combinations

Simple Summary Chemotherapy is a key modality in today’s practice of clinical oncology. The potential for systemic treatment of cancer patients with cytotoxic agents was discovered in the mid 20th century and its major shortcomings namely, off target toxicity and resistance to treatment, were apparent from the very beginning. These limitations pushed the scientific and medical communities to search for improvements, which as a final result, shaping modern research and clinical practice in the field. For minimizing off target toxic effects, drug discovery efforts became more focused on targeted therapies and on combinations of anti-cancer drugs in order to overcome the resistance problem. Here we outline the evolution of chemotherapy from its beginning as a single-agent based therapy to poly-drug treatment that involves targeted drugs, and discuss the concept of drug-conjugation based treatment as a strategy for further optimization of treatment regimes. Abstract It is well recognized today that anticancer drugs often are most effective when used in combination. However, the establishment of chemotherapy as key modality in clinical oncology began with sporadic discoveries of chemicals that showed antiproliferative properties and which as a first attempt were used as single agents. In this review we describe the development of chemotherapy from its origins as a single drug treatment with cytotoxic agents to polydrug therapy that includes targeted drugs. We discuss the limitations of the first chemotherapeutic drugs as a motivation for the establishment of combined drug treatment as standard practice in spite of concerns about frequent severe, dose limiting toxicities. Next, we introduce the development of targeted treatment as a concept for advancement within the broader field of small-molecule drug combination therapy in cancer and its accelerating progress that was boosted by recent scientific and technological progresses. Finally, we describe an alternative strategy of drug combinations using drug-conjugates for selective delivery of cytotoxic drugs to tumor cells that potentiates future improvement of drug combinations in cancer treatment. Overall, in this review we outline the development of chemotherapy from a pharmacological perspective, from its early stages to modern concepts of using targeted therapies for combinational treatment.
Aqueous Extract of Adansonia digitata reversed Cotton Seed Extract-Induced Testicular Damage in Wistar rats

Objective: Infertility is the inability of sexually active couples without using birth control to get pregnant after one year of uninterrupted sexual intercourse. Cotton Seed Extract (CSE) has been linked to male infertility by causing oxidative damage to the testes due to the action of its active component, Gossypol. Adansonia digitata has been known to have many medically useful properties, including antioxidant effects. This study aimed at evaluating the effects of Adansonia digitata on Cottonseed extract-induced testicular damage. Methods: Forty (40) Adult male Wistar rats were divided into 8 groups of five rats per group (n=5). Group 1 served as the control and received 0.5 ml of phosphate buffer orally; Group 2 received 800 mg/kg b.wt A. digitata orally; Group 3 received 300 mg/kg b.wt Vitamin E only orally; Group 4 received 60 mg/kg b.wt CSE intraperitoneally; Group 5 received 20 mg/kg b.wt CSE intraperitoneally; Group 6 received 60 mg/kg b.wt CSE intraperitoneally and 800 mg/kg b.wt A. digitata orally; Group 7 received 20 mg/kg b.wt CSE intraperitoneally and 800 mg/kg b.wt A. digitata orally; Group 8 received 60 mg/kg b.wt CSE intraperitoneally and 300 mg/kg Vit. E orally. It was administered for 21 days. The testes and epididymis were dissected following abdominal incision. The epididymis was used for semen analysis while the testes was processed for histological analysis and biochemical assay. All the data was analyzed by ANOVA, using the SPSS version 17.0 software. A p<0.05 was considered significant. Results: CSE administration caused significant (p<0.05) decrease in sperm count, found in the group treated with CSE only. However, the Administration of A. digitata caused significant increase (p<0.05) in sperm count, G6PDH, LDH, GPx and SOD; however, MDA levels were decreased. Histological observations showed a decrease in the number of Spermatogonia and differentiating cells in the testes of rats treated with CSE. Conclusions: The results obtained revealed the antioxidant ability of A. digitata in counter-acting the testicular damage caused by CSE administration.
Walking Initiated 20 Minutes before the Time of Individual Postprandial Glucose Peak Reduces the Glucose Response in Young Men with Overweight or Obesity: A Randomized Crossover Study.

BACKGROUND Although a single bout of postmeal exercise can lower postprandial glucose (PPG), its optimal timing remains unclear. OBJECTIVE This study aimed to investigate the effect of exercise timing using an individualized approach on PPG in overweight or obese young men. METHODS Twenty men [age: 23.0 ± 4.3 y; BMI (kg/m2): 27.4 ± 2.8] each completed three 240-min trials in a randomized order separated by 6-14 d: 1) sitting (SIT), 2) walking initiated at each participant's PPG-peak time (PPGP) (iP), and 3) walking initiated 20 min before the PPGP (20iP). For each participant, PPGP was predetermined using continuous glucose monitoring. Walking was performed at 50% maximal oxygen consumption for 30 min. Venous blood was collected at 15- and 30-min intervals for 0-120 min and 120-240 min, respectively. The primary outcome was plasma PPG. Generalized estimating equations were used for comparison between trials. RESULTS Compared with SIT, the 4-h incremental AUCs (iAUCs) for plasma PPG (-0.6 mmol · L-1 · h; P = 0.047) and insulin (-28.7%, P < 0.001) were reduced in 20iP only, and C-peptide concentrations were lower after iP (-14.9%, P = 0.001) and 20iP (-28.7%, P < 0.001). Plasma insulin (-11.1%, P = 0.006) and C-peptide (-8.3%, P = 0.012) were lower due to the 20iP compared with iP treatment. Finally, PPG reductions due to iP and 20iP occurred only in men with a BMI > 27.5 kg/m2 (iP, -11.2%; 20iP, -14.7%; P = 0.047) and higher glucose iAUC values during SIT (iP, -25.5%; 20iP, -25.7%; P < 0.001). CONCLUSIONS Walking initiated 20 min before PPGP lowered PPG and plasma insulin and C-peptide concentrations in young men with overweight or obesity, in particular in those with high BMI or glucose iAUC values during SIT; it also lowered plasma insulin and C-peptide concentrations more effectively than did exercise initiated at PPGP. This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) as ChiCTR1900023175.
A qualitative study of VHA clinicians' knowledge and perspectives on cannabis for medical purposes.

BACKGROUND The legalization of cannabis is expanding across the USA, and its use has increased significantly, including among Veterans. Although the Veterans Health Administration (VHA) abides by the classification of cannabis as a Schedule I substance, it recently recommended that clinicians discuss cannabis with their patients. Little is known about VHA clinicians' perspectives on and knowledge of cannabis. OBJECTIVE We sought to better understand clinicians' attitudes, beliefs, knowledge and communication with patients regarding cannabis. METHODS We conducted semi-structured phone interviews with 14 VHA clinicians. Interviews were audio-recorded, transcribed verbatim and analysed using qualitative thematic analysis. RESULTS VA clinicians described ambivalence towards cannabis for therapeutic purposes and identified several factors that inhibit conversations about cannabis use with their patients including discomfort with the lack of product standardization; lack of research examining the effectiveness and risks of cannabis use; unfamiliarity with pharmacology, formulations, and dosing of cannabis; and uncertainty regarding VHA policy. Clinicians had differing views on cannabis in the context of the opioid crisis. CONCLUSIONS VA clinicians face challenges in navigating the topic of medical cannabis. Educational materials about cannabis products, dose and harms would be helpful to clinicians.
Predictors of Mental Health Status among Older United States Adults with Pain

Poor mental health is common among older adults with pain, resulting in high economic burden and impaired quality of life. This retrospective, cross-sectional database study aimed to identify characteristics associated with good mental health status among United States (US) adults aged ≥50 years with self-reported pain in the last four weeks using a weighted sample of 2017 Medical Expenditure Panel Survey data. Hierarchical multivariable logistic regression models were used to identify statistically significant predictors of good (versus poor) perceived mental health status. From a weighted population of 57,074,842 individuals, 85.5% (95% confidence interval (CI) = 84.4%, 86.7%) had good perceived mental health. Good mental health was associated most strongly with physical health status (adjusted odds ratio (AOR) = 9.216, 95% CI = 7.044, 12.058). Employed individuals were 1.7 times more likely to report good mental health versus unemployed (AOR = 1.715, 95% CI = 1.199, 2.452). Individuals who had completed less than high school education (AOR = 0.750, 95% CI = 0.569, 0.987) or who reported having a limitation (AOR = 0.513, 95% CI = 0.384, 0.684) were less likely to report good mental health. These key characteristics can be utilized to predict mental health status, which may be investigated to better manage concurrent pain and poor mental health.
ADVERSE EFFECTS OF HUMIC SUBSTANCES FROM DIFFERENT ORIGIN ON LUPIN AS RELATED TO IRON SOURCES

Humic substances improve the efficiency of different iron (Fe) sources overcoming Fe deficiency chlorosis of plants. However, applied at high rates, they can promote negative effects on plants. The main objective of this work was to study the potential adverse effect of three humic acids from different origin when they were applied with two effective Fe sources for plants: Fe- ethylenediaminedihydroxyphenylacetic acid (EDDHA) and Vivianite. To this end, an experiment with lupin (Lupinus albus L.) was performed involving two factors: (i) Fe source, and (ii) humic substances from three different origin (composted cork, leonardite, and compost obtained from a mixture of olive husk with cotton gin trash) applied at 0, 0.1, and 0.5 g organic carbon (C) kg−1 of growing media. At the rates used, humic substances promoted adverse effects on plant development, chlorophyll meter readings, and Fe content in lupin grown in calcareous media. Overall, the effect on dry matter and Fe content in plants was more relevant when Fe was supplied with Vivianite, the effect on chlorophyll meter readings being more significant when Fe was applied as Fe-EDDHA. Differences were also observed depending on the source of humic substances, those from leonardite promoting the greatest decrease in dry matter in roots and shoots. These humic substances possessed the highest values of spectroscopy index for aromaticity (A254 ). On the other hand, the application of humic substances from olive husk compost, which exhibited the lower aromaticity index, resulted in the smallest decrease in dry matter production and chlorophyll meter readings. Dry matter in roots decreased logarithmically with increased values of the estimates of the amounts of aromatic compounds accumulated in the growing media (R2 = 0.92; P < 0.01) with Vivianite as Fe source. Thus, the effects decreasing dry matter production, particularly in roots, and chlorophyll meter readings can be ascribed at least partially to the presence of phytotoxic aromatic compounds in humic substances.
In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy

Until the recent development of disease-modifying therapeutics, spinal muscular atrophy (SMA) was considered a devastating neuromuscular disease with a poor prognosis for most affected individuals. Symptoms generally present during early childhood and manifest as muscle weakness and progressive paralysis, severely compromising the affected individual’s quality of life, independence, and lifespan. SMA is most commonly caused by the inheritance of homozygously deleted SMN1 alleles with retention of one or more copies of a paralog gene, SMN2, which inversely correlates with disease severity. The recent advent and use of genetically targeted therapies have transformed SMA into a prototype for monogenic disease treatment in the era of genetic medicine. Many SMA-affected individuals receiving these therapies achieve traditionally unobtainable motor milestones and survival rates as medicines drastically alter the natural progression of this disease. This review discusses historical SMA progression and underlying disease mechanisms, highlights advances made in therapeutic research, clinical trials, and FDA-approved medicines, and discusses possible second-generation and complementary medicines as well as optimal temporal intervention windows in order to optimize motor function and improve quality of life for all SMA-affected individuals.
The effect of different colored light emitting diode illumination on egg laying performance, egg qualities, blood hormone levels and behavior patterns in Brown Tsaiya duck

Objective The objective of this experiment was to investigate the effects of different colors produced by light emitting diode (LED) on Brown Tsaiya ducks. Methods A total of 144 female Brown Tsaiya ducks were randomly allocated into three individual cage rearing chambers with different LED illumination colors as treatments. Three different treatments were: i) white color, ii) blue color, and iii) red color. The experiment periods were from ducks 21 to 49 weeks of age, determined traits included i) egg laying performance, ii) feed intake, iii) egg shell breaking strength, iv) egg shell thickness, v) egg Haugh unit, vi) egg weight, vii) serum Estradiol and Progesterone concentration, and viii) behavior pattern. Results The results indicated that when compared with white and blue color, red color could stimulate ducks sexual maturation and raised the egg laying performance. The red light group was also observed to have the highest feed intake among three treatments. The blue treatment had the lowest egg shell breaking strength and the highest egg weight among three treatments, nevertheless, no significant difference was observed among three treatments on egg shell thickness and egg Haugh unit. The red light group had higher serum estradiol concentration than the white and blue groups, but no significant difference among treatments on the serum Progesterone concentration was found. The results of behavior pattern indicated that red light group showed more feeding and less resting behavior compared to the blue light group. Conclusion We found a potential of applying red light illumination in the indoor laying duck raising system with positive results on egg laying performance and acceptable egg weight, equivalent egg qualities compared to white and blue light.
Preventive action with a population of excavator drivers exposed to whole-body vibration

BACKGROUND: Whole-body vibration is a major cause of lower back pain among employees, and the medical and preventive care teams of occupational health departments are often confronted with lower back pain problems among machine operators. OBJECTIVES: The objectives of this research are to determine the number of excavator drivers exposed to whole-body vibration levels above 0.5m/s2, identify other exposure factors that may contribute to back pain, and propose corrective measures. METHODS: Vibration measurements were carried out on individual excavator drivers while they were observed carrying out working tasks, after which prevention advice is given. Factors which determine vibration levels are logged on to a database. RESULTS: The multivariate analysis of several determining factors shows vibration exposure levels vary depending on the varied work tasks being carried out. CONCLUSION: This study identifies exposed employees among excavator operators. For each workstation, the determining factors that could explain the high exposures to vibrations are identified. This work shows the important role of tasks on exposure levels. A better adaptation of the tools used to carry out work tasks would allow a decrease in the vibration level of this type of machine.
Placental genomic risk scores and early neurodevelopmental outcomes

Significance Environmental and genetic risk factors, and the early antecedents of schizophrenia, represent pieces of a puzzle still far from completion. We show that, in infants with a history of prenatal complications, a measure of genomic risk for schizophrenia linked with placental gene expression is associated with early neurodevelopmental trajectories of risk, particularly in male individuals. While the majority of individuals on this altered neurodevelopmental path likely “canalize” back toward normal development, some may not be rescued and instead “decanalize” toward illness. Specific strategies of prevention may benefit from understanding the unique placental effects of schizophrenia genomic risk and from defining which factors contribute to decanalize the neurodevelopmental trajectories of individuals with a history of risk factors who develop schizophrenia. Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., Nat. Med. 24, 792–801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia’s PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.
A Case of Critical Essential Thrombocythemia Complicated by Severe Lower-Extremity Arterial Disease

Patient: Male, 66-year-old Final Diagnosis: Essential thrombocythemia with CML • peripheral artery disease Symptoms: Fever • infection • necrosis • pain Medication: — Clinical Procedure: — Specialty: Cardiology • Dermatology • Diagnostics, Laboratory • Hematology Objective: Unusual clinical course Background: Atherosclerosis and malignancies are leading causes of morbidity and mortality worldwide. In lower-extremity arterial disease (LEAD), progressing or ruptured atherosclerotic plaques are the main culprit for limb ischemia and may cause claudication, chronic wounds, or necrotic lesions. In those cases, standard of care includes revascularization in addition to best medical therapy. Other sources for acute or chronic limb ischemia different from atherosclerosis are often overlooked, especially once atherosclerotic plaques have been detected. Case Report: We report the rare case of a patient presenting with painful necrotic ulcerations of the lower extremity due critical essential thrombocythemia that was complicated by an atherosclerotic disease. Based on the clinical presentation, 4 major differential diagnoses were initially considered: Martorell’s ulcer, pyoderma gangrenosum, LEAD, and recurrent thromboembolic occlusions due to a malignant disease. Following a thorough, holistic diagnostic work-up, we identified the first diagnosis of critical essential thrombocythemia, which was aggravated by LEAD. Conclusions: This case report highlights the importance of taking malignancies into consideration as a differential diagnosis in patients with repetitive arterial occlusions. With a broad variety of differential diagnoses to be considered for the presented ulcerations, this case report highlights the crucial importance of a rapid interdisciplinary approach to treat and relieve symptoms and prevent further arterial thrombotic events. The learning objective is to give a clear diagnostic work-up to navigate through the most important differential diagnoses of non-atherosclerotic conditions aggravating LEAD.
The effect of experimental pain on the excitability of the corticospinal tract in humans: A systematic review and meta‐analysis

Pain influences motor control. Previous reviews observed that pain reduces the excitability of corticospinal projections to muscles tested with transcranial magnetic stimulation. However, the independent effect of the type of pain models (tonic, phasic), pain location and tissues targeted (e.g. muscle, skin) remains unexplored. The objective of this review was to determine the influence of experimental pain and of different methodological factors on the corticospinal excitability.