Miracle-dz/UniFAR-FTUs huggingface dataset:
CDER Experience With Juvenile Animal Studies for CNS Drugs

A survey was undertaken to evaluate juvenile animal studies conducted for drug applications reviewed by the Center for Drug Evaluation and Research between 2009 and 2014. Some conclusions about the nonclinical pediatric safety assessment based on studies performed in support of central nervous system–active compounds are presented here. A total of 44 completed studies from 32 New Drug Applications submitted to the Divisions of Psychiatry and Neurology Products were evaluated. Data on animal species and age range used, endpoints evaluated, and outcomes included in labeling were analyzed. Of the drugs evaluated, all but one had studies conducted in rats. In some cases, a second study in a nonrodent species (dog) was also conducted. Indices of growth and development and standard general toxicity parameters were included in all of the studies. Expanded neurohistopathology evaluations, bone mineral density measurements, and reproductive and neurobehavioral functional assessments were also generally carried out. A variety of neurological and neurobehavioral tests were employed. In the majority of rat studies, the potential for long-term cognitive impairment was evaluated using a complex water maze. Juvenile animal studies provided safety information considered relevant to drug use in children and that was included in labeling for 78% of the applications surveyed. The most commonly reported findings in labeling were for neurobehavioral effects, including changes in locomotor activity, auditory startle habituation, and learning and memory. Of the studies described in labeling with neurobehavioral effects, 54% found these effects to be persistent and to provide evidence of developmental neurotoxicity.
A Protocol to Assess Feasibility, Acceptability, and Usability of Mobile Technology for Symptom Management in Pediatric Transplant Patients.

BACKGROUND Pediatric blood and marrow transplant patients (PBMT) experience significant symptom distress, and the use of mobile health technologies may enhance symptom management by providing patient generated health data to foster personalized health strategies. OBJECTIVES To present a study protocol to explore feasibility, acceptability and, usability of integrating mobile health technologies to collect and monitor symptom data for PBMT patients. METHODS An exploratory mixed method design is employed for 20 PBMT patients to monitor symptoms using real-time data from two mobile health (mHealth) devices: 1) a self-developed mHealth application (app); and 2) a wearable tracking device. Patient-Reported Outcome Measurement Information System surveys (PROMIS) for fatigue, pain, and sleep disturbance are obtained monthly. Interviews are conducted to obtain further feasibility and usability data. RESULTS The study began in October 2017, data collection should be completed in 2018. Feasibility and usability results to monitor and record symptom-related data daily via mobile devices will be reported. PROMIS surveys and interviews will further explore patients' symptoms and experiences with the mobile devices.This study will be among the first to explore the feasibility, acceptability, and usability of integrating multiple mHealth technologies to obtain patient generated symptom data for the PBMT population. Results will enhance our understanding of how these data present, interact, and cluster together throughout the post-transplant period for these children and lead to symptom management strategies. Results will focus on a high-risk population that potentially stands to benefit from the use of mobile technologies.
Potential effects of reduced red meat compared with increased fiber intake on glucose metabolism and liver fat content: a randomized and controlled dietary intervention study.

Background Epidemiological studies suggest that an increased red meat intake is associated with a higher risk of type 2 diabetes, whereas an increased fiber intake is associated with a lower risk. Objectives We conducted an intervention study to investigate the effects of these nutritional factors on glucose and lipid metabolism, body-fat distribution, and liver fat content in subjects at increased risk of type 2 diabetes. Methods This prospective, randomized, and controlled dietary intervention study was performed over 6 mo. All groups decreased their daily caloric intake by 400 kcal. The "control" group (N = 40) only had this requirement. The "no red meat" group (N = 48) in addition aimed to avoid the intake of red meat, and the "fiber" group (N = 44) increased intake of fibers to 40 g/d. Anthropometric parameters and frequently sampled oral glucose tolerance tests were performed before and after intervention. Body-fat mass and distribution, liver fat, and liver iron content were assessed by MRI and single voxel proton magnetic resonance spectroscopy. Results Participants in all groups lost weight (mean 3.3 ± 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001). These changes did not differ between groups. Liver fat content decreased significantly (P < 0.001) with no differences between the groups. The decrease in liver fat correlated with the decrease in ferritin during intervention (r2 = 0.08, P = 0.0021). This association was confirmed in an independent lifestyle intervention study (Tuebingen Lifestyle Intervention Program, N = 229, P = 0.0084). Conclusions Our data indicate that caloric restriction leads to a marked improvement in glucose metabolism and body-fat composition, including liver-fat content. The marked reduction in liver fat might be mediated via changes in ferritin levels. In the context of caloric restriction, there seems to be no additional beneficial impact of reduced red meat intake and increased fiber intake on the improvement in cardiometabolic risk parameters. This trial was registered at clinicaltrials.gov as NCT03231839.
Indoleamine 2,3-dioxygenase 1 and Programmed Cell Death-ligand 1 Co-expression Predicts Poor Pathologic Response and Recurrence in Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy

This study aimed to investigate the impact of indoleamine 2,3-dioxygenase 1 (IDO1) expression, programmed cell death-ligand 1 (PD-L1) expression, CD8+ tumor-infiltrating lymphocyte (TIL) status, and their combination on pathologic complete response (pCR) and recurrence in esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (CRT). Indoleamine 2,3-dioxygenase 1, PD-L1, and CD8+ TIL statuses were evaluated by immunohistochemical analysis on pre-CRT biopsies of 158 patients. Sixty-eight patients (43.0%) achieved pCR after neoadjuvant CRT and 48 patients (30.4%) developed recurrences after surgery. IDO1 and PD-L1 proteins were co-expressed in 28 patients (17.7%). Indoleamine 2,3-dioxygenase 1 positive patients showed a significantly lower pCR rate than IDO1 negative patients (28.6% vs. 51.0%, P = 0.007). Similarly, PD-L1 high expression was significantly negatively correlated with pCR rate (27.3% vs. 51.5%, P = 0.004). On multivariate analysis, IDO1 expression was an independent prognostic factor for developing recurrences. Stratification analysis revealed that patients with co-expression of IDO1 and PD-L1 were significantly associated with a lower pCR rate and worse recurrence-free survival than those with one or none positive protein. In conclusion, IDO1 and PD-L1 co-expression could predict poor pathologic response and high risk of recurrence in ESCC after neoadjuvant CRT, indicating a subset of patients who may benefit from CRT combined with immunotherapy.
Postnatal undernutrition alters adult female mouse cardiac structure and function leading to limited exercise capacity

Impaired growth during fetal life can reprogramme heart development and increase the risk for long‐term cardiovascular dysfunction. It is uncertain if the developmental window during which the heart is vulnerable to reprogramming as a result of inadequate nutrition extends into the postnatal period. We found that adult female mice that had been undernourished only from birth to 3 weeks of age had disproportionately smaller hearts compared to males, with thinner ventricle walls and more mononucleated cardiomyocytes. In females, but not males, cardiac diastolic function, and heart rate responsiveness to adrenergic stimulation were limited and maximal exercise capacity was compromised. These data suggest that the developmental window during which the heart is vulnerable to reprogramming by inadequacies in nutrient intake may extend into postnatal life and such individuals could be at increased risk for a cardiac event as a result of strenuous exercise.
Estimating flow distributions from sampled flow statistics

Passive traffic measurement increasingly employs sampling at the packet level. Many high-end routers form flow statistics from a sampled substream of packets. Sampling is necessary in order to control the consumption of resources by the measurement operations. However, knowledge of the statistics of flows in the unsampled stream remains useful, for understanding both characteristics of source traffic, and consumption of resources in the network.This paper provide methods that use flow statistics formed from sampled packet stream to infer the absolute frequencies of lengths of flows in the unsampled stream. A key part of our work is inferring the numbers and lengths of flows of original traffic that evaded sampling altogether. We achieve this through statistical inference, and by exploiting protocol level detail reported in flow records. The method has applications to detection and characterization of network attacks: we show how to estimate, from sampled flow statistics, the number of compromised hosts that are sending attack traffic past the measurement point. We also investigate the impact on our results of different implementations of packet sampling.
A roadmap for enterotoxigenic Escherichia coli vaccine development based on volunteer challenge studies

ABSTRACT Enterotoxigenic Escherichia coli (ETEC) is a major cause of travelers’ diarrhea and of diarrhea among young children in developing countries. Experimental challenge studies in adult volunteers have played a pivotal role in establishing ETEC as an enteric pathogen, elucidating its pathogenesis by identifying specific virulence attributes, characterizing the human immune response to clinical and sub-clinical ETEC infection and assessing preliminarily the clinical acceptability, immunogenicity and efficacy of prototype ETEC vaccines. This review provides a historical perspective of experimental challenge studies with ETEC. It summarizes pioneering early studies carried out by investigators at the University of Maryland School of Medicine to show how those studies provided key information that influenced the directions taken by many research groups to develop vaccines to prevent ETEC. In addition, key experimental challenge studies undertaken at other institutions will also be cited.
Botulinum toxin A for pain reduction in pediatric patients with Parry‐Romberg syndrome

Parry‐Romberg syndrome (PRS) is characterized by hemiatrophy of facial structures, including skin, subcutaneous fat, muscle, bone, and cartilage. Complications associated with PRS include headaches, seizures, and chronic facial pain. Protocol for the treatment of chronic facial pain is not clear; reports on the use of botulinum toxin A injections for pain reduction in adults but not in the pediatric/adolescent population are available. Here, we discuss two pediatric PRS cases in which treatment with botulinum toxin A injections reduced or eliminated facial pain.
Patient-Centered Outcomes for Skin Cancer Management: Utilization of a Patient Delphi Process to Identify Important Treatment Themes

BACKGROUND Patient-reported outcomes are critical to research directed at maximizing patient benefit. The outcomes patients consider most relevant in the treatment of skin cancer have not been directly investigated. OBJECTIVE To develop a ranked list of outcomes deemed most important by patients with skin cancer through a proctored Delphi process. METHODS Twenty-one patients with a history of skin cancer volunteered to participate in the patient summit. The patient members participated in a guided discussion to generate a long list of potentially relevant outcomes. The list was then condensed and ranked through 2 rounds of a proctored Delphi process. RESULTS Patients were diverse in their skin cancer histories and complexities, ages, and states of residence. Twelve themes were rated as highly important by 70% or more of participants. Most of these themes related to patient education and the collaborative nature of the physician–patient relationship. Fear of recurrence and cosmetic outcome were also highly rated. Limitations include a preponderance of older patients and patients from the midwest and northeast. CONCLUSION Patients with skin cancer overwhelmingly prioritize a shared decision-making process, in which they are actively engaged and value detailed education regarding their disease. This should inform future research directed at skin cancer treatment and current physician–patient interactions.
Dose Optimization of Colistin Combinations against Carbapenem-Resistant Acinetobacter baumannii from Patients with Hospital-Acquired Pneumonia in China by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model

Colistin-based combination therapy has become an important strategy to combat the carbapenem-resistant Acinetobacter baumannii (CRAB). However, the optimal dosage regimen selection for the combination with maximum efficacy is challenging. ABSTRACT Colistin-based combination therapy has become an important strategy to combat the carbapenem-resistant Acinetobacter baumannii (CRAB). However, the optimal dosage regimen selection for the combination with maximum efficacy is challenging. Checkerboard assay was employed to evaluate the synergy of colistin in combination with meropenem, rifampin, fosfomycin, and minocycline against nine carbapenem-resistant A. baumannii isolates (MIC of meropenem [MICMEM], ≥32 mg/liter) isolated from Chinese hospital-acquired pneumonia (HAP) patients. A static time-kill assay, in vitro dynamic pharmacokinetic/pharmacodynamic (PK/PD) model, and semimechanistic PK/PD modeling were conducted to predict and validate the synergistic effect of the most efficacious combination. Both checkerboard and static time-kill assays demonstrated the superior synergistic effect of the colistin-meropenem combination against all CRAB isolates. In the in vitro PK/PD model, the dosage regimen of 2 g meropenem daily via 3-h infusion combined with steady-state 1 mg/liter colistin effectively suppressed the bacterial growth at 24 h with a 2-log10 decrease, compared with the initial inocula against two CRAB isolates. The semimechanistic PK/PD model predicted that more than 2 mg/liter colistin combined with meropenem (2 g, 3-h infusion) was required to achieve the killing below the limit of detection (<LOD; i.e., 1 log10CFU/ml) at 24 h with an MICMEM of ≥32 mg/liter. Colistin combined with meropenem exerted synergistic killing against CRAB even with an MICMEM of ≥32 mg/liter and MIC of colistin (MICCST) of ≤1 mg/liter. However, it is predicted that a higher concentration of colistin combined with meropenem was crucial to kill bacteria to <LOD. Our study provides important PK/PD information for optimization of the colistin and meropenem combination against CRAB.
The Foodborne Strain Lactobacillus fermentum MBC2 Triggers pept-1-Dependent Pro-Longevity Effects in Caenorhabditis elegans

Lactic acid bacteria (LAB) are involved in several food fermentations and many of them provide strain-specific health benefits. Herein, the probiotic potential of the foodborne strain Lactobacillus fermentum MBC2 was investigated through in vitro and in vivo approaches. Caenorhabditis elegans was used as an in vivo model to analyze pro-longevity and anti-aging effects. L. fermentum MBC2 showed a high gut colonization capability compared to E. coli OP50 (OP50) or L. rhamnosus GG (LGG). Moreover, analysis of pumping rate, lipofuscin accumulation, and body bending showed anti-aging effects in L. fermentum MBC2-fed worms. Studies on PEPT-1 mutants demonstrated that pept-1 gene was involved in the anti-aging processes mediated by this bacterial strain through DAF-16, whereas the oxidative stress protection was PEPT-1 independent. Moreover, analysis of acid tolerance, bile tolerance, and antibiotic susceptibility were evaluated. L. fermentum MBC2 exerted beneficial effects on nematode lifespan, influencing energy metabolism and oxidative stress resistance, resulted in being tolerant to acidic pH and able to adhere to Caco-2 cells. Overall, these findings provide new insight for application of this strain in the food industry as a newly isolated functional starter. Furthermore, these results will also shed light on C. elegans molecular players involved in host-microbe interactions.
Experiences with rotavirus vaccines: can we improve rotavirus vaccine impact in developing countries?

ABSTRACT Rotavirus vaccines have been introduced into over 95 countries globally and demonstrate substantial impact in reducing diarrheal mortality and diarrheal hospitalizations in young children. The vaccines are also considered by WHO as “very cost effective” interventions for young children, particularly in countries with high diarrheal disease burden. Yet the full potential impact of rotavirus immunization is yet to be realized. Large countries with big birth cohorts and where disease burden is high in Africa and Asia have not yet implemented rotavirus vaccines at all or at scale. Significant advances have been made demonstrating the impact of the vaccines in low- and lower-middle income countries, yet the modest effectiveness of the vaccines in these settings is challenging. Current research highlights these challenges and considers alternative strategies to overcome them, including alternative immunization schedules and host factors that may inform us of new opportunities.
Bats and Viruses: Emergence of Novel Lyssaviruses and Association of Bats with Viral Zoonoses in the EU

Bats in the EU have been associated with several zoonotic viral pathogens of significance to both human and animal health. Virus discovery continues to expand the existing understating of virus classification, and the increased interest in bats globally as reservoirs or carriers of zoonotic agents has fuelled the continued detection and characterisation of new lyssaviruses and other viral zoonoses. Although the transmission of lyssaviruses from bat species to humans or terrestrial species appears rare, interest in these viruses remains, through their ability to cause the invariably fatal encephalitis—rabies. The association of bats with other viral zoonoses is also of great interest. Much of the EU is free of terrestrial rabies, but several bat species harbor lyssaviruses that remain a risk to human and animal health. Whilst the rabies virus is the main cause of rabies globally, novel related viruses continue to be discovered, predominantly in bat populations, that are of interest purely through their classification within the lyssavirus genus alongside the rabies virus. Although the rabies virus is principally transmitted from the bite of infected dogs, these related lyssaviruses are primarily transmitted to humans and terrestrial carnivores by bats. Even though reports of zoonotic viruses from bats within the EU are rare, to protect human and animal health, it is important characterise novel bat viruses for several reasons, namely: (i) to investigate the mechanisms for the maintenance, potential routes of transmission, and resulting clinical signs, if any, in their natural hosts; (ii) to investigate the ability of existing vaccines, where available, to protect against these viruses; (iii) to evaluate the potential for spill over and onward transmission of viral pathogens in novel terrestrial hosts. This review is an update on the current situation regarding zoonotic virus discovery within bats in the EU, and provides details of potential future mechanisms to control the threat from these deadly pathogens.
There and back again: natal homing by magnetic navigation in sea turtles and salmon

ABSTRACT Diverse marine animals migrate across vast expanses of seemingly featureless ocean before returning as adults to reproduce in the area where they originated. How animals accomplish such feats of natal homing is an enduring mystery. Growing evidence suggests, however, that sea turtles and salmon imprint on the magnetic field of their home area when young and then use this information to return as adults. Both turtles and salmon have the sensory abilities needed to detect the unique ‘magnetic signature’ of a coastal area. Analyses have revealed that, for both groups of animals, subtle changes in the geomagnetic field of the home region are correlated with changes in natal homing behavior. In turtles, a relationship between population genetic structure and the magnetic fields that exist at nesting beaches has also been detected, consistent with the hypothesis that turtles recognize their natal areas on the basis of magnetic cues. Salmon likely use a biphasic navigational strategy in which magnetic cues guide fish through the open sea and into the proximity of the home river where chemical cues allow completion of the spawning migration. Similarly, turtles may also exploit local cues to help pinpoint nesting areas once they have arrived in the vicinity. Throughout most of the natal homing migration, however, magnetic navigation appears to be the primary mode of long-distance guidance in both sea turtles and salmon. Summary: New findings indicate that long-distance natal homing in salmon and sea turtles involves an ability to navigate back to the magnetic signature of the home area.
Association between Multiple Recurrent Events with Multivariate Modeling: A Retrospective Cohort Study

Background: Recurrent event data are often encountered in biomedical research, for example, recurrent infections or recurrent hospitalizations for patients after renal transplant. In many studies, there are more than one type of events of interest. We aimed to identify the association between two types of events using multivariate joint modeling and then apply this statistical method in the clinical data set. Study design: A retrospective cohort study Methods: Overall, 342 subjects with breast cancer whose records were registered for follow-up in a Cancer Research Center at Shohadaye Tajrish Hospital, Tehran, Iran from 2006 to 2015 were investigated. These patients were monitored for at least 6 months after diagnosis and their latest status were recorded. Joint frailty model was used for modeling the relationship between two types of recurrences with Frailty package in R software. Results: When the terminal event was considered as death, three-year and five-year survival rates for the patients were 0.79 and 0.68, respectively. Given the results obtained from a fitted joint frailty model, the risk of multiple recurrences (local and metastases) increased for the patients with tumor grades greater than I. Conclusion: With regard to the significant variance of the frailty component of the metastases event, it can be inferred that patients with the same predictive variables are prone to different levels of metastases risk and, on the other hand, given the low frequency of types of recurrences, caution should be exercised when considering the obtained results.