Miracle-dz/UniFAR-FTUs huggingface dataset:
Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS

(PrP) the kinetics of prion replication and a genetically and pharmacologically validated therapeutic target for prion disease. evaluate PrP concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across 6 species of interest and applicable to and cerebrospinal fluid (CSF). PrP concentration varied dramatically across different brain regions in cynomolgus macaques, and humans. PrP expression did not appear to contribute to the known risk factors of age, sex, or common PRNP genetic variants. CSF PrP was lowered in the presence of rare pathogenic PRNP variants, with heterozygous carriers of P102L displaying 55%, and D178N just 31%, of the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA was reflected in brain parenchyma PrP and, in turn in CSF PrP, validating CSF as a sampling compartment for the effect of PrP-lowering therapy. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.
Prevalence of malaria and associated factors among symptomatic pregnant women attending antenatal care at three health centers in north-west Ethiopia

Background Malaria is the disease caused by Plasmodium species and primarily transmitted by the bite of female Anopheles mosquitoes. During pregnancy, malaria causes life threatening outcomes to the mother, the fetus and the new born. Even though, malaria symptomatic pregnant women highly attract mosquitoes and have higher potential of transmitting the disease in communities, most of the previous studies focused on pregnant women with asymptomatic Plasmodium infections. Therefore, the aim of this study was to assess the prevalence of malaria and associated factors among symptomatic pregnant women attending antenatal care at three health centers in northwest Ethiopia. Methods A health facility based cross-sectional study was conducted from February to April, 2021. A total of 312 malaria symptomatic pregnant women were involved from three health centers and enrolled by convenient sampling technique. A questionnaire was used to collect socio demographic and clinical data through face to face interview. Capillary blood samples were collected and used to prepare thin and thick blood smears, which were then stained using 10% Giemsa and examined under light microscope. Logistic regression was used to assess factors associated with malaria. Adjusted odds ratio with 95% confidence interval was calculated and P-value < 0.05 was considered statistically significant. Results The prevalence of malaria among symptomatic pregnant women was 20.8% (65/312) of which 12.2% (38/312), 4.8% (15/312) and 3.8% (12/312) were P. falciparum, P. vivax and mixed infections, respectively. Being illiterate (p< 0.001), first trimester (p = 0.036), primigravidae (p<0.001), living far from health center (p<0.001), not sleeping under long lasting insecticide treated nets (p<0.001) and living near irrigation areas (p = 0.006) were significantly associated with prevalence of malaria in malaria symptomatic pregnant women. Conclusions Even though prevalence of malaria is decreasing in the country because of scale-up of intervention and prevention measures, this study showed that, malaria is still the major public health problem among pregnant women. Being illiterate, first trimester, primigravidae, living far from health centers, not sleeping under long lasting insecticide treated nets and living near irrigation areas were factors that increased the prevalence of malaria in malaria symptomatic pregnant women. Therefore, special attention should be given to pregnant women prone to these factors.
The effect of temperature conditioning (9°C and 20°C) on the proteome of entomopathogenic nematode infective juveniles

Entomopathogenic nematodes (EPN) of the genera Steinernema and Heterorhabditis are parasites which kill and reproduce within insects. While both have life cycles centred around their developmentally arrested, nonfeeding and stress tolerant infective juvenile (IJ) stage, they are relatively distantly related. These IJs are promising biocontrol agents, and their shelf life and stress tolerance may be enhanced by storage at low temperatures. The purpose of this study was to investigate how the proteome of the IJs of two distantly related EPN species is affected by storage at 9°C (for up to 9 weeks) and 20°C (for up to 6 weeks), using label-free quantitative proteomics. Overall, more proteins were detected in S. carpocapsae (2422) than in H. megidis (1582). The S. carpocapsae proteome was strongly affected by temperature, while the H. megidis proteome was affected by both time and temperature. The proteins which increased in abundance to the greatest extent in S. carpocapsae IJs after conditioning at 9°C were chaperone proteins, and proteins related to stress. The proteins which increased in abundance the most after storage at 20°C were proteins related to the cytoskeleton, cell signalling, proteases and their inhibitors, which may have roles in infection. The proteins which decreased in abundance to the greatest extent in S. carpocapsae after both 9°C and 20°C storage were those associated with metabolism, stress and the cytoskeleton. After storage at both temperatures, the proteins increased to the greatest extent in H. megidis IJs were those associated with the cytoskeleton, cell signalling and carbon metabolism, and the proteins decreased in abundance to the greatest extent were heat shock and ribosomal proteins, and those associated with metabolism. As the longest-lived stage of the EPN life cycle, IJs may be affected by proteostatic stress, caused by the accumulation of misfolded proteins and toxic aggregates. The substantial increase of chaperone proteins in S. carpocapsae, and to a greater extent at 9°C, and the general decrease in ribosomal and chaperone proteins in H. megidis may represent species-specific proteostasis mechanisms. Similarly, organisms accumulate reactive oxygen species (ROS) over time and both species exhibited a gradual increase in proteins which enhance ROS tolerance, such as catalase. The species-specific responses of the proteome in response to storage temperature, and over time, may reflect the phylogenetic distance and/or different ecological strategies.
Enhancement of Closed-Loop Cognitive Stress Regulation Using Supervised Control Architectures

Goal: We propose novel supervised control architectures to regulate the cognitive stress state and close the loop. Methods: We take information present in underlying neural impulses of skin conductance signals and employ model-based control techniques to close the loop in a state-space framework. For performance enhancement, we establish a supervised knowledge-based layer to update control system in real time. In the supervised architecture, the controller parameters are being updated in real-time. Results: Statistical analyses demonstrate the efficiency of supervised control architectures in improving the closed-loop results while maintaining stress levels within a desired range with more optimized control efforts. The model-based approaches would guarantee the control system-perspective criteria such as stability and optimality, and the proposed supervised knowledge-based layer would further enhance their efficiency. Conclusion: Outcomes in this in silico study verify the proficiency of the proposed supervised architectures to be implemented in the real world.
Respiratory symptoms and use of dust-control measures in New Zealand construction workers – A cross-sectional study

Dust-exposed construction workers have an increased risk of respiratory symptoms, but the efficacy of dust-control measures remains unclear. This study compared respiratory symptoms, using a modified European Community Respiratory Health Survey questionnaire, between construction workers (n = 208) and a reference group of bus drivers and retail workers (n = 142). Within the construction workers, we assessed the effect of collective (on-tool vacuum/’wet-cut’ systems) and personal (respirators) exposure controls on symptom prevalence. Logistic regression assessed differences between groups, adjusted for age, ethnicity, and smoking status. Construction workers were more likely to cough with phlegm at least once a week (OR 2.4, 95% CI 1.2–4.7) and cough with phlegm ≥3 months/year for ≥2 years (OR 2.8, CI 1.2–7.0), but they had similar or fewer asthma symptoms. Construction workers who had worked for 11–20 years reported more cough/phlegm symptoms (OR 5.1, 1.7–15.0 for cough with phlegm ≥3 months/year for ≥2 years) than those who had worked <10 years (OR 1.9, 0.6–5.8), when compared to the reference group. Those who used ‘wet-cut’ methods reported less cough with phlegm, although the evidence for this association was weak (OR 0.4, CI 0.2–1.1 for cough with phlegm at least once a week); use of on-tool extraction showed a similar trend. No associations between respiratory protective equipment-use and symptoms were found. In conclusion, construction workers reported more symptoms suggestive of bronchitis, particularly those employed in the industry for >10 years. Use of collective dust exposure controls might protect against these symptoms, but this requires confirmation in a larger study.
Heavy metal pollution and environmental risks in the water of Rongna River caused by natural AMD around Tiegelongnan copper deposit, Northern Tibet, China

Acid mine drainage (AMD) is one of the biggest environmental challenges associated with in the mining process. Most of the current research on AMD focuses on developed deposits, whereas there is almost no research on naturally-produced AMD from undeveloped deposits. In this study, river water and AMD were collected to analyze the distribution characteristics of heavy metals and the phytoplankton community. In addition, the environmental risks of heavy metals were evaluated by single-factor pollution index, Nemerow pollution index and health risk assessment model. The results show that the pH of the Rongna River water ranged from 6.52 to 8.46, and the average concentrations of Mn and Ni were 867.37 and 28.44 μg/L, respectively, which exceed the corresponding Grade III Environmental Quality Standard of Surface Water. The results of the environmental health risk assessment show that the river section of the Rongna River was seriously polluted by the heavy metal Mn after AMD confluence, and the health risk assessment indicates that oral ingestion of Mn posed a potential non-carcinogenic risk to children and adults. A total of 35 phytoplankton species were found in the Rongna River. The phytoplankton biomass was negatively correlated with the concentration of major heavy metals, indicating that the heavy metal concentration exceeded the tolerance limit of phytoplankton, thereby affecting their normal growth. Finally, statistical analysis shows that Cu, Zn, Ni, Mn and Cd in the Rongna River were mainly derived from AMD.
DNA methylation in relation to gestational age and brain dysmaturation in preterm infants

Abstract Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from the saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes or regions. We tested the hypothesis that variation in DNA methylation could underpin the association between low gestational age at birth and atypical brain development by linking differentially methylated probes with measures of white matter connectivity derived from diffusion MRI metrics: peak width skeletonized mean diffusivity, peak width skeletonized fractional anisotropy and peak width skeletonized neurite density index. Gestational age at birth was associated with widespread differential methylation at term equivalent age, with genome-wide significant associations observed for 8870 CpG probes (P < 3.6 × 10−8) and 1767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell–cell contacts and cell–extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component that explained 23.5% of the variance in DNA methylation, and this was negatively associated with gestational age at birth. The first principal component was associated with peak width of skeletonized mean diffusivity (β = 0.349, P = 8.37 × 10−10) and peak width skeletonized neurite density index (β = 0.364, P = 4.15 × 10−5), but not with peak width skeletonized fraction anisotropy (β = −0.035, P = 0.510); these relationships mirrored the imaging metrics’ associations with gestational age at birth. Low gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome that is apparent at term equivalent age. Enriched gene ontology terms related to cell–cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNA methylation and image markers of white matter tract microstructure suggest that variation in DNA methylation may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterizes atypical brain development in preterm infants.
Cues to improve antibiotic-allergy registration: A mixed-method study

Background Approximately 2% of patients in primary care practice and up to 25% of hospital patients are registered as being allergic to an antibiotic. However, up to 90% of these registrations are incorrect, leading to unnecessary prescription of 2nd choice antibiotics with the attendant loss of efficacy, increased toxicity and antibiotic resistance. To improve registration, a better understanding is needed of how incorrect labels are attributed. Objective To investigate the quality of antibiotic allergy registration in primary care and identify determinants to improve registration of antibiotic allergies. Design Registration of antibiotic allergies in primary care practices were analysed for 1) completeness and 2) correctness. To identify determinants for improvement, semi-structured interviews with healthcare providers from four healthcare domains were conducted. Participants A total of 300 antibiotic allergy registrations were analysed for completeness and correctness. Thirty-four healthcare providers were interviewed. Main measures A registration was defined as complete when it included a description of all symptoms, time to onset of symptoms and the duration of symptoms. It was defined as correct when the conclusion was concordant with the Salden criteria. Determinants of correct antibiotic allergy registrations were divided into facilitators or obstructers. Key results Rates of completeness and correctness of registrations were 0% and 29.3%, respectively. The main perceived barriers for correct antibiotic allergy registration were insufficient knowledge, lack of priority, limitations of registration features in electronic medical records (EMR), fear of medical liability and patients interpreting side-effects as allergies. Conclusions The quality of antibiotic allergy registrations can be improved. Potential interventions include raising awareness of the consequences of incomplete and the importance of correct registrations, by continued education, and above all simplifying registration in an EMR by adequate ICT support.
Improved solubility and corneal permeation of PEGylated curcumin complex used for the treatment of ophthalmic bacterial infections

Naturally occurring curcumin can be used for the treatment of corneal bacterial infections with its limitation of poor solubility. Aim of the present study was to enhance solubility and permeation of curcumin for the treatment of corneal bacterial infections. For increasing solubility, curcumin and polyethylene glycol (PEG 6000) complex (1:3) was prepared by fusion melting method. Phase solubility studies were used for the calculation of Gibbs free energy of curcumin. Central composite rotatable design (CCRD) was applied for optimization of Curcumin (CUR), PEGylated Curcumin (PEG-CUR), penetration enhancer cremophore (CR). Optimized ointments were further evaluated by mucous permeation, membrane permeability and cell toxicity studies by Transwell cell, ussing chamber and Caco-2 cells respectively. Antibacterial test was also performed by agar well diffusion method. Solubility of PEG-CUR was increased up to 93±3.2% as compared to pure curcumin and content uniformity was in the range of 95–110%. Curcumin permeation from PEG-CUR ointment was increased up to 12 folds. No toxicity of Caco-2 cells for PEG-CUR even after 24h was observed. Activity index of pure CUR, PEG-CUR ointment with or without CR against S. aureus and P. aeruginosa was 97±2.3, 96±1.6, 95±2.5% respectively. Ointment with solubility enhanced PEG-CUR and cremophore can be used as a promising tool for the treatment of corneal bacterial infections.
Prevalence and factors associated with acute respiratory infection among under-five children in selected tertiary hospitals of Kathmandu Valley

Background Acute respiratory infection (ARI) is responsible for about 30–50 percent of visits to health facilities and for about 20–30 percent of admissions to hospitals in Nepal for children under 5 years old. Incidence of ARI in children among under-five years of age is 344 per 1000 in Nepal. Hence, the study aims to find out the prevalence and factors associated with acute respiratory infection among under-five children. Methods A cross-sectional study was conducted at Nepal Medical College and Teaching Hospital and International Friendship Children’s Hospital (IFCH) in Kathmandu among children of age 2–59 months attending Pediatric OPD. A total of 286 children were selected using the non-probability (convenient) sampling technique. Data were collected using pre-tested semi-structured tool through interview schedule, and descriptive and inferential statistical analyses were used. Results Out of 286 children, more than half of children (60.8%) had Acute Respiratory Infection (ARI). Nearly one-fifth of the children had severe or very severe pneumonia. Acute respiratory infection was significantly associated with religion followed by the family (p = 0.009, OR = 4.59 CI = 1.47–14.36), presence of the child in the kitchen while cooking (p = 0.001, OR = 2.03 CI = 1.17–3.51), and presence of respiratory tract infection in family (p = <0.001 OR = 2.83 CI = 1.59–5.05). Conclusion The study concluded that male children are more susceptible to acute respiratory infection than female children. Parents and family members should be aware of the prevention of acute respiratory infection by addressing and minimizing the factors contributing to ARI.
Impaired trigeminal control of ingestive behavior in the Prrxl1-/- mouse is associated with a lemniscal-biased orosensory deafferentation

Although peripheral deafferentation studies have demonstrated a critical role for trigeminal afference in modulating the orosensorimotor control of eating and drinking, the central trigeminal pathways mediating that control, as well as the timescale of control, remain to be elucidated. In rodents, three ascending somatosensory pathways process and relay orofacial mechanosensory input: the lemniscal, paralemniscal, and extralemniscal. Two of these pathways (the lemniscal and extralemniscal) exhibit highly structured topographic representations of the orofacial sensory surface, as exemplified by the one-to-one somatotopic mapping between vibrissae on the animals’ face and barrelettes in brainstem, barreloids in thalamus, and barrels in cortex. Here we use the Prrxl1 knockout mouse model to investigate ingestive behavior deficits associated with disruption of the lemniscal pathway. The Prrxl1 deletion disrupts somatotopic patterning and axonal projections throughout the lemniscal pathway but spares patterning in the extralemniscal nucleus. Our data reveal an imprecise and inefficient ingestive phenotype with deficits that span timescales from milliseconds to months, tightly linking trigeminal input with ingestion, from moment-to-moment consummatory to long term appetitive control. We suggest that ordered assembly of trigeminal sensory information along the lemniscal pathway is critical for the rapid and precise modulation of motor circuits driving eating and drinking action sequences.
Cost-effectiveness of Vitamin A supplementation among children in three sub-Saharan African countries: An individual-based simulation model using estimates from Global Burden of Disease 2019

Background Vitamin A Supplementation (VAS) is a cost-effective intervention to decrease mortality associated with measles and diarrheal diseases among children aged 6–59 months in low-income countries. Recently, experts have suggested that other interventions like large-scale food fortification and increasing the coverage of measles vaccination might provide greater impact than VAS. In this study, we conducted a cost-effectiveness analysis of a VAS scale-up in three sub-Saharan African countries. Methods We developed an individual-based microsimulation using the Vivarium simulation framework to estimate the cost and effect of scaling up VAS from 2019 to 2023 in Nigeria, Kenya, and Burkina Faso, three countries with different levels of baseline coverage. We calibrated the model with disease and risk factor estimates from the Global Burden of Disease 2019 (GBD 2019). We obtained baseline coverage, intervention effects, and costs from a systematic review. After the model was validated against GBD inputs, we modeled an alternative scenario where we scaled-up VAS coverage from 2019 to a level that halved the exposure to lack of VAS in 2023. Based on the simulation outputs for DALYs averted and intervention cost, we determined estimates for the incremental cost-effectiveness ratio (ICER) in USD/DALY. Findings Our estimates for ICER are as follows: $860/DALY [95% UI; 320, 3530] in Nigeria, $550/DALY [240, 2230] in Kenya, and $220/DALY [80, 2470] in Burkina Faso. Examining the data for DALYs averted for the three countries over the time span, we found that the scale-up led to 21 [5, 56] DALYs averted per 100,000 person-years in Nigeria, 21 [5, 47] DALYs averted per 100,000 person-years in Kenya, and 14 [0, 37] DALYs averted per 100,000 person-years in Burkina Faso. Conclusions VAS may no longer be as cost-effective in low-income regions as it has been previously. Updated estimates in GBD 2019 for the effect of Vitamin A Deficiency on causes of death are an additional driver of this lower estimate of cost-effectiveness.