Validity and reliability of the Persian version of the Gastroesophageal Reflux Disease Health-Related Quality of Life questionnaire.

OBJECTIVE: The Gastroesophageal Reflux Disease Health-Related Quality of Life (GERD-HRQL) is one of the most widely used questionnaires for assessing typical gastro-oesophageal reflux disease (GORD) symptoms. It is simple, concise, and treatment responsive, yet it has not been validated in the Persian language. This study aimed to translate the GERD-HRQL questionnaire into Persian and assess its validity and reliability. DESIGN: In this cross-sectional validation study, a team of gastroenterologists, general surgeons, and professional translators conducted the forward-backward translation. A gastroenterologist interviewed 10 patients with GORD to insure understandability of the questionnaire. Fifty-four patients with GORD and 60 patients with gastrointestinal complaints other than GORD were enrolled using convenience sampling method. To assess concurrent validity, patients with GORD completed the Persian GERD-HRQL and the WHO Quality of Life Brief Version (WHOQOL-BREF) questionnaires. To assess discriminant validity, GERD-HRQL scores were compared between GORD and non-GORD patients. After 2 weeks, the patients with GORD completed the GERD-HRQL questionnaire again to assess test-retest reliability. The internal consistency was measured using Cronbach's alpha. RESULTS: The mean age of the GORD participants was 36.90±10.44, and the majority were women (78%). All GERD-HRQL domains and total scores exhibited significant negative correlations with WHOQOL-BREF domains (ranging from -0.28 to -0.97). The GERD-HRQL scores were significantly different in GORD and non-GORD patients (p<0.001). Test and retest scores did not show any significant differences (p=0.49). Cronbach's alpha was 0.85. CONCLUSION: The Persian GERD-HRQL questionnaire is valid and reliable and can effectively assess the GORD symptoms in Persian-speaking individuals.

Filtering ASVs/OTUs via mutual information-based microbiome network analysis.

Microbial communities are widely studied using high-throughput sequencing techniques, such as 16S rRNA gene sequencing. These techniques have attracted biologists as they offer powerful tools to explore microbial communities and investigate their patterns of diversity in biological and biomedical samples at remarkable resolution. However, the accuracy of these methods can negatively affected by the presence of contamination. Several studies have recognized that contamination is a common problem in microbial studies and have offered promising computational and laboratory-based approaches to assess and remove contaminants. Here we propose a novel strategy, MI-based (mutual information based) filtering method, which uses information theoretic functionals and graph theory to identify and remove contaminants. We applied MI-based filtering method to a mock community data set and evaluated the amount of information loss due to filtering taxa. We also compared our method to commonly practice traditional filtering methods. In a mock community data set, MI-based filtering approach maintained the true bacteria in the community without significant loss of information. Our results indicate that MI-based filtering method effectively identifies and removes contaminants in microbial communities and hence it can be beneficial as a filtering method to microbiome studies. We believe our filtering method has two advantages over traditional filtering methods. First, it does not required an arbitrary choice of threshold and second, it is able to detect true taxa with low abundance.

A SARS-CoV-2 spike ferritin nanoparticle vaccine protects hamsters against Alpha and Beta virus variant challenge.

The emergence of SARS-CoV-2 variants of concern (VOC) requires adequate coverage of vaccine protection. We evaluated whether a SARS-CoV-2 spike ferritin nanoparticle vaccine (SpFN), adjuvanted with the Army Liposomal Formulation QS21 (ALFQ), conferred protection against the Alpha (B.1.1.7), and Beta (B.1.351) VOCs in Syrian golden hamsters. SpFN-ALFQ was administered as either single or double-vaccination (0 and 4 week) regimens, using a high (10 µg) or low (0.2 µg) dose. Animals were intranasally challenged at week 11. Binding antibody responses were comparable between high- and low-dose groups. Neutralizing antibody titers were equivalent against WA1, B.1.1.7, and B.1.351 variants following two high dose vaccinations. Dose-dependent SpFN-ALFQ vaccination protected against SARS-CoV-2-induced disease and viral replication following intranasal B.1.1.7 or B.1.351 challenge, as evidenced by reduced weight loss, lung pathology, and lung and nasal turbinate viral burden. These data support the development of SpFN-ALFQ as a broadly protective, next-generation SARS-CoV-2 vaccine.

mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates.

B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log10 reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log10 reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.

Decoding influenza outbreaks in a rural region of the USA with archetypal analysis.

We present the first application of archetypal analysis for influenza data from 2010 to 2018 in Montana, USA. Using archetypes, we decompose the data into spatial and temporal components, allowing for a more informed analysis of spatial-temporal dynamic trends during an influenza season. Initially, we reduce the dimension of the set of counties by using a mutual information measure on the influenza time series to create a smaller, maximal mutual information network. Archetypal analysis then describes the relationship between influenza cases across counties and regions in Montana. Finally, we discuss the potential implications this analysis can have for infectious disease modeling, particularly where data is sparse and limited.

A SARS-CoV-2 spike ferritin nanoparticle vaccine protects against heterologous challenge with B.1.1.7 and B.1.351 virus variants in Syrian golden hamsters.

The emergence of SARS-CoV-2 variants of concern (VOC) requires adequate coverage of vaccine protection. We evaluated whether a spike ferritin nanoparticle vaccine (SpFN), adjuvanted with the Army Liposomal Formulation QS21 (ALFQ), conferred protection against the B.1.1.7 and B.1.351 VOCs in Syrian golden hamsters. SpFN-ALFQ was administered as either single or double-vaccination (0 and 4 week) regimens, using a high (10 µg) or low (0.2 µg) immunogen dose. Animals were intranasally challenged at week 11. Binding antibody responses were comparable between high- and low-dose groups. Neutralizing antibody titers were equivalent against WA1, B.1.1.7, and B.1.351 variants following two high dose two vaccinations. SpFN-ALFQ vaccination protected against SARS-CoV-2-induced disease and viral replication following intranasal B.1.1.7 or B.1.351 challenge, as evidenced by reduced weight loss, lung pathology, and lung and nasal turbinate viral burden. These data support the development of SpFN-ALFQ as a broadly protective, next-generation SARS-CoV-2 vaccine.

Evaluation of mRNA-1273 against SARS-CoV-2 B.1.351 Infection in Nonhuman Primates.

BACKGROUND: Vaccine efficacy against the B.1.351 variant following mRNA-1273 vaccination in humans has not been determined. Nonhuman primates (NHP) are a useful model for demonstrating whether mRNA-1273 mediates protection against B.1.351. METHODS: Nonhuman primates received 30 or 100 µg of mRNA-1273 as a prime-boost vaccine at 0 and 4 weeks, a single immunization of 30 µg at week 0, or no vaccine. Antibody and T cell responses were assessed in blood, bronchioalveolar lavages (BAL), and nasal washes. Viral replication in BAL and nasal swabs were determined by qRT-PCR for sgRNA, and histopathology and viral antigen quantification were performed on lung tissue post-challenge. RESULTS: Eight weeks post-boost, 100 µg x2 of mRNA-1273 induced reciprocal ID 50 neutralizing geometric mean titers against live SARS-CoV-2 D614G and B.1.351 of 3300 and 240, respectively, and 430 and 84 for the 30 µg x2 group. There were no detectable neutralizing antibodies against B.1351 after the single immunization of 30 µg. On day 2 following B.1.351 challenge, sgRNA in BAL was undetectable in 6 of 8 NHP that received 100 µg x2 of mRNA-1273, and there was a ∼2-log reduction in sgRNA in NHP that received two doses of 30 µg compared to controls. In nasal swabs, there was a 1-log 10 reduction observed in the 100 µg x2 group. There was limited inflammation or viral antigen in lungs of vaccinated NHP post-challenge. CONCLUSIONS: Immunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls lower and upper airway viral replication against the B.1.351 variant in NHP.

Infection and vaccine-induced neutralizing antibody responses to the SARS-CoV-2 B.1.617.1 variant.

SARS-CoV-2 has caused a devastating global pandemic. The recent emergence of SARS-CoV-2 variants that are less sensitive to neutralization by convalescent sera or vaccine-induced neutralizing antibody responses has raised concerns. A second wave of SARS-CoV-2 infections in India is leading to the expansion of SARS-CoV-2 variants. The B.1.617.1 variant has rapidly spread throughout India and to several countries throughout the world. In this study, using a live virus assay, we describe the neutralizing antibody response to the B.1.617.1 variant in serum from infected and vaccinated individuals. We found that the B.1.617.1 variant is 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and Moderna and Pfizer vaccinated individuals. Despite this, a majority of the sera from convalescent individuals and all sera from vaccinated individuals were still able to neutralize the B.1.617.1 variant. This suggests that protective immunity by the mRNA vaccines tested here are likely retained against the B.1.617.1 variant. As the B.1.617.1 variant continues to evolve, it will be important to monitor how additional mutations within the spike impact antibody resistance, viral transmission and vaccine efficacy.

High-throughput, single-copy sequencing reveals SARS-CoV-2 spike variants coincident with mounting humoral immunity during acute COVID-19.

Tracking evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within infected individuals will help elucidate coronavirus disease 2019 (COVID-19) pathogenesis and inform use of antiviral interventions. In this study, we developed an approach for sequencing the region encoding the SARS-CoV-2 virion surface proteins from large numbers of individual virus RNA genomes per sample. We applied this approach to the WA-1 reference clinical isolate of SARS-CoV-2 passaged in vitro and to upper respiratory samples from 7 study participants with COVID-19. SARS-CoV-2 genomes from cell culture were diverse, including 18 haplotypes with non-synonymous mutations clustered in the spike NH2-terminal domain (NTD) and furin cleavage site regions. By contrast, cross-sectional analysis of samples from participants with COVID-19 showed fewer virus variants, without structural clustering of mutations. However, longitudinal analysis in one individual revealed 4 virus haplotypes bearing 3 independent mutations in a spike NTD epitope targeted by autologous antibodies. These mutations arose coincident with a 6.2-fold rise in serum binding to spike and a transient increase in virus burden. We conclude that SARS-CoV-2 exhibits a capacity for rapid genetic adaptation that becomes detectable in vivo with the onset of humoral immunity, with the potential to contribute to delayed virologic clearance in the acute setting.

High-Throughput, Single-Copy Sequencing Reveals SARS-CoV-2 Spike Variants Coincident with Mounting Humoral Immunity during Acute COVID-19.

Tracking evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within infected individuals will help elucidate coronavirus disease 2019 (COVID-19) pathogenesis and inform use of antiviral interventions. In this study, we developed an approach for sequencing the region encoding the SARS-CoV-2 virion surface proteins from large numbers of individual virus RNA genomes per sample. We applied this approach to the WA-1 reference clinical isolate of SARS-CoV-2 passaged in vitro and to upper respiratory samples from 7 study participants with COVID-19. SARS-CoV-2 genomes from cell culture were diverse, including 18 haplotypes with non-synonymous mutations clustered in the spike NH 2 -terminal domain (NTD) and furin cleavage site regions. By contrast, cross-sectional analysis of samples from participants with COVID-19 showed fewer virus variants, without structural clustering of mutations. However, longitudinal analysis in one individual revealed 4 virus haplotypes bearing 3 independent mutations in a spike NTD epitope targeted by autologous antibodies. These mutations arose coincident with a 6.2-fold rise in serum binding to spike and a transient increase in virus burden. We conclude that SARS-CoV-2 exhibits a capacity for rapid genetic adaptation that becomes detectable in vivo with the onset of humoral immunity, with the potential to contribute to delayed virologic clearance in the acute setting. AUTHOR SUMMARY: Mutant sequences of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) arising during any individual case of coronavirus disease 2019 (COVID-19) could theoretically enable the virus to evade immune responses or antiviral therapies that target the predominant infecting virus sequence. However, commonly used sequencing technologies are not optimally designed to detect variant virus sequences within each sample. To address this issue, we developed novel technology for sequencing large numbers of individual SARS-CoV-2 genomic RNA molecules across the region encoding the virus surface proteins. This technology revealed extensive genetic diversity in cultured viruses from a clinical isolate of SARS-CoV-2, but lower diversity in samples from 7 individuals with COVID-19. Importantly, concurrent analysis of paired serum samples in selected individuals revealed relatively low levels of antibody binding to the SARS-CoV-2 spike protein at the time of initial sequencing. With increased serum binding to spike protein, we detected multiple SARS-CoV-2 variants bearing independent mutations in a single epitope, as well as a transient increase in virus burden. These findings suggest that SARS-CoV-2 replication creates sufficient virus genetic diversity to allow immune-mediated selection of variants within the time frame of acute COVID-19. Large-scale studies of SARS-CoV-2 variation and specific immune responses will help define the contributions of intra-individual SARS-CoV-2 evolution to COVID-19 clinical outcomes and antiviral drug susceptibility.

Cohnella 1759 cysteine protease shows significant long term half-life and impressive increased activity in presence of some chemical reagents.

Thermostability and substrate specificity of proteases are major factors in their industrial applications. rEla is a novel recombinant cysteine protease obtained from a thermophilic bacterium, Cohnella sp.A01 (PTCC No: 1921). Herein, we were interested in recombinant production and characterization of the enzyme and finding the novel features in comparison with other well-studied cysteine proteases. The bioinformatics analysis showed that rEla is allosteric cysteine protease from DJ-1/ThiJ/PfpI superfamily. The enzyme was heterologously expressed and characterized and the recombinant enzyme molecular mass was 19.38 kD which seems to be smaller than most of the cysteine proteases. rEla exhibited acceptable activity in broad pH and temperature ranges. The optimum activity was observed at 50℃ and pH 8 and the enzyme showed remarkable stability by keeping 50% of residual activity after 100 days storage at room temperature. The enzyme Km and Vmax values were 21.93 mM, 8 U/ml, respectively. To the best of our knowledge, in comparison with the other characterized cysteine proteases, rEla is the only reported cysteine protease with collagen specificity. The enzymes activity increases up to 1.4 times in the presence of calcium ion (2 mM) suggesting it as the enzyme's co-factor. When exposed to surfactants including Tween20, Tween80, Triton X-100 and SDS (1% and 4% v/v) the enzyme activity surprisingly increased up to 5 times.

The delayed effect of wildfire season particulate matter on subsequent influenza season in a mountain west region of the USA.

Particularly in rural settings, there has been little research regarding the health impacts of fine particulate matter (PM2.5) during the wildfire season smoke exposure period on respiratory diseases, such as influenza, and their associated outbreaks months later. We examined the delayed effects of PM2.5 concentrations for the short-lag (1-4 weeks prior) and the long-lag (during the prior wildfire season months) on the following winter influenza season in Montana, a mountainous state in the western United States. We created gridded maps of surface PM2.5 for the state of Montana from 2009 to 2018 using spatial regression models fit with station observations and Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol optical thickness data. We used a seasonal quasi-Poisson model with generalized estimating equations to estimate weekly, county-specific, influenza counts for Montana, associated with delayed PM2.5 concentration periods (short-lag and long-lag effects), adjusted for temperature and seasonal trend. We did not detect an acute, short-lag PM2.5 effect nor short-lag temperature effect on influenza in Montana. Higher daily average PM2.5 concentrations during the wildfire season was positively associated with increased influenza in the following winter influenza season (expected 16% or 22% increase in influenza rate per 1 µg/m3 increase in average daily summer PM2.5 based on two analyses, p = 0.04 or 0.008). This is one of the first observations of a relationship between PM2.5 during wildfire season and influenza months later.

Data Driven Models of Short-Term Synaptic Plasticity.

Simple models of short term synaptic plasticity that incorporate facilitation and/or depression have been created in abundance for different synapse types and circumstances. The analysis of these models has included computing mutual information between a stochastic input spike train and some sort of representation of the postsynaptic response. While this approach has proven useful in many contexts, for the purpose of determining the type of process underlying a stochastic output train, it ignores the ordering of the responses, leaving an important characterizing feature on the table. In this paper we use a broader class of information measures on output only, and specifically construct hidden Markov models (HMMs) (known as epsilon machines or causal state models) to differentiate between synapse type, and classify the complexity of the process. We find that the machines allow us to differentiate between processes in a way not possible by considering distributions alone. We are also able to understand these differences in terms of the dynamics of the model used to create the output response, bringing the analysis full circle. Hence this technique provides a complimentary description of the synaptic filtering process, and potentially expands the interpretation of future experimental results.

Effect of Neuromodulation of Short-term Plasticity on Information Processing in Hippocampal Interneuron Synapses.

Neurons in a micro-circuit connected by chemical synapses can have their connectivity affected by the prior activity of the cells. The number of synapses available for releasing neurotransmitter can be decreased by repetitive activation through depletion of readily releasable neurotransmitter (NT), or increased through facilitation, where the probability of release of NT is increased by prior activation. These competing effects can create a complicated and subtle range of time-dependent connectivity. Here we investigate the probabilistic properties of facilitation and depression (FD) for a presynaptic neuron that is receiving a Poisson spike train of input. We use a model of FD that is parameterized with experimental data from a hippocampal basket cell and pyramidal cell connection, for fixed frequency input spikes at frequencies in the range of theta (3-8 Hz) and gamma (20-100 Hz) oscillations. Hence our results will apply to micro-circuits in the hippocampus that are responsible for the interaction of theta and gamma rhythms associated with learning and memory. A control situation is compared with one in which a pharmaceutical neuromodulator (muscarine) is employed. We apply standard information-theoretic measures such as entropy and mutual information, and find a closed form approximate expression for the probability distribution of release probability. We also use techniques that measure the dependence of the response on the exact history of stimulation the synapse has received, which uncovers some unexpected differences between control and muscarine-added cases.

Gastrointestinal Stromal Tumors in Northeastern Iran: 46 Cases During 2003-2012.

BACKGROUND Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. They are usually C-kit positive and seen slightly more common in men. These tumors are seen in the GI tract from the esophagus to the anus with occasional invasion or metastasis. METHODS In this retrospective study, we evaluated the prevalence of c-kit positive stromal tumors of the GI tract based on age, site of involvement, size of tumor, local invasion, and Immunohistochemical markers. The study was conducted in Mashhad University of Medical Sciences in Iran during 2003-2012. RESULTS Of the total 46 patients, 18 (39.1%) were men and 28(60.9%) were women with a mean age of 58.07 years (range: 18-93). Common sites of tumor were stomach, small intestine, esophagus and rectum, respectively. The number of mitoses per 50 HPF varied between zero and 160 mitoses. Overall, 23 cases had 5 mitoses 50/HPF (50%) and 23 tumors expressed <5 mitoses/50 HPF (50%). Local invasion and metastasis were observed in seven cases with extension to liver, pancreas, pregastric tissue, omentum, mesentery and appendix. Positive reaction for CD34, S100, actin and desmin was seen in 47.8%, 13%, 21.7%, and 4.3% of the patients, respectively. CONCLUSION Most patients were women. The prevalence of tumors in the esophagus was higher than the rectum. Invasion and metastasis did not correlate with mitotic rate, site and size of tumor. We suggest evaluation of genetic, racial and geographical or other unknown risk factors.

Study of the knowledge of pediatricians and senior residents relating to the importance of hearing impairment and deafness screening among newborns.

INTRODUCTION: Newborn hearing screening leads to the early detection of hearing impairment. The aim of screening is to decrease or remove the effect of hearing impairment on development of speech and language by timely diagnosis and effective treatment. A number of risk factors lead to delayed start of decreased hearing ability including: 1. Congenital infection with cytomegalovirus (CMV) virus, 2. Meningitis, 3. Mumps, 4. Positive family history, 5. Head trauma, 6. Chemotherapy,7. Syndrome pertaining to delayed start of decreased hearing. Unfortunately, lack of attention to early diagnosis of hearing impairment is becoming a general health problem. No research has yet been carried out relating to the knowledge of pediatricians on this issue, particularly the importance of hearing impairment and hearing screening. The aim of this study was to determine the attitude to newborn hearing screening among pediatricians. MATERIALS AND METHODS: This cross-sectional, descriptive-analytic study was conducted in Isfahan in 2012 among 300 pediatricians and final-year pediatric residents. An adjusted 22-question version of the Early Hearing Detection and Intervention (EHDI) questionnaire was used to collect data. The validity and reliability of the EHDI questionnaire was previously demonstrated by Boys Town National Research Hospital and its Farsi translated version was validated by the EDC Center at the Isfahan University of Medical Sciences. RESULTS: In our study, 83% of pediatricians agreed on the importance of hearing impairment screening for all infants. However 65% were not aware of special needs for hearing-impaired patients. CONCLUSION: Newborn hearing impairment and deafness screening is important, irrespective of the costs, and lack of timely diagnosis results in both individual and social consequences. The majority of physicians use textbooks to gain information about hearing screening, but recognize that this is insufficient. Although it is now one of the most useful tools for gathering and applying new information, the physicians in our study rely very little on the Internet as a source of information.