Since the publication of the American Gastroenterological Association’s (AGA) recommendations in 2017, there have been no significant changes in the biological monitoring recommendations. Lack of evidence on proactive therapeutic drug monitoring (pTDM) over the reactive therapeutic drug monitoring (rTDM) and the absence of recommendations on the individualized dosage methods have been limiting. The aims of this review were to identify updates on TDM strategies and in individualized dosing methods. For the analysis of the TDM strategies and individualized dosing method, a search was carried out in PubMed and Cochrane Central. In TDM case, since 2017. A total of 263 publications were found. Only 7 related to pTDM. Two of them were clinical trials and one systematic review. Of the 8 studies analyzed, 7 found benefit from pTDM over rTDM and one found no difference. Only one study was prospective. Regarding the individualized dosing method, 229 results were found. Population pharmacokinetics was the most widely used technique to explore and develop individual dosage models. It has been used to analyze the influence of factors on drug concentrations (serum albumin, weight… etc. We have not found major changes in TDM strategies. The available evidence is limited and of low quality. Retrospective designs and low power of the studies are the main problems. Population pharmacokinetics methods are the most widely used. But are more used to identify factors that affect drug concentrations than for dosage individualization.

Introduction. Locking the humanity in their homes, COVID-19 forced people to use the technology at hand to keep informed about the outbreak and to keep close to their loved ones. During this time, even if physical health is theoretically unaffected, keeping calm and sane can be challenging. The aim of this research was to evaluate whether exposure to COVID-19 information available in the digital space has a different impact on the mental condition of Romanian medical staff, compared to general population, particularly searching for depression and anxiety symptoms. Materials and methods. An online survey was conducted from April 6 to 16, 2020 within the Romanian users of Social Media platforms. The questionnaire assessed depression with the WHO-Five Well-Being Index, anxiety with the Generalized Anxiety Disorder Scale and Social Media exposure by asking how often the respondents saw COVID-19 related information on the most popular Social Media channels in Romania. Information about: gender, age, educational level, occupation, area of living and risk category was also collected. The risk categories were defined as no risk, medium risk, and medical staff. Results. Almost 90% of the 402 participants received daily through at least one Social Media channel information related to the COVID-19 outbreak. The Social Media Exposure significantly associated with the risk group only for Facebook and LinkedIn. However, exposure to information regarding COVID-19 was neither associated with anxiety nor depression. No significant association was identified neither between age class and self-assessed anxiety nor self-assessed depression. The self-assessment of depression was significantly more frequent as compared to self-assessment of anxiety. Conclusion. The results of this research are opposite to most of the already published literature. Depression and anxiety could not be correlated with the context of lockdown and excessive COVID-19-related information.

Coronavirus disease 2019, an infectious viral disease caused by severe acute respiratory syndrome coronavirus 2 has been declared a global pandemic by World Health Organisation. The race to find an effective cure for it is on. Most of the candidate drugs in various clinical trials are being re-purposed but none has been approved as at date. It is pertinent for the bedside physicians to understand the mechanisms of action of these agents and their peculiar adverse effects so they are properly guided on the risk/benefit of the drugs they choose in managing COVID-19 patients. In this review, we aimed to review the mechanisms of action and adverse effects of the major drugs in clinical trials for COVID-19 therapeutics. Clinicaltrials.gov, the international clinical trials platform of the WHO, the EU clinical trials register and the Cochrane Central Register of Controlled Trials were searched for registered clinical trials. Studies in therapeutic trials were considered eligible for the work. Frequency table was made for the most common trialled drugs and the mechanisms of actions and adverse effects of the selected drugs were reviewed. 10 studies were selected for review in a descending order of their frequency in different therapeutic trials and these are ritonavir, lopinavir, chloroquine/hydroxychloroquine, interferon, remdesvir, favipravir, umifenovir, darunavir, tocilizumab and methylprednisolone. The bedside physicians need to understand the mechanisms of action of these agents and their peculiar adverse effects so they are properly guided on the risk/benefit of the drugs they choose in managing COVID-19 patients.

Background: The COVID19 pandemic gripped every nation’s healthcare system and provisions on all levels. In cardiac and aortic surgery, as it is with most specialities, elective surgeries were halted. Aims of the study: We captured reflections, contingencies, and current practices across of high-volume centres in cardiac and aortic surgery globally. We also aimed this study to assess decision on prioritization of the surgical patients, the need for personal protection equipment and choice of preoperative investigations in current dynamic and fluid climate. Methods: A validated web-based questionnaire was constructed and was circulated to the international surgeons amongst high volume cardiac and aortic surgery centres. Their intrinsic feedback on decision making, impact of the lockdown and perspectives for the future ahead us all were noted. Mixed method approach was constructed. Qualitative data analysis was introduced to signify the impact globally. Results: Overall, 23 centers from 18 countries participated in this international study. 91.7% of the respondents stopped operating on elective patients during the pandemic. Majority of the surgeons agreed that acute aortic dissection (87.1%) should be operated as emergency procedure and stable triple vessel disease (87.1%) to be considered as elective procedure. Three-fifth (60%) of the respondents relied on CT chest as a preoperative screening modality. Conclusion: In the present climate where there is paucity of evidence, this will give an interim consensus for the cardiac surgeons. With the increase in cumulative number of COVID19 patients, careful utilization of the resources regarding hospital beds and manpower is of paramount importance.

Introduction: COVID-19 is a global catastrophic event that causes severe acute respiratory syndrome. The mechanism of the disease remains unclear, and hypoxia is one of the main complications. There is no currently approved protocol for treatment. The microbial threat as induced by COVID-19 causes the activation of macrophages to produce a huge amount of inflammatory molecules and nitric oxide (NO). Activation of macrophages population into a pro-inflammatory phenotype induces a self-reinforcing cycle. Oxidative stress and NO contribute to this cycle, establishing a cascade inflammatory state that can kill the patient. Interrupting this vicious cycle by a simple remedy may save critical patients’ lives. Methods: Nitrite, nitrate (the metabolites of NO), methemoglobin, and prooxidant-antioxidant-balance levels were measured in 25 ICU COVID-19 patients and 25 healthy individuals. As the last therapeutic option, five patients were administered methylene blue-vitamin C-N-acetyl Cysteine (MCN). Results: Nitrite, nitrate, methemoglobin, and oxidative stress were significantly increased in patients in comparison to healthy individuals. Four of the five patients responded well to treatment. Discussion: NO, methemoglobin and oxidative stress may play a central role in the pathogenesis of critical COVID-19 disease. MCN treatment seems to increase the survival rate of these patients. Considering the vicious cycle of macrophage activation leading to deadly NO, oxidative stress, and cytokine cascade syndrome; the therapeutic effect of MCN seems to be reasonable. Accordingly, a wider clinical trial has been designed. It should be noted that the protocol is using the low-cost drugs which the FDA approved for other diseases.

A document by Jan Willem de Leeuw, written on Authorea.

Climate change is expected to systematically alter the distribution and poEurycea pulation dynamics of species around the world. The effects are expected to be particularly strong at high latitudes and elevations, and for ectothermic species with small ranges and limited movement potential, such as salamanders in the southern Appalachian Mountains. In this study, we sought to establish baseline abundance estimates for plethodontid salamanders (family: Plethodontidae) over an elevational gradient in Great Smoky Mountains National Park. In addition to generating these baseline data for multiple species, we describe methods for surveying salamanders that allow for meaningful comparisons over time by separating observation and ecological processes generating the data. We found that Plethodon jordani had a mid-elevation peak (1500 m) in abundance and Desmognathus wrighti increased in abundance with elevation up to the highest areas of the park (2025 m), whereas Eurycea wilderae increased in abundance up to 1600 m and then plateaued with increasing uncertainty. In addition to elevation, litter depth, herbaceous ground cover, and proximity to stream were important predictors of abundance (dependent upon species), whereas daily temperature, precipitation, ground cover, and humidity influenced detection rates. Our data provide some of the first minimally biased information for future studies to assess changes in the abundance and distribution of salamanders in this region. Understanding abundance patterns along with detailed baseline distributions will be critical for comparisons with future surveys to understand the population and community-level effects of climate change on montane salamanders.

The theory of ecological divergence provides a useful framework to understand the adaptation of many species to anthropogenic (‘domestic’) habitats. The mosquito Aedes aegypti, a global vector of several arboviral diseases, presents an excellent study system. Ae. aegypti originated in African forests, but the populations that invaded other continents have specialized in domestic habitats. In its African native range, the species can be found in both forest and domestic habitats like villages. A crucial behavioral change between mosquitoes living in different habitats is their oviposition choices. Forest Ae. aegypti lay eggs in natural water containers like tree holes, while their domestic counterparts heavily rely on artificial containers such as plastic buckets. These habitat-specific containers likely have different environmental conditions, which could drive the incipient divergent evolution of oviposition in African Ae. aegypti. To examine this hypothesis, we conducted field research in two African locations, La Lopé, Gabon and Rabai, Kenya, where Ae. aegypti live in both forests and nearby villages. We first characterized a series of environmental conditions of natural oviposition sites, including physical characteristics, microbial density, bacterial composition, and volatile profiles. Our data showed that in both locations, environmental conditions of oviposition sites did differ between habitats. To examine potential behavioral divergence, we then conducted field and laboratory oviposition choice experiments to compare the oviposition preference of forest and village mosquitoes. The field experiment suggested that forest mosquitoes readily accepted artificial containers. In laboratory oviposition assays, forest and village mosquito colonies did not show a differential preference towards several conditions that featured forest versus village oviposition sites. Collectively, there is little evidence from our study that environmental differences lead to strong and easily measurable divergence in oviposition behavior between Ae. aegypti that occupy nearby forest and domestic habitats within Africa, despite clear divergence between African and non-African Ae. aegypti.

A document by Rafael Oliveira, written on Authorea.

Zwitterionic materials have attracted increasing attentions in the underwater super-oleophobic applications for its strong hydration via electrostatic interactions. Herein, molecular dynamics simulations were used to investigate the hydration and underwater oleophobicity of sulfobetaine-terminated self-assembled monolayers (SB-SAMs) with different carbon spacer lengths (CSL) between oppositely charged groups of SB molecules. Simulation results show that the hydration of SB-SAMs is positively dependent on CSL; the underwater oleophobicity is strengthened and then weakened with the increase of CSL, reaching optimal performance when CSL = 3; Adhesion force of oil droplet on SB-SAMs is inversely correlated with their contact angles, reaching the minimum value when CSL = 3. Moreover, the addition of NaCl can weaken the self-association of SB molecules resulted from interactions between cationic and anionic groups, which promotes hydration and enhances underwater oleophobicity of SB-SAMs. These results will benefit for the design of novel zwitterion-based materials for anti-fouling and oil-water separation applications.

Background: Previous studies demonstrated that acupuncture is a safe treatment in general population, however, the safety of acupuncture during menstruation remains controversial. This study aimed to evaluate the safety of acupuncture during menstruation, using change of menstrual cycle as primary outcome. Methods: women who were going to receive at least 12 times acupuncture in the coming one month regardless of diagnosis, and experienced at least one menstruation during the period were recruited from four hospitals in Northern China from March 2017 to March 2018. Patients were followed up 3 menstrual cycles since acupuncture treatment, and data was collected through a questionnaire at baseline and 3 follow-up visits. Chi-square tests and logistic regression were used to test the associations between timing of acupuncture and change of menstrual cycle. Result: there were 373 female patients included in analysis, of which 208(55.8%) had acupuncture during menstruation(AM group) and 165(44.2%) did not(NM group). Nearly one fifth(68, 18.2%) of all patients experienced a change in menstrual cycle. The percentage of patients with changed menstrual cycle in AM group(19.7%) was higher than that of NM group(16.4%), but the difference was not significant(OR 1.254, 95% CI 0.647 to 2.431, P=0.503) when adjusted for age, history of menstrual cycle and diagnose. Conclusion: This study indicated that the rate of menstrual cycle change did not differ among patients who received acupuncture during menstruation or not. However, the interpretation and conclusion of the results should be cautious due to the limitations of the study. Key Words: acupuncture, timing, menstrual cycle change, adverse events, safety

Urban evolutionary biology is the study of rapid evolutionary change in response to humans and our use of lands to support city dwellers. Because cities are relatively modern additions to the natural world, research on urban evolution tends to focus on microevolutionary change that has happened across a few to many hundreds of generations. These questions still fall under the broad purview of evolutionary ecology. But the severity, rapidity, and replication of environmental changes that drive evolution in this context make it worthy of specific attention. Urban evolution provides the opportunity to study the earliest stages of evolution in a context that is scientifically interesting and societally important. The newness of urban populations and their proximity to natural populations also creates challenges when trying to detect population genetic change. In a From the Cover article in this issue of Molecular Ecology, Mueller et al. (2020) use whole genome resequencing data to address some of these challenges while exploring genetic changes associated with urbanization in 3 replicate urban-rural burrowing owl (Athene cunicularia) populations. Combining multiple approaches across these sample sites Mueller et al. find evidence for selection on genes whose function is related to synapses, neuron projections, brain connectivity, and cognitive function in general. That selection was parallel suggests brain processes were likely important for urban adaptation.

A document by Nidhi Bajpai, written on Authorea.

Escherichia coli has been considered as the most used model bacteria in the majority of studies for several decades. However, a new faster chassis is emerging in the form of the fast-growing gram-negative bacterium Vibrio natriegens. Different methodologies, well established in E. coli, are currently being adapted for the Vibrio natriegens in the hope of enabling a much faster platform for general lab-work. Amongst the vast technologies available for E. coli, genetic code expansion, the incorporation of unnatural amino acids into proteins, serves as a robust tool for protein engineering and biorthogonal modifications. Here we designed and adapted the genetic code expansion methodology for Vibrio natriegens and demonstrate an unnatural amino acid incorporation into a protein for the first time in this organism.

BACKGROUND No scoring models for IS-CTO have been established because of its in-stent characteristics. The purpose of this study was to develop a scoring model to predict the technical success of recanalizing in-stent chronic total occlusion (IS-CTO) by percutaneous coronary intervention (PCI). METHODS We retrospectively collected data from 474 patients who underwent an IS-CTO PCI from January 2015 to December 2018, consecutively. We selected clinical and angiographic factors and utilized a derivation and validation cohort (4:1 sampling ratio) analysis. Factors with strong correlations with technical failure, according to multivariable analysis, were assigned 1 point, and a scoring system with a 4-point maximum was established. The model was then validated with a validation cohort. RESULTS The overall procedural success rate was 77.4%. On multivariable analysis, the factors that correlated with technical failure were proximal bending (beta coefficient [β] = 2.142), tortuosity (β = 2.622), stent under expansion (β = 3.052), and poor distal landing zone (β = 2.004). The IS-CTO score demonstrated good calibration and excellent predicting capacity in the derivation (receiver-operator characteristic [ROC] area = 0.973 and Hosmer-Lemeshow Chi-squared = 5.252; p = 0.072) and validation (ROC area = 0.976 and Hosmer-Lemeshow Chi-squared =0.916; p = 0.632) cohorts. In the validation subset, the IS-CTO score demonstrated superior performance to the J-CTO and PROGRESS CTO scores for predicting technical success (area under the a curve [AUC] 0.976 vs 0.662 vs 0.579, respectively; difference in AUC between the IS-CTO score and J-CTO score = 0.314, p < 0.01; difference in AUC between the IS-CTO score and PROGRESS score = 0.397, p < 0.01). CONCLUSIONS Our results suggest that the IS-CTO score system is a helpful tool to predict the technical success of IS-CTO PCI. Key words: In-stent chronic total occlusion; Percutaneous coronary intervention; Predicting factor; Scoring sys

Background and Purpose Previously we reported our hypothesis that the high distribution of antiviral drugs in the lung is a key factor that results in reducing viral loads in COVID-19 patients. So far, chloroquine, lopinavir, hydroxychloroquine, azithromycin, favipiravir, ribavirin, darunavir, remdesivir, and umifenovir have been tested in COVID-19 clinical trials. Here we validate our hypothesis by comparing the pharmacokinetics profiles of these drugs and their capabilities of reducing viral load in clinical trials. Experimental approach The RNA-seq data were obtained from public database and re-analyzed and visualized by Single Cell Portal and Seurat. The tissue/plasma ratio of antiviral drugs were calculated by AUC or Mean values that were compiled from publications. Key Results High expression of both ACE2 and TMPRSS2 makes the lung and intestine vulnerable to SARS-CoV-2. Hydroxychloroquine, chloroquine, and favipiravir, which were highly distributed to the lung, were reported to reduce viral loads in respiratory tract of COVID-19 patients. Conversely, drugs with poor lung distributions, including lopinavir/ritonavir, umifenovir and remdesivir, were insufficient to inhibit SARS-CoV-2 replication. Lopinavir/ritonavir might inhibit SARS-CoV-2 in the GI tract according to their distribution profiles. Conclusion and Implications The antiviral drugs should be distributed straight to or accumulate in the lung for reducing viral loads in respiratory tract of COVID-1 9 patients. Additionally, to better evaluate antiviral drugs that target the intestine, the stool samples should also be collected for viral RNA test in the future.

A document by Indrani Roy, written on Authorea.

Introduction: A rapidly evolving evidence suggests that smell dysfunction is a common symptom in COVID-19 infection with paucity of data on its duration and recovery rate. Objectives: delineate the different patterns of olfactory disorders recovery in patients with COVID-19. Methods: This cross-sectional cohort study included 96 patients with olfactory complaint confirmed to be COVID-19 positive with recent onset of anosmia. All patients were inquired for smell recovery patterns using self-assessment questionnaires. Results: ninety six patients completed the study with mean age 34.26±11.91 years. Most patients had sudden anosmia 83%. Loss of smell was accompanied by nonspecific inflammatory symptoms as low-grade fever (17%) and generalized body ache (25%). Nasal symptoms were reported by 33% of patients. Some patients reported comorbidities as D.M (16%), hypertension (8%) or associated allergic rhinitis (25%), different patterns of olfactory recovery showed 40 patients experiencing full recovery (33.3%) while, 32 patients showed partial recovery (41.7%) after a mean of 11 days while 24 patients (25 %) showed no recovery within one month from onset of anosmia. Conclusion: The sudden olfactory dysfunction is a common symptom in patients with COVID-19. Hyposmia patients recover more rapidly than anosmic ones while the middle age group carried the best prognosis in olfactory recovery. Females possess better potentiality in regaining smell after recovery and the association of comorbidities worsen the recovery rate of olfactory dysfunction in patients with COVID19.

1. Studies on the effects of human-driven forest disturbance usually focus on either biodiversity or carbon dynamics but much less is known about ecosystem processes that integrate trophic levels. Herbivory is one fundamental ecological process for ecosystem functioning that remains underexplored and is poorly quantified in human-modified tropical rainforests. 2. Here, we present the results of the largest study to date on the impacts of human disturbances on herbivory. We quantified the incidence and severity of herbivory caused by chewers, miners and gall-formers in 199,869 canopy leaf blades from 1,102 trees distributed across 20 forest plots located along a gradient of human disturbance in the Amazon. 3. We found that chewers dominated herbivory incidence, yet were not a good predictor of the other forms of herbivory either at the stem or plot level. Herbivory severity was correlated with disturbance intensity, being greater at more disturbed sites. 4. Synthesis. Although our large-scale study of canopy herbivory in Amazonian forests suggests that human disturbance increases the severity of leaf herbivory, effects were weak. Additionally, we found no effect of human disturbance in incidence of leaf herbivory. These results combined indicate that herbivory is a relatively resilient process to human impacts.

A document by Indrani Roy, written on Authorea.

ants share the phytobiome with other members of the ecological community by sharing their physiology. The phytobiome is a collective ecological entity that senses external and internal stimuli via its member’s sensing apparatus (senome). The activated senome generates intercellular, and intra- and inter-organismal signals that induce genetically and epigenetically dependent modifications of phytobiome member transcriptomes. Ultimately, these genetic modifications alter the phenotypes of the collective phytobiome members. Mycorrhiza, epiphytic fungi, and dodder can physically transfer signals between kin and non-kin plants. Phytobiome members can release infochemicals by themselves, or modify plant volatile emissions and root exudates to act as signals for plant–plant interactions. These signals can change plant physiology and induce holobiont updates in receiver plants via a facilitative or competitive mechanism. Receiver plants eavesdrop on phytobiome cues and signals to anticipate responses to unfolding challenges. An emerging body of information in plant–plant interactions through inter-kingdom communication can be exploited in integrated crop management under field conditions. However, a holistic view is crucial for the manipulation of complex systems, such as the phytobiome, to avoid potential butterfly effects.

In this research different formulations of calcium aluminate cement pastes (CACP) with 71wt% Al2O3 (CACP 71wt%), (wt% -percentage by weight) were made, at 0.4 water to cement ratios (W/C), with additions of 0wt%, 10wt% and 20wt% of silica (CACP 71-0wt%, 10wt% and 20wt%, respectively). All samples were exposed to oxidative environment for 4 hours at 1000˚C, in a furnace under an air atmosphere. Chemical and mineralogical characterization was done using X-ray fluorescence (XRF), X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR). The behavior of the constituent phases according to temperature was also studied, through thermal gravimetric analysis (TGA). Activation energies were calculated using Friedman’s method. The values of the activation energies obtained for the formulation of CACP 71- 0wt% for different phases were in the range of 12.02 to 16.41 kJ/mol; and for the formulation of CACP 71-20wt% the values were in the range of 7.7 to 16.23 kJ/mol.

Thyrotoxic periodic paralysis is rare in pediatric population. An adolescent male presented to the emergency department with a syncopal episode, muscle weakness, and shortness of breath. We present the clinical characteristics and laboratory evaluation and summarize the treatment and outcome of an adolescent with Thyrotoxic periodic paralysis.

Nontuberculous mycobacteria are rare causes of cardiac implantable electronic device (CIED) pocket infections and may lead to device-related endocarditis, so preventing them is key. Diagnosis is by presence of acid-fast bacilli on smears and culture takes around 3-7 days on grow on standard agar media.