Dysregulation of proinflammatory cytokines promotes immune-mediated injuries. Epithelial-cell proliferation and an increase in lung macrophages have both been associated with the 2003 SARS-CoV infection. Proinflammatory cytokines as well as lipopolysaccharide and pathogen-associated molecular patterns (PAMPs) promote macrophage transition which promotes ongoing inflammation. PAMPs are primarily sensed by Toll-like receptors and/or by angiotensin-converting enzyme 2; this interaction serves to activate NF-κB to promotes synthesis and secretion of proinflammatory cytokines. Activated immune cells secrete large amounts of specific proinflammatory cytokines including IL-1, IL-6, IL-8, TNF-α, and TGF-β1 which can promote severe lung injury. As such, immunomodulatory drugs alone may have an impact on the cytokine storm even without the addition of antiviral agents. The central transcription factor, NF-κB, induces angiogenesis during cancer progression; combinations of pharmacological agents, including thalidomide and celecoxib, show promising results in cancer treatment studies. This may be due to a low-level, chronic cytokine storm similar to that described for acute and chronic hepatitis as well as for cirrhosis and hepatoma. As previously described, I have used thalidomide, celecoxib, and low dose cytotoxic agents since 2000 for the successful treatment of a variety of cancers. This regimen is cited or introduced in leading medical journals. Thalidomide is an immunomodulatory agent that modulates the activities of NF-κB in combination with the cyclooxygenase-2 inhibitor, celecoxib. The combination of thalidomide and celecoxib might limit the inflammatory symptoms when used to treat severe COVID-19 pneumonia due to infection with SARS-CoV-2.

Transcatheter repair systems are becoming increasingly popular as a potential solution for high-risk and inoperable patients with mitral regurgitation. The Cardioband (Edwards Lifesciences, Irvine, California) is a transcatheter direct annuloplasty device, based on the concept of an undersized ring annuloplasty. We report a case of minimally invasive surgical explantation of a failed Cardioband device 21 months after its implantation. Intraoperatively, it was found that3 anchors of the Cardioband device were detached from the posterior annulus at P2. In this report, a “cut and unscrew” technique with some tips and tricks is presented for the removal of the device.

Introduction Given infections in patients with PPM are responsible for adverse outcomes such as an increased rate of mortality, one important reduction strategy of the incidence of SSIs is to identify and predict patients at high risk. Methods A retrospective cohort study was conducted in patients with PPM discharged from a large academic health center in New York City from 2006 through 2016. Risk factors identified through bivariate analysis were used to build predictive models. Five-fold cross-validation was applied to build models. The performance of the three machine learning models–logistic regression, decision tree (DT), and support vector machine (SVM)– for predicting surgical site infection (SSI) in patients with a permanent pacemaker (PPM) was compared. Results A total 205/9,274 (2.16%) patients with PPMs were diagnosed with a hospital-acquired SSI. Overall, the logistic regression algorithm had the highest prediction ability with the largest AUC at 72.9%. But the SVM model showed the highest sensitivity at 43.8% and positive predictive value at 32.5%. All three models showed excellent specificity and accuracy (over 98% and 96%, respectively). Conclusion Despite that this study showed the comparison of three predictive models, it has very limited clinical implications because of the low predictability of models (i.e., low PPV). Therefore, future researchers may improve the model by incorporating text data from clinical notes through natural language processing. Each algorithm had strengths and weaknesses in terms of accurate prediction, and interpretable clinical decision support. However, logistic regression was more accurate for predicting low-prevalence diseases such as SSI.

Key Points Most of the ENT surgeries are aerosol generating procedures and pose a risk of infection to health care workers. Povidone-iodine irrigation has been used in surgery and has proven to reduce surgical site infection. Povidone iodine has good virucidal action even in low concentrations. The novel technique of wet tonsillectomy with povidone iodine flush would possibly reduce the viral load. This technique, in adjunct to other safety measures and personal protective equipment, could be a safe way to restart elective oral, ear and nasal procedures in asymptomatic patients during the pandemic.

Background：Cardiotoxicity has been one of the most common causes for withdrawing drugs from the market, and its important manifestation is the prolongation of QT interval. Iptakalim hydrochloride (ITKL) is a selective ATP-sensitive potassium (KATP) channel opener, it is crucial to assess the risk of cardiac repolarization of ITKL in clinical trials. Objective: This study was conducted to determine the effect of ITKL on corrected QT (QTc) interval. Method: A randomized, double-blind, placebo-controlled, single- and multi-dose regimen was carried out to investigate the QTc and ITKL concentration correlation. ITKL was administered at doses of 5 mg, 10mg, 15mg, and 20mg with single oral administration and 10 mg, 20 mg with multiple oral administration, along with placebo, in 83 healthy subjects. Electrocardiograms (ECGs) and blood samples were collected on a preset time schedule. Result: The highest dose (20mg) of ITKL did not cause QTc prolongation with a predicted ΔΔQTcF (Baseline and placebo-corrected QTc interval) effect under geometric Cmax of 1.67 milliseconds, meeting the criteria for negative effect on QT. The Exposure Response (ER) analysis indicated the effect of the drug on ΔΔQTcF was relatively small. Conclusion: The upper bounds of the 90% confidence interval (CI) of the model-predicted ΔΔQTcF at Cmax in all dose groups were bellow 10ms, suggesting that ITKL did not prolong QT interval.

Aim: To assess the potential of interleukin-6 (IL-6) signaling blockade in the lung to treat SARS-CoV-2 infection via model-based simulation by exploring soluble IL-6 receptor (sIL-6R) sequestration by tocilizumab (TCZ) and IL-6 sequestration by siltuximab (SIL). Methods: Literature values of IL-6, the IL-6 antagonist SIL, sIL-6R, the IL-6R antagonist TCZ, and their respective binding constants were used to develop a model to predict the impact of treatment on IL-6 signaling. Models were used to generate simulated bronchoalveolar lavage (BAL) concentrations for normal subjects, subjects at risk of developing acute respiratory distress syndrome (ARDS), and subjects with ARDS were simulated under four conditions: without treatment, treatment with TCZ, treatment with SIL, and treatment with TCZ + SIL. Results: With TCZ intervention, IL-6 levels are unaffected and sIL-6R is reduced somewhat below the Normal case. IL-6:sIL-6R complex only slightly decreased relative to the no-intervention case. With SIL intervention, sIL-6R levels are unaffected and IL-6 is greatly reduced below the Normal case. IL-6:sIL-6R complex is greatly decreased relative to the no-intervention case. With TCZ + SIL intervention, IL-6 and sIL-6R levels are reduced below the Normal case and achieve suppression equivalent to monotherapy results for their respective targets. IL-6:sIL-6R complex reduction is predicted to be greater than monotherapy. This reflects sequestration of both components of the complex and the nonlinear binding equilibrium. Conclusion: Co-administration of both IL-6 and IL-6R sequestering products such as SIL and TCZ may be necessary to effectively treat COVID-19 patients who have or are at risk of developing ARDS.

Objective: To explore the incidence and risk factors of preeclampsia (PE) among high- risk pregnant women in South India. Design: Nested case-control study Setting: Tertiary referral hospital Population or Sample: Pregnant women with risk for PE. Methods: Maternal characteristics were prospectively collected, and risk factors were assessed comparatively between women with risk for developing PE and normotensive pregnant women using risk ratio (RR) (95% CI) plus multivariate analysis. One hundred and seventy-four risk group pregnant women were followed-up once in each trimester till delivery and noted for the development of PE. Main Outcome Measures: Incidence and risk factors of PE among high-risk pregnant women. Results: 67/174 women developed PE, corresponding to an incidence of 38.51% among pregnant women with risk for PE. Women in the age group of 30 and older reported a higher incidence. Maternal factors like absence of a family history of chronic hypertension, history of abortion, non-consanguineous marriage, and AB blood group were significant protective factor and sex of the new-born being female was a significant risk factor for developing PE. Conclusion: This is the first Indian study that explored the incidence and risk factors for PE among high-risk pregnant women. Incidence of PE was higher among South Indian risk population. Female infants significantly contributed to the PE risk. Funding: JIPMER Intramural Research fund. Keywords: Preeclampsia; Incidence; South India; High-risk women; Follow-up; Risk factors Tweetable abstract: The incidence of PE is 38.51% and the significant risk factor is female foetus among high-risk pregnant women.

Researchers typically perform winemaking experiments using small amounts of grapes. Few studies have actually evaluated both the repeatability and reproducibility of small-scale fermentations in Tempranillo and Cabernet Sauvignon. This study examines, for two different phenolic potential varieties, the repeatability and reproducibility of the small-scale red winemaking in 4 tank sizes (10, 25, 50 and 100 L), and how volume size may affect to the composition of the wine. Additionally, for each variety we carried out a commercial fermentation using a 2500 L tank. Medium size-tanks gave the best extraction for the phenolic composition. High repeatability was observed for alcohol content, pH and total acidity, anthocyanins and procyanidins for both varieties. This research gives a solid basis for validating the reproducibility of the small-scale fermentations of two different phenolic potential red grapevines andsheds new light on small-scale winemaking potentiality and limitations.

The novel coronavirus (SARS-CoV-2) binds to Angiotensin II- Converting-Enzyme (ACE2) on cell membrane, allowing the virus entrance, replication and host commitment. ACE2 is expressed by different cell types, which include the enterocytes in the gut. Such cells are highly active in metabolism, as they internalize molecules to be processed and used by the organism. ACE2 disruption leads to intestinal inflammation and impairs tryptophan absorption by enterocytes. Low tryptophan levels are also associated with intestinal inflammation and decreased synthesis of serotonin, affecting motility. During postnatal development, breastfeeding is the first source of nutrition, and tryptophan is milk component, together with mucin1, growth factors and secretory immunoglobulin A (sIgA). By reviewing the pathways and effects of SARS-CoV-2 and the gut responses to early weaning, we suggest that it is important to evaluate the benefits of maintaining breastfeeding during SARS-CoV-2 infection, as it might be essential to protect newborns from gastrointestinal-associated disorders.

We propose a new hypothesis that the established drug pentoxifylline deserves attention as a potential repurposed therapeutic for COVID-19. Pentoxifylline is an anti-inflammatory agent that suppresses adenosine responses, reduces Tumour Necrosis Factor alpha, Interleukin 1, Interleukin 6 and Interferon gamma and may act to reduce tissue damage during the cytokine storm response to SARS-CoV-2 infection. This agent has been used clinically for many years and has a favourable profile of safety and tolerability. Pre-clinical data support pentoxifylline as effective in cytokine-driven lung damage. Clinical studies of pentoxifylline in radiation and cytokine-induced lung damage in humans are positive and consistent with anti-inflammatory efficacy. Pentoxifylline is a readily available, off-patent, inexpensive drug suitable for large scale use, including in resource-limited countries. Current trials of therapeutics are largely focussed on the inhibition of viral processes. We advocate urgent randomised trials of pentoxifylline for COVID-19 as a complementary approach to target the host responses.

Abstract: This study attempted to molecular characterization of marine and coastal fishes of Bangladesh based on mitochondrial cytochrome c oxidase subunit I (COI) gene as a marker. A total of 376 mitochondrial COI barcode sequences were obtained from 185 species belonging to 146 genera, 74 families, 20 orders and two classes of fishes. The mean length of the sequences was 652 base pairs. For all the samples, %G was significantly lower compared to the other nucleotides and %GC was significantly lower compared to %AT (p ˂ 0.005). Also, a significantly lowered %GC content was observed in second and third codon position compared to the first codon position in all the samples (1st>2nd>3rd, p-value ˂ 0.005). In Elasmobranchii (Sharks and rays) the average Kimura two parameter (K2P) distances within species, genera, families and orders were 1.2%, 6.07%, 11.08% and 14.68%, respectively and for Actinopterygii, the average K2P distances within species, genera, families and orders were 0.40%, 6.36%, 14.10% and 24.07%, respectively. The mean interspecies distance was 16-fold higher than the mean intraspecies distance. The K2P neighbor-joining (NJ) trees based on the sequences generally clustered species in accordance with their taxonomic position. A total of 21 species were newly recorded in Bangladesh. High efficiency and fidelity in species identification and discrimination were demonstrated in the present study by DNA barcoding, and we concluded that COI sequencing can be used as an authentic identification marker for Bangladesh marine fish species. Key words: COI, Barcoding, Elasmobranchii, Actinopterygii, Genetic diversity, Phylogeny

Sturmberg and Martin in 2020 argue that Universal Health Care (UHC) is mainly about financing and Primary Health Care (PHC) is about the right care at the right time to ensure health. They maintain the World Health Organisation (WHO) has recently sent the wrong message about the “pillars” of PHC in their relationship to UHC. An understanding of political economy is required in order to come to terms with the bases of PHC and the fundamentals of UHC, that dealing with inequities is not only an economic issue but fundamentally a political issue. Neoliberal decision making can enhance inequities in society. Two chronic health conditions, diabetes and multiple sclerosis are examples of conditions that lead to costly and debilitating consequences for patients but also lead to substantial economic costs in terms of lost workforce participation and lost productivity. These cases demonstrate the socio-political issues involved in the management of care for a number of illnesses. The upsurge of COVID–19 has placed an enormous strain on health and broader social and economic resources and challenged the pretext of UHC as health for all: substantial differences in equity and political commitment have emerged. Sturmberg and Martin argue that the joining of UHC and PHC needs leadership which involves local communities and resourcing. PHC is a changing system based on power relationships involving funders and the health community. In Australia as in several countries out of pocket costs have grown rapidly and have affected access for some groups to PHC and have challenged the pretext of equity in UHC. In the context of PHC and UHC we support the position that health for all goes beyond healthcare for all, to embrace healthy lives promoting wellbeing.

Rational, aims, and objectives: To probe into the status of medication adherence in patients after PCI and its correlation with health literacy. Methods: A total of 260 patients after PCI in cardiology department of three hospitals in Zhengzhou, were investigated by two questionnaire, which are 8-item Morisky Medication Adherence Scale and Chronic Disease Health Literacy Scale. Results: The score of medication adherence was 5.21±2.04, the score of health literacy was 80.8±24.43; Multivariate linear regression analysis results showed that degree of education, the number of hospitalization, monthly income, course of diseases were the influencing factors of medication adherence, which could explain 61.2% of the total variation; The medication adherence in patients after PCI was positively correlated with health literacy. Conclusion: The higher levels of health literacy positively influenced medication adherence scores in patients after PCI. Nursing staff should assist the patients after PCI to establish self-health management awareness, in order to improve their medication adherence.

This Editorial Comment explores important issues raised by this manuscript.

We want to thank Dr. Raveenthiran and Dr. Harky for their interest in our paper and in the topic of Marfans in the setting of pregnancy. Certainly, the reduction of adverse outcomes would be improved with early knowledge of Marfans syndrome in the mother which would aid in preparation and clinical consideration during the perioperative period, and, prior to pregnancy.

In this report, we looked at the day by day Open, High, Low, and Close prices of Bitcoin from 2012-2020 and tested common ideas about the characteristics of the Cryptocurrency. In particular, we took a look as to whether or not Bitcoin is correlated to the movements of the stock market, and analyzed its movements in relation to the time of year. Using various forms of regression analysis, we found that Bitcoin is very tightly correlated with the stock market. We also found that time of year seems does not seem to have a uniquely large effect of the price movement of Bitcoin.

Long term environmental variation often drives local adaptation and leads to trait differentiation across populations. Additionally, when traits change in an environment-dependent way through phenotypic plasticity, the underlying genetic variation will also be under selection, but only in the inducing environment. Both of these processes will create a landscape of differentiation across populations in trait means as well as their plasticity. However, studies uncovering environmental drivers of this variation are scarce. With this work, we studied drought responses in seedlings of a shrub species from the Cape Floristic Region, the common sugarbush (Protea repens). We measured morphological and physiological traits as well as whole transcriptomes in 8 populations that represent both the climatic and the geographic distribution of this species. We found that there is substantial variation in how populations respond to drought, but we also observe common patterns such as reduced leaf size and thickness and upregulation of stress- and down-regulation of growth-related gene groups. Both environmental heterogeneity and milder source site climates were associated with higher plasticity in various traits and co-expression gene networks. By uncovering associations between traits, trait plasticity, co-expression gene networks with source site climate, we showed that temperature plays a bigger role in shaping these patterns when compared to precipitation, in line with recent changes in the region due to climate change. We also found that traits respond to climatic variation in a context dependent manner: some associations between traits and climate were apparent only under certain growing conditions.

Objective Does the combined analysis of compounds in vaginal secretions plus vaginal microbiota composition improve the ability to predict risk for spontaneous preterm birth (SPTB) in women with a short cervix. Design Prospective observational study Setting Three hospitals in Brazil Samples Vaginal secretions from 568 women at 21-24 weeks gestation with cervical length measurement. Method Vaginal microbiome composition was determined by analysis of the V1-V3 region of the bacterial 16S ribosomal RNA gene. D- lactic acid and tissue inhibitor of matrix metalloproteinase (TIMP)-1 in vaginal secretions were measured by ELISA. Main outcome measures SPTB in relation to cervical length and dominant vaginal bacteria. Results When Lactobacillus crispatus was the dominant bacterium the concentration of TIMP-1 was lower, and D-lactic acid was higher, than when either L. iners or Gardnerella vaginalis predominated (p < 0.001). By ROC analysis, a D-lactic acid level < 0.7 mM, and a TIMP-1 level > 1.5 ng/ml best predicted the absence of L. crispatus dominance. Vaginal levels of TIMP-1 were highest (p = 0.024) and D-lactic acid levels were lowest (p=0.032) in women with the shortest cervical length. The absence of L. crispatus dominance increased the sensitivity for predicting a SPTB from 22.4% to 81.8% or 78.3% in women with a cervical length <25mm or <30mm, respectively. Conclusions Low vaginal D-lactic acid and high TIMP-1 indicates the loss of L. crispatus dominance and increased risk for SPTB in women with a short cervix.

Objective - To compare the Fetal Scalp Stimulation (FSS) to Fetal Blood Sampling (FBS) as an adjunctive test of fetal wellbeing in labor in order to reduce Fetal Blood Sampling. Design – A retrospective study from February to December 2019 Setting – Monocentric study, CHRU Lille Population - Singleton pregnancy with gestational age of more than 36 weeks, cephalic fetal presentation Methods –191 FBS procedures performed for non-reassuring fetal heart rate during labor were included. A gentle digital scalp stimulation was performed for 15 seconds, two minutes before each FBS. It was considered as positive when accelerations and/or normal variability were elicited. The FBS was classified as normal when pH was < 7.25. Results - Of the 191 FBS procedures, 163 (85.3%) found a normal pH result, 122 (63.9%) and 154 (80.6%) had an acceleration and a normal variability post-FSS, respectively. When accelerations were observed after FSS, FBS pH result was normal in 91.6% cases (95%CI, 85-95). When normal variability was observed after FSS, FBS pH result was normal in 87.4% cases (95% CI, 81-92). Conclusion - This study suggests that FSS could be an interesting alternative adjunctive test to FBS as it seems to be reliable, non-invasive and easy to perform. Thus, FSS could be performed in the first instance when non-reassuring fetal heart rate is observed in order to limit FBS only to absence of acceleration after FSS.

Aspen Plus® simulations using the Peng-Robinson (PR-EOS) and the COSMO-SAC models were performed to study absorption power cycles (APCs) using mixtures of R-134a with two ionic liquids, [C2C1im][Tf2N] or [C6C1im][Tf2N], and compared against an R-134a organic Rankine cycle (ORC) operating under similar conditions. The PR-EOS results were in agreement with calculations from a PR model fitted to the R-134a+IL experimental phase equilibrium data. The APCs have similar efficiencies and outperform the ORC by 3-46%, with the largest differences observed when operating with lower grade (lower TH) heating sources, lower quality cooling (higher TL) and lower subcooling in the pump inlet stream. The PR-EOS and the COSMO-SAC results follow similar trends, but numerical discrepancies are observed in the cycle efficiencies and stream flow rates and compositions due to differences in solubilities and enthalpy changes between both models, suggesting that improvements are needed to increase the accuracy of COSMO-SAC for these systems.

AbstractThis article discusses a variant of the altered microbiota hypothesis, the leading hypothesis to explain the increase in allergic/autoimmune/inflammatory diseases with westernization. Instead of emphasizing the microbes that are missing/reduced due to westernization, this article focuses on those that are relatively novel. Environmental microbes encountered in association with a pre-agricultural lifestyle would presumably be the most coevolved with the human immune system, and thus they would be less likely to promote debilitating chronic disease. Post-hunter-gatherer era microbes (PHM) are microbes that are encountered more frequently and/or at higher levels since humans ceased to live as nomadic hunter-gatherers. Research will be discussed that suggests that some PHM suppress/dysregulate the immune system, potentially causing chronic inflammatory diseases and increased vulnerability to severe infections. PHM colonization or infection, hypersensitivity reactions and associated chronic stress could significantly impact multiple diseases. Exploration of this hypothesis might generate insights into pathogenic mechanisms and improved treatment approaches.IntroductionThis article proposes an extension of the altered microbiota hypothesis[1], which is the dominant hypothesis to explain the increase in many chronic inflammatory diseases in the last 75 years in association with westernization. The altered microbiota hypothesis is an updated version of the hygiene hypothesis. The hygiene hypothesis suggested that the recent increase in allergies is due to reduced exposure to pathogens. Instead, the altered microbiota hypothesis proposes that it is primarily a reduction of commensal and environmental microbes that we coevolved with that is responsible for increased rates of chronic inflammatory diseases.The absence/reduction of certain coevolved microbes likely plays an important role; however, this article focuses on microbes that are relatively novel. The category of post-hunter-gatherer era microbes (PHM), as discussed here, comprises microbes that are encountered more frequently and/or at higher levels since the advent of agriculture and permanent settlements.The microbial communities (microbiotas) that humans have been exposed to have changed as human activities have changed. The most intense and rapid changes in these microbiotas likely occurred recently in association with westernization and industrialization. A large proportion of the human genetic makeup evolved during the 200 million years during which humans and their mammalian ancestors lived as hunter-gatherers or gatherers. Microbes commonly encountered in that era would presumably be the most coevolved with the human immune system and would thus tend to cause less disease and/or be beneficial. In contrast, humans are now exposed to many microbes that they did not coevolve with[1]. It is proposed here, in the PHM hypothesis, that some proportion of the less coevolved PHM suppress/dysregulate the immune system, contribute to multiple chronic inflammatory diseases and increase vulnerability to severe outcomes in acute infections through their colonization or infection and accompanying hypersensitivity reactions and chronic stress.Microbes could be considered to be PHM due to being novel, such as mutated strains found in association with newer products/substances or novel conditions[1]. Alternatively, microbial species or strains could be PHM due to being increased by changing lifestyles (e.g., intestinal Candida albicans overgrowth due to factors such as high dietary refined carbohydrates and antibiotics).The PHM hypothesis focuses on the sources of microbes that may contribute to disease and emphasizes microbes’ cross-reactions with varied internal and external antigens. In addition, it integrates the environmental chemical (xenobiotic) hypothesis with the PHM hypothesis by noting the likelihood of PHM being associated with chemicals from certain occupations and air pollution from burning fossil fuels[1]. In addition, it is compatible with the cold chain hypothesis that links Crohn’s disease with cold-tolerant bacteria (e.g., Yersinia spp and Listeria spp) in refrigerated food[2]. PHM are more likely to be present in certain types of food consumed commonly in westernized societies, including refrigerated and ultra-processed foods/beverages[1]. Microbes associated with food additives are also potential sources of PHM (e.g., halophilic Archaea from salt[1,3]).The term westernization, as used here, refers to factors associated with a modern lifestyle that may be associated with health effects. It includes a sedentary lifestyle and increased exposure to xenobiotics/pollutants. New exposures from western medicine, like antibiotics, are also included. The westernized diet typically includes increased consumption of animal products, fat (especially saturated animal-derived fat and vegetable oils), sugar, ultra-processed foods/beverages, salt, and food additives.The role of other hypotheses and mechanistic explanations could be complementary to the role of the PHM or be related to the processes that stem from the effects of the PHM.

Dear Nuria,

Open Peer–Reviewer Details for this article are openly available here:•          Peer-Reviewer Report #1 DOI: 10.22541/au.159182659.98933679•          Peer-Reviewer Report #2 DOI: 10.22541/au.159182658.82141376•          Editor’s Comment DOI: 10.22541/au.159182678.86670339

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