Drug therapy in pregnancy may cause anxiety to both physicians and patients due to uncertainty regarding dosing and safety. Nevertheless, the need for medication is high given that maternal chronic illnesses such as hypertension or diabetes are on the rise1. In a national study in the United States over 33 years, the prevalence of prescription medication use by pregnant women in the first trimester increased by 62.5% between the first 2 years of the study and the last 2 years2. Furthermore, the average number of medications used anytime in pregnancy has increased two-fold 2. More recent research from different countries has found that medications are widely used in pregnancy, with the prevalence of using at least one drug ranging from 60 to 90 percent, excluding vitamins and minerals 3-5. Prescription of drugs with potential teratogenicity has also increased in pregnancy, including folate antagonists or angiotensin converting enzyme inhibitors3,4. This suggests that many women go into pregnancy with chronic conditions that require medications, including those may pose some degrees of risk to the fetus, since the maternal benefit may outweigh the risk or if the pregnancy is unplanned. Successful treatment of pregnant patients requires a correct diagnosis and providing treatment that not only is effective but also balances risks and benefits, as maternal health is the best defense for fetal health. However, concomitant health conditions, and the intrinsic complex physiological changes associated to pregnancy can make prescribing in this population a particularly challenging balancing act. Very few drugs have specific pregnancy dosing regimens supported by scientific evidence in spite of well-known pharmacokinetics changes during pregnancy affecting a large proportion of medications (Table 1)6-10. Data on drug efficacy and safety is sorely lacking for pregnant women, even for drugs that have been available for decades. Pregnant patients are commonly excluded from clinical trials during the drug development process due to ethical and safety concerns, which implies that the majority of drug therapy data in pregnancy have been extrapolated from males and to a much lesser extent, from non-pregnant females11. However, using extrapolated data in pregnancy has a number of major drawbacks such as that the extrapolation commonly fails to account for the changes in drug metabolism related to pregnancy 6. Multiple physiological changes in pregnancy, including those affecting pharmacokinetics, must be considered when prescribing. Furthermore, these changes can also be affected by genetic variability10. Some drugs need to be used at higher doses in pregnancy due to increasing metabolic demand. A classic example is thyroid hormone, which requires a 30 to 45 percent higher dose in order to maintain euthyroid state due to limited compensation in pregnant patients with underlying thyroid disease 12. One of the biggest physiologic changes in pregnancy is the expansion of plasma volume by approximately 50 percent due to hormone-mediated vasodilation, leading to activation of the renin-angiotensin-aldosterone system10. This change results in and increased volume of distribution for hydrophilic drugs and reduced peak concentrations 6. Increased glomerular filtration rate in pregnancy also increases elimination of renally cleared drugs; a classic example of this effect is lithium13. Changes in hepatic enzyme activity in pregnancy, including upregulation of cytochrome P450 and glucuronidation, are another cause of increased metabolism and elimination of drugs14. Increased metabolism of lamotrigine by glucuronidation results in low drug levels in pregnancy and this can be further affected by polymorphism of UDP-glucuronosyltransferases 15. One strategy to address changes in drug metabolism is to use therapeutic drug monitoring (TDM) with blood levels; however, TDM analysis is not readily available for the majority of drugs used in pregnancy, limiting the usefulness of this strategy in clinical practice. Furthermore, lower total drug levels do not necessarily translate to less free drug due to volume expansion in pregnancy leading to relative hypoalbuminemia 6. For some drugs, many clinicians modify the dosing regimen on their own based on limited pharmacokinetic data. For example, labelatol, a common antihypertensive used in pregnancy, has a half-life of only 1.7 ± 0.27 hours in patients in the 3rd trimester of pregnancy, compared to 6-8 hours outside of pregnancy16. This difference leads many clinicians to prescribe labelatol three times per day based on patient response instead of twice-per-day as per drug monograph16. However, there is considerable variation among clinicians due to lack of scientific evidence. For example, in patients diagnosed with acute pulmonary embolism, twice-per-day dosing and once-per-day dosing of low molecular weight heparin are both commonly used 17. Enoxaparin once-per-day versus twice-per-day in a population pharmacokinetics study both achieved target plasma concentration in pregnancy18; however, once daily regimen has not been universally adopted in clinical practice and no similar data are available for other low molecular weight heparins. Pregnancy is also a vulnerable period for the occurrence of cardiac events. In particular consideration must be given to patients known to have long QT syndrome or on QT prolonging drugs. The adrenergic nature of labor and delivery may lead to catecholaminergic polymorphic ventricular tachycardia in these patients. Furthermore, patients with congenital long QT syndrome are also at risk during a nine-month post-partum period 19. Treatment with beta-blockers are the mainstay of therapy during pregnancy and in the post-partum period19. There is a lack of data for therapeutics that may be urgently needed intrapartum that may prolong the QT interval in susceptible patients. For example, oxytocin and carbetocin are both known to prolong the QT interval but may be required for prevention or treatment of postpartum hemorrhage20,21. Clinical guidelines for using oxytocin for augmentation or induction of labour are lacking and some obstetricians may choose to do an elective Caesarian section to avoid prolonged oxytocin in these patients although this is not evidence based due to lack of studies. In addition to the challenges in proper prescribing in pregnancy, the information on teratogenicity of drugs is also limited. Management of the care of a pregnant patient must balance the benefits of treating the maternal medical condition with possible adverse effects on the fetus. Clinicians must rely on animal data, data from pregnancy registries, and published case control studies and case reports to make these risk/benefit assessments. These resources are by no means ideal as results are confounded by recall bias, selection bias, and inconsistency, as well as lack of ability to extrapolate safety between species 22. Other than a few specific drugs with clear evidence of harm, many drugs have limited information, leading to variable practice among clinicians and inconsistent information provided to patients. For example, while angiotensin-converting enzyme inhibitor induced fetopathy has been described since the 1990s and accepted by medical community consistently23, the risk of maternal corticosteroid use with increased risk of cleft lip and palate has not been consistent among studies24,25. In addition, long term corticosteroid use is also linked to increased risk of preeclampsia which needs to be taken into consideration for treatment and monitoring26. The US Food and Drug Administration recognized the limitation of the prior FDA classifications for medication use in pregnancy (A, B, C, D, X category system). Thus, the “Pregnancy and Lactation Labeling Rule” went into effect by the FDA in June 2015, requesting manufacturers to provide available information regarding risks in pregnancy and lactation in a narrative summary; however, according to a recent survey, less than 50 percent of prescribers were aware of this change, while more than half deemed the narrative summary not helpful 27. Lack of quality data is one of the barriers identified in this survey. In addition to the rating systems used in various jurisdictions, an evidence-based medicine classification system has been developed by toxicologists, which can be used to assist clinical decision making. Unfortunately, all of the currently available systems are of limited utility due to reliance on small studies and inability to be updated frequently with new data22. Since the thalidomide story in the 1960s, much advancement has been made in medical therapy in pregnant women. However there remains a significant knowledge gap in pharmacological information which may expose patients to either toxicity or under treatment with reduced efficacy. In addition, numerous commonly used medications lack concrete data on teratogenicity. Supported by the NIH, the Pediatric Trials Network is currently conducting a multicentre trial studying the pharmacokinetics and safety of commonly used drugs in lactating women and breastfeeding infants in North America (NCT03511118); similar studies in pregnancy are also warranted to guide appropriate dosing. Long term data on children with fetal exposure for developmental toxicity are also urgently needed, and while some data for newer medications is systematically collected by international registries, in general information on fetal risks of maternal exposures is limited to incidental data obtained from accidental exposures. Finally, making all up-to-date information readily available to clinicians should also be a priority. References1. Sun AJ, Li S, Zhang CA, Jensen TK, Lindahl-Jacobsen R, Eisenberg ML. Parental comorbidity and medication use in the USA: a panel study of 785 000 live births. Hum Reprod.Mar 18 2020.2. Mitchell AA, Gilboa SM, Werler MM, et al. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. American journal of obstetrics and gynecology. Jul 2011;205(1):51 e51-58.3. Ventura M, Maraschini A, D’Aloja P, et al. Drug prescribing during pregnancy in a central region of Italy, 2008-2012. BMC Public Health. May 15 2018;18(1):623.4. Engeland A, Bjorge T, Klungsoyr K, Hjellvik V, Skurtveit S, Furu K. Trends in prescription drug use during pregnancy and postpartum in Norway, 2005 to 2015.Pharmacoepidemiology and drug safety. Sep 2018;27(9):995-1004.5. Lutz BH, Miranda VIA, Silveira MPT, et al. Medication Use among Pregnant Women from the 2015 Pelotas (Brazil) Birth Cohort Study. International journal of environmental research and public health. Feb 5 2020;17(3).6. Koren G, Pariente G. Pregnancy- Associated Changes in Pharmacokinetics and their Clinical Implications.Pharmaceutical research. Feb 12 2018;35(3):61.7. Yerby MS, Friel PN, McCormick K, et al. Pharmacokinetics of anticonvulsants in pregnancy: alterations in plasma protein binding. Epilepsy research. Apr 1990;5(3):223-228.8. Prevost RR, Akl SA, Whybrew WD, Sibai BM. Oral nifedipine pharmacokinetics in pregnancy-induced hypertension. Pharmacotherapy. 1992;12(3):174-177.9. Philipson A. Pharmacokinetics of ampicillin during pregnancy. J Infect Dis. Sep 1977;136(3):370-376.10. Blackburn S. Chapter 9. Cardiovascular System. Maternal, Fetal, & Neonatal Physiology . 5th ed. London, United Kingdom: Elsevier; 2018:251-259.11. Huybrechts KF, Bateman BT, Hernandez-Diaz S. Use of real-world evidence from healthcare utilization data to evaluate drug safety during pregnancy.Pharmacoepidemiology and drug safety. Jul 2019;28(7):906-922.12. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. Mar 2017;27(3):315-389.13. Wesseloo R, Wierdsma AI, van Kamp IL, et al. Lithium dosing strategies during pregnancy and the postpartum period. The British journal of psychiatry : the journal of mental science. Jul 2017;211(1):31-36.14. Betcher HK, George AL, Jr. Pharmacogenomics in pregnancy. Seminars in perinatology. Jan 25 2020:151222.15. Milosheska D, Lorber B, Vovk T, Kastelic M, Dolzan V, Grabnar I. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: Influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. British journal of clinical pharmacology. Aug 2016;82(2):399-411.16. Rogers RC, Sibai BM, Whybrew WD. Labetalol pharmacokinetics in pregnancy-induced hypertension.American journal of obstetrics and gynecology. Feb 1990;162(2):362-366.17. Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood advances. Nov 27 2018;2(22):3317-3359.18. Patel JP, Green B, Patel RK, Marsh MS, Davies JG, Arya R. Population pharmacokinetics of enoxaparin during the antenatal period. Circulation. Sep 24 2013;128(13):1462-1469.19. Garg L, Garg J, Krishnamoorthy P, et al. Influence of Pregnancy in Patients With Congenital Long QT Syndrome. Cardiology in review. Jul/Aug 2017;25(4):197-201.20. Clunies-Ross N, Roston TM, Taylor J, et al. The Effect of Carbetocin Dose on Transmural Dispersion of Myocardial Repolarization in Healthy Parturients Scheduled for Elective Cesarean Delivery Under Spinal Anesthesia: A Prospective, Randomized Clinical Trial. Anesthesia and analgesia. Mar 5 2020.21. Liou SC, Chen C, Wong SY, Wong KM. Ventricular tachycardia after oxytocin injection in patients with prolonged Q-T interval syndrome–report of two cases. Acta anaesthesiologica Sinica. Mar 1998;36(1):49-52.22. Wilmer E, Chai S, Kroumpouzos G. Drug safety: Pregnancy rating classifications and controversies.Clinics in dermatology. May-Jun 2016;34(3):401-409.23. Barr M, Jr., Cohen MM, Jr. ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection.Teratology. Nov 1991;44(5):485-495.24. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies.American journal of medical genetics. Sep 17 1999;86(3):242-244.25. Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology. Nov 1997;56(5):335-340.26. Cai E, Czuzoj-Shulman N, Abenhaim HA. Maternal and fetal outcomes in pregnancies with long-term corticosteroid use. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet. Aug 20 2019:1-8.27. Namazy J, Chambers C, Sahin L, et al. Clinicians’ Perspective of The New Pregnancy and Lactation Labeling Final Rule (PLLR): Results from an AAAAI/FDA Survey. The journal of allergy and clinical immunology. In practice. Feb 18 2020.

High-throughput sequencing technology was used to analyse the species diversity, richness and dynamics of fungal communities in healthy and infected walnut leaves. The dominant phyla included Ascomycota, Basidiomycota, and Glomeromycota; the dominant classes were Tremellomycetes, Dothideomycetes, and Leotiomycetes; the dominant orders were Tremelellas, Capnodiales, and Erysiphales; the dominant families were Bulleribasidiaceae, Mycosphaerellaceae, and Erysiphaceae; the dominant genera were Vishniacozyma, Cercospora, and Ramularia; and the dominant species were Vishniacozyma heimaeyensis, Cercospora asparagi, and Cladosporium chasmanthicola. The results of this study also provided a new understanding of the succession of the walnut phyllosphere fungal community, filling a void in the knowledge of the microbial diversity associated with walnut leaf spot disease. At the same time, these results provide a scientific basis for early intervention and micro-ecological regulation of walnut phyllosphere fungal communities to prevent and control leaf spot or anthracnose.

Rationale, aims, and objectives Pharmacological treatment for bronchiolitis is primarily supportive because bronchodilators, steroids, and antibiotics, show little benefit. Clinical studies have suggested that nebulized 3% HS is useful for infants with bronchiolitis. The aim of this study was to evaluate the cost-effectiveness of the HS nebulized in infant bronchiolitis in a middle-income tropical country Methods A decision tree model was used to estimate the cost-effectiveness of the use of nebulized hypertonic saline (3-7%) compared with treatment without hypertonic saline nebulization (control) in bronchiolitis. Cost data were obtained from a retrospective study on bronchiolitis from tertiary centers in Rionegro, Colombia, while utilities were collected from the literature. The analysis was carried out from a societal perspective. Results The control strategy was dominated by HS nebulized group. The expected costs per patient were US$ 200 (CI 95% US$ 178- 222) in the HS nebulized group and US$ 240 (CI 95% US$ 213- 267) in controls. The expected utilities were 0.923 (CI 95% 0.922- 0.924) in the HS nebulized group and 0.91 (CI 95% 0.918- 0.920) in controls. Sensitivity analyses of parameters in the model showed that the cost-effectiveness of HS was only sensitive to the probability of hospitalization. Conclusion The strategy treatment without hypertonic saline nebulization was dominated by the strategy with HS nebulized in infants with bronchiolitis. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines and should be replicated to validate their results in other tropical countries.

Abstract Introduction: Left atrial dissection is a rare complication of cardiac surgery, most commonly associated with mitral valve surgery. Herein, we report on successful conservative treatment of left atrial dissection by avoiding anticoagulation. Case Report: A 64-year-old man developed left atrial dissection due to retrograde cardioplegia cannulation during operation for acute type A aortic dissection. As there was no connection between the left atrial dissection cavity and the left atrium on enhanced computed tomography, we did not administer anticoagulants to prevent expansion of the left atrial dissection cavity. However, the patient developed atrial fibrillation, which was successfully managed by beta-blocker and amiodarone administration. Follow-up imaging showed gradual left atrial dissection reduction, and the patient was started on anticoagulation therapy. Conclusion: We were able to resolve left atrial dissection by preventing the use of anticoagulation therapy in the acute stage by managing the atrial fibrillation with antiarrhythmic drugs.

A 34-year-old woman was referred to our hospital for inspection before operation for liver transplantation as a donor for her son. She had no symptoms and remarkable medical history. Echocardiography showed a defect in lower part of the atrial septum with a cleft of left atrioventricular valve and right atrioventricular valve regurgitation. She was diagnosed as incomplete atrioventricular septal defect for the first time. She underwent double valve repair and patch closure of the atrioventricular septal defect. It is a rare case for atrioventricular septal defect in adulthood incidentally detected without symptoms.

Introduction: Adhesion is associated to delayed delivery of the neonate and higher incidence of intraoperative and postoperative complications. Currently, there is no definite consensus regarding the use of adhesion barriers at cesarean section. Objective: To analyze the postoperative outcomes among two adhesion barrier groups and control group at the primary and the secondary cesarean section. Methods: This retrospective study includes 199 Asian women undergoing primary and secondary cesarean section between January1, 2011, and September 31, 2019. We used regression to analyze risk factors of postcesarean fever at primary cesarean section. Further we used interaction analysis to examine the effect of surgical site infection risk factors and use of adhesion barrier on postcesarean fever rates at the primary cesarean section. Results: We found that use of adhesion barrier at the primary cesarean section is associated with a significantly higher incidence of postcesarean fever (p=0.045). The risk factor for postcesarean fever is the use of anti-adhesion filmduring emergency cesarean section (p=0.041). In the subgroup of labor before operation and emergency cesarean section, adhesion barrier user had significant higher risk of postcesarean fever than nonuser (p<0.05). Conclusion: The patients used of anti-adhesion films during emergency cases and when a woman has labor before operation is associated with a significantly higher risk of postcesarean fever which potentially means increased risk of surgical site infection.

Objective: To simultaneously detect fetal aneuploidies and single gene diseases using a novel noninvasive prenatal testing (NIPT) method called the Targeted And Genome-wide simultaneous sequencing (TAGs-seq). Design: Comparison of TAGs-seq NIPT results with conventional NIPT and diagnostic results. Setting: Shenzhen People’s Hospital and Chinese PLA General Hospital Population or Sample: 26 normal pregnancies, 7 pregnancies with fetal aneuploidies, 7 pregnancies with fetal achondroplasia (ACH) or thanatophoric dysplasia (TD), 18 pregnancies with ACH/TD-like ultrasound findings, and 10 pregnancies with fetal risk of beta-thalassemia. Methods: Plasma cfDNA was amplified by TAGs-seq to simultaneously obtain the whole-genome sequence of 0.1-3× depth and reads on target genes of >1000× depth. The whole-genome sequence was analyzed for fetal aneuploidy risk using a binary hypothesis T-score, and the reads on target genes were analyzed for single gene diseases by calculating minor allelic frequency of loci on FGFR3 and HBB. Main Outcome Measures: Concordance between the TAGs-seq NIPT, conventional NIPT and diagnostic results. Results: Consistent to conventional NIPT and diagnostic results, all cases of fetal aneuploidies and fetal ACH/TD were correctly identified from 58 pregnancies by TAGs-seq NIPT with high sensitivities and specificities. Two cases of paternal mutations of beta-thalassemia were correctly identified by TAGs-seq NIPT from 10 pregnancies, although one false-negative result was obtained. Conclusions: The TAGs-seq assay demonstrated a good potential to simultaneously detect fetal aneuploidies and single gene diseases as a novel NIPT method.

Objective As the population ages, increasing number of older patients are undergoing adult cardiac surgery. The purpose of the study is to assess the impact of age on postoperative outcomes in patients that undergo coronary artery bypass grafting (CABG). Methods Patients that are ≥70 years old who underwent CABG were selected from the Nationwide/National Inpatient Sample from 2010 to 2015 using ICD-9-CM diagnosis and procedure codes. The patients who were 70–79 years old were compared to patients aged 80–89 years old to determine if the age difference of the patients had an impact on surgical outcomes. In addition, the gender of the patients 80-89 years old were compared. The rates of postoperative complications, and mortality were compared. Results A total of 67,568 patients were identified who were ≥70 years old and underwent CABG. Compared to the Septuagenarians, the Octogenarians were more likely to develop cardiac complications (OR [odds ratio] =1.20, 95% CI [confidence interval] 1.12-1.23. They were also more likely to develop renal complications (P <0001), and respiratory complications (P <0001). The Octogenarians were also more likely to bleed postoperatively (P <0.0001) and have a higher mortality (P <0001). Furthermore, the female Octogenarians had a higher mortality (OR 1.25 95% CI 1.07–1.46) compared to males in the same age group. Conclusions The patients who were ≥80 – 89 years old had worse postoperative outcomes. The Octogenarians who were females had a higher mortality compared to their male counterparts.

We proposed several hypotheses to explain the low rate of Covid19 in Sub-Sahara Africa (SSA). The small number of people tested for Covid19, a younger population, higher immunity to covid19, and seasonality emerged as potential factors influencing the Covid 19 rate in SSA. Rigorous responses to covid19 to flatten the curve are urgently needed and will include (1) a substantial increase of Covid19 testing and the use of cellphone location to trace contact, (2) complete lockdowns with social distancing measures followed by an assessment of the impact of those interventions to flatten the curve, (3) the use of prior experience with Ebola outbreak to increase awareness about the Covid-19 and its fatal complications, (4) warnings about potential side effects associated with the use of chloroquine/hydroxychloroquine with azithromycin and (5) the maintenance of essential health services

In To Have or to Be? , psychoanalyst Erich Fromm writes about pursuit after domination of nature, material abundance, and unlimited happiness, which made modern society become more interested inhaving than in being . Income, in his view, should not be as accentuated as to create different experiences of life for different groups [1]. Of the concepts that Fromm presents, the domination of nature, which facilitates zoonotic spillover events by increasing the overlap between the habitat of various species with that of humans [2-5], and the gap between the rich and the poor, which recently has become the widest in years [6], become particularly relevant in context of the COVID-19 pandemic.Even though susceptibility to COVID-19 does not know socioeconomic boundaries, a critical and worrisome finding is emerging from preliminary data and may re-shape infectious disease outbreak management strategies for the future. An early analysis of COVID-19 data from several jurisdictions in the United States found that counties with a majority of African American residents had three-times higher infection rates and six-times higher mortality rates than counties with a majority of Caucasian residents [7]. Another analysis, of March 2020 COVID-19 hospitalization data from 14 states in the United States, found more African American individuals among hospitalized patients whose race or ethnicity was recorded [8]. These and other findings reveal a disproportionately higher risk of serious or fatal COVID-19 in minorities. What makes these observations remarkable is that hypertension, diabetes, and obesity, which are risk factors for more severe or fatal COVID-19 [9-13], are exactly the chronic conditions that have long been recognized as disproportionately affecting racial/ethnic minorities and socioeconomically disfavored individuals and groups [14].Obesity affects minorities and low-socioeconomic-status groups disproportionately at all ages [15], a finding that was reported in several countries [16-19]. Some of the risk factors that account for disparities in obesity include low socioeconomic status [20], food insecurity, restricted access to healthy diet and recreational facilities [21-24], residence in areas with fast food restaurants [25], a high neighborhood density of small grocery stores [26], distance to a store [27], exposure to obesogenic environments [28, 29], shift work [30] and irregular sleep patterns [31-33].Obesity increases the risk for other chronic diseases [12], including diabetes and hypertension [34]. African American adults in the United States have among the highest rates of hypertension worldwide [35]. Several factors were implicated in disparities in hypertension, including socioeconomic status [36], differences in awareness [37], residence in a food desert [38], chronic stress [39, 40], fewer healthcare resources [41], and income [42]. Disparities for diabetes were described in minority populations in terms of increased prevalence [43, 44], worse management and control [45, 46], and higher rates of complications [45, 47]. Over the past three decades the socioeconomic disparities for type 2 diabetes have widened [48].Racial, ethnic and socioeconomic disparities also shape inequities in the access to mental health care [49-52]. This is very relevant for COVID-19, in context of the quarantine that was implemented in many countries in various forms, including school closures, allowing non-essential personnel to work from home, closure of mass transit systems, cancellation of public events, and restrictions on the assembly of groups of people [53-55]. Social isolation negatively impacts mental health and, with > 70% of the young people and adults not receiving adequate mental health treatment from health care personnel worldwide [56], the implications in the wake of COVID-19 are extensive and far-reaching. The 2002-2003 SARS pandemic revealed that a substantial proportion of the quarantined individuals may display PTSD and depression symptoms, with longer duration of the quarantine being associated with more severe PTSD [57]. During the same pandemic, hospital employees from Beijing who were quarantined had higher PTSD levels than those who were not, even three years later [58]. Among individuals from South Korea isolated for two weeks during the 2015 MERS outbreak, anxiety and anger were still present 4-6 months after the quarantine [59].The disproportionately higher suffering of socio-economically disadvantaged individuals at a moment of crisis is, unfortunately, nothing new. In the 14th century, in the Black Death pandemic, the poorest populations were also the most extensively impacted ones in terms of mortality [60, 61], and low-income individuals had a considerably worse outcome after the 1918 flu pandemic [62]. The disproportionate effect on socio-economically disadvantaged individuals was also apparent in the wake of natural disasters, such as Hurricane Katrina [63] or the Deepwater Horizon oil spill [64]. One aspect that makes COVID-19 different is that several segments of the population become more vulnerable not simply due to socioeconomic disparities, but as a result of chronic medical conditions that these disparities have at least partly fueled over decades. The partial overlap between the risk factors for these two groups of diseases is reminiscent of debates on whether the broad classification of diseases into non-communicable and communicable ones is a meaningful one, considering that the two groups often overlap and interact markedly with one another [65-67]. Another aspect that sets COVID-19 aside from other pandemics in recent history is the extent and the duration of the quarantine and the resulting increase in unemployment rates [68, 69], which only promise to prolong and exacerbate the extent of social inequities and the burden of chronic diseases.COVID-19 provides a steep and perplexing learning curve that underscores the imperative need to envision infectious diseases not simply from a biomedical perspective, but as part of a complex framework that incorporates ethnic, socioeconomic, and political dimensions. Racial/ethnic and socioeconomic disparities are conducive to the development of chronic medical conditions that could increase the risk of severe COVID-19, widening the disparities and accentuating the chronic disease burden and, as a result, further marginalizing already vulnerable individuals and groups. The implications of this positive feedback loop for individuals, groups, and society, extend beyond COVID-19 and beyond infectious diseases in general. The current pandemic eloquently demonstrates, albeit at a high cost, that societies function on the basis of a social contract, as described by Jean-Jacques Rousseau and, undoubtedly, offers an important moment to reflect on the profound, far-reaching, and multi-layered consequences of disparities in society.References1. Fromm E. To Have or to be. Continuum: New York 1977;

Background and Purpose. Drug resistance is a major problem in cancer treatment with traditional or targeted therapeutics. Gemcitabine, a traditional chemotherapeutics, is approved for several human cancers and the first line treatment for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, gemcitabine resistance is frequently observed and a major problem in successful treatments of these cancers and the mechanism of gemcitabine resistance remains largely unknown. In this study, we aim to seek new and understand the molecule mechanisms of gemcitabine resistance in PDAC. Experimental Approach. Using whole genome Reduced Representation Bisulfite Sequencing analysis, we investigated a gemcitabine resistant PDAC cell line M3K compared with its parental MiaPaCa-2 cells and the resistance revertant cell line Rev followed by detailed analyses of PDGFD in gemcitabine resistance using MTT survival assay, bisulfite sequencing, Western blot, siRNA knockdown and over-expression. Key Results. We found that 65 genes had reversible methylation changes in their promoters in gemcitabine resistant PDAC cells. One of these genes, PDGFD, was further studied in detail for the reversible methylation change in its promoter and shown to reversibly up-regulate in expression, contribute to gemcitabine resistance in vitro and in vivo via activating STAT3 signaling in both autocrine and paracrine manners. Its expression also positively associates with poor outcome of PDAC patients. Conclusion and Implications. Reversible epigenetic regulation may play an important role in gemcitabine resistance and targeting PDGFD signaling may alleviate gemcitabine resistance for PDAC treatment.

In a recent issue of Br J Clin Pharmacol Smith et al1 published an outstanding commentary titled ‘Dosing will be a key success factor in repurposing antivirals for Covid-19’. They highlighted that the success in our repurposing efforts will be dependent on ‘getting the dose right’ for drugs which have been developed for different indications and stressed some of the unique challenges of treating this particular disease. They pointed the reader to lopinavir/ritonavir (LPV/r) as an example of a repurposed antiviral and the limited experience of this drug regimen (and other treatments) in the elderly population with comorbidities – ie those most at risk from Covid-19. It is on the issue of comorbidities, polypharmacy and drug-drug interactions (DDIs) that we wish to comment.

Drug disposition in children is impacted by developmental changes in drug absorption, distribution, metabolism and excretion. This mandates the need for dosing regimens specifically tailored to children. Yet, there are gaps in the knowledge on these developmental changes, for example regarding hepatic and renal drug transport and drug metabolism, putting children at risk for subtherapeutic or toxic drug exposure. Pediatric drug research is faced with ethical and analytical challenges. This review addresses how these knowledge gaps can be filled and challenges can be overcome by using innovative study designs.

Objectives: In December 2019, a pneumonia like illness was first reported in Wuhan-China caused by a new coronavirus named corona virus disease -2019 (COVID-19) which then spread to cause a global pandemic. Most of the available data in the literature is derived from Chinese cohorts and we aim to contribute the clinical experience of a single British clinical centre with the characteristics of a British cohort. Design: A prospective case series. Setting: A single clinical centre in the UK. Methods: We have collected the demographics and medical characteristics of all COVID-19 positive cases admitted over two-week period. All cases were diagnosed by PCR. Results: Total of 71 COVID-19 patients were included in this case series. Majority of patients (75%) were ≥75 years old and 58% were men. Pre-existing comorbidities was common (85% of patients). Most patients presented with respiratory symptoms such as fever (59%), shortness of breath (56%) and cough (55%). Gastrointestinal symptoms were second most common presenting compliant such as diarrhoea (10%) and abdominal pain (7%). Opacification in chest X-rays were demonstrated in 45% of patients. All patients received supportive treatment and no specific antiviral therapy was administered in this cohort. So far, 18 (25%) patients have fully recovered, 9 patients (13%) escalated to a higher level of care and 10 (14%) have died. Patients who died were non-significantly older than those who have recovered (78.0 v 69.2 years, p=0.15) but they had a significantly higher clinical frailty scores (5.75 v 3.36, p=0.005). Conclusion: This case series demonstrated that the characteristics of British COVID-19 patients were generally similar to what is published in literature although we report more gastrointestinal symptoms at presentation. We have identified frailty as a risk factor for adverse outcome in COVID-19 patients and suggest that it should be included in the future vaccination recommendations.

Understanding the workings of the novel coronavirus (SARS-CoV-2) is crucial to develop counter therapeutic measures. SARS-CoV-2 gains entry into human cell by binding its receptor Binding Domain (RBD) of Spike protein (S1) to ACE2 receptors. In order to study the effect of mechanical stress on the RBD of SARS-CoV-2, it is modelled as viscoelastic material using Burgers Model. Strain response of RBD under constant stress is analyzed, which gives useful insights into the conformational transitions of RBD at 0K and physiological temperatures. The theoretical underpinning has shown that with increase in the number of stress cycles, the binding affinities of RBD conformational states to ACE2 receptor decrease, decreasing the binding reaction rate between ACE2 receptor and SARS-CoV-2. This analysis gives theoretical evidence that ultrasonic therapy and photo therapy (UV) can be potential candidates to reduce binding reaction rates between ACE2 and SARS-COV-2.

The prediction of protein-protein interfaces requires both the identification of interface residues and the proper spatial orientation of the component proteins. Many methods have been developed to identify interface residues, often using relative interface propensity (RIP), the enrichment of a particular amino acid type at the interface compared to the rest of the protein surface. We aimed to improve RIP for interface identification by incorporating the solvent accessibility of each amino acid. We studied the surface residues of 290 unbound structures corresponding to components of protein complexes and compared the relative solvent accessible surface area (rSASA) distributions of residues that end up in the interface and those that do not. Our results show that the side-chains of amino acids that become interface residues are more solvent exposed than non-interface surface residues on the unbound protein structure. Using this knowledge, we created an rSASA-dependent probability of becoming an interface residue for each amino acid type. Our results show that the solvent accessible surface area of residues should be taken into account when identifying interface residues and can be applied to other interface prediction techniques that use RIP to improve their results.

This clinical image indicates the importance of the early diagnosis and treatment of acute supraglottitis during COVID-19 pandemic.

Here we present a case report of Xylophagia

Background and Purpose Fibroblast growth factor 2 (FGF2) plays an important role in multiple physiological functions such as tissue repair. However, it has a short half-life in vivo, thus limiting its clinical application. Experimental Approach Based on the crystal structure of FGF2, surface-exposed sites near the receptor and heparin binding region or separated from both binding regions, were selected and PEGylated to investigate the effects of these sites on protein stability and bioactivity. The efficacy of FGF2 conjugates for wound healing in vitro was screened by cell proliferation, migration of human dermal fibroblasts (HDFs) and human umbilical vein endothelial cells (HUVECs). Angiogenesis activity was assessed by tube forming and aortic ring assays. The stability was confirmed in plasma and wound fluid. The in vivo wound healing of FGF2 conjugates were further evaluated on a cutaneous wound model using H&E, IHC, IF, and collagen staining. Key Results Compared with native FGF2, all PEG-FGF2 conjugates exhibited significantly improved stability in plasma and wound fluid. Compound 6 more effectively promoted proliferation and migration in HDFs and HUVECs than FGF2, and exhibited excellent angiogenesis and wound healing activity in vivo. However, conjugates with the PEGylated sites near the receptor and heparin binding regions showed some reduction in bioactivity, with a greater loss of bioactivity for protein with site near the heparin binding domain. Conclusion and Implications Heparin binding domain may be a key contribution region to activity of FGF2. Compound 6 is a potential therapeutic candidate for wound healing, deserving further investigation.

Hypopharyngeal squamous cell carcinoma (SCC) has the highest mortality of all head and neck SCC subsites and typically presents in patients with history of tobacco and alcohol use. We present a case of hypopharyngeal SCC in a patient with no traditional risk-factors and a germline BRCA2 mutation.

We report a rare case of monoclonal gammopathy of renal significance with immunotactoid glomerulopathy and severe nephrotic syndrome. The patient was diagnosed with a B-cell IgM κ clone and her nephrotic syndrome is responding well to bortezomib, dexamethasone, and rituximab.

Co-transplantation of MSCs and HSCs has showed controversial results for treatment of GvHD. In this study, the level of predictor factors and GvHD biomarkers have been checked. The co-transplantation of HSCs and MSCs did not show a significant difference compared to the group received MSCs alone.

In previous publications the role of kininogen system has been postulated. On those publications the possible role of Icatibant, Ecallantide and Aprotinin in treatment of SARS Cov-2 has been raised. In this paper we raise the hypothetical potential of Methylene Blue in treatment of SARS COV 2. This medication may abort effects of Bradykinin by inhibition of NO Synthase inhibitor and promote oxygen saturation while it is inexpensive and ubiquitously accessible. Clinical studies can not be over emphasized.

Compartmental model is the classic and widely used approach in pharmacokinetics. Recently, fractional calculus is introduced to describe the time course of drugs in human body which follow the anomalous diffusion mechanism. To consider the different fractional order transmission process, the two compartmental fractional model has been proposed and studied. And, it will be of great significance to find out a simple and efficient numerical method to solve the model and estimate model parameters. This work investigates two numerical methods of the two compartmental fractional model using finite difference schemes, which are based on the shifted Grünwald-Letnikov approximate formula and L1 formula, respectively. The hybrid Nelder-Mead simplex search and particle swarm optimization, denoted as NMSS-PSO, is provided to estimate the fractional model parameters. Comparison between the numerical solution and the solution by the numerical inverse Laplace transform method establishes the validity of the developed numerical algorithms. Then, the influence of the order of fractional derivative on the drug amount in human body is also discussed. Finally, the two compartmental fractional model is applied to fit the amiodarone pharmacokinetics data based on the NMSS-PSO algorithms. This work will be of importance for the development of fractional pharmacokinetics.