Nucleic acid real-time PCR test has become the main diagnostic tool for SARS‐CoV‐2 infection, and there are also drawbacks to these real-time PCR test kits. Additionally, it has reported high false-negative rates. A reliable and rapid test method is urgently required to briskly detect antibody response in a large number of infected patients and ensure prompt care for patients. Therefore, we report here a Luminex bead based multiplexed immunoassay to serologically diagnose the SARS-CoV2 infection and detect IgM and IgG response in COVID-19 patients. The technology can provide sensitive and specific detection using a low amount of serum samples in high-throughput screening platforms.

The occurrences of atmospheric precipitation and runoff do not coincide with each other, but rather demonstrate a certain lag in time. Meanwhile the lagged time and intensity are affected by the water storage capacities, which is related to the occurrence of droughts. This paper will develop the lagging index (LI) based on the measured data of 56 rainfall stations and 11 hydrological stations in the Central Guizhou of China, and analyze the spatio-temporal evolution characteristics of rainfall-runoff. The studies show that (1) the lagged effect of runoff to rainfall in the Central Guizhou of China mainly shows the 3 lagged periods with the lagged distribution areas accounting for more than 80% of the total areas. (2) The order of spatio-temporal distribution differences of the lagged intensities is the lagged period 2（Cv=0.62）

Bushfires are common in Australia and can cause vegetation loss and affect hydrological processes such as interception, evapotranspiration, soil water storage and streamflow. This study investigates bushfire impacts on catchment mean annual streamflow for 14 Australian catchments that have been severely impacted by the 2009 Victoria bushfire, the second worst bushfire disaster in Australia. A statistical approach based on sensitivity coefficients was used for quantifying the climate variability impacts on streamflow and the time-trend analysis method was used to estimate the annual streamflow changes due to bushfire respectively. Our results show that bushfire has caused a noticeable increase in mean annual streamflow in majority of burnt catchments for an immediate post bushfire period (2009-2015), when the bushfire impact on streamflow is evidently larger than the climate change impact. Furthermore, the bushfire impact on mean annual streamflow linearly increases with the burnt percentage area. These results provide strong evidence for evaluating large-scale bushfire impact on streamflow at small to medium sized catchments, and guidance for process-based hydrological models for simulating bushfire impacts on hydrological processes for the immediate period after bushfire.

Objectives: This study performed a competing‐risks analysis using data from the SEER database on stage Ⅱ colon cancer patients with the aim of identifying more accurate prognostic factors. Methods: Data on patients with stage Ⅱ colon cancer were extracted from the SEER database. A univariate analysis used the cumulative incidence function and Gray’s test, while multivariate analysis was performed using the Fine‐Gray model. Cumulative hazards were compared with a competing‐risks model constructed using KaplanMeier estimation. Results: The multivariate Fine‐Gray analysis indicated that grade Ⅲ/Ⅳ, stage T4, number of lymph nodes (nLN<12) were statistically significant. The results obtained using multivariate Cox regression were different, while Kaplan‐Meier curve analysis led to an overestimation of the cumulative risk of stage Ⅱ colon cancer patients. Conclusions: This study established a competing‐risks analysis model for the first time based on the SEER database for the risk assessment of stage Ⅱ colon cancer patients. The results may help clinicians to better understand stage Ⅱ colon cancer and provide these patients with more appropriate support.

The COVID-19 has posed a wide range of urgent questions: about the disease, testing, immunity, treatments, and outcomes. Extreme situations, such as pandemics, call for exceptional measures. However, this threatens the production and application of evidence. This paper directs evidence production towards four types of uncertainty in order to address the challenges of the pandemic: Risk, Fundamental uncertainty, Ignorance, and Ambiguity. Eliminating ambiguity, being alert to the unknown, and gathering data to estimate risks are crucial to preserve evidence and save lives. Hence, in order to avoid fake facts and to provide sustainable solutions we need to pay attention to the various kinds of uncertainty. Producing high quality evidence is the solution, not the problem.

Persistent pain affects 20% of adults and can impair one’s daily functioning and well-being. Psychoeducational group interventions can be effective in aiding pain management and coping strategies, however the time commitment for most evidence-based programs (10-20 hours) leads to access barriers and delivery challenges in primary care. A mixed-methods, program evaluation was conducted on a low intensity, three-session, manualized group pilot psychoeducational intervention in a primary care practice, emphasizing pain education, behavioral strategies, and pain-alleviating activities. Eighty-two percent of the clinic’s panel of individuals with persistent pain (N=128) and being prescribed opioid pain medication attended at least one class (N=105). Attendees experienced significant pre-post improvements in self-reported pain functioning and favorable satisfaction ratings by patients and medical staff. However only 51% attended all three groups, despite frequent class offerings and heavily encourage by the patient’s medical providers. This study reviews the potential promise and limitations of a low-intensity, limited session pain group to aid pain-related functioning. Additional investigation is warranted to optimize participant attendance, group format and frequency, and outcome assessment.

Sir ,We read with great interest the study by Zhou et al.1, where the authors demonstrated a significant association between preconception paternal smoking and birth defects in the offspring. The study is timely given the increasing recognition of the role that paternal factors play in pregnancy outcomes. The authors must be congratulated on performing a large scale, nationwide study, in which a potential link between preconception paternal smoking and birth defects in offspring was made.A salient point discussed by Zhou and colleagues is the difficulty in estimating the effect of paternal smoking as an independent variable on the risk of birth defects due to a myriad of confounding factors. Although the authors had adequately adjusted for maternal biological, environmental and behavioural factors, as well as paternal alcohol consumption, it may be prudent to note that paternal age could be a potentially significant confounder in this relationship.Advanced paternal age has shown robust links with increases in sperm DNA fragmentation.2 DNA damage is attributed to environmental, hormonal and degenerative changes.2Over time, multiple cycles of mitotic replications generate greater stress on the DNA repair mechanisms.2 The failure to control the DNA repair mechanisms invariably amounts to ejaculated spermatozoa containing a higher proportion of abnormal paternal DNA.2 In the same vein, children born to fathers of advanced age are at a slightly increased risk of birth defects including cardiac, respiratory, gastrointestinal tract and musculoskeletal abnormalities.3 It has been speculated that mutations accumulate over repeated spermatogenesis, subsequently increasing the number of birth defects in the offspring.3 At the opposite end of the age spectrum, young paternal age has also been associated with a slight increased risk of selected birth defects.3At large, prenatal smoke exposure has unfavourable effects on pregnancies. Effects of maternal smoking has been comprehensively studied and is associated with fetal and developmental conditions. Harmful substances in tobacco smoke such as nicotine, carbon monoxide and polycyclic aromatic hydrocarbons are able to cross the placenta and negatively affect the fetal development.4 On the other hand, the extent of paternal smoking has not been well-established. Exposure to cigarette smoke has been found to affect sperm parameters, as well as increase sperm chromatin structural abnormalities and DNA damage.5 Infant low birth weight, increased obesity risk in childhood and high blood pressure have been identified as potential complications of paternal smoking.4 This study provides new evidence that birth defects are also complications of paternal smoking.In conclusion, Zhou et al. have accomplished a tremendous job of investigating the effects of paternal smoking on birth defects. The current study has laid the groundwork for future research to be built upon and to elucidate the true effects of paternal smoking during pregnancy. As exposure to first or second-hand smoke poses a major risk to pregnancies, it might be worthwhile to recommend smoking cessation in both parents during preconception counselling.Jania J. Y. Wu1, Kyla Ng Yin2, Keng Siang Lee3, John J. Y. Zhang11Yong Loo Lin School of Medicine, National University of Singapore, Singapore2Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK3Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, UK

Landslide and debris flows are typically triggered by rainfall-related weather conditions, including short-duration storms and long-lasting rainfall. The critical precipitation of landslide and debris flow occurrence is different under various hydrometeorological conditions. In this study, the daily hydrological states were evaluated by the SWAT model, and the trigger sensitivities of different daily hydrological variables were assessed with 50 days recorded landslide and debris flows between 2010 and 2013. Based on modeled wetness states, the event days were divided into LLR-trigger event days (long-lasting rainfall) and SDS-trigger event days (short-duration storm) with six determinate criteria. The landslide and debris flow prediction model was built using nine hydrometeorological variables and the predictive performance was tested with simulated data from 2010 to 2012. The results suggest that: Historical hydrological variables and their development provide important information for triggering debris flows, though rainfall is the most important factor for triggering debris flows. The landslides and debris flows in the selected subbasins region are triggered on 33 days by LLR and on 17 days by SDS. Specifically, LLR type landslide and debris flow account for a large proportion in July, while SDS type landslide and debris flow occur more frequently in September. The prediction model with the AUC value of 0.85, can capture most of the landslide debris flow. The temporal distribution of the two triggering-event predicted by the model is consistent with the annual distribution of precipitation. Besides, there are spatial variations of the specific trigger types in the different subbasins, which attribute to the different land cover. Despite some uncertainty, this study thereby provides an idea of improving the landslide and debris flow prediction model.

Dear Editor,Almost half a year into the COVID-19 pandemic, the one lesson that we all have probably learned is that the novel coronavirus infection is not an issue to be taken lightly. With millions of confirmed cases, and thousands of death reports, it has become absolutely clear that there is no magic bullet at our disposal in case of COVID-19. Due to the lack of medications specific to the etiological cause of COVID19, i.e., SARS-CoV-2, clinicians in all parts of the world are left with an exceedingly limited array of therapeutic options, that is mostly restricted to supportive and palliative care (Sheervalilou et al., 2020).To this date, several treatment modalities and numerous drugs of different classes have been evaluated for their efficacy in treatment of the novel viral pneumonia, with only a few of them showing promising clinical results. Despite the clinical administration of certain classes of drugs such as the antimalarial hydroxychloroquine, ACE inhibitors, and lopinavir/ritonavir, there is still inadequate evidence that would support their efficacy in treatment of COVID-19 (Sheervalilou et al., 2020). However, according to the most recent findings, statins or cholesterol lowering drugs might be of unappreciated therapeutic value in the ongoing fight against COVID-19. This is a possibility of great importance for individuals with atherosclerotic cardiovascular disease (ASCVD), who are most commonly treated with statins, and of course, fall into the category with an increased susceptibility to severe COVID-19 (Reiner et al., 2020).Traditionally known as cholesterol lowering drugs, statins do more than simply regulating the level of cholesterol in the blood, as they possess anti-inflammatory properties, and can potentially counteract the pathologies that might result in thrombotic events, e.g., septic shock (Angus & van der Poll, 2013). With their immune-modulatory functions, statins are thought to have the potency to interfere with the infectivity of several strains of viruses, as they can very well inhibit the processing of viral glycoproteins by disrupting the activity of the main viral protease. Impairment of the protease activity, and the consequential fall in the amount of processed glycoproteins are postulated to be the mechanisms behind the unappreciated antiviral effects of statins (Shrivastava-Ranjan et al., 2018).In the case of coronaviruses, the main protease or “Mpro” is a cleaving enzyme, that leads a prominent role in the maturation of viral glycoproteins. The enzyme has been indicated to be a potential target of antiviral medications, that seek to halt further spread of the infection by stopping the cleaving of polyproteins, that are basically the precursors to viral glycoproteins (Xue et al., 2008). This could be the reason behind the potential efficacy of statins as a treatment option for COVID-19. The recent successful attempt at crystallization of the Mpro of SARS-CoV-2 paved the way for a study to investigate the effect of statins on the novel coronavirus. The study measured the affinity of several well-known statins including rosuvastatin, pitavastatin, fluvastatin, and lovastatin, along with a few others, as standard ligands to a certain receptor, that in this case was the SARS-CoV-2 Mpro (Reiner et al., 2020).Known previously to have antiviral activity against Ebola virus (Fedson, 2014), statins can bind to the Mpro of SARS-CoV-2 with a higher affinity than that of the protease inhibitors. This is a groundbreaking finding in several contexts, indicating the potential therapeutic value of statins in the treatment of COVID-19, as these cholesterol lowering drugs are possibly capable of stopping the replication of SARS-CoV-2. Arguably, the most optimal results are achieved with pitavastatin, as it binds SARS-CoV-2 Mpro with a binding energy higher than that of the other statins, e.g., rosuvastatin, fluvastatin and lovastatin.Statins comprise the primary line of treatment for individuals with familial hypercholesterolemia, which is one of several underlying conditions that predispose the patients to acute cardiovascular complications, ultimately putting them at an increased risk of severe COVID-19 (Vuorio, Watts, & Kovanen, 2020). The anti-inflammatory properties of statins, along with their regulatory effects on the immune system, and potential antiviral activity against SARS-CoV-2, collectively comprise an incontrovertible body of evidence that warrants further clinical research, especially in the case of pitavastatin.Keywords : statins, Mpro, pitavastatin, SARS-CoV-2, COVID-19

Objective: Re-exploration after cardiac surgery still remained a troublesome complication. There is still scarcity of data about the effect of re-exploration after off-pump coronary arterial bypass grafting (OPCABG). We here represent our experience of re-exploration following OPCABG. Method: Total 5990 OPCABG were performed at our center, out-off these 132 (2.2%) patients were re-explored in the OR and were included in this study. The medical records of these patients were retrospectively reviewed. Results: The most common cause of re-exploration was bleeding (83.3%) and most common site of bleeding was from graft/anastomosis (53.8%). Mean time to re-exploration was 9.75±8.65 hours. 30-day mortality was 1.41%.On univariate and multiple regression analysis, emergency surgery, preoperative low platelet count, and number of grafts were found to be an independent risk factor for re-exploration. On multiple regression, emergency surgery, euroscoreII, low platelet count, low ejection fraction, re-exploration, time to re-exploration, blood products used, high post-op serum creatinine and bilirubin, were found to be an independent factor (p<0.001) for mortality. On receiver-operating characteristic analysis, optimum cut off for time to re-exploration was 14 hours with sensitivity 81.3%, specificity of 80% and area under curve of 0.798. Patients who re-explored late (>14 hour) had significantly high mortality (30.55%vs7.3%) and morbidity. Conclusion: Delaying the re-exploration is associated with three-fold increase in mortality and morbidity. So strategy of minimizing the incidence of re-exploration like use of minimally invasive surgery and early re-exploration with judicial use of products should be use to improve outcome after re-exploration following off-pump CABG.

Following the increase in wild boar population recorded in urban and peri-urban areas through Europe, the present survey aimed to assess the occurrence of zoonotic tick-borne bacteria in animals and their ticks collected from southern Italy, in order to evaluate the potential risk of infection for animals and humans. From October to December 2019, a total of 176 ticks collected from 93 wild boars and their spleen samples were molecularly screened for Borrelia burgdorferi sensu lato complex, Coxiella burnetii and spotted fever group (SFG) Rickettsia species. Overall, all the wild boars were infested by ticks (mean intensity, 1.9) with Dermacentor marginatus and Ixodes ricinus being identified in 99.4% and 0.6%, respectively. Out of 93 wild boars, 17 (18.3%) were infested by ticks positive to spotted fever group (SFG) Rickettsia species. Rickettsia slovaca and Rickettsia raoultii were identified in 16 (9%) and 1 (0.6%) D. marginatus, respectively, whereas a single I. ricinus (0.6%) was infected by R. slovaca. A single wild boar (1.1%) scored positive to R. slovaca. All ticks and wild boars scored negative to C. burnetii and B. burgdorferi s.l. complex. Data herein obtained suggest wild boars are involved in the dissemination of D. marginatus, especially in peri-urban settlements of the study area. An integrated management approach is advocated for wild boar population control and preventing the potential risk of tick-borne bacteria in animals and humans.

Risk assessment to target aspirin is accurate but not universalLow dose aspirin, for the prevention of early onset pre-eclampsia is an established antenatal intervention; it is safe, effective, cheap and accessible in many health care settings.Optimal implementation strategies including dose, timing and screening are currently debated. The evidence supports starting aspirin early (before 16 weeks), prescribe at night, give up to 150mg and continue until at least 36 weeks gestation ((Poon et al. Int J Gynaecol Obstet. 2019 May;145 Suppl 1(Suppl 1):1-33). From the women’s perspective, many may not be happy to routinely medicate an apparently normal pregnancy, to prevent an unknown or unfamiliar disease.Despite campaigns by APEC and others, too many women only hear of pre-eclampsia when it affects them. Generally, as perceived risks escalate the acceptance of taking aspirin is greater which improves compliance by both physicians prescribing, and by pregnant women. Any strategy that allows targeting of aspirin is likely to prevent unnecessary treatment and would be welcomed. It should be noted that the MBRAACE Report (Knight et al. University of Oxford 2019. ISBN: 978-0-9956854-8-2) called for a national patient direction for midwives to prescribe aspirin which has not yet happened.This current analysis compared two such strategies to target antenatal aspirin NICE guidance uses history to establish risk (Guy et al. BJOG 2020 xxxx). It is relatively simple, requiring either a combination of minor risk factors or a single major risk factor to dictate the need for aspirin. The FMF algorithm uses a combination of tests, including scans, blood pressure and blood markers to dictate risk; this requires skill and more resource which may not be consistently available in lower income settings.When compared in a real-world setting, in a London teaching hospital, the FMF algorithm had a screen positive rate that was half that of NICE, while aspirin was given to far more high-risk women. The FMF algorithm was changed to suit local circumstances, including details of the tests used (PAPPA, rather than PLGF) and thresholds adopted for treatment, but the real-world findings are impressive.The dosage of aspirin was higher in the FMF group, (150mg vs 75mg) which could explain some of the additional clinical benefit. Aspirin has recently been shown to impact on preterm birth when given routinely to all women who have never given birth in a low resource setting. In these settings, the cost and practicalities of implementing the algorithm maybe prohibitive. However, elements of the algorithm such as blood pressure measurement are simple and potentially more generalisable.It is exciting we have an intervention that can impact on one of the world’s most significant pregnancy disorders; but if resources allow, we clearly now have the tools to predict risk and improve outcomes. The challenge is how to deliver this to the global south, where most of pre-eclampsia occurs.At Action on Pre-Eclampsia, in the UK, we will continue to push for easy availability of aspirin. This paper is a welcome piece of the jigsaw and we hope it offers further tools in the armoury to defeat pre-eclampsia.No disclosures: Completed disclosure of interest forms are available to view online as supporting information.

Reply to Morais-Almeida.To the Editor,We appreciate Dr. Morais-Almeida’s comments 1 about our Letter to the Editor, presenting additional literature about asthma prevalence in severe COVID-19 patients and highlighting data that contrasts our hypothesis that asthma, particularly type 2 asthma, may be protective against severe disease.The data that protection may be dependent on type 2 immunity is derived from the higher percentage of asthmatics being atopic2, also reflected in the series of ~2,500 patients regularly followed up in our Allergy Unit. Yu et al. 3 provided preliminary evidence about this in a single-center retrospective study, where COVID-19 atopic patients had less severe infections, milder lung damage compared to age- and gender- matched COVID-19 controls.ACE-2, the SARS-CoV-2 receptor, is linked to type 1 and 2 interferon signatures, and found to be overexpressed in type 2-low asthmatics4. Nevertheless, different outcomes in distinct asthma phenotypes still need to be addressed in COVID-19 studies.Besides Italy and China, reports from Russia 5 on ~1,300 intensive care unit patients with SARS-CoV-2 infection confirm the observation of a low prevalence of chronic lung diseases (i.e. asthma as well as COPD).Although preliminary data on the first COVID-19 cases in the US6 seem to contrast these observations, the higher prevalence of asthma in US COVID-19 hospitalised patients should be considered alongside a higher overall prevalence in these countries compared to Europe and China, as well as on the influence of other comorbidities (i.e. obesity) and host factors (i.e. age, race: 33% were non-Hispanic black patients in the study by Garg et al.) impacting COVID-19 outcomes. Another report from Sweden 7highlights the association between severe asthma and severe COVID-19.The severe asthma phenotype is often characterized by mixed granulocytic populations (neutrophilic and eosinophilic), prevalent type 1 inflammation, increased IFN-γ levels in the airways and ineffectiveness of ICS. This severe phenotype by itself, although accounting for less than 5% of asthmatic patients, would justify the CDC (and other institutions) including asthma as a risk factor for COVID-19. Data from the UK 8, apart from confirming the role of additional comorbidities, draw attention to the recent use of oral steroids, which, indeed, may be a clue for uncontrolled and/or severe asthma.Uncontrolled asthma is a risk factor for viral exacerbations and hospitalizations and we embrace the opportunity to stress the importance of optimal adherence to asthma controlling medications, regular follow-up and specialist-assessment of disease activity. Moreover, treatable comorbidities, which may impair asthma control, should always be managed. Promoting vaccination for preventable respiratory infections (i.e. Influenza and Pneumococcal pneumonia) is also advisable. Future studies may help better distinguishing the impact of different asthma phenotypes and comorbidities on COVID-19 outcome.Carli G.1, Cecchi L.1, Stebbing J.2, Parronchi P.3, Farsi A.11 SOS Allergy and Clinical Immunology, USL Toscana Centro, Prato Italy2 Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK3 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

Introduction: The objective was to compare transoral robotic surgery (TORS) vs. non-TORS tongue resection procedures performed for obstructive sleep apnea from 2010-14 using a national database, focusing on patient characteristics, performance of concurrent procedures, operative time, length of hospital stay, and postoperative complications Methods: A cohort of adults undergoing TORS and non-TORS tongue resection procedures was identified in the Nationwide Inpatient Sample, a publicly-available national administrative database incorporating a stratified sample of hospital discharge records. Outcomes were annual case volumes, prolonged (≥3 days) hospital stay, and complications for TORS and non-TORS tongue resection procedures. Statistical analyses examined potential associations between the use of TORS and prolonged hospital stay and complications, with adjustment for the performance of concurrent procedures and specific patient and hospital characteristics. Results: From 2010-14, 5185 hospital discharges included tongue resection surgery to treat obstructive sleep apnea. There was a gradual decline in overall volumes, with the proportion of TORS use showing an initial increase, followed by a decrease. TORS patients were less likely to undergo concurrent nasal surgery (14% vs. 45%, p<0.01), but there was no association between the use of TORS and concurrent palate/oropharyngeal or other hypopharyngeal surgery. TORS use was associated with patient age, payor, and certain hospital characteristics. TORS use was associated with an increased risk of prolonged hospital stay (33% vs. 25%, p=0.045) and pulmonary complications (8.4% vs. 6.0%, p=0.04) but not total complications (7.7% vs. 7.4%, p=0.2). Conclusion: This study provides insight into TORS use in tongue resection surgery for obstructive sleep apnea during this period of early TORS adoption.

Objective: To identify pregnancies at risk for adverse outcomes in the late preterm (LP) period, we investigated how gestational age (GA) at delivery, circumstances at parturition, and specific prenatal risk factors may affect neonatal outcomes. Study design: Prospective, area-based cohort study of neonatal morbidity and mortality among singleton infants born between 34+0 and 36+6 weeks, at 21 L&D units in Emilia Romagna county, Italy, during 2013-15. The primary neonatal outcome was a composite of Apgar 5’ ≤ 3, umbilical-cord-blood arterial pH < 7.0, RDS, TTN, hypoglycemia, sepsis, confirmed seizures, stroke, IVH, cardiopulmonary resuscitation, invasive respiratory support and hospitalization ≥ 5 days. Multivariate logistic regression models were used to respectively investigate the effects on study outcomes of 1) GA at delivery and circumstances at parturition 2) GA at delivery and prenatal risk factors, after controlling for confounding Results: Among 1867 births, 302, 504 and 1061 infants were born at 34, 35 and 36 weeks, respectively. There were no neonatal deaths. When studying circumstances at parturition, an increased risk of composite neonatal outcome was observed among 34 weeks births, 35 weeks deliveries, and indicated deliveries. When studying prenatal risk factors, neonatal morbidity was associated with delivery 34 weeks, birth at 35 weeks, pregestational diabetes, pPROM, maternal BMI, bleeding and polyhidramnios; instead, preeclampsia had a protective effect. Conclusion: LP with indicated deliveries at 34 or 35 weeks, or with specific prenatal risk factors have worse neonatal outcome when compared to 36. Such differences should be considered when counseling patients and planning interventions.

Due to the proximity of the transvers sinus (TS) to the left atrial appendage (LAA) and pulmonary veins (PV), a mass in the TS can be misinterpreted as a LAA or PV thrombus, and considered as a source of emboli in a patient with stroke or TIA . The incorrect identification of a mass as a LAA thrombus would initiate unnecessary anticoagulation therapy or potentially, an evaluation for the excision of the mass if there is a concern about dislodgement . We are presenting a case illustrating this confusion and review the literature for similar cases.

Background: Atrial fibrillation (AF) is common in abdominal solid organ transplant recipients and a cause of morbidity and mortality in this population. However, the outcomes of catheter ablation (CA) in transplant recipients with AF remain unclear. This study aimed to elucidate the outcomes of CA in renal and hepatic transplant recipients. Methods and Results: Between 2015 and 2019, 14 transplant recipients (9 with kidney transplantation and 5 with liver transplantation) were enrolled from among 10,741 AF patients and underwent CA at Anzhen Hospital. Another 56 patients matched by age, sex and AF type were selected as the control group (4 controls for each transplant recipient). During a mean follow-up of 30.0±13.3 months after the initial procedure, 10 (71.4%) of the transplant patients, compared to 41 (73.2%) of the control patients, remained free from AF recurrence(P=1.000). A repeated procedure was performed in 1 transplant patient and in 6 control subjects. Consequently, 11 (78.6%) of the transplant patients, compared to 46 (82.1%) of controls, were in sinus rhythm after the repeated ablation (P=0.715). Notably, Kaplan–Meier analysis did not demonstrate any significant differences in the atrial arrhythmia-free rate after the initial and repeated procedure between the two groups. Vascular complications were identified in 1 transplant patient and 2 control subjects, while no life-threatening complications were observed in either group. There was no transient allograft dysfunction in transplant recipients after CA. Conclusion: CA is safe and effective in abdominal solid transplant recipients, and may be an optimal therapeutic strategy for this group.

Atrial fibrillation (AF) is a common arrhythmia that has major morbidity and mortality. Hypoxia plays an important role in AF initiation and maintenance. Hypoxia inducible factor (HIF), the master regulator of oxygen homeostasis in cells, plays a fundamental role in the regulation of multiple chemokines and cytokines that are involved in different physiological and pathophysiological pathways. HIF is also involved in the pathophysiology of AF induction and propogation mostly through structural remodeling such as fibrosis, however some of the cytokines discussed have even been implicated in electrical remodeling of the atria. In this article, we highlight the association between HIF and some of its related cytokines with AF. Additionally, we provide an overview of the potential diagnostic benefits of using the mentioned cytokines as AF biomarkers. Research discussed in this review suggests that the expression of these cytokines may correlate with patients who are at an increased risk of devleoping AF. Furthermore, cytokines that are elevated in patients with AF can assist clinicians in the diagnosis of suspect paroxysmal AF patients. Interestingly, some of the cytokines have been elevated specifically when AF is associated with a hypercoaguable state, suggeting that they could be helpful in the clinician’s and patient’s decision to begin anticoagulation. Finally, more recent research has demonstrated the promise of targeting these cytokines for the treatment of AF. While still in its early stages, tools such as neutralizing antibodies have proved to be efficacious in targetting the HIF pathway and treating or preventing AF.

An 82-year-old woman received pacemaker implantation for sick sinus syndrome. Two days after the implantation, electrocardiography showed 2:1 atrial pacing failure, followed by bradycardia-dependent increase in the atrial pacing threshold during a pacemaker examination. However, transient 1:1 atrial pacing capture recovered by adenosine triphosphate (ATP) administration, which was performed to evaluate the bradycardia-dependent pacing failure mechanism. We considered this phenomenon to be caused by phase 4 depolarization and avoided replacing this atrial lead. Three weeks later, the atrial pacing threshold had improved. We report the potential role of phase 4 depolarization in bradycardia-dependent increase in pacing threshold by using ATP.

Introduction: Remote monitoring (RM) has profoundly transformed the standard of care for patients with cardiac electronic implantable devices. It provides easy access to valuable information about arrhythmic events, acute decompensation manifestations and device-related issues without the need of continuous in-person visits. Methods: Starting March 1st, 332 patients were introduced to a RM program during the Italian lockdown in order to limit the risk of in-hospital exposure to Severe Acute Respiratory Syndrome Coronavirus-2. Patients were categorized in two groups based on the modality of RM delivery [home (n=229) vs office (n= 103) delivered]. The study aimed at assessing the efficacy of the new follow-up protocol, reported as the mean RM Activation Time (AT) and the need for technical support for its activation. Patients’ acceptance and anxiety status was also quantified by means of the Home Monitoring Acceptance and Satisfaction Questionnaire and the Generalized Anxiety Disorder 7-item scale. Results: AT time was <48 hours in 93% of patients and 7% of them required further technical support. Despite a higher number of trans-telephonic technical support in home-delivered RM group, AT was comparable between groups (1.33±0.83 days in home-delivered vs 1.28±0.81 days in office-delivered patients; p=0.60). Twenty-eight (2.5%) urgent/emergent in-person examinations were planned. High degree of patient’s satisfaction was reached in both groups while anxiety status was higher in office-delivered group. Conclusions: RM was effective, safe and well tolerated by patients during the Italian lockdown. Our findings confirm the efficacy of this approach to reduce in-hospital visits, guaranteeing patients’ safety and quality of care.

Understanding of the term ‘Precision Medicine’ is variable. For clinicians, pharmacists and clinical pharmacologists, it refers to the right decision (treat or not), right drug, right combination, right timing and right dose, taking into account the clinical trial data for the patient group being treated, and finessing that to the individual biological and pharmacological variables either evident, or likely to be evident based on knowledge about comorbidity and body size.To scientists, precision medicine can mean either developing a new molecule to fit a specific target or cell of interest, or ‘finding’ based on mathematical and chemical profiling existing drugs that might ‘fit’ the target of interest (1). However, this focus on ‘targets’ as the method to improve precision has seemingly ignored the well-known principles of radiobiology, cancer biology and pharmacology, and has not delivered the improved health outcomes expected (2). Similarly, since 2015, U.S. and other government’s multi-billion-dollar investments into ‘precision’ drugs “delivering the right treatments, at the right time, every time to the right person whilst helpful to understand some aspects of disease pathophysiology, has also fueled this single target focus (3).In this Themed issue discussion on aspects of science and medicine people refer to as precision medicine approach are covered. Although varied, much discussion is related to the importance of understanding the way each individual both handles and responds to a drug, and specific dose. How to implement individualized dosing into practice however can be an even more challenging area, with different levels of precision costing different amounts, with a spectrum of clinical and economic benefits.Added to this difficulty is the systematizing of regimen and dose for specific cancers which have come into oncology practice over the last few years. Moynihan et al argue that the financial dependence of research on industry funding creates a “sponsorship bias” that overplays efficacy and underplays toxicity. This was confirmed in a systematic review comparing industry sponsored with independently funded trials (4).This is not just an issue with interpretation of results but goes back to trial design. The choice of a comparator may make the outcome of the study drug more favorable (4). Over the years in cancer trials, there has certainly been a move from the principle of treating until maximum response and then allowing a patient time without symptoms or side effects of treatment to studies which are designed to continue treatment until relapse or unacceptable toxicity. This maximizes drug use but is there evidence that prolonging use of a drug maximizes outcomes?Maintenance strategies in metastatic disease can be simply continuing the drug used in induction or switching to another drug, which really can be considered as early second line treatment (5). Although established in lymphomas, randomized studies of continuous maintenance therapy in non-small cell lung cancer (NSCLC) led to no improvement in response or survival and similarly for survival in colorectal cancer (5,6). Prolonging first line therapy in breast cancer only showed a marginal survival benefit. There are ongoing studies, but prolonging induction therapy lacks the evidence for widespread adoption. Switching to another drug or targeted therapy, as an early second line treatment, has shown prolonged survival over induction alone in several tumour types (5).The duration of targeted therapies provides examples of how trial design influences practice. The initial studies of trastuzumab in adjuvant breast cancer initially reported at the American Society of Clinical Oncology in 2005 were designed to give 12 months of therapy and that became the standard of care (7). An ongoing study at the time was comparing 12 months with 24 months. (8). However, an independent French group looked at 6 months compared to 12 months and it is only in 2019 that the final analysis could not show non-inferiority of 6 months of treatment (9). Meanwhile the FinHER study in Finland showed the efficacy and cost-effectiveness of only 9 weeks of adjuvant trastuzumab after chemotherapy (10, 11).In terms of the dose given, the current common method of dosing cytotoxic drugs is based on a patient’s body surface area (BSA). This can be inaccurate with considerable variation between patients because patient-related factors such as organ function, age, gender, activity of metabolizing enzymes, drug resistance and concomitant drugs can influence the pharmacokinetics and pharmacodynamics (12). This gives rise to pharmacologically-based dosing being explored to make individual patient dosing more precise.The first step, however, in the treatment of cancer is to select the drug or drugs most likely to be effective. In the era of precision medicine what is being investigated is identifying mutations in genes or changes in the expression of genes or proteins specific to a tumour, which can be targeted by therapeutics (13). Detecting multiple genomic changes has been made possible by technological advances like next generation sequencing (NGS) replacing older single gene testing. Use multiple platforms combining sequencing of DNA with RNA sequencing and with the more established techniques such as immunohistochemistry (IHC) maximizes the potential to discover druggable targets (14). IHC detects changes at the protein level that reflect gene amplifications such as HER-2 in breast cancer, gastric and colorectal cancer which can be targeted with trastuzumab. Rearrangements include EML4-ALK translocation in non-small cell lung cancer which can be targeted by drugs such as crizotinib. Now there is testing for biomarkers related to PD-L1 expression in various tumours which can be targeted by checkpoint inhibitors such as atezolizumab.Molecular profiling which allows matching treatments for cancers to their targets has resulted in a boost for new drug development in rare cancers by using drugs targeted to molecular biomarkers that they have in common with more common cancers, in basket trials (15).Limitations of gene expression profiling and IHC can be illustrated in diffuse large B-cell lymphoma (DLBCL) as summarized by Ofori et al in this issue of the Journal (16). Its subtypes defined by the cell of origin can predict survival and response to chemotherapy, and were initially classified by gene expression profiling. However, fresh tissue had to be available and often only major centers had the capability. IHC methods were subject to observer error. The other issue was that serial tumour profiling during treatment may be able to detect emerging resistance but serial biopsies may not be feasible and surveillance post treatment was only available by imaging, which has not been shown to be associated with a survival benefit.Liquid biopsies have the potential for solving these issues. Biomarkers in blood or other body fluids can be identified, including from circulating tumour DNA (ctDNA), circulating tumour cells (CTC) or exosomes. Circulating tumour DNA fragments are shed from tumour cells and show mutations and methylation profiles of the tumour which could be used to identify targets or predict recurrence in tumours such as DLBCL (17).Circulating tumour cells are derived from primary tumours or their metastases and either actively or passively enter the circulation. Their DNA, RNA and proteins could be used to discover the molecular profile of the tumour and their numbers can correlate with treatment outcome (16). De Souza et al have identified technological and interpretive challenges to overcome before CTCs are used routinely in the clinic (18).Exosomes, formed when a cell membrane buds off with contents including protein, nucleic acids, sugars and lipids are taken up by other cells and represent communication between cells. They can circulate in many body fluids. The potential advantage of exomes is their abundance in the fluids and their contents that may reveal multiple biomarkers which in a disease such as DLBCL could be used to subtype and therefore predict prognosis, be used as surveillance during therapy and reveal resistance mechanisms. They could then be used to follow-up post treatment (16).A further tool to guide dosing of anti-cancer drugs and predicting toxicity and response prior to their administration is pharmacogenomics reviewed by Carr et al (19). Examples with the strongest evidence are assaying for dihydropyrimidine dehydrogenase (DPYD) which is the rate limiting enzyme for 5-FU metabolism, encoded by a gene with multiple variants. Identifying the variant alleles of thiopurine methyltransferase (TMPT) can identify a low activity genotype which metabolizes 6-mercaptopurine to an inactive mercaptopurine resulting in less metabolism of 6-MP to toxic thioguanine nucleotide metabolites. There are many other potential applications of pharmacogenomics, but with equivocal or less evidence. The more widespread use of NGS will allow easier identification of rarer mutations associated with adverse drug reactions. The lack of routine use of pharmacogenomics is multifactorial including the expense, accessibility, the time for processing and the complex interactions including between genomics, clinical factors and the microbiome which account for the individual variations (19).Personalised drug dosing is important in oncology to prevent overdosing, which otherwise may only become evident when a patient develops severe side effects, or underdosing resulting in lack of efficacy, which may not be revealed until scans show a lack of tumour response . The evidence for some drugs that drug exposure is related to efficacy and toxicity allows for therapeutic dose monitoring (TDM) such as is used for dosing antimicrobials. Some examples of attempting TDM with cytotoxics illustrate the challenges.For intravenous 5-FU while DPYD genotyping is useful, more precision is needed for bolus and infusional regimens in a variety of cancers, including head and neck and colorectal cancer. In articulating the importance of TDM dosing Schneider JJ et al. in this themed issue, reiterate that 5-FU dosing by BSA only results in 20-30% patients achieving the therapeutic range. Exploring the relationship between 5-FU area under the curve (AUC) and a target dose resulted in the recommendation of a therapeutic exposure range of 20-30mgh/L for 46-hour infusion schedules (20). Unfortunately, data is lacking to apply TDM dosing to the oral prodrug capecitabine, which is just as effective as 5-FU but better tolerated.Other common cytotoxic drugs are more problematic. Muth et al reviewed the taxanes; paclitaxel, docetaxel, nab-paclitaxel and cabazitaxel which illustrate some of the complexities of TDM dosing (21). Paclitaxel which is commonly dosed weekly or 3 weekly has non-linear pharmacokinetics, undergoes hepatic metabolism and biliary excretion and there are interactions with its solvent cremophor, however the time above a plasma concentration of 0.05 µmol/L does predict neutropenia and polyneuropathy and may be associated with a favourable clinical outcome, making TDM dosing desirable. Docetaxel, is also extensively metabolised in the liver, has linear kinetics, but is formulated with polysorbate 80 rather than cremophor. Weekly docetaxel has a more favourable toxicity profile that 3-weekly dosing but it is AUC that predicts febrile neutropenia, mucositis and diarrhoea. Less research has been done than with paclitaxel but a small randomized study of TDM and target concentration intervention (TCI) compared to BSA didn’t show a clear advantage for TDM and TCI for docetaxel (22). Unfortunately, is no prospective TDM data for carbazitaxel or nab-paclitaxel.Early in the development of carboplatin the relationship between drug exposure and efficacy and toxicity was established and dosing was more accurately based on renal function (glomerular filtration rate- GFR) than BSA. However, for specific groups such as infants, anephric patients and those receiving high-dose carboplatin, TDM dosing is more desirable that dosing based on (GFR) as summarized by Barnett S et al (23).For TDM to be translated into clinical practice, the evidence base must expand, and sampling strategies need to be simplified, perhaps by micro sampling such as using dried blood spots or using body fluids other than blood. There must be better access to TDM laboratories, and the provision of clinical decision support for interpreting the results of pharmacometrics which use Bayesian estimations to combine pharmacokinetics, individual patient characteristics and drug concentrations (24).Finally, a barrier which must be addressed to allow clinical translation of TDM is the demonstration of its economic efficacy which Vithanachchi DT et al present in a descriptive review (25). They reviewed 11 studies and noted that only a few drugs have been studied. However, all studies reviewed found TDM to be cost effective, based on established incremental cost-effectiveness ratios. In future newer therapeutics should have an economic analysis of TDM, incorporating the associated clinical evidence, which in the short term is reduced toxicity and the long term, a survival advantage.REFERENCES1. Martin JH, Bowden NA. Drug Repurposing – Overcoming the translational hurdles to clinical use. Pharmacol Res Perspect 2019, Nov 26, https://doi.org/10.1002/prp2.548.2. Fay M, Head R, Martin J. Where is the radiobiology and pharmacology research to improve outcomes on glioblastoma? J Neurooncol 2015, 124: 1-3.3. Obama B. The Precision Medicine Inititive https://obamawhitehouse.archives.gov/precision-medicine [Last Accessed 11 Dec 2020]4. Moynihan R, Beros L, Hill S et al. Pathways to independence: towards producing and using trustworthy evidence. BMJ 2019, Dec 3; 367:16576. Doi: 10.1136/bmj.e3502.5. Rowinski E, Fournel P, Bernichon E, Bouleftour W, Magné N, Mery B. Maintenance therapy in metastatic solid tumours. Innovative strategy or simply second-line treatment? Am J Clin Oncol 2019, 42: 615-623.6. von Plessen C, Bergman B, Anderson O et al. Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.Br J Cancer 2006, 95: 966-9737. Perez EA, Romond EH, Suman VJ et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011, 29: 3366-3372.8. Cameron D, Piccart-Gebhart MJ, Gelber RD et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-postive early breast cancer: final analysis of the HERceptin Adjuvant (HERA trial. Lancet 2017, 389: 1195-1205.9. Pivot X, Romieu G, Debled M et al. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicenter, open-label, phase 3 randomized trial. Lancet 2019, 393: 2591-2598.10. Joensuu H, Kellokumpu-Lehtinen PL, Bono P et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl JK Med 2006, 354: 809-820.11. Purmonen TT, Pänkäläinen E,Turunen JH, Asseburg C, Martikainen JA. Short-course adjuvant trastuzumab therapy in early stage breast cancer in Finland: cost-effectiveness and value of information analysis based on the 5-year follow-up results of the FinHer trial. Ann Oncol 2011, 50: 344-352.12. Kaestner SA, Sewell GJ. Chemotherapy dosing part I: scientific basis for current practice and use of body surface are. Clin Oncol (R Coll Radiol) 2007, 19: 23-37.13. Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med 2020 12:8 https://doi.org/10.1186/s13073-019-0703-1. [Last accessed Jun 10 2020].14. Zimmer K, Kochner F, Spizzo G, Salem M, Gastl G, Seeber A. Treatment according to molecular profiling in relapsed/refractory cancer patients: a review focusing on latest profiling studies. Comput Struct Biotechnol J 2019, 17: 447-453.15. Wang S, Chen R, Tang Y et al. Comprehensive genomic profiling of rare tumour: routes to targeted therapies. Front Oncol 2020, https://doi.org/10.3389/fonc.2020.00536 [Last accessed 10 Jun 2020]16 Ofori K, Bhagat G, Rai A. Exosomes as liquid biopsy biomarkers in diffuse large B-cell lymphoma (DLBCL) – Current. State-of-the -art and unmet needs. Br J Clin Pharmacol 2020, X: XX-XX17. Roschewski M, Dunleavy K, Pittluga S et al. Circulating DNA and CT monitoring in 124 patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol 2015, 16: 541-549.18. De Souza P, Po J, Scott K et al. Can on study changes in circulating tumour cell (CTC) counts be used as a predictive measure for therapeutic efficacy in caner clinical trials? A review of the literature. Br J Clin Pharmacol 2020, X: XX-XX.19 Carr DF, Turner RM, Pirmohamed M et al. Pharmacogenomics of anticancer drugs: personalising the choice and dose to manage drug response. Br J Clin Pharmacol 2020, XX: XX-XX.20. Schneider J, Galettis P, Martin J. Overcoming barriers to implementing precision dosing with 5-Fluorouracil and capecitabine. Br J Clin Pharmacol 2020, X:XX-XX.21 Muth M, Ojara FW, Joerger M. Role of TDM-based dose adjustments for major taxane anticancer drugs. Br J Clin Pharmacol 2020, X: XX-XX.22. Engel FK, Loos WJ, van der Bol JM et al. Therapeutic drug monitoring for the individualization of docetaxel dosing: a randomised pharmacokinetic study. Clin Cancer Res 2011, 17: 353-362.23 Barnett S, Kong J, Makin G, Veal GJ. Over a decade of experience with carboplatin therapeutic drug monitoring in a childhood cancer setting in the United Kingdom. Br J Clin Pharmacol 2020, X: XX-XX.24 Menz BD,, Stocker SL, Verougstraete N et al. Barriers and opportunities for the clinical implementation of therapeutic drug monitoring in oncology. Br J Clin Pharmacol 2020, X: XX-XX.25. Vithanachchi D, Maujean A, Downes MJ, Scuffham P. A systematic review of economic evaluations of therapeutic drug monitoring interventions for cancer treatments. Br J Clin Pharm 2020, X: XX-XX.

Dextro-transposition of the great arteries (D-TGA) is the second most common cyanotic congenital heart disease with variable coronary artery anatomy. Outcomes have improved significantly with the advent of the arterial switch procedure for this defect, with coronary artery anatomy being a very important parameter for both short and long term outcomes following surgical repair. Assessment of coronary artery anatomy is usually undertaken in the postnatal period by transthoracic echocardiography. Prenatal delineation will help with surgical planning, parental counseling and tertiary care referral as needed due to the critical importance of this variable in successful outcome. We describe our experience with prenatal coronary artery assessment in a cohort of patients with fetal diagnosis of D-TGA and highlight the importance of its assessment with both 2-dimensional (2D) and Color Doppler imaging, especially after 25 weeks gestation.

This study explores the application of metabolic engineering in Aspergillus terreus to re-route the precursor flow towards the lovastatin biosynthetic pathway by simultaneously overexpressing the gene for acetyl-CoA carboxylase (acc) to increase the precursor and eliminating (+)-geodin biosynthesis (competing metabolite), by knocking out emodin anthrone polyketide synthase (gedC). Alterations to metabolic flux in the double mutant (gedCΔ*accox) strain and the effects of using two different substrate formulations were examined. Cultivation of gedCΔ*accox strain with a mixture of glycerol and lactose, had greatly increased levels of precursors malonyl-CoA (48%) and acetyl-CoA (420%), complete inhibition of (+)-geodin biosynthesis and a maximum production of lovastatin (152 mg/L), 143% more than the wild-type (WT) strain. This study demonstrates the manipulation of A. terreus metabolic pathways to increase the efficiency of carbon flux towards lovastatin, elevating its production. It provides a framework for new opportunities to synthesize valuable compounds using cheap and renewable carbon sources.

Streptococcus pneumoniae is one of the most frequently isolated pathogens that colonize the upper and lower respiratory tract. This colonization can be responsible for diverse diseases, including otitis media, pneumonia, among others. Despite the use of pneumococcal conjugate vaccines, the number of isolated S. pneumoniae continues to be alarming. In this work, we identified and characterized a novel endolysin (MSlys) encoded in the pneumococcal phage MS1. We further performed antimicrobial assays with MSlys against planktonic and biofilm cells, evaluating their viability before and after treatment. Additionally, the activity of MSlys on cells was also analyzed using scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). MSlys is a modular endolysin carrying a catalytic domain with amidase activity and a choline-binding domain, folding mostly in β-sheets. MSlys is active against clinical S. pneumoniae collected from children with otitis media and in conditions close to those found in the middle ear. Treatment for 2 h with MSlys (4 µM) reduced planktonic cultures by 3.5 log10 CFU/mL, and 24- and 48-h-old biofilms by 1.5 and 1.8 log10 CFU/mL, respectively. Imaging of biofilms by SEM and CLSM after MSlys treatment showed damaged and thinner biofilm structures compared to the control samples. The recombinantly expressed MSlys may be a suitable candidate for the treatment of pneumococcal infections, including middle ear infections.