Dear Dr Harky et. al,We appreciate your inquiry regarding our case report. Dr Harky et. al suggested that TEVAR for a Marfan patient could be an unnecessary approach even during the COVID-19 pandemic.We believe in this particular case, the endovascular approach was fully justified as the patient had clear signs of end organ ischemia at presentation. He presented with extreme right leg ischemia with diffuse numbness. There was no detectable distal arterial flow of the right extremity by a Doppler and physical evaluation. Contrast computed tomography scan showed a completely occluded right common iliac artery and diminished flow to the right renal and celiac arteries due to the compression of the true lumen from the false lumen. Preoperative creatinine was elevated to 1.2 mg/dl. She was also suffering ongoing right kidney malperfusion.It was during the time when COVID-19 epidemic started spreading rapidly in New York City. Our hospital beds were filled with COVID-19 patients and there was a shortage of medical supplies with no ventilators immediately available. It was important to reduce exposure of the individual to the hospital environment and minimize length of stay and ventilator needs. As such, we chose to proceed with TEVAR to minimize the risk of lung injury which can occur in open repair. Postoperative respiratory failure is a major issue in open thoracic aortic repair [1]. The patient did not have a risk of respiratory comorbidities but we believed that this pandemic placed all patients at risk for contracting COVID-19 and subsequent acute respiratory distress [2].Due to the high risk of spinal cord ischemia in this particular patient, we performed TEVAR with a distal bare metal component to preserve the blood flow into spinal cord arteries [3]. The initial clinical treatment plan was to perform the TEVAR as a bridge to open repair. We obviously will need to follow-up with her carefully and if any signs of failure of TEVAR is detected, open repair will ultimately be required.Dr Harky et. al suggested axillary femoral artery bypass to rescue the ischemic leg, however, this patient also suffered malperfsuion of the renal and celiac arteries, so further intervention was required.Thank you for your insightful suggestions.References1) Khan FM, Naik A, Hameed I, et al. Open repair of descending thoracic and thoracoabdominal aortic aneurysms: a meta-analysis. Ann Thorac Surg . 2020;S0003-4975(20)30865-1.2) Bai Y, Yao L, Wei T, et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA.  2020;323:1406–7.3) Lombardi JV, Cambria RP, Nienaber CA, et al. Five-year results from the study of Thoracic Aortic Type B Dissection Using Endoluminal Repair (STABLE I) study of endovascular treatment of complicated type B aortic dissection using a composite device design. J Vasc Surg. 2019; 70:1072-81.

Bluetongue (BT) is a non-contact infectious disease of domestic or wild ruminants caused by the Bluetongue virus (BTV). It is transmitted by Culicoides biting midges. BTV mainly infect sheep, and animals infected with BTV usually show clinical symptoms such as fever, mucosal edema, and ulcers. BTV virus is an icosahedral symmetric RNA virus with 27 different serotypes. BTV consists of 7 structural proteins (VP1-VP7) and 4 non-structural proteins (NS1, NS2, NS3/NS3a, NS4, NS5). The VP3 encoded by the L3 gene is relatively high conserved structural protein, and constitute the inner symmetric icosahedral core shell of virus particle. In this study, VP3 recombinant protein of bluetongue I virus was successfully expressed and purified by prokaryotic expression system. Moreover, to increase the amount of soluble protein, we used chaperone protein ptf16 and two fusion proteins NusA and TRX. The results show that chaperone protein can increase the solubility of VP3. Then the expression conditions were optimized and VP3 was purified by nickel affinity chromatography. The VP3 immunize Balb/c mice and the results show that the serum titer is 1:1.28×105. In the Dot-ELISA assay, we found recombinant protein VP3 react with the serum from immunized mice by inactivate BTV-1. The results of IFA showed that the antibody produced by immunized mice with recombinant protein VP3 could react with the VP3 protein expressed in 293T cell. In conclusion, we expressed the recombinant protein VP3 with the same conformation as eukaryotic expression system and had same immunogenicity with inactivated virus, which laid a foundation for further study on the structure and function of BTV.

Aims The impact of nutrient increase on nutrient resorption from senescent leaves is an important topic, which is not completely understood. Mangrove species are characterized by nutrient conservation mechanisms as a consequence of adaptation to nutrient-poor environments. The understanding of the response of the traits related to nutrient conservation strategies to nutrient availability is limited. This study aims to address whether nutrient resorption of mangrove species is responsive to long-term nutrient enrichment. Methods A field-based study was carried out in a Kandelia obovata dominated mangrove stand where a nutrient gradient was generated by the long-term discharge of aquaculture wastewater. Seasonal variations of nutrient resorption and nutrient availability were assessed. Important findings The data from summer and winter showed the same results: 1) resorption proficiency or the nutrient concentrations (N and P) in senescent leaves did not varied with nutrient increases except the plot that the N availability was extremely high; 2) the resorption efficiency of both N and P was positively correlated with nutrient availability, and N resorption efficiency was also positively correlated to leaf N: P ratio; 3) N resorption was complete while the resorption of P was incomplete. These results indicate that resorption proficiency of K. obovata is less sensitive than resorption efficiency to nutrient availability, and the positive response of N resorption efficiency is related to the imbalance of nutrient availability, while the positive response of P resorption efficiency is unrelated to plant nutrient status. We suggest that caution should be taken in using resorption efficiency of mangrove species to predict plant nutrient status.

We argue the advantages of field-based learning experiences for undergraduates, the societal imperative for training the next generation of field biologists, and the opportunity to increase the reach of field education dictate that we must meet the challenges of delivering field experiences in the context of a distanced educational environment. We report on our experiences as faculty and students in a spring 2020 Field Ornithology course adapted for remote delivery with an example of a student-centered framework for supporting independent field study. Feedback from students and instructors in this course indicate that remote field instruction is both possible and desirable. We suggest that an instruction model involving guided, independent field study can yield strong learning outcomes and promote self-directed inquiry. Based on reflections of the challenges and successes of our experiences, we provide an prompts for a for assessing the feasibility and desirability of proceeding with field-based education in a distanced environment with an emphasis on supporting student success.

Rational, Aims and Objectives: Prolonged symptoms after a mTBI, known as Post-Concussion Syndrome (PCS), remains a challenging area of rehabilitation. Evidence shows that an active approach can improve prognosis, however PCS is a multifaceted condition with many comorbidities and large variety in patient response. This study investigated the use of submaximal aerobic exercise and body awareness therapy, and the influence on symptoms in PCS cases, viewed through the lens of evidence-based practice (EBP). Method: Four cases were separated into two case studies. Cases in Study A received an aerobic exercise protocol consisting of 8 individual sessions distributed twice a week over 4 weeks, with additional cervical endurance training. Cases in Study B received a body awareness therapy protocol consisting of 6 guided practices distributed twice a week over 3 weeks. Using method triangulation, both quantitative and qualitative data were gathered through the use of the Rivermead Post-Concussion Questionnaire (RPQ) and semi-structured interviews, as well as the Craniocervical Flexion Test (CCFT) in Study A, and the Short Form-36v2 (SF-36) questionnaire in study B. Lastly, research evidence on PCS was included to contextualize cases. Results: Both cases in Study A showed marked improvements in their RPQ scores, but only one showed improvement in the CCFT. In Study B, one case improved in RPQ score and in the mental component of SF-36v2, while the other case did not experience any significant change. All cases expressed positive associations with the interventions during the interviews. Conclusion: These results illustrate how an active and individualized approach can represent important qualities that can be applied to further and larger studies. Based on the results and discussion of this paper, relevant findings and suggestions are summarized in a modified EBP model, which may be of help to practitioners in dealing with PCS patients in the clinical practice.

Rationale, aims and objectives; For asthma strategy, to avoid the aggravation of bronchial inflammation and contraction, the addition of long acting beta agonist (LABA) to inhaled corticosteroids (ICS) has been recommended. To know whether there is any clinical difference between the additional efficacies of formoterol (FOR) and tulobuterol (TUL) onto budesonide (BUD) may be useful for the elderly patients’ asthma treatment strategy. Method: Eighteen outpatients with mild to moderate bronchial asthma with FEV1.0% < 80% treated by intermediate ICS dosages visited Respiratory Division of Nagasaki University Hospital or Isahaya General Hospital, Japan Community Health care Organization were subjected. Subjects were randomly assigned (9 cases per group) to either the FBC group (BUD/FOR 160/4.5 mcg: 2 inhalations twice daily) or BUD + TUL group (BUD 200 mcg: 2 inhalations twice daily + TUL 2mg daily) and were compared in parallel with 2 arms for 12 weeks prospectively. PEF, FEV1, impulse oscillometry (IOS), fractional exhaled nitric oxide, Asthma Control Questionnaire and mini-Asthma Quality of Life Questionnaire (mini-AQLQ), and occurrence of adverse reactions were compared. Results; The “Fres” of IOS was improved (p=0.03) in FBC group. The “emotion” domain of mini-AQLQ was improved (p=0.03) in BUD+TUL group. Conclusions; By changing the drug formulation, the patch was superior in terms of satisfaction, but it was thought that the inhaled combination was superior in improving the respiratory function itself. It is necessary to pay attention to the characteristics of the patient when selecting treatment.

High volume ECMO centers have developed mobile ECMO programs in recent years to facilitate implementation of ECMO support at hospitals with lower capabilities, and transfer these patients for further care. We report a case of mobile ECMO on patient with COVID-19 related ARDS, and discuss the potential application in current SARS-CoV-2 pandemic.

Background. No specific clinical signs of influenza are defined, although type A is thought to dominate and be responsible for more severe cases of influenza diseases. Our study aimed to determine the value of clinical signs and routine laboratory results on influenza diagnose among children, reveal possible differences among different influenza subtypes. Methods. A retrospective study was conducted at Vilnius University Hospital Santaros Klinikos during two influenza seasons (2016/2017 and 2017/2018 year). Basic demographic, clinical data, vaccination for influenza status and results of laboratory testing, were collected. Results. Data of 655 influenza cases were analysed. Among them 355 (54.2%) were boys. Influenza A cases from 2016/2017 season and influenza B cases from 2017/2018 season were compared. Average age of influenza patients was 6.25±2.1 years: in influenza A group - 5.5±4.5 years, and in influenza B - 7.2±4.3 years. The main symptoms were fever 647 (98.8%), cough 387 (59.1%) and rhinitis 302 (46.1%). Diarrhoea, stomach ache, muscle pain, headache were more prominent in the influenza B group. Complications were found more common in influenza A group (82 (55.4 %)) and among children above 12 years of age (28/112 (25 %)). Overall 159 (24.3%) children were hospitalized (influenza A dominated (56.6%)). Conclusions. The incidence of influenza B is increasing in children under 12 years of age and the incidence of influenza A is decreasing with increasing age of children (p =0.00). No significant statistical difference was found in clinical signs, complications and hospitalisation rate among two influenza virus types.

Sixty-three patients with LCH (54 adults, 9 children), with unifocal or multifocal bone lesions were treated with indomethacin. All but one patient achieved a response, that was complete in 52% of them. Overall, 5-year reactivation-free survival was 72%, significantly higher in patients treated with indomethacin as first-line (81.7% vs 52.5%; p=0.01); in those who received indomethacin as single agent (80.5% vs 36.5%, p=0.005); and in those with unifocal disease (90.9% vs 48.1%, p=0.003). Our results confirmed the efficacy of indomethacin in bone LCH both as front-line treatment and after reactivations, in localized, or more extended disease, with minimal side effects.

Background and aim: High technical difficulty has stimulated further studies regarding improving myectomy approaches and reducing the difficulty of myectomy. This study aimed to evaluate the efficacy and repeatability of transaortic septal myectomy with the aid of special surgical instruments for the treatment of hypertrophic obstructive cardiomyopathy (HOCM). Methods: Between March 2016 and March 2019, 168 HOCM patients (83 males, mean 56.8 ± 12.3 years) were included who underwent isolated transaortic septal myectomy with the aid of special surgical instruments. Intraoperative, in-hospital and follow-up results were analyzed. The incidence of major adverse events per surgeon was compared. Results: Nine (5.4%) patients received immediate repeat surgery. Surgical mortality was 0.6%. Five (3.0%) patients developed complete atrioventricular block and required permanent pacemaker implantation. The median follow-up time was 6 months. No follow-up deaths occurred with a significant improvement in New York Heart Association functional status. The maximum gradients decreased sharply from the preoperative value (11.5 ± 7.4 mmHg vs. 94.4 ± 22.6 mmHg, p<0.001). The median degree of mitral regurgitation fell to 1.0 (vs. 3.0 preoperatively, p<0.001) with a significant reduction in the proportion of moderate or more regurgitation (1.2% vs. 57.7%, p<0.001). In addition, no significant difference was found among six surgeons with varied operation volume regarding the incidence of major adverse events (p=0.739). Conclusions: The transaortic septal myectomy with the aid of special surgical instruments achieved favorable and reproducible results, and thus may be a promising treatment option for HOCM.

Background: Stress echocardiography (SE) is an established technique for assessment of coronary artery disease (CAD) which is difficult to perform and interpret. Left ventricular stroke volume (SV) is readily estimated with Doppler echocardiography. It can be affected by myocardial ischemia, with possible adjunctive value during SE. Methods: Patients underwent Bruce protocol SE with SV estimated before and after maximal treadmill exertion post routine regional wall analysis. Incremental change in SV (ΔSV) with exercise was measured. Results: A derivation cohort (n=273) was established to test the hypothesis. An optimal cut-off for detection on inducible ischemia was ΔSV ≤ +10ml. The validation cohort of consecutive patients (n = 1093, 376 [34%] female; age 59±12 years) were followed clinically after SE for 20,460 patient-months. There were 1000 patients with non-ischemic SE, and 93 patients with studies suggestive of myocardial ischemia. Secondary analysis yielded 831 patients with a normal exercise response (ΔSV > +10ml) and 192 with an abnormal ΔSV ≤ +10ml. Time to first combined adverse cardiac event (composite of angina, acute coronary syndrome, cardiac revascularization, worsening New York Heart Association (NYHA) class, a reduction in EF, and cardiovascular death) was analysed and adjusted using Cox proportional hazards regression. The hazard ratio for an adverse event with an abnormal ΔSV response (≤10ml) was 10.3 (95% confidence intervals 5.6-19.1, p<0.0001). Conclusions: SV assessment during SE is feasible and readily performed. It is simple, practical and has incremental diagnostic and prognostic value when added to exercise regional wall motion analysis.

The survival of waterbirds depends heavily on habitat, particularly aquatic plants. Previous studies usually focused on the use of hydrological management to achieve protection and restoration of aquatic plants. However, the hydrological processes in many lakes have been greatly changed and their ecological objectives usually cannot be achieved by hydrological management alone. This study proposes a new method to satisfy waterbird habitat requirements, by combining the management of hydrological processes and plant structure. In this study, the Hongze Lake National Wetland Nature Reserve was taken as the research area. Based on the water levels that different hydrophytes require for survival, and on waterbirds' needs for foraging and nesting area, we determined plantable area and plant structures under the current hydrological process. We then set three representative hydrological process scenarios and determined appropriate plantable area and plant structures under these hydrological processes. The results show that the current hydrological process of Hongze Lake is not conducive to the planting of the hydrophytes needed by waterbirds. A combination of hydrophyte planting and hydrological process management, however, can effectively expand the area of these aquatic plants. Within the constraints of flood control, the water level in March should be reduced, and the water level in July should be increased as much as possible. Therefore, a management method is provided for aquatic plant restoration and waterbird habitat protection in wetlands.

­Letter to the Editor, BJOG Exchange

It is not unbeknownst to us that since the very onset of the COVID-19 outbreak, many patients from different age groups have suffered greatly, and in a remarkable number of cases, succumbed to their untimely demise as a result of infection with the novel coronavirus or SARS-CoV-2. The elderly are perhaps the most vulnerable group of people, who stand at the pinnacle of morbidity and mortality rates due to contracting severe forms of COVID-19. Hopefully, based on the recent findings and the present evidence, there might be a number of medications that would possibly be of great prophylactic and therapeutic value to the elderly patients diagnosed with COVID-19. According to an interventional study, Thymosin α1 is arguably one such medication that has recently been indicated to be an effective therapeutic agent for inpatient correction of lymphocytopenia and T cell exhaustion caused by COVID-19.

Dear editor,Given time, drug discovery programmes will undoubtedly yield highly potent drugs to form the basis of optimised COVID-19 regimens. However, if efficacious therapies can be identified from current medicines, repurposing represents the fastest route to establish deployable interventions and buy time for vaccine and novel drug development. It is important to note that effective medicines were rigorously optimised for the treatment of specific indications. Route of administration, dosage and schedules for existing therapies were optimised to provide adequate plasma/tissue pharmacokinetics and safety for their target disease or condition. These cannot be assumed to be optimal for COVID-19 but are often highly predictable from pre-existing data and clinical experience. For example, hydroxychloroquine and lopinavir/ritonavir recently failed to deliver benefits in RCTs for mild/moderate and severe disease,1, 2 but the clear disconnect between reportedin vitro antiviral activity and known human pharmacokinetics after administration of approved doses was predictable.3Interpretation of laboratory-based antiviral activity assessments is complicated by current uncertainty regarding the appropriateness of the existing model systems. The majority of in vitro antiviral screening assays have utilised Vero cells, which were derived from the kidney of African Green Monkey in the 1970s, and the lack of clinical evidence for which to validate the exposure-response relationship in humans is problematic. Evidence is emerging that the anti-SARS-CoV-2 activity of drugs may be higher in cells derived from humans. However, the question of which cell types are most representative of in vivo performance is yet to be addressed, and all that can really be concluded from current knowledge is that the susceptibility of SARS-CoV-2 to antivirals is cell-type-dependent. The consequences of this in terms of the variety of cell types known to be infected and/or sustain productive infection in vivo is equally uncertain, and further exacerbated by the lack of robustly validated animal models. However, repurposed drugs cannot be assumed to be active against SARS-CoV-2 at a dose that was optimised on the basis of potency for and accumulation at their initial therapeutic target.Nucleoside/nucleotide polymerase inhibitors have proven highly successful for other viruses, but usually require combination with another drug class. Remdesivir and favipiravir have in vitro anti-SARS-CoV-2 activity across multiple studies, and the unprecedented speed at which they have transitioned through COVID-19 RCTs can only be commended.4, 5, 6 Daily IV infusion may make inherent sense for severely ill patients, but a transformational impact for COVID-19 can only be realised if wide compatibility with global healthcare systems and equitable access across all country contexts is achieved. While reduction in symptom duration may mitigate healthcare saturation in high-income countries, the absence of a clear benefit for mortality diminishes game-changing potential. However, the clinical validation of the antiviral activity of such drugs will make them clear candidates for implementation as part of community-based interventions if other challenges are addressed. Importantly, the combination of nucleoside analogues with a secondary target such as the protease has stood the test of time in antiviral pharmacology. The recent reports of low-dose dexamethasone leading to an impact on mortality7 is a significant step forward but long-term mitigation of viral transmission, with subsequent economic and social restrictions, requires antiviral treatment or prevention to minimise hospitalisation through a community-targeted approach.Focussing on existing single drugs, and not appropriately formulated medicines, will require the rethinking of a number of medicine development parameters such as posology, reformulation and therapeutic index (Figure 1); current HIV medicines, for example, are formulated for chronic (life-long) dosing to moderate and control disease but a successful COVID-19 therapy will likely require only a short term acute administration to rapidly cure the patient. Conversely, different considerations are required for longer-term applications in COVID-19 chemoprophylaxis, which could have a dramatic effect on control of the pandemic.Many advanced drug delivery technologies have emerged in recent years. Long-acting drug delivery involving injectable, implantable or microarray patch mediated delivery have attracted enormous recent interest for prevention of other infectious diseases,8, 9 and the ability to deliver potent antiviral combinations for a period of months could play a transformational role in the absence of a safe and efficacious vaccine. The physicochemistry and activity of the polymerase inhibitors, and other drugs with known anti SARS-Cov-2 activity, also warrants investigation of pulmonary delivery via nebuliser or metered dose inhaler for direct dosing to the upper airways to supplement systemic drug delivery as pre- or post-exposure prophylaxis. Several advanced drug delivery strategies can be applied rapidly and do not need to be prohibitively expensive for global community programmes. It seems unlikely that a global pandemic can be ended if effective medicines are only available to the few and equitable access is therefore of benefit to all. Importantly, relying solely upon pre-existing formulations and posologies optimised for other diseases carries inherent risk of rejecting drug candidates with an otherwise high potential for global impact.

Aim This study aimed to examine trends in prescribing of anti-dementia drugs in primary care in England between 2009-2019 and to investigate the impact of deprivation, regional demography and disease prevalence on prescribing practices. Methods Analysis of publicly available government data from various sources pertaining to primary care prescribing and demographics was conducted. All primary care prescription data pertaining to anti-dementia drugs and antipsychotic drugs in England between 2009-2019 were extracted and adjusted for inflation and populations changes. Data across English Clinical Commissioning regions and groups were compared to explore the association between prescribing trend, deprivation, regional demography and dementia prevalence. Anti-psychotic drugs prescribing trends were used as reference comparators. Results The number of prescription items for anti-dementia drugs in England increased by approximately three-folds from 24 items/1,000 populations in 2009 to 70.9 items/1,000 populations in 2019; prescribing of antipsychotics increased by 37.6%. In 2019, the least deprived areas had approximately twice the rate of prescribing of anti-dementia drugs compared to the most deprived areas [median (IQR) values of 46.7 (36.6-64.8) vs 91.23 (76.2-95.1) items/1,000 populations respectively]. A weak positive correlation (Pearson’s correlation-coefficient 0.371, p=0.413) was observed between dementia prevalence and prescribing rates. Conclusions The three-fold rise in the number of prescription items for anti-dementia drugs in the study period reflects the policy emphasis on early diagnosis and treatment of dementia. Higher rates of prescribing in the least deprived areas may be reflective of higher life expectancy, better diagnoses and access to treatments. Such differences need to be investigated further.

A document by Désirée Larenas-Linnemann. Click on the document to view its contents.

BACKGROUND Although evidence suggests a weak association of single environmental risk factors with asthma and allergy risk in children, the influence of a combination of multiple environmental pollutants and household air pollution in the relationship of asthma and allergy remains unclear. We aimed to assessed the association of environmental composite quality index scores with asthma and allergy. METHOD Environmental composite quality indices were collected using the questionnaire that contains asthma and allergy, Chinese residential living habits, and outdoor environment items. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using the binary logistic regression model after adjusting the most known asthma or allergy risk factors. RESULTS In this cross-sectional study, a total of 1636 girls and 1446 boys were included in the final analyses. Higher environmental quality index score was correlated with higher risk of asthma, eczema, and rhinitis. Comparing the top (≥5) to bottom group (0-2), the multivariable ORs were 2.47 (95% CI, 1.41-4.33, P trend = 0.004) for asthma, 1.51 for eczema (95% CI, 1.18-1.93; P trend = 0.002) and 1.83 for rhinitis (95% CI, 1.12-3.00; P trend = 0.017). Similar findings were observed in the stratified analyses. CONCLUSION The study showed that there is a harmful association between environmental quality and asthma with allergic diseases in children living in northeast China, and further research was needed to confirm the findings in other areas and clarify the specific mechanism.

Safety of omalizumab administration in chronic spontaneous urticaria during COVID-19 infection: a case report.Marisa Paulino1, Célia Costa1, Elisa Pedro11Immunoallergology department, Hospital de Santa Maria – Centro Hospitalar Universitário Lisboa Norte, PortugalDr. Marisa Paulino has nothing to disclose.Dr. Célia Costa has nothing to disclose.Dr. Elisa Pedro has nothing to disclose.Keywords : Omalizumab, COVID-19, urticariaTo the Editor:COVID-19 pandemic affected millions of people worldwide since was first reported in December 20191. As the pandemic expanded around the world medical practice suffered substantial changes. Healthcare systems worldwide had to adapt to provide the best and safest care for patients as well as ensure the safety of medical personnel. Patients with severe allergic disease provide the major challenge for allergists2. Biologicals are widely used in the management of severe allergic diseases and have long become part of our daily practice, however, SARS-CoV-2 infection risks in these patients lacks evidence2. Recent reports regarding Dupilumab (anti-IL3 and IL-4) administration in infected patients with chronic rhinosinusitis with nasal polyps3 and severe atopic dermatitis4,5 showed no increase in risk of severe COVID-19.Omalizumab is a monoclonal antibody targeting IgE approved for the treatment of severe asthma, chronic spontaneous urticaria (CSU)6. We report a case of a 45-year-old female with CSU treated with omalizumab that contracted COVID-19.Urticaria symptoms began at 42 years-old, 1 year prior to the first appointment, initially with only symptomatic dermographism: wheeling and itching 5-10 minutes after scratching the skin or in areas of friction from clothes. After six months she had an episode of generalized maculopapular, itching lesions with individual duration of less than 24hours that worsened after sun exposure developing areas of angioedema. She recurred to her general practitioner that prescribed bilastine 20mg/day, topical corticosteroid and referred her to our urticaria Unit.At first appointment she was medicated with bilastine 20mg/day maintaining daily wheals with a weekly urticaria activity score (UAS7) between 24-25 for the following 12 weeks. H1-Antihistamine dosage was increased until a maximum dosage of 4/day was achieved. Skin prick tests for aeroallergens and food allergens were negative. Autologous serum skin test (ASST) was negative. Blood workup was clear. She had a positive respiratory test for Helicobacter pylori that required two eradication treatments to achieve a negative result but without influence on the urticaria activity.The patient quality of life deteriorated further as the disease progressed with an increased absenteeism from work (health care assistant), strained personal and social relationships and reduced self-esteem.After failure of the second line of treatment (H1-Antihistamine 4/day), omalizumab was proposed. She started treatment in November 2019 with 300mg subcutaneously every 4 weeks at our day care unit. At first administration she was medicated with bilastine 20mg 4/day. The UAS7 was 21, urticaria control test (UCT) was 7 and Dermatology Life Quality Index (DLQI) was 7. At the fourth administration she had her CSU controlled: UAS7 0, UCT 16 and DLQI 0, and reduced the dose of bilastine 20mg to 2/day.Due to the COVID-19 pandemic, the patient chose not to take omalizumab in March 2020, imposing an 8-week interval between administrations. At that time she reported only a slight increase in pruritus (UAS7 7). Omalizumab was resumed on April 28th. Triage was performed before administration excluding COVID-19 symptoms, fever or contact with infected individuals.Her husband started exhibiting COVID-19 symptoms on May 3rd (fever, cough, dyspnea, diarrhea) and 1 day later she noticed anosmia and arthralgia, both were positive to SARS-CoV-2 (RT-PCR of nasopharyngeal exudate) on May 5th. CSU was controlled and she reported only a slight increase in pruritus with the need for increasing H1-Antihistamine dosage from 2 to 4/day. She maintained mild symptoms and tested negative after 3.5 weeks. Only anosmia persisted but with a slight improvement. As she was quarantined at the time, she was unable to attend treatment in May but maintained the scheduled treatments in June 23rd as CSU was controlled.No worsening of CSU symptoms or increase in COVID-19 severity was observed in this case despite the administration of omalizumab in the week prior to SARS-CoV-2 infection.Viral infections are known as triggers or eliciting factors for chronic urticaria6, SARS-CoV-2 infection as also been reported to manifest with acute urticaria7. The effects of COVID-19 in CSU control are unknown, in the reported case, no worsening of symptoms was observed.According to the EAACI consensus on biologicals, patients with severe allergic disease should maintain treatment with biologicals if there is a safe environment, and at-home administration should be encouraged. Regardless of disease severity, patients with COVID-19 should interrupt treatment until recovery is established2.More evidence is needed to assert the safety of biologicals during COVID infection and effect of the disease in severe allergic patients.1. Zhang J jin, Dong X, Cao Y yuan, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy Eur J Allergy Clin Immunol . Published online 2020. doi:10.1111/all.142382. Vultaggio A, Agache I, Akdis CA, et al. Considerations on Biologicals for Patients with allergic disease in times of the COVID‐19 pandemic: an EAACI Statement. Allergy Eur J Allergy Clin Immunol . Published online 2020. doi:10.1111/all.144073. Förster-Ruhrmann U, Szczepek AJ, Claus Bachert habil, Heidi Olze habil. COVID-19 infection in a patient with severe chronic rhinosinusitis with nasal polyps during therapy with dupilumab. J Allergy Clin Immunol . Published online 2020. doi:10.1016/j.jaci.2020.05.0054. Carugno A, Raponi F, Locatelli AG, et al. No evidence of increased risk for COVID-19 infection in patients treated with Dupilumab for atopic dermatitis in a high-epidemic area - Bergamo, Lombardy, Italy.J Eur Acad Dermatol Venereol . Published online 2020. doi:10.1111/jdv.165525. Ferrucci S, Romagnuolo M, Angileri L, Berti E, Tavecchio S. Safety of dupilumab in severe atopic dermatitis and infection of Covid-19: two case reports. J Eur Acad Dermatol Venereol . Published online 2020. doi:10.1111/jdv.165276. Zuberbier T, Aberer W, Asero R, et al. 7. The EAACI/GA2LEN/EDF/WAO guideline for the definition,classification, diagnosis and management of urticaria.Allergy Eur J Allergy Clin Immunol . 2018;73(7):1393-1414.7. Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol . Published online 2020. doi:10.1111/bjd.19163

Decrease in asthma exacerbation prevalence during the Covid-19 lockdown in a moderate-severe asthma cohortTo the editor,Following the recent Covid-19 lockdown, in Canada a reduction in emergency healthcare visits was reported (1). Infectious diseases were less often diagnosed, probably due to social distancing and increased hygiene measures. However, also fear of acquiring Covid-19 infection at medical facilities might have led to a decrease in visits (1, 2).Recent studies indicated that controlled asthma is not a risk factor for severe disease in the current Covid-19 pandemic (2-5). Entry of the SARS-CoV2 virus is mediated by the receptor for angiotensin-converting enzyme-2 (ACE2). The expression of ACE2 seems to be modulated by type 2 inflammation, which is present in the majority of asthma patients and might thus confer protection against severe Covid-19 symptoms (3, 4, 6).Social distancing is known to reduce the spread of seasonal influenza and viral respiratory tract infections (RTI) (2, 7). We hypothesize that this reduction in viral transmission during the Covid-19 lockdown is responsible for a decrease in asthma exacerbations (AE), which are often elicited by viral RTI. Therefore, we analyzed in a cohort of patients with moderate-severe asthma and recurrent AE the effect of the Covid-19 lockdown on the frequency of severe AE requiring oral corticosteroids and health care avoidance.This study comprises a follow-up from the recently completed Breathe study (NL5752) that included adult asthma patients on step GINA 3-4 treatment with recurrent exacerbations. Control individuals without asthma from the cross-sectional Grandma study (NCT03278561) were included as a reference population (see: online supplementary material).Participants were invited to fill out a short survey by e-mail or post (see: online supplementary material), including an asthma control questionnaire (ACQ), an asthma quality of life questionnaire (AQLQ) and a hospital anxiety and depression scale (HADS), as well as questions on exacerbation frequency and care avoidance between April 12th and June 1st 2020. Two reminders were sent out. Exacerbation frequencies until July 1st were verified with the hospitals’ and general practitioner’s medical records and pharmacy. Covid-19 restrictions in The Netherlands started mid-March and were partly lifted since early June 2020 in a stepwise fashion.Clinical parameters from the original study visits were used for baseline characteristics. Primary outcome was the difference in number of AE between the second quarters (Q2) of 2020 and the three years prior to the Covid-19 pandemic. Only severe AE needing oral corticosteroids and/or antibiotics were included. Secondary outcomes were ACQ, AQLQ, HADS, health care avoidance and fear of COVID-19. ACQ and AQLQ were compared with April 2019.Differences between asthma and controls were evaluated with the chi-square-test, Student’s-t-test or the Mann-Whitney-U-test depending on the variable and its distribution. Differences between time points were compared with a Friedman test, Bonferroni correction was applied for the Wilcoxon-signed-rank-test where a p-value was set at 0.0083. Data is shown in median [25th–75th] or mean values ± standard deviation. A p-value <0.05 was deemed significant. Statistical analyses were conducted with SPSS 26.0.Out of 94 invited participants (67 asthma; 27 controls), 67 participants (~71%) were included. No significant differences were observed in age, BMI, comorbidities and other demographics such as prevalence of proven Covid-19 (Table 1).In quarter 2 (Q2) of 2020 mean exacerbation frequency per patient was significantly lower (χ2 (3) = 9.91, p=0.019), compared to Q2 of 2017 (Z =-2.67, p=0.008), 2018 (Z =-2.50, p=0.012) and 2019 (Z =-3.26, p=0.001). No difference in mean exacerbation frequency was seen between Q1 of 2017, 2018, 2019 and 2020. Mean exacerbation frequency per patient per quarter did not differ between the years 2017, 2018 and 2019 (Figure 1). AE in 2020 were not related to positive SARS-CoV2 polymerase chain reaction or hospitalizations. Asthma control and AQLQ in Q2 of 2020 was comparable with April 2019.Asthma patients were more likely to avoid (38.8%; controls, 0.0%, p<0.01) or delay (24.5%; controls, 0.0%, p=0.02) essential medical visits due to fear of SARS-CoV2 infection at those facilities. In case of AE, e-consults were used by most patients (83.3%).Fear was objectified by a clinically relevant higher HADS score reflecting a possible anxiety or depression disorder in asthma patients compared to controls (8.00 (5.00-12.50) vs. 4.00 (1.00-7.00), p<0.01).In this study, we identified a decrease in AE during the Covid-19 lockdown measures in patients with moderate-severe asthma. We expect social distancing to be responsible for this decrease. Asthma patients experienced more fear of SARS-CoV2 infection compared with controls. Nevertheless, fear of acquiring a SARS-CoV2 infection at medical facilities did not lead to missed AE or seriously delayed care for an AE because of e-consulting possibilities.Recent studies indicate that asthma is not a risk factor for severe disease in the current Covid-19 pandemic and that type 2 inflammation might be protective (2-6). Thus, an increased fear of Covid-19 experienced by asthma patients seems irrational. Following the warnings from the Dutch National Institute for Public Health and reports in the media, however, it is conceivable that asthma patients considered themselves at risk (3).Although the sample size in our study was low, it is of note that frequencies of AE during the Covid-19 pandemic could be compared with baseline data acquired by quarterly monitoring of AE over the past three years.While asthma patients would rather delay or avoid visits to medical care facilities, they did reach out for medical assistance if needed via e-consult, thereby preventing delay of essential medical care.In conclusion, we found a significantly reduced AE frequency during Covid-19 social distancing measures compared to previous years. However, asthma patients also showed more general anxiety and anxiety towards acquiring Covid-19 infection. Because the risk for acquiring Covid-19 infection will be present for a yet unknown period, it is important to accurately inform asthma patients about the real risks. This would contribute to a reduction of unnecessary anxiety and may encourage them to contact their practitioner by e-consults.

Purpose: We aimed to evaluate whether early TRAP exposure is associated with the development of AR during preschool years, stratified by sex, parental allergy, or stressful family events. Methods: A nested case-control study including 398 was conducted in Shenyang. TRAP exposure in early childhood was estimated by nitrogen oxides (NOx) air dispersion modeling. We used multinomial logistic regression models to assess the association between early TRAP exposure and preschool children AR, stratified by potential confounders including sex, parental allergy, or stressful family events. Results: Life-time prevalence of AR in children aged 4 years (6.4%) was associated with TRAP exposure during early children, with an increased odds ratio (OR) [adjusted OR=2.18; 95% confidence interval (CI),1.35 to 3.52] for an interquartile range (38 μg/m3) increase in NOx levels. A relative risk for AR of of 1.88 (95% CI, 1.26 to 2.81) with boys, of 1.91 (95% CI, 1.28 to 2.85) among with eczema during the first year, of 2.94 (95% CI, 1.77 to 4.87) with parents allergy, of 4.14 (95% CI, 2.65 to 6.49) with stressful family events, was also observed. TRAP exposure was significantly associated with AR in preschool children who are boys (adjusted OR=2.13; 95% CI, 1.31 to 3.45), with parental having allergy (adjusted OR=2.06, 95% CI, 1.27 to 3.36), and a history of stressful family events (adjusted OR=1.94, 95% CI, 1.18 to 3.20). Conclusions: Early childhood TRAP exposure, boys, parental allergy, stressful family events may contribute to AR in children at 4 years of age.

Background and Purpose Phytosterols and phytostanols are natural products present in vegetable oils, nuts, and seeds, or added to consumer food products and intake is inversely associated with incidence and prognosis of several cancers. Randomised cancer prevention trials in humans are unfeasible due to time and cost yet the cellular processes and signalling cascades that underpin anti-cancer effects of these phytochemicals have been explored extensively in vitro and in preclinical in vivo models. Experimental Approach Here we have performed an original systematic review, meta-analysis, and qualitative interpretation of literature published up to June 2020. MEDLINE, Scopus, and hand-searching identified 408 unique records that were screen leading to 32 original articles that had investigated the effects of phytosterols or phytostanols on cancer biology in preclinical models. Data was extracted from 22 publications for meta-analysis. Key Results Phytosterols were most commonly studied and found to reduce primary and metastatic tumour burden in all cancer sites evaluated. Expression of pAKT, and markers of metastasis, angiogenesis, and proliferation were consistently reduced in breast and colorectal cancer. Very high dose treatment (not easily achievable through diet or supplementation in humans) was associated with adverse events including poor gut health and intestinal adenoma development. Conclusion and Implications Phytosterols and phytostanols are already clinically recommended for cardio-vascular disease risk reduction, and represent promising anti-cancer agents that could be delivered in clinic and to the general population at low cost, with a well understood safety profile, and now with a robust understanding of mechanism-of-action.

BACKGROUND AND PURPOSE Anaplastic thyroid carcinoma (ATC) is the least common but most lethal of thyroid cancers despite various therapeutic options with limited efficacy. Some prognostic factors were identified in patients with ATC and a few patients survive for a relatively long time after modern intensive treatment. In order to help therapeutic decision-making, the purpose of this study was to develop a new prognostic score providing survival estimates in patients with ATC. METHODS Based on a multivariate analysis of 149 retrospectively analyzed patients diagnosed with ATC from 1968 to 2017 at a referral center, a propensity score was developed. A model was generated providing survival probability at 6 months and median overall survival estimates. RESULTS The median survival was 96 days. The overall survival rate was 35% at 6 months, 20% at 1 year and 13% at 2 years. Most of the patients (86%) died within 17 month, 17% died within the first month, 35% lived for 1–6 months and 47 % of the patients lived longer than 6 months after the initial consultation. The stepwise Cox regression revealed that the most appropriate death prediction model included metastatic spread, tumor size and age class as explanatory variables. This model made it possible to define three categories of patients with survival profiles which seems different: patients with no pejorative prognostic factor which had a survival probability at 6 months = 0,84 (95% CI: 0,69-1), patients with one or two pejoratives prognostics factors which have a survival probability at 6 months = 0,32 (95% CI: 0,22-0,46), and those with three pejoratives prognostics factors which had a survival probability at 6 months = 0,11 (95% CI: 0,018 - 0,71). CONCLUSION Distant metastasis, age and primary tumor size are strong independent factors that affect prognosis in patients with ATC. Using these significant pretreatment factors, we developed a score to predict survival in these poor prognosis patients in order to provide easy-to-use tools for clinical practice. External validation in an additional dataset is needed for further outlooks.

Background: Nasal bone fracture is the most common facial fracture (approximately 40 % of all the facial fractures) and is mostly treated with closed reduction. It is performed either with general or local anesthesia. Local anesthesia is fast and cheap but pain can’t be fully suppressed. We designed this study to see if pre-emptive analgesia with Acetaminophen can reduce the pain associated with nasal reduction under local anesthesia. Methodology/Principal: in this triple-blind randomized clinical trial we had 100 participants divided into two arms (either placebo or Acetaminophen 500 mg Tablet 45 minutes before reduction). Medication was randomly delivered via packages and the surgeon, patients, and data analyzer were all unaware of the nature of the medication. Then demographic data along with VAS pain scores (1-10 score from least to most severe pain) during local anesthesia, during reduction, and 24 hours after reduction were analyzed. Results: The patients were mostly men (74%) and the most common mechanism was involvement in fight. (30%). Left depression was the most seen type of fracture (53%). Pain scores as well as surgeon satisfaction analysis returned no statistical difference between the two groups. Correlation analysis was done and the only factor for pain severity during reduction was the number of tries needed. Conclusions: Acetaminophen pre-treatment can’t add analgesia any more than that of Placebo. Its use before reduction of nasal bone is not justified