While there is a very large focus on the abnormalities of parenchymal lung development and extensive efforts to minimize alveolar damage with “gentle ventilation” and non-invasive respiratory support for neonates with bronchopulmonary dysplasia (BPD), there is relatively little consideration for the implications of central airway disease in this patient population. There are significant changes in the structure and conformation of the central airway during the last half of gestation, and premature birth disrupts this natural developmental process. Arrest of maturation results in a smaller airway that is more compliant, easier to deform, and more susceptible to damage. Consequently, neonates with BPD are prone to developing central airway pathology, particularly for patient that require intubation and positive pressure ventilation. Central airway disease can be divided in dynamic and fixed airway obstruction and results in increased respiratory morbidity in neonates with chronic lung disease of prematurity.

Today, immunotherapy is one of the effective treatments along with chemotherapy. This is especially true in cancers, which cause the immune system’s failure. As a valuable tool, a mathematical model is developed in the form of ordinary differential equations (ODEs) to show the immune-tumor cells interaction. The macrophages polarization and cytokine dynamics are also regarded using standard pharmacokinetics-pharmacodynamics assumptions for better presenting the tumor-immune cells interaction. Its lack in researches of chemo-immunotherapy of cancer is what motivated us to come with an ODE model. The positivity of solutions, the equilibrium points, and their stabilities are studied. Moreover, the sensitivity of the final tumor population and response time to initial conditions and parameters’ values are investigated. Initial conditions of the adaptive immune system and the parameters related to tumor cells proliferation, tumor carrying capacity, and exponent of fractional tumor cell kill by CD8+T cells have more effect on the final tumor population and the response time of tumor growth. Then, numerical simulations for pulsed chemotherapy, pulsed immunotherapy, and chemo-immunotherapy are presented and compared. Three patients with different immune responses are regarded to show the effect of immune response on treatment strategy. Numerical simulations show the effectiveness of the immunotherapy along with chemotherapy for cancer treatment. Also, it is shown that the immune system’s strength has a remarkable role in cancer cure.

Objective: To verify if the extent of structural lung damage visible on chest CT is correlated with change in ppFEV1 after start of CFTR modulating therapy in CF patients. Methods: In our retrospective observational study, we included patients aged ≥6 years starting ivacaftor or lumacaftor/ivacaftor treatment who were in routine follow up. FEV1 and BMI were recorded every 3 months. From the group of patients who had started lumacaftor/ivacaftor, patients were selected who underwent chest CT within 18 months before or after start of treatment. Patients who had started ivacaftor all underwent chest CT just before the start of treatment. These CT scans were reviewed to determine Brody score. ppFEV1 data was retrieved. To assess correlations, Spearman R and Pearson R tests were applied. Results: Thirty patients met the inclusion criteria, with Brody scores between 0.46-55.30 (median: 19.97, normalized score out of 100) and ppFEV1 before treatment of 19-113 (median: 67). Twenty-three and 7 patients had started lumacaftor/ivacaftor and ivacaftor respectively. Change in ppFEV1 after 6 months of treatment ranged from -19 to +24 (median: +5). For patients using lumacaftor/ivacaftor, the correlation between Brody score and change in ppFEV1 was not significant: Spearman R=-0.213, (p=0.164), but for patients using ivacaftor, there was a significant correlation between Brody score and ppFEV1 change, with a Spearman R=0.679 (p=0.029). Conclusion: The extent of structural damage to the lungs of CF patients is correlated with the response in ppFEV1 to ivacaftor, however this correlation was not demonstrable in patients treated with lumacaftor/ivacaftor.

In this paper, we consider the estimates of Dirichlet eigenvalues for Grushin type degenerate elliptic operator in weighted divergence form with a potential $-{\rm div}_{G}(A\nabla_{G})+\langle A\nabla_{G}\phi,\nabla_{G}\rangle-V$. Using the method of Fourier transformation, we get precise lower bound estimates for the eigenvalues. Then, through the way of trail function, we obtain Yang-type inequalities which give upper bounds of eigenvalues.

Introduction: Prior results of rotor migration past electrodes did not exhibit frequency changes typical of classic Doppler effect (CDE) physics. Rotors exhibited fastest and slowest frequencies at either side when migrating past electrodes, not directly in front and behind as in CDE. A new spiral wave frequency effect (SFE) equation required derivation to more accurately predict WF frequency changes observed near moving spiral sources SSp. Methods and Results: Rotational and spiral math were developed. As a prerequisite to solve SFE equation, a wave source of a rotating linear ray (SR) was used to derive rotational frequency effect equation (RFE). WF strikes from SSp occurred when the spiral summation angle equaled LOS angle. SFE is analyzed by varying spiral size and distance from SSp. New RFE and SFE equations predict the diverging frequency changes (increasing and decreasing) that occur simultaneously on either side of a passing rotor. Conclusions: Frequency effects of moving SR and SSp exhibit 3 main differences compared to CDE: side-dependent frequency changes, strong-side unpaired WF strike, and reversal of activation sequence. These 3 differences are predicted by RFE and SFE equations and constitute the unique diametrical property of rotational waves and spinning bodies in motion. Moving bodies that spin, or moving sources of rotating WFs, result in observed frequency differences that are relative to side of observation. One can no longer assume that higher frequencies and lower frequencies observed, represent always an approaching and receding SR and SSp respectively, especially when observers are near to the source.

Objective Human Papillomavirus (HPV) that is an epitheliotropic virus that infects basal keratinocytes on epithelia of skin and mucosal membranes has been isolated in genital warts (GWs). The relationships between cancer caused by HPV and some vitamins such as B12 and vitamin D and iron metabolism, as well as leukocytes and their ratios have been investigated in the literature. Our aim is to evaluate these relatioships at the level of GW as well as to analyse if there is a relationship between the investigated parameters and lesion numbers. Materials and Methods Data were obtained from 98 and 94 patients for group 1 and 2, including GW patients and healthy people, respectively. The blood parameters and lesion numbers in the GW patients were reported and analysed in terms of vitamin B12 and D, ferritin and leucocytes. Results A correlation was established between lesion numbers, age and midcorpusculer volume (MCV) (p<0.05). There was no any correlation between lesion numbers and recurrent cases. According to the comparative analysis, there were a difference in terms of ferritin, neutrophil, monocyte, hemoglobine, MCV and neutrophil/monocyte ratio between groups. The cutoff values for neutrophil, monocyte and N/M ratios were 56.45, 4.91, and 7.825, respectively Conclusion While our study showed that GW development may be affected by blood ferritin levels and in this situation, MCV, neutrophil, monocyte and N / M ratios may change, a relation was found between lesion numbers and age and mean MCV values only. However, further studies are needed to clarify this issue.

Purpose:In the present study, the impact of penile nerve block(PNB) on postoperative pain and CRBD in transurethral resection of prostate(TURP) patients were evaluated. Methods:Participants of the present study were selected from patients who performed TURP under spinal anesthesia for benign prostatic hyperplasia(BPH) between January 2018-July 2020. This study was planned as a single center, randomized-controlled prospective study. The patients were divided into two groups; Group 1 was administered Control(n:40), and Group 2 ultrasonography(USG) guided PNB(n:40). The patients were included in the Groups respectively. Visual analogue scale(VAS) scores were questioned and recorded in order to evaluate the postoperative pain complaints of the patients after the operation. In addition, in order to evaluate the CRBD, VAS scores were questioned and recorded as 0-1th hour, 1st-2nd hours, 2nd – 4th hours, 4th-8th hours, 8th-12th hours, and 12th-24th hours. In addition, postoperative pain and analgesic need were recorded. Tramodol was given to patients with moderate to severe CRBD. The findings was compared between to the Groups. Results:There was no statistical difference between Group 1 and Group 2 between demographic and per-operative data. The CRBD and pain-related VAS scores was significantly higher in Group 1 between the 0-8th hours. There was no difference between VAS scores in the postoperative 8-24th hours. In total 24 hours, Group 2’s need for tramodol for CRBD and pain was significantly less than Group 1. On examining the factors affecting CRBD in the multivariate analysis, age, body mass index(BMI), prostate volume, operation time do not affect CRBD statistically, only PNB reduces CRBD (p: 0.029). While less drug-related complications were observed in Group 2, no serious complications related to PNB were observed. Conclusion:PNB is the effective method for the decrease pain and CRBD after urological surgery.It will also reduce the need for analgesics, and provide the painless patients in postoperative period.

Background: Following the remarkable spread of coronavirus disease 2019 (COVID-19), worldwide, it quickly became apparent that many public health systems worldwide were not prepared to manage such a pandemic. We aimed to assess the perceptions of primary care physicians (PCPs) in Jordan toward their role during COVID-19. Methods: A cross-sectional study using a self-administered questionnaire was performed. The study participants included PCPs from the Ministry of Health, academic institutions, and the private sector in Jordan. Results: A total of 221 PCPs participated in the study. Most participants reported not having received any training on infection control (59.7%) or COVID-19 (81%). More than half PCPs (53.4%) felt positive about the way patients received and/or complied with their instructions. More than half PCPs (55.7%) educated their patients on protective measures against COVID-19 infection and considered this as part of their role and responsibility. Over 80% of the participants would apply social distancing, hand sanitation, facial masks, and patient education, but only half (51.1%) reported planning to order COVID-19 test kits. Conclusions: PCPs had a positive attitude toward controlling COVID-19 infection and showed a willingness to educate patients on how to protect themselves. However, PCPs should be provided special training on COVID-19.

SARS-CoV-2 is neutralized by proteins that block receptor-binding sites on spikes that project from the viral envelope. In particular, substantial research investment has advanced monoclonal antibody therapies to the clinic where there are signs of partial efficacy in reducing viral burden and hospitalization. An alternative is to use the host entry receptor, ACE2, as a soluble decoy that broadly blocks SARS-associated coronaviruses with limited potential for viral escape. Here, we summarize efforts to engineer higher affinity variants of soluble ACE2 that rival the potency of affinity-matured antibodies. Strategies have also been used to increase the valency of ACE2 decoys for avid spike interactions and to improve pharmacokinetics via IgG fusions. Finally, the intrinsic catalytic activity of ACE2 for the turnover of the vasoconstrictor angiotensin II may directly address COVID-19 symptoms and protect against lung and cardiovascular injury, conferring dual mechanisms of action unachievable by monoclonal antibodies. Soluble ACE2 derivatives therefore have the potential to be next generation therapeutics for addressing the immediate needs of the current pandemic and possible future outbreaks.

Manifest AP on the electrocardiogram (ECG) predispose patients to atrioventricular reentry tachycardia, atrial fibrillation (AF), malignant arrythmias and sudden cardiac death. [1,2] The authors report a case of a male patient admitted to the emergency room (ER) with a wide QRS complex tachycardia with no response to antiarrhythmic therapy with adenosine. The arrhythmia terminated with amiodarone perfusion and basal ECG showed ventricular pre-excitation. An electrophysiologic study (EPS) was performed diagnosing two different accessory pathways (AP) which were successfully ablated. However, 6 months later the ECG showed recurrence of the ventricular preexcitation. A new EPS was proposed with successful ablation of a third AP.

Danielle Smithabc, Marcus Hawardbc, Jeffrey McGeeabc, Graham Woodd, Geoff Symee, Rowan Trebilcobce, Larelle Bossibcd, Piers Dunstance, Joanna Vincecfa Faculty of Law, College of Arts, Law and Education, University of Tasmania, Private Bag 89, Hobart 7001, Tasmania, Australia.b Institute for Marine and Antarctic Studies, University of Tasmania, Private Bag 129, Hobart 7001, Tasmania, Australia.c Centre for Marine Socioecology, University of Tasmania, Private Bag 129, Hobart 7001, Tasmania, Australia.d School of Humanities, College of Arts, Law and Education, University of Tasmania, Private Bag 41, Hobart, 7001, Tasmania, Australia.e CSIRO Oceans and Atmosphere, Castray Esplanade, Battery Point, Hobart 7004, Tasmania, Australia.f School of Social Sciences, College of Arts, Law and Education, University of Tasmania, Locked Bag 1340, Launceston, 7250, Tasmania, Australia.Keywords: Fairness, Equity, Marine Protected Areas, Sustainable Development Goals

Objectives: Vitamin B12 deficiency has been associated with certain serious disorders such as megaloblastic anemia as well as cardiovascular, neurological, and psychological disorders. Vitamin B12 deficiency is a worldwide health concern and a severe health problem in certain developing countries. In the current study, we aimed to evaluate the situation of vitamin B12 and estimate the prevalence of vitamin B12 deficiency in southern Jordan. Methods: The study population included 281 participants from Aqaba city: 71.2% females and 28.8% males with a mean age of 30.01±13.5. Results: The results showed that the average vitamin B12 level was 277.34±103.70 pg/mL. The study population showed that 69 (24.6%) participants had a vitamin B12 deficiency. The current findings showed a lower frequency of vitamin B12 deficiency in the studied population compared to the rest of Jordan, especially in the north. The females reported a significantly higher frequency of vitamin B12 deficiency (29.0%) compared to the male group (13.6%). In addition, the CBC parameters showed a significant association between the level of vitamin B12 and Hb, RBC, PCV, and platelet count with a p-value = 0.044, <0.001, 0.021, 0.025, respectively. On the other hand, the results showed a lack of association between the vitamin B12 level and MCV and age group. Conclusion: In conclusion, the current study supports our previous findings regarding the correlation between geographical locations and the deficiency of vitamin B12. These findings can be attributed to the lifestyle and nutrient situation in Aqaba city which relies more on seafood. Moreover, other factors such as genetic predisposition can be excluded as an association factor. Therefore, more studies are required to evaluate vitamin B12 levels in Jordan at a higher scale that will include genetic analysis as well as food habits.

Background: A common ostium of inferior pulmonary veins (COIPV) is a kind of unusual pulmonary veins variation. Limited data are available about the safety and efficacy using the second‐generation cryoballoon (CB) ablation in patients with atrial fibrillation with such an anatomical variation. Methods: A total of 10 (0.57%) patients with a common ostium of inferior pulmonary veins from a consecutive series of 1751 consecutive patients with atrial fibrillation (AF) were included. Pulmonary vein isolation was performed using the second‐generation CB. Results: PV isolation was successfully achieved in all PVs without the need of additional focal catheter procedures. CB could occlude and cryotherapy each inferior PV respectively. The mean number of freeze cycles of inferior PVs in each patient was 2.5±1.6, and 2.1±0.9, respectively. The mean time to isolation and nadir temperature were 54.3±22.1, 53.2±22.2 seconds and -39.7±3.4°C, -43.9±7.5°C, respectively. No procedure-related complications occurred in any of the 10 patients. 8 of 10 patients (80%) had no atrial arrhythmia recurrences without the use of antiarrhythmic drugs during a follow-up period of 24±13 months. Conclusion: The incidence of a common ostium of inferior pulmonary veins is 0.57% in present study. PV isolation with this unusual anatomic variation using the second‐generation 28‐mm CB is effective and safe.

ABSTRACT Aims of Study: To compare dynamic thiol/disulfide homeostasis between patients with with lung tuberculosis and healthy controls. Methods: Our study included 50 patients with active lung tuberculosis and 50 healthy controls. Serum thiol/disulfide was measured with a new automated spectrometric method developed by Erel and Neselioglu, and results were compared statistically. Results: We found that native and total thiol levels were significantly decreased in patients with lung tuberculosis, disulfide/native thiol and disulfide/total thiol levels were found to be higher in lung tuberculosis patients when compared with the control group. However, disulfide levels were higher in the control group than in the patient group. Conclusions: Based on the results of this study, it can be said that oxidative stress is closely associated with lung tuberculosis pathogenesis. There is a need for new studies that will show the possible effects of oxidative stress on lung tuberculosis pathogenesis.

Eltrombopag is relatively new drug used in Thrombocytopenia. Its dose should be adjusted based on platelets count. It should be stopped when platelets count reach 400,000/mm³. Here, we share our case report of stopping Eltrombopag based on platelets increment in secondary reactive thrombocytosis irrespective of Eltrombopag treatment.

This study proposes a multiperiod mixed integer linear programming model for the management of a single municipal solid waste (MSW) treatment plant with sustainability as the objective. Discrete and continuous variables define the capacity selections for diverse MSW technologies, and the operation of the MSW network, respectively. The economic target is considered to maximize the net present value. The environmental impact is the minimization of a normalized environmental objective function (NEOF). The social target is the maximization of jobs. An interesting feature about the research work is the requirement of biodrying technologies for MSW moisture content control. Due to the conflicted nature among the sustainability components, a multi-objective optimization (MO) is carried out to find the Pareto optimal solutions. The MO results show that the Pareto optimal solutions vary around profit range of US$ 4.9-8.5 billion, NEOF impact range of 3.2-3.6 units, and social benefit range of 2700-4828 jobs.

Nivolumab is used for patients with recurrent/metastatic head and neck cancer resistant to platinum. We report a 76-year-old man with squamous cell carcinoma of the tongue, who developed toxic epidermal necrolysis (TEN) after nivolumab treatment. TEN is a fatal disease, and early treatment of the adverse events are important.

Wildlife species are challenged and threatened by various infectious diseases that act as important selective forces and demographic drivers of populations. Yet, studies about host genetic factors and disease susceptibility are very limited. Cetacean morbillivirus (CeMV) has emerged as a major viral threat to cetacean populations worldwide, contributing to the death of tens of thousands of individuals of multiple dolphin and whale species. To understand the genomic basis of immune responses to CeMV, we generated and analysed whole genomes of 53 Indo-Pacific bottlenose dolphins (Tursiops aduncus) exposed to Australia’s largest CeMV-related mortality event known to date. The genomic dataset consisted of 7,720,686 SNPs anchored onto 23 chromosome-length scaffolds and 77 short scaffolds. Allele frequency estimates between survivors and non-survivors of the outbreak revealed 11,009 candidate SNPs, of which 498 were annotated to 220 protein coding genes. These included 36 genes with functions related to innate and adaptive immune responses, and cytokine signalling pathways. The list also included genes known to be involved in immune responses to other morbilliviruses, such as measles in humans and the phocine distemper virus in pinnipeds. Our study characterised genomic regions and pathways that likely contribute to CeMV susceptibility and resistance in dolphins, representing a stride towards clarifying the complex interactions of the cetacean immune system. It also emphasises the relevance of whole genome datasets to study the genetics of wildlife diseases.

The weakly entangled UHMWPE was synthesized by a Ziegler-Natta catalyst, where the titanium tetrachloride was anchored on the polystyrene (PS) modified silica. The PS chains were incorporated into silica pores through the in-situ free-radical polymerization of styrene. This incorporated PS was proved to be coated on the surface of pore walls. The self-diffusion coefficients and crystallization of probed molecules were investigated by the pulsed field gradient NMR and thermoporosimetry to address the swollen behavior of the coated PS phase. This swollen PS formed numerous horizontal isolators to compartmentalize the active sites and adjacent chains. The ubiquitous isolators effectively limited the formation of chains overlaps during the polymerization, showing a long-term efficiency to reduce the entanglements of nascent UHMWPE with an exceptional activity. The toughness/stiffness/strength balance of weakly entangled UHMWPE was significantly improved, since the enhanced chain diffusion rate limited the formation of forming defects.

Passive restoration (without any intervention) has been proposed as an effective strategy for degraded cropland restoration. However, whether the vegetation in abandoned cropland can change towards the desired state and the time needed to reach a stable state are still uncertain. We investigated three abandoned croplands with different recovery times (5, 15 and 20 years) and one natural grassland in each of two different types of grassland (desert steppe and typical steppe) in the agro-pastoral ecotone of northern China to assess the restoration potential of abandoned cultivated grassland. Above- and below-ground productivity as well as species biodiversity increased gradually with increasing recovery time. After 20 years of restoration there was no significant difference between abandoned cropland and natural grassland in the typical grassland site, but above- and below-ground productivity and species biodiversity were still lower in abandoned cropland in the desert steppe site. At the beginning of restoration, the communities were dominated mainly by annual species, especially in the desert steppe. As recovery time increased, the biomass and richness of perennial grasses and forbs increased significantly and replaced annual species as the dominant species. In both desert steppe and typical grassland, species similarity between restored and natural grassland increased over time, suggesting that previously cultivated grassland recovered towards the desired state. Our results indicate that 20 years was long enough for the restoration of previously cultivated grassland in the typical steppe, but more time may be needed in the desert steppe.

Amaranthus palmeri is a widespread glyphosate-resistant (GR) weed in the USA. Since 2015, GR populations of A. palmeri have been confirmed in South America, raising the prospect of an ongoing invasion. We used RAD-Seq genotyping to explore genetic differentiation amongst A. palmeri populations from Brazil, Argentina and Uruguay. We also quantified gene copy number amplification of the glyphosate target, 5-enolpyruvyl-3-shikimate phosphate synthase (EPSPS) and the presence of an extra-chromosomal circular DNA (eccDNA) replicon in these populations. Genetic analyses indicated that populations in Brazil, Argentina, and Uruguay were only weakly differentiated (pairwise FST  0.043) in comparison to USA populations. STRUCTURE analysis did, however, assign Argentinean populations to a discrete cluster to those from Brazil and Uruguay. Neither elevated EPSPS copy number, nor the eccDNA EPSPS replicon were present in Argentinean populations, this being consistent with recent observations of other GR mechanisms in Argentina, and an independent in situ evolution of glyphosate resistance. Elevated EPSPS copy number and the EPSPS replicon were identified in all populations from Brazil and Uruguay. The presence of this mechanism and the very high sequence similarity of the EPSPS replicon to that found in the USA are strongly suggestive of the recent invasion of GR into Brazil and Uruguay. Our results are consistent with a single introduction of A. palmeri into South America sometime before the 1980s, and subsequent local evolution of GR in Argentina but with a secondary invasion of GR A. palmeri from the USA into Brazil and Uruguay during the 2010’s.

Marciano Lee1, Elise Anderson1, Ali Farooq1, Mohammed Yasin1, Yazan Alkawaleet1, Frank Annie2Charleston Area Medical Center, Department of Cardiology, 3200 MacCorkle Ave. SE,Charleston, WV 25304CAMC Health Education and Research Institute, 3200 MacCorkle Ave. SE,Charleston, WV 25304Corresponding:Frank Annie MA; MPA; PhDResearch Scientist (Department of Cardiology)CAMC Health Education and Research Institute3200 MacCorkle Ave. SE,Charleston, WV 25304Cell 304 -395 – 3830Phone 304-388-9921Fax: 304-388-9921Email: Frank.H.Annie@camc.orgKeywords:COVID-19, GEMFIBROZIL, IMMUNE MODULATING TREATMENTAbstract:The current Covid-19 viral infection has been declared a pandemic causing significant global morbidity and mortality predominantly from the manifestation of severe acute respiratory syndrome (SARS). It has been designated as SARS-CoV 2. Epidemiological studies show predilection in patients with associated chronic medical conditions including those with cardiovascular disease. Exaggerated host immune response known as cytokine storm syndrome (CSS) leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is the proposed mechanism for the development of SARS in Covid-19 infection. Gemfibrozil has proven benefits in patients with cardiovascular disease. More importantly, it has established anti-inflammatory, anti-oxidative, and anti-migratory properties. Gemfibrozil has shown survival benefits as immune modulation of ALI/ARDS from viral pathogens. This article reviews the potential of gemfibrozil as adjuntive immue modulating therapy for SARS associated with Covid-19 infected patients who have associated cardiovascular disease.Introduction:The severe acute respiratory syndrome (SARS) seen in Covid-19 infection share similarities with previous coronavirus epidemics, particularly SARS-CoV 1 and the Middle East Respiratory Syndrome (MERS-CoV). (1) It has been designated SARS-CoV 2. Acute lung injury (ALI) with subsequent development of acute respiratory distress syndrome (ARDS) from robust host hyper-immune response is the proposed pathophysiological mechanism. This so called ”cytokine storm” may be independent of viral load and replication. (2) Thus, the rationale for adding immune modulating strategies on top of antiviral/antimicrobial therapies is warranted to prevent this complication and hopefully improve survival. The development of ALI/ARDS amplifies mortality in Covid-19 infection, more so in patients with associated chronic medical conditions including cardiovascular disease. (3)Gemfibrozil, a drug discovered over 40 years ago, have beneficial effects and safety profile in both primary and secondary prevention of cardiovascular disease. (4) In addition to its lipid lowering ability, it has important immune modulating properties that inhibit pro-inflammatory factors involved in cytokine storms.(5) It is a peroxisome proliferators-activated receptor (PPAR) agonist known to reduce the release of inflammatory cytokines including interleukin-6 (IL-6), tumor necrosing factors (TNF) and interferon-gamma (IFN-g).IL-6 elevation have been reported as an important marker of severity with Covid-19 infection. (3) Together with other markers for inflammation such as CRP, the degree of IL-6 elevation correlates with increased morbidity and mortality.Gemfibrozil has shown survival benefits by attenuating ALI/ARDS development from viral etiologies. (6) Since gemfibrozil is currently indicated for patients with cardiovascular disease, its adjunctive use does not have to be repurposed for SARS associated with Covid-19 infection. Therefore, Gemfibrozil’s potential as an immune modulating strategy to prevent ALI/ARDS cannot be ignored.Immune Modulating Targets for Gemfibrozil in Covid-19 SARS pathogenesis:Gemfibrozil has been shown to attenuate pro-inflammatory effects of disease states through its immune-modulating, anti-inflammatory and anti-migratory properties. (5). It belongs to the fibrate family of drugs used to lower plasma lipds and cholesterol. They are one of several known synthetic lignads acting as agonists to the PPARs. (7) Their action in turn decrease serum levels of TNF, IFN-g and IL-6. (8,9)As an an anti-inflammatory, gemfibrozil reduces superoxide production and expression of nuclear factor kB (NF-kB). (10) Moreover, it inhibits astrocyte production of TNF, IL-1b, IL-6 and nitric oxide (NO) production. (11) Gemfibrozil also promotes the production of anti-inflammatory cytokine IL-4. (12) It reduces the production of C-reactive protein (CRP), TNF-a and IL-6 in peripheral blood mononuclear cells. It inhibits the production of cyclooxygenase-2 (COX-2) and prostaglandins. (13)As an immune-modulating agent, gemfibrozil attenuates pro-inflammatory transcription factor activation. This includes IFN-g regulatory factor 1 (IRF-1)bidning to gamma activation site (GAS), nuclear factor-kB (NF-kB), activator protein 1 (AP-1), and CCAT/enhancer binding protein beta (C/EBPb). (5) It also promotes switching of T helper (Th) cells from the pro-inflammatory Th1 to anti-inflammatory Th2. Production of Th2-specific cytokines is amplified including IL-4, IL-5 and IL-10. (14)As an anti-oxidant, gemfibrozil not only prevents low density lipoprotein (LDL) peroxidation but also acts on other signals of inflammation. Reactive oxygen species (ROS) have emerged as important signaling molecules during inflammatory conditions. Excessive ROS generation results in damage to most cellular components of the living organism. Gemfibrozil is known to inhibit ROS-mediated inflammation. (15) It has free radical scavenging ability as well. Its para-hydroxyl metabolite has been shown to reduce the burden of ROS. (16)As an anti-migratory agent, gemfibrozil affects the expression of cell-surface adhesion molecules icluding intracellular adhesion molecule 1 (ICAM-1), VCAM-1 and selectins inhibiting trans endothelial migration of mononuclear cells and macrophages. (17) It also down-regulates the expression of chemokines including monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1), monokines induced by IFN-g (MIG) and IL-8. The expression of IL-8 induces inflammation, monocyte/macrophage recruitment, angiogenesis and vascular smooth muscle migration. Thus, gemfibrozil can function as an anti-migratory factor by down-regulating the expression of different soluble chemokines and inhibit the expression of different cell surface proteins and selectins.Discussion:Over the years, viral pathogens including Influenzas and Coronaviruses cause ALI/ARDS from excessive release of pro-inflammatory cytokines and chemokines described in cytokine storm syndromes. They induce much higher transcription and up regulation of TNF genes including TNF related aptoptosis-inducing lignad and TNF-mRNA in human monocyte-derived macrophages. (18) This macrophage activation syndrome (MAS) seen with the current SARS-CoV 2 may be a dysregulated host response to Covid-19 viral induced immunosuppression and lymphopenia leading to unintended ALI/ARDS consequences at the site of infection. (19) The development of ALI/ARDS and the need for ventilator support portends to increased mortality rates. Markers of inflammation including CRP and IL-6 have been used as surrogates for MAS, and their degree of elevation have correlated well with disease severity. (3)Experiments with SARS-CoV indicate that MAS induced cytokine storms result more from amplification of gene related inflammatory signals regardless of viral load. In one model, immune modulation of receptor sites or alteration of recruitment signals resulted in dramatic improvement in host survival with viral load remaining constant. (20) This suggests that immune modulating therapy may have as important a role in addition to antiviral therapy in altering the course of Covid-19 infection. Reports of clinical improvement have been reported with the adjuvant use of IL-6 antagonists including tocilizumab. However, cost and repurposing use of these medications may be limiting factors.Gemfibrozil has been in clinical use for patients with cardiovascular disease and has achieved generic status. In addition, it has vital immune modulating properties against cytokine storms that mitigate the development of ALI/ARDS from both viral and nonviral pathogens. (21). It not only reduces the levels of IL-6, TNF and IFN-g. But it has also been shown to attneuate gene recruiting signals of inflammation utlizing human equivalent dosing. In one animal study, the adjuvant use of gemfibrozil resulted in enhanced host survival that developed ALI/ARDS from viral pathogens. (6) Enhanced survival is seen even after exposure to the virus. This implies that gemfibrozil has the potential to be a treatment rather than a preventive therapy in human disease.Therefore, the potential of gemfibrozil as adjunct immune modulating therapy in conjunction with antiviral treatment for SARS associated with Covid-19 infection in patients with associated cardiovascular disease is emphasized.References:1. Petrosillo N, Vicenconte G, et al. Covid-19, SARS and MERS: are they closely related? JCMI. 20202. Smits S, Lang A, et al. Exacerbated inane host response to SARS-CoV in aged non-human primates. PLos Patholog. 20103. Zhou F, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with Covid-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020. 3954. Rubins HB, Robins SJ, et al. Gemfibrozil for the secondary prevention of coronary aretery disease inmen with low levels of high-density lipoprotein cholesterol. Veterans Affairs high-density lipoprotein cholesterol intervention trial group. N Engl J Med. 1999. 341: 410-4185. Roy A, Pahan K, et al. Gemfibrozil, stretching the arms beyond lipid lowering. Immunopharmacol Immunotoxicol. 2009. 31: 339-3516. Budd A, Alleva L, et al. Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrobial Agents and Chemotherapy. 2007. 2965-29687. Berger J, Moler DE. The mechanisms of action of PPARs. Annu Rev Med. 53: 409-4358. Madej A, Okopien B, et al. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. Int J Clin Pharmacol. 36: 345-3499. Staels B, Koenig W, et al. Activation of human oartic smooth muscle cells is inhibited by PPARa. Nature. 303: 790-79310. Calkin AC, Cooper KA, et al. Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation. Diabetologia. 49: 766-77411. Xu J, Chavis JA, et al. Gemfibrozil reduces release of tumor necrosis factor-alpha in peripheral blood mononuclear cells from healthy subjects and patients with coronary heart disease. Clin Chem Acta. 332: 61-6712. Lovette-Racke AE, Hussain RZ, et al. Peroxisome proliferator-activated receptor-alpha agonists as therapy for autoimmune diesease. J Immunol. 172: 5790-579813. neve BP, Frutchart JC, et al. Role of PPAR in atherosclerosis. Biochem Pharmacol. 2000. 60: 1245-125014. Heyworth PG, Bohl BP, et al. Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its ineteraction with flavocytochrome b558. J Biol Chem. 1994. 269: 30749-3075215. Aviram M, Rosenblat M, et al. Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation. Ahterosclerosis. 1998. 138: 271-28016. Dasgupta S, Roy A, et al. Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis of peroxisome proliferator-acivated receptor-alpha. Molecular Pharmacol. 2007. 72: 934-94617. Zhou JF, Law HK, et al. Functional tumor necrosis factor-related apoptosis-inducing ligand production by avian flu influenza virus-infected macrophages. J Infect Dis. 193: 945-95318. Xu J, Shi I, et al. Pathological findings of Covid-19 associated with acute respiratory distress syndrome. Lancet. 2020. Epub ahead of print19. McGonagle D, Sharif K, et al. The role of cytokines including interleukin-6 in Covid-19 induced pneumonia and macrophage activation syndrome-like disease. J AutRev. 2020. 10253720. Channappanavar AR, Fehr R, et al. Dysregulated type 1 interferon and inflammatory monocytes-macrophage responses cause lethal pneumonia in SARS-CoV infected mice. Cell Host Microbe. 2016.19: 181-19321. Kim YS, Kim JK, et al. The peroxisome proliferator-activated receptor-alpha agonist gemfibrozil promotes defense against mycobacterium abcessus infections. Cells. 2020. 9: 648

Background: There is growing interest in physical medicine treatment options for renal colic. In this study, we aimed to determine whether or not heat-patch treatment with no drug was effective in relieving renal colic. Methods: For this purpose, patients who were diagnosed with renal colic in the emergency department were randomized to have either heat-patch or sham treatment. The Visual Analog Scale (VAS) scores of renal colic, body temperature (Btemp), and sub-patch skin temperature (Stemp) values were measured at 0,15,30,45, and 60 min. In addition, the salvage treatment needs of the groups were compared. Results: The average age of the study group was30.5 ± 8.3 years and that of the sham group was 31.0 ± 8.2 years (p = 0.75). According to the baseline VAS score of the patients, 15, 30, 45, and 60min VAS scores significantly decreased in the heat-patch group (p<0.001). The Btemp values did not differ significantly between the heat-patch and sham groups. In addition, no statistically significant difference was found between the two groups in terms of Stemp values at 0 and 15 min (p = 0.39and p = 0.10, respectively). However, there was a significant difference in the heat-patch group in terms of Stemp values at30, 45, and 60 min compared to the sham group (p<0.001). The salvage treatment rates for the heat-patch and sham groups were 11.5% and 31.4%, respectively (p = 0.01). Conclusion: As non-pharmaceutical treatment, the heat-patch has been shown to be a possible candidate for pain relief in patients with urolithiasis. Further research should concentrate on multicenter and large-scale randomized studies.

Background: Coronavirus Disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with its cardiovascular, gastrointestinal, hematologic, mucocutaneous, respiratory, neurological, renal and testicular manifestations and further complications constitutes one of the deadliest pandemics in modern history. A common pathogenetic mechanism of these complications seems to be the Covid-19-induced excessive immune response of uncontrolled release of interleukins, chemokines, interferons, tumor necrosis factors and colony-stimulating factors, the so called cytokine storm syndrome. Severe anaphylactic reactions with profound hypotension or hypoxemia can be also associated with release of pro-inflammatory cytokines. Aim: Careful investigation for similarities in clinical manifestations and correlated multi-organ complications of Covid-19 with other viral infections including dengue and human immunodeficiency viruses together with the action of inflammatory cells inducing the Kounis syndrome could provide a better understanding on pathophysiolgy and trigger mechanisms, elucidating potential preventing and therapeutic strategies. Methods: A search was performed in Medline (via PubMed), for current literature on the pathophysiology, causality, clinical appearance, variance, prevention, and treatment of Covid-19, anaphylaxis with profuse hypotension and the Kounis anaphylaxis associated acute coronary syndrome. Results: Insights from research in allergy/anaphylaxis-associated cardiac syndromes and Covid-19, suggest that the same key immune cells are invollved in cardiovascular complications of Covid-19 and the anaphylaxis-associated Kounis syndrome. The myocardial injury in patients with Covid-19 has been attributed to coronary spasm, plaque rupture and microthrombi, hypoxic injury or cytokine storm and shares the same patho-physiology with the 3 clinical variants of Kounis syndrome. Conclusion: The patho-physiology, etiology, clinical manifestations and therapeutic approaches of the severe Covid-19 and their associations might be proved beneficial for future treatments. Early immunological interventions targeting inflammatory markers that are predictive of worse disease outcome would be more beneficial than those blocking late-appearing cytokine related storm. Individualized, tailored to each patient treatment approach is required in Covid-19 cases