A 34-year-old woman with flank pain was referred for suspicious lymphadenopathy. PET/CT scan revealed disseminated lesions without apparent primary origin. Although she did not complain of any symptoms, after rapid deterioration, she died of respiratory distress and cardiac arrest. Her strong beliefs contribute to symptoms tolerance and late diagnosis.

The effect of COVID-19 imposed lockdown on Italian children with Vernal Keratoconjunctivitis

Fe-Ni materials with varying Ni loading are developed for separate H2 and CO production by CH4-CO2 chemical looping. The product streams are obtained by first feeding CH4, which decomposes to H2 and carbon. The latter acts as reductant for the subsequent CO2 feed, which together with Fe re-oxidation yields CO. After 25 CH4-CO2 cycles, 10Fe5Ni@Zr has a higher H2 space-time-yield than 10Fe0Ni@Zr (〖20mmol∙s〗^(-1)∙kg_(Fe+Ni)^(-1) vs. 〖15mmol∙s〗^(-1)∙kg_(Fe+Ni)^(-1)), a 2.6 times higher CO (〖57mmol∙s〗^(-1)∙kg_(Fe+Ni)^(-1)) and lower deactivation. This improvement has two reasons: (i) CH4 activation over Ni leading to cracking, (ii) product hydrogen causing deeper FeO reduction. Deactivation follows from accumulated carbon, non-reactive for CO2. On Ni and Fe sites, carbon can be removed by lattice oxygen or CO2, yielding more CO compared to the theoretical value for Fe oxidation. However, carbon that migrates away from the metals requires oxygen for removal, which restores the activity of the Ni-containing samples.

Homogeneous hydrogen transfer reactions of methacrolein (MAL) and isopropanol (IPA) to methallyl alcohol (MAA) were investigated in batch reactor (Conv.89%, Select 93.1%) and tubular reactor (Conv.88.1%, Select 95%) using aluminum isopropoxide (Al(OPri)3) as catalyst. Kinetic experiments on hydrogen transfer reactions and reaction order were investigated in batch reactor and tubular reactor. Response surface methodology (RAM) was applied to optimize the optimum reaction conditions of hydrogen transfer reaction. Purification process of MAA from product mixture after hydrogen transfer reaction was simulated with Aspen Plus software, theoretical stages, reflux ratio and feed stage of distillation tower were optimized. Density Functional Theory (DFT) was used to investigate viable reaction pathway and to probe the catalytic mechanism between reactants and catalyst, including dehydrogenation, coupling and hydrogenation reaction. Microscopic mechanisms of hydrogen transfer reaction from MAA to MAL were acquired in detail and could be easily extended to other series of hydrogen transfer reaction.

Background: Type 2-high asthma is characterized by elevated levels of circulating Th2 cells and eosinophils, cells that express chemoattractant-homologous receptor expressed on Th2 cells (CRTh2). Severe asthma is more common in women than men; however, the underlying mechanism(s) remain elusive. Here we examined whether the relationship between severe asthma and type 2 inflammation differs by sex and if estrogen influences Th2 cell response to glucocorticoid (GC). Methods: Type 2 inflammation and the proportion of blood Th2 cells (CD4 +CRTh2 +) were assessed in whole blood from subjects with asthma (n = 66). The effects of GC and estrogen receptor alpha (ERα) agonist on in vitro differentiated Th2 cells were examined. Expression of CRTh2, type 2 cytokines and degree of apoptosis (Annexin V +, 7-AAD) were determined by flow cytometry, qRT-PCR, western blot and ELISA. Results: In severe asthma, the proportion of circulating Th2 cells and hospitalizations were higher in women than men. Women with severe asthma also had more Th2 cells and serum IL-13 than women with mild/moderate asthma. Th2 cells, eosinophils and CRTh2 mRNA correlated with clinical characteristics associated with asthma control in women but not men. In vitro, GC and ERα agonist treated Th2 cells exhibited less apoptosis, more CRTh2 as well as IL-5 and IL-13 following CRTh2 activation than Th2 cells treated with GC alone. Conclusion: Women with severe asthma had higher levels of circulating Th2 cells than men, which may be due to estrogen modifying the effects of GC, enhancing Th2 cell survival and type 2 cytokine production. (249)

Portal vein aneurysm (PVA) is a rare vascular entity of uncertain etiology. Saccular PVA is the less frequently reported morphology but often with more symptoms or complications. Ultrasound, along with color doppler study, is a valuable tool in the diagnosis and follow-up.

Male infertility has become a serious health and social problem troubling approximately 15% of couples worldwide; however, the genetic and phenotypic heterogeneity of human infertility poses a substantial obstacle to effective diagnosis and therapy. A previous study reported that heterozygous mutations in solute carrier family 26 member 8 (SLC26A8, NG_033897.1) were causatively linked to asthenozoospermia. Interestingly, in our research, three deleterious heterozygous mutations of SLC26A8 were separately detected in three unrelated patients who were suffered from teratozoospermia. These three heterozygous mutations resulted in the reduce of SLC26A8 expression in transfected cells, while no disrupt expression of SLC26A8 was observed in sperm from the affected individuals. Noticeably, two of the three SLC26A8 heterozygous mutations detected in the patients were inherited from their fertile fathers. Thus, we suggested that male infertility associated with SLC26A8 mutations should be involved in a recessive-inherited pattern, considering the infertile homozygous Slc26a8 KO male mice. Given that SLC26A8 heterozygous mutations were detected in the infertile patients, and SLC26A8 is predominantly expressed in the various germ cells during spermatogenesis, the heterozygous mutations in SLC26A8 may not be the direct genetic cause but contribute to male infertility to a certain degree.

Response to Letter to Editor Regarding: Equivalent outcomes with minimally invasive and sternotomy mitral valve repair for degenerative mitral valve disease. J Card Surg. 2021; 36:2636-43.Authors: Ramsey S. Elsayed, MD MS1, Brittany Abt, MD1, and Michael E. Bowdish, MD MS1,2Institutions and Affiliations: 1Division of Cardiac Surgery, Department of Surgery, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA2Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USAAddress for Correspondence: Dr. Michael E. Bowdish, Associate Professor of Surgery and Preventive Medicine; Department of Surgery, Keck School of Medicine of USC; University of Southern California; 1520 San Pablo Street, HCC II Suite 4300; Los Angeles, CA 90033; Phone: (323)-442-5849; Email: Michael.Bowdish@med.usc.eduConflicts of Interest/Competing Interests: NoneFunding: Research reported in this publication was supported by the Department of Surgery of the Keck School of Medicine of USC. MEB is partially supported by UM1-HL11794 from the National Heart Lung and Blood Institute of the National Institutes of Health.To the editor,We would like to thank Song et. al. for their letter regarding our recent publication in the Journal of Cardiac Surgery titled “Equivalent outcomes with minimally invasive and sternotomy mitral valve repair for degenerative mitral valve disease”1. They asked some important questions and brought up valuable points that are worthy of discussion.Regarding the selection criteria we use for operative approach for mitral valve repair operations, it is primarily based on collective surgeon-patient decision making. However, patients with a previous history of cardiac surgery or peripheral vascular disease (which would render peripheral cannulation difficult), and those in need of concomitant cardiac procedures such as coronary artery bypass grafting, aortic replacement, or biatrial ablation, are not offered a minimally invasive approach. Regarding the role of artificial chordae (neochordae) in mitral valvuloplasty, we use elongated polytetrafluorethylene made of interrupted GoreTex (Gore-Tex, WL Gore and Associates, Inc., Flagstaff, AZ) sutures placed in a horizontal mattress fashion. These neochordae are routinely used to repair elongated or ruptured chordae causing mitral valve prolapse or regurgitation.2 Typically, the neochordae are used in the anterior leaflet of the mitral valve. The etiologies of degenerative mitral valve disease are comprised of myxomatous degeneration of the MV, fibroelastic deficiency including so called Barlow’s valves, and dystrophic calcification of the mitral annulus.3 While the etiologies are not mutually exclusive and may overlap, myxomatous degeneration and fibroelastic deficiencies resulting in severe, symptomatic MR were the most common indications for operation in our patient population. As mentioned by Song and colleagues, the success and durability of MVr can vary depending on etiology, particularly on how much of the valve apparatus is affected by pathology. While not examined in this paper specifically, previous papers (including Tatum et al. conducted at our institution), have demonstrated that anterior leaflet repair is significantly associated with recurrence and progression of MR after surgery, whereas isolated posterior repair is protective.3,4The operative team was similar in all cases, whereas the senior author (VAS) performed over 85% of the total procedures and nearly 100% of the minimally invasive procedures. The success rate of the minimally invasive cohort was 100% (as defined by the Society of Thoracic Surgeons). There was one conversion to conventional sternotomy in the minimally invasive cohort (.003%) for bleeding control.Finally, Song and colleagues are to be congratulated on their robotic and thoracoscopic mitral valvuloplasty results. Their 10-year total robotic mitral valve valvuloplasty results showing excellent cardiac function with 93% of patients in NYHA classes I and II.5 Furthermore, their early thoracoscopic results were very good with one operative mortality and only two reoperations demonstrating thoracoscopic mitral valvuloplasty is a technically feasible, safe, effective, and reproducible technique.6References:Bowdish ME, Elsayed RS, Tatum JM, Cohen RG, Mack WJ, Abt B, Yin V, Barr ML, Starnes VA. Equivalent outcomes with minimally invasive and sternotomy mitral valve repair for degenerative mitral valve disease. J Card Surg. 2021 Aug;36(8):2636-2643. PMID: 33908645.Bortolotti U, Milano AD, Frater RW. Mitral valve repair with artificial chordae: a review of its history, technical details, long-term results, and pathology. Ann Thorac Surg. 2012 Feb;93(2):684-91. PMID: 22153050.David, Tirone E. ”Durability of mitral valve repair for mitral regurgitation due to degenerative mitral valve disease.” Annals of cardiothoracic surgery 4.5 (2015): 417.Tatum, James M., et al. ”Outcomes after mitral valve repair: a single-center 16-year experience.” The Journal of thoracic and cardiovascular surgery 154.3 (2017): 822-830.Zhao H, Gao C, Yang M, Wang Y, Kang W, Wang R, Zhang H. Surgical effect and long-term clinical outcomes of robotic mitral valve replacement: 10-year follow-up study. J Cardiovasc Surg (Torino). 2021 Apr;62(2):162-168. PMID: 33302613.Cui H, Zhang L, Wei S, Li L, Ren T, Wang Y, Jiang S. Early clinical outcomes of thoracoscopic mitral valvuloplasty: a clinical experience of 100 consecutive cases. Cardiovasc Diagn Ther. 2020 Aug;10(4):841-848. PMCID: PMC7487400.

Mitogen-Activated Protein 3 Kinase 7 (MAP3K7, MIM 602614) encodes the ubiquitously expressed transforming growth factor β (TGF-β)–activated kinase 1 (TAK1), which plays a crucial role in many cellular processes. Variants in the MAP3K7 gene have been linked to 2 distinct disorders: frontometaphyseal dysplasia type 2 (FMD2, MIM #617137) and cardiospondylocarpofacial syndrome (CSCF, MIM #157800). The fact that different variants can induce 2 distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here we significantly expand the cohort and the description of clinical phenotypes for individuals with CSCF and FMD2 who carry variants in MAP3K7. We show that in contrast to FMD2-causing variants, CSCF-causing variants in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic variants in MAP3K7 are at risk for cardiac disease, have symptoms associated with connective tissue disease and we show overlap in clinical phenotypes of CSCF with Noonan syndrome. Together, we provide evidence for a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 variants and conclude that variants in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders and in the differential diagnosis of Noonan syndrome.

COVID 19 is associated with pulmonary cavitation as rare late complication . Cavitatory lesion in COVID 19 recovered patient is very rare and can cause significant morbidity and mortality. we present case series associated with pulmonary cavitation as late complication.

A commentary on the discrepancy between blood and tumorBRCA testing: an open question Elisa De Paolis1, Claudia Marchetti2;3, Paola Concolino1, Giovanni Scambia2;3, Andrea Urbani1,3, Anna Fagotti2;3, Angelo Minucci1*1Molecular and Genomic Diagnostics Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy;2Division of Oncological Gynecology, Department of Women’s and Children’s Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy;3Catholic University of the Sacred Heart, Rome, Italy.Running title: Understanding discordant BRCA test cases.*Corresponding author:Angelo MinucciMolecular and Genomic Diagnostics Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.angelo.minucci@policlinicogemelli.itMolecular evaluation of BRCA1/2 (BRCA ) genes represents a well-known example of precision oncology. The availability of Poly ADP Ribose Polymerase inhibitors (PARPi) as target therapy option for several BRCA mutated cancers types (e.g. ovarian, breast, prostate, and pancreatic)1 changed the course ofBRCA testing over the last years. In this context, an emerging path of molecular evaluation is represented by the BRCA testing performed directly on tumor tissue (tBRCA ): this increased the chance to identify more patients with higher likelihood of benefiting from PARPi treatment. This approach leads to the simultaneous identification of both constitutional and somatically acquired variants, with a lower turnaround time: the identification of BRCApathogenic variants (PVs) could lead to a secondary “reflex” germlineBRCA (gBRCA) testing in order to assess personal and familiar risks. In contrast, performing gBRCA as first molecular test causes the loss of a relevant proportion of patients with tissue acquired BRCA PVs, needing of a following tumor test2;3.However, challenges exist in tBRCA that may lead to inefficient germline variant call. A recently published paper by Kordes et al. reported a pancreatic adenocarcinoma patient with a germlinenovel BRCA2 c.516+4A>G variant classified as deleterious by the authors based on in silico and functional data4. Also the tumor tissue was sequenced in order to achieve the enrolment criteria for a clinical trial of Olaparib in combination with pembrolizumab (KEYLYNK-007). Unexpectedly, the germline variant was not stated in the final report. The authors took into account all the relevant basis of the experienced discrepancy, without identifying a confident reason.In our opinion it is crucial to investigate about the reliability of tBRCA in the identification of both somatic and germline variants. Inspired by the recently published commentary of Gourley5 and taking into account that several troubling cases of discrepancy between blood and tBRCA testing have been reported in literature, we collected the recent relevant studies covering the comparison between gBRCA and tBRCA to give a critical opinion about some shared key points of the somatic testing that could affect the final genotyping and reporting (Table 1).Major reasons of discrepancies are related to: (1) differences in input DNA quality, (2) type of BRCA gene alteration, (3) inherent limitations of the Next Generation Sequencing (NGS), (4) bioinformatics pipeline features (e.g. the ability to predict the occurrence of Copy Number Alterations (CNAs) and the evaluation of the intron/exon boundaries), and finally (5) the issues related to the BRCAvariants interpretation and classification.To date, tBRCA testing is mainly performed on two sample types: Fresh Frozen Tissue (FFT) and Formalin-Fixed Paraffin-Embedded (FFPE). Here, we focused on tBRCA performed on FFPE being the most common tissue type used for clinical diagnostic purpose. Pre-analytical procedures regarding fixation step, tissue section size, and neoplastic cell content assessment, are well-known crucial aspects of the tBRCA testing reliability. In fact, sub-optimal DNA quality represents a relevant reason of inaccuracy of tBRCA and also it is the cause of around 5% of FFPE tBRCA NGS testing fails, with the consequent need of additional new samples9. In Bekos et al. only the retesting of a newly extracted tumor DNA solved two cases of discrepancies with gBRCA : the BRCA1c.1881_1884del variant was not recognized due to poor NGS quality data related to the input materials, as well as for theBRCA2 c.8537_8538del variant2. Also in Careet al. the test failure rate was related to fixation methods or storage of FFPE material8. Ad hocrecommendations for the “ideal” starting tissue material are available9;14.Furthermore, different approaches should be used in the analytical step for the BRCA genes amplification and sequencing, with several types of sequencing chemistries (e.g. amplicon-based, capture-based), platforms (e.g. Illumina, IonTorrent) and data analysis pipelines (e.g. full-coding regions or hot spot analysis, different size of splice site region analysed, CNAs detection). Each one of these could be characterized by specific pitfalls that affect the downstream bioinformatics variants filtering and calling. For example, in amplicon-based approaches, a reason leading to the missing of a variant detection may be related to the experimental design of the primers distribution along the genomic region of interest. Variants located at the 3’ or 5’ ends of overlapping amplicons could be covered by only one read and could be consequently identified with a “strand bias” flag and filtered out at the bioinformatics quality check3.Also the use of different bioinformatics pipeline for the NGS data analysis derived from the germline and the somatic tests of the same patient could be the cause of apparent inconsistent results. For example, in a large cohort of patients affected by several types of malignancies and analysed for the evaluation of the utility of germline test following tumor test, Lincoln et al. identified several cases of discrepancies between the two tests (n=4)15. Among these, the germline BRCA2 c.8967_8973del variant was not detected in tumor sequencing due to the characteristic of somatic panel (hot spot type), not comparable to the germline one. Moreover, in case of discrepancy involving splice site variants could be useful to check the concordance of the splice site region size included in the germline and somatic bioinformatics pipelines3. Regarding data analysis, it should be acknowledged that some tumor testing platforms filter out germline variants in the final reports in order to improve the accuracy of somatic variant calling.A well-known cause of gBRCA /tBRCA non-concordance resulted from the challenge in the bioinformatics calling of CNAs in tissue samples2;3;15. NGS sensitivity in CNAs detection mostly depends on DNA quality, tumor heterogeneity, library preparation, type of algorithms, and size of rearrangement. As a consequence, the somatic bioinformatics pipeline must require computational algorithms developed ad hoc and specific characteristics of sequencing raw data (e.g. maximum amount, coverage uniformity and sufficient reads depth)1. Even if the majority of methods are optimized for somatic CNAs identification6;8, attention should be given in the comparison of blood and tissue tests results13. As an example, Bekos et al. failed to identify in the tumor sample a verified pathogenic germline deletion of BRCA1 exon 20. Only a careful re-evaluation of the bioinformatics variant calls finally revealed the deletion and leaded to the correction of the report2.Relevant role in the evaluation of non-concordant results is played by the post-analytical step involving the BRCA variants interpretation. Complex issues underlying the classification ofBRCA variants exist. The American Collage of Medical Genetics (ACMG) and the Association for Molecular Pathology (AMP) have established the best practice for germline variant interpretation providing the well-known classification using a five-tier system16. Conversely, the interpretation of somatic variants should be focused on their impact on clinical care. Specifically, evidence-based categorization of somatic variants released by the AMP, the American Society of Clinical Oncology (ASCO), and the College of American Pathologists (CAP) includes a four-tier system: (1) variants of strong clinical significance (level A and B of evidence); (2) variants of potential clinical significance (level C and D of evidence); (3) variants of unknown clinical significance; (4) benign of likely benign variants17. To date, with the publication of an increasing number of large-scale tumor sequencing projects, a plenty of information is being collected into several public databases useful for the querying about the significance of aBRCA variant. Cancer-specific variant databases are available as: BRCAexchange, OncoKB, Catalog of Somatic Mutations in Cancer, My Cancer Genome, cBioPortal, Memorial Sloan Kettering Cancer Center, International Cancer Genome Consortium, and VARSOME. Likewise, constitutional variant databases available are mainly: ClinVar, Human Gene Mutation Database, ENIGMA, Leiden Open Variation Database, and VARSOME. Differences in the germline- and somatic-based annotation may exist between the abovementioned tools. Consequently, the risk of non-concordant annotations of a BRCA variant could occur. This is crucial in the comparison between the same molecular test performed by different labs and it is exacerbated in the case of tBRCA and gBRCA concordance evaluation: variants that met germline guidelines16 to be considered pathogenic may not meet the criteria17 to be considered oncogenic in the somatic test. This situation could more likely affect the missense Variants of Unknown Significance (VUSs)15. As reported by Bekos et al. , after the inclusion of BRCA VUSs in the secondary data analyses, the concordance rate of tumor testing compared to germline one decreased, mainly due to VUSs classification2. Moreover, in a large study investigating the differences in variant interpretation between germline and somatic variants accounted in several cancer-related genes, Moodyet al. highlighted a relevant percentage of discrepancies in variants classification. Among these, the authors reported fourBRCA2 variants with discordant somatic/germline annotations15.In a retrospective cohort of 57 subjects tested for both germline and somatic BRCA status, Kim et al. highlighted one case of a germline variant not identified in the tissue evaluation10. This discrepancy derived from a true reversion of the germline BRCA1 variant accounted via restoration of the wild-type allele in the tissue cells. Finally, tBRCAshould follow specific criteria that maximize molecular information, improving the clinical relevance of the test and giving a more comprehensive interpretation of each variant. With these purposes, peculiar role is played by the “naturally occurring” BRCAsplicing isoforms. As we recently described for the BRCA1c.788G >T variant, complex considerations should be done for rare variants that not only are different germline and somatic annotations, but also are characterized by variability in final effect and annotation in the context of all gene relevant transcripts19.In conclusion, we underline as the systematic and careful checking of tumor tissue suitability could prevent and solve non-concordance cases. Moreover, the robust identification of BRCA variants in FFPE sample correlates with the confidence of the bioinformatics pipeline adopted for the variant filtering and calling, especially for the CNAs detection. In addition, translation of variant calls into clinical decisions relies on proper annotations and discrepancies in classifications of specific variants between tumor and germline contexts could represent a relevant pitfall.We argue that only harmonized guidelines encompassing the abovementioned methodological and post-analytical steps could solve the BRCAgermline and somatic testing bias. In our laboratory, BRCAgenetic testing is routinely performed on blood, FFT and FFPE samples1. In many cases, we routinely analyze matched blood and tissue samples belonging from the same patient, in order to perform an efficient BRCA test comprehensive of both germline and somatic evaluation. This approach pointed out also the relevance of multi-disciplinary and skilled resources for a solid molecular characterization of the tumor. Together with the need of standardization, we suggest as performing BRCA molecular test at both germline and somatic levels in the same laboratory could improve the reliability of the entire molecular path taken by the patient and his clinicians.Disclosure of interests: none declared.Contribution to Authorship: E.D.P. and A.M. conceived of the presented paper and wrote the manuscript with support from P.C. and C.M.. G.S., A.U. and A.F. supervised the project. All authors discussed, edited and contributed to the final manuscript.Details of Ethics Approval: not applicable.Funding: no funding was received for this commentary.

We report a case of a 34-year-old female with low-grade dyspnea on exertion despite markedly dilated left atrium (LA) on chest radiography which clouded our interpretation of the cause of enlarged cardiac silhouette. However, echocardiogram proved useful in demonstrating severe mitral stenosis and the giant LA.

Lepidic growth adenocarcinoma is defined as tumor cells proliferating along the surface of intact alveolar walls without stromal or vascular invasion pathologically (1).

A document by Asha Kumari. Click on the document to view its contents.

BACKGROUND: Characterization of disease endotypes will open a new window for the treatment of allergic rhinitis (AR). Herein we provide the first attempt to identify specific AR phenotypes/endotypes and/or any biomarker/predictor for specific treatment response based on local biological parameters. METHODS: This observational study was carried out in 142 patients with seasonal AR and 20 non-allergic controls. Total IgE levels, specific IgE to 112 allergenic molecules and 92 proinflammatory and immunologic proteins were measured in both serum and nasal secretions (NS). RESULTS: We found increased values of MCPs and MMPs in adults both in NS and serum when compared with pediatric patients (p<.05). MCPs and MMPs might represent two effective predictors of chronic inflammation. CXCL9, CXCL10, CXCL11, MCPs and MMP1 showed an upward trend both in serum and NS for patients with ≥ 3 comorbidities vs non-allergic controls(p<.05). These data suggest the involvement of these chemokines in the late phase of chronic allergic inflammation in the nose. Serum levels of IL-6, IL-8 and IL-10 (p<.05) were significantly higher in patients with AR+asthma compared to patients with different comorbidities. Conversely, serum levels of neurotrophin-3 values (p<.05) were significantly higher in those with AR+eczema vs other comorbidities groups. A subgroup of patients with a nasal hypersecretory state,called “hypersecreter endotype” was characterized by paediatric age, male gender, grass pollen sensitization and distributed among persistent, mild or moderate to severe cases of AR. CONCLUSIONS: Our study sets the groundwork for an AR endotypization at molecular level, which is highly desirable to deliver a patient-tailored approach.

Title: Paradoxical response during a Para-Hisian pacing in a case with fasciculo-ventricular pathway.Short title : Para-Hisian pacing in fasciculo-ventricular pathway

A 70-year-old man presented to our hospital with non-ST elevation myocardial infarction and severely depressed left ventricular systolic function. Coronary angiogram revealed a giant fusiform aneurysm of the proximal left anterior descending artery with significant stenoses immediately proximal and distal to it and a left circumflex chronic total occlusion. The patient was treated surgically, with ligation and bypass of the aneurysm using a radial artery graft and a vein graft to the first obtuse marginal branch.

Multiple ventricular septal defects (m-VSD), are a challenging clinical problem. m-VSD can be onerous to manage. Besides the inability to close all the defects in one operative setting due to inadequate visualization, previously undetected defects may become clinically apparent after the closure of the dominant defects, leading to inadequate ventricular septation. This increases the morbidity from the progression of pulmonary hypertension, persistence of congestive cardiac failure, higher incidence of postoperative heart block, and the need for reoperations.

Mitral valve repair (MVR) is undisputedly associated with better clinical and functional outcomes than any other type of valve substitute. Conventional mitral valve surgery in dedicated high-volume centers can assure excellent results in terms of mortality and freedom from mitral regurgitation (MR) recurrence but requires cardiopulmonary bypass (CPB) and cardioplegic heart arrest. Trying to replicate the percentage of success of surgical MVR is the aim of all new transcatheter mitral dedicated devices. In particular transapical beating-heart mitral valve repair by artificial chordae implantation with transesophageal echocardiography (TEE) guidance is an expanding field. The safety and feasibility of the procedure have already been largely demonstrated with Neochord and more recently with Harpoon systems. Wang et al. present the outcomes of the first-in-human experience using a novel artificial chordae implantation device, the Mitralstitch system. Despite a quite small cohort of only 10 patients treated, 1-year results are satisfying and comparable to the early experience with former devices (4 patients with moderate or more MR recurrence). The comparison with surgical MVR is still unfavorable and requires further studies and significant procedure improvement. However, the device permits the treatment of anterior and posterior leaflets prolapse and performs quite easily edge-to-edge reparation. It will be interesting to evaluate longer follow-up in larger cohorts of patients as well as the possibility to shift to the transfemoral approach.

Background: As in LMICs, the prognosis of childhood ALL in Indonesia was lower than in HICs. Indonesian-ALL2013 protocol resulted in more toxicities and abandonments than expected. Therefore, it was modified into a pilot ALL2016 protocol. Changes to the ALL2013 protocol: no anthracyclines in SR, dexamethasone replaced prednisone in reinduction for HR and some drugs were rescheduled. Procedure: We compare the outcome of ALL2013 and ALL2016. Results: A total of 383 children with ALL were diagnosed, 21 were excluded. ALL2013 included 174 patients (106 SR and 68 HR) and ALL2016 188 (91 SR and 97 HR). The outcome of the ALL2016 was better than the ALL2013 (pOS 67.0% vs 60.3%; p=0.087 and pEFS 50.0% vs 37.9%; p=0.012) even when the number of HR patients was significantly higher in ALL2016 (51.6% vs 39.1%). The ALL2016 showed an early advantage for SR patients (pEFS 56.7% vs 47.2%; p=0.114 and pOS 74.4% vs 69.8%; p=0.298) due to the decrease of toxic deaths (10.4% vs 5.5%; p=0.211) however the number of late relapses were still high (19.5% vs 13.2%; p=0.282). In the HR group, both pEFS and pOS were significantly better in ALL2016 (pEFS 43.3% vs 23.5%; p=0.010 and pOS 59.8% vs 45.6%; p=0.036) due to less relapses (14.4% vs 29.4%; p=0.019). Both SR and HR showed a smaller number of abandonments in ALL2016. Conclusions: After small changes in protocol, initial toxicity and abandonments were reduced and the pOS and pEFS were improved. However, relapses still need to be lessened in the next protocol.

Background The aim of this study was to analyse the perioperative results and long term survival of re-sternotomy for surgical aortic valve replacement (SAVR) in octogenarians. Methods This is a retrospective, single centre study (Apr 2000 – Dec 2019). Perioperative data were compared for re-sternotomy with isolated SAVR (Isolated redoSAVR) and re-sternotomy with SAVR and concomitant cardiac procedure (Associated redoSAVR). Regression analyses were performed to identify predictors of in patient mortality. Hazard ratios were calculated, and Kaplan Meier survival curves were compared for groups. Results There were 163 patients (Isolated redoSAVR; 69, Associated redoSAVR; 94). Mean age was 83±3 years and mean logEuroSCORE was 21±12. Follow up was 4.2±3.5 years. Inpatient mortality was 4.9% (1.4% versus 7.4% for Isolated redoSAVR and Associated redoSAVR respectively, p=0.08). TIA/stroke rate was 8% (9% versus 7% for Isolated redoSAVR and Associated redoSAVR respectively, p=0.78). COPD was a predictor of inpatient mortality (OR; 8.86, 95%CI; 1.19, 66.11, p=0.03). Survival was 88.7% at 1 year, 86.4% at 2 years, 70.1% at 5 years, 49.5% at 7 years and 26.3% at 10 years. There was no survival difference between Isolated redoSAVR and Associated redoSAVR (logrank p=0.36, Wilcoxon p=0.84). Significant predictors of adverse long term survival were COPD, postoperative TIA/stroke and length of stay. Survival is lower than age and gender matched first time SAVR and general population of UK. Conclusions RedoSAVR in octogenarians is associated with acceptable but significant morbidity and mortality. Shared decision making should consider emerging transcatheter therapies as viable options in selected patients.

We first consider the nonlinear time fractional diffusion equation D^{1+α}u+D^β u−∆_{H} u=|u|^p posed on the Heisenberg group H, where 1 < p is a positive real nimber to be specified later; D^δ_{0|t} is the Liouville-Caputo derivative of order δ. For 0 < α < 1,0 < β ≤ 1. This equation interpolates the heat equation and the wave equation with the linear damping D^β_{0|t}u. We present the Fujita exponent for blow-up. Then establish sufficient conditions ensuring non-existence of local solutions. We extend the analysis to the case of the system D^{1+α}u+D^β u−∆_{H} u=|v|^q D^{1+δ}v+D^γ v−∆_{H} v=|u|^p. Our method of proof is based on the nonlinear capacity method.

The information detection of complex systems from data is currently undergoing a revolution,driven by the emergence of big data and machine learning methodology. Discovering governingequations and quantifying dynamical properties of complex systems are among central challenges. Inthis work, we devise a nonparametric approach to learn the relative entropy rate from observationsof stochastic differential equations with different drift functions. The estimator corresponding tothe relative entropy rate then is presented via the Gaussian process kernel theory. Meanwhile, thisapproach enables to extract the governing equations. We illustrate our approach in several examples.Numerical experiments show the proposed approach performs well for rational drift functions, notonly polynomial drift functions.

The cytochrome oxidase subunit I (COI) gene was amplified and analyzed for 70 Mediterranean Chondrosia reniformis, collected from eight localities in Tunisia. Polymorphism results revealed high values of haplotype diversity (Hd) and very low nucleotide diversity (π). Thus, these results suggest that our sponge populations of C. reniformis may have undergone a bottleneck followed by rapid demographic expansion. This suggestion is strongly confirmed by the results of neutrality tests and “mismatch distribution”. The important number of haplotypes between localities and the high genetic differentiation (Fst ranged from 0.590 to 0.788) of the current C. reniformis populations could be maintained by the limited gene flow Nm (0.10 - 0.18). Both haplotype Network and the biogeographic analysis showed a structured distribution according to the geographic origin. C. reniformis populations are subdivided into two major clades: Western and Eastern Mediterranean. This pattern seems to be associated with the well-known discontinuous biogeographic area: the Siculo-Tunisian Strait, which separates two water bodies circulating with different hydrological, physical, and chemical characteristics. The short dispersal of pelagic larvae of C. reniformis and the marine bio-geographic barrier created high differentiation among populations. Additionally, it is noteworthy to mention that the “Mahres / Kerkennah” group diverged from Eastern groups in a single sub-clade. This result was expected, the region Mahres / Kerkennah, presented a particular marine environment.