Ebstein's anomaly is an uncommon congenital malformation that can associated with atrial septal defect and atrio-fascicular Mahaim. Here we report a known case of Ebstein's anomaly with atrial septal defect and concomitant atrio-fascicular Mahaim pathway who underwent atrial septal defect device closure and concurrent ablation of accessory pathway.

In the world, the most significant change in the ecosystems structure is the conversion from natural land surface into cultivated systems. In 2018, 26.8% of the Brazilian territory was occupied by agricultural activities, from which 73% is pasture. Considering that the management adopted in Brazilian pastures is incipient and leads to degradation, there is a need to characterize the state of the pastures to diagnose the intensity of this use on the soil. However, the diagnosis of large areas using satellites with more detailed resolution is limited by cloud coverage and low temporal resolution. In this sense, the present work aims to diagnose the intensity of land use by pastures (ILUP) in large areas based on the mosaic of images from Landsat 8 (LS8), Landsat 7 (LS7), Sentinel-2 (S2), and MODIS. The methodology consists of harmonizing the NDVI from LS7 and S2 satellites with LS8. For MODIS, the harmonization was carried out based on ILUP obtained previously from NDVI LS8. The methodology was applied at the Doce river basin (DRB). The combination of different sensors allowed to overcome the cloud coverage limitation. DRB has 61.3% of its area occupied by pastures and 78.2% of them have some degree of degradation. ILUP was dependent on DRB’s pedological and climatic characteristics. This dependence is enhanced due to pasture management in the basin, mainly characterized by continuous grazing, which commonly leads to overgrazing scenarios. The areas with great rainfall seasonality and associated with Acrisols/Cambisols are the most susceptible to degradation.

In order to study the fracture properties of dam concrete under post-peak cyclic loading, wedge splitting tests with three loading rates (0.001 mm/s, 0.01 mm/s, 0.1 mm/s) were performed on notched cubic dam concrete specimens. Meanwhile, the acoustic emission (AE) and digital image correlation (DIC) technologies were used to record the crack propagation process of specimens. Test results show that the fracture of dam concrete has a significant rate effect: with the loading rate increases, the peak load increases, the slope of the post-peak P-CMOD curve gradually decreases and the stiffness degradation of dam concrete becomes more serious. The cumulative AE count shows a step increasing trend and has a Kaiser effect. The Kaiser effect decreases with the post-peak cyclic loading procedure, and with the loading rate increases, the Kaiser effect increases. With the increasing of loading rate, AE energy fluctuates violently and b value fluctuates frequently, indicating the damage of dam concrete becomes more serious. As the loading procedure, the damage of the specimen accumulates gradually, and the strain recovery rate decreases gradually. With the loading rate increases, the strain recovery rate decreases and the permanent crack increases. Based on the fictitious crack model, the effective crack length shows a gradual and steady rising trend. As the loading rate increases, the growth rate of the effective crack length becomes large.

Time history data collected from a Direct Current Potential Drop (DCPD) fatigue experiment at a range of temperatures was used to train a Bidirectional Long-Short Term Memory Neural Network (BiLSTM) model. The model was trained on high sampling rate experimental data from crack initiation up through the Paris regime. The BiLSTM model was able to predict the progressive crack extension at intermediate temperatures and stress intensities. The model was able to reproduce crack jumps and overall crack progression. The BiLSTM model demonstrated the potential to be used as a tool for future investigation into fundamental mechanisms such as high-temperature oxidation and new damage models.

The Yunnan-Guizhou Plateau (YGP) is characterized by the distinctive isolated habitat of limestone Karst Islands and features the Wumeng Mountains (Mts), which divide the YGP into the two Plateaus of Yunnan and Guizhou. This study aims to assess the effects of past geographic and environmental isolation and climate fluctuation on the flora distribution in the YGP. To this effect, we analyzed the phylogeographical pattern and genetic structure for Myrica nana, a vulnerable species endemic to the YGP, based on chloroplast and nuclear ribosomal DNA sequence. The results suggest that the genetic and haplotype network structures are divided into at least two groups—cpDNA haplotype H2 (or nrDNA haplotypes h1, h2, and the native haplotype) mainly distributed to the east of the Wumeng Mts, and cpDNA haplotype H1 and haplotypes H3–H10 (or nrDNA haplotype h3) distributed to the west of the Wumeng Mts. A deep genetic split was noted within the two groups to reach 25 steps, especially for the cpDNA fragment variation. The east–west divergence reveals the existence of a natural geographical isolation boundary in the form of the Wumeng Mts, which divides the YGP into the Yunnan and Guizhou Plateaus. Therefore, there existed at least two glacial refugia during the Quaternary glacial period, along with a genetic diversity center, and at least two large geographic protection units for the vulnerable species of M. nana, distributed throughout the eastern and western sides of the Wumeng Mts. This study not only clarifies that the phylogeographical pattern and genetic structure for M. nana can be attributed to geographic and environmental isolation and climate fluctuation, but it also proposes an effective strategy to protect vulnerable species and the important wild flora of the YGP.

Objectives: Innominate artery compression syndrome (IAS) is caused by an anterior compression of the trachea by an abnormally originating innominate artery. One option to relieve such a compression is an anterior aortopexy (AA). In this paper we describe our technique of an AA via a partial upper median sternotomy. Methods: A retrospective review of a prospectively maintained database of patients with IAS (July 2017 to November 2020) treated with AA via a partial upper median sternotomy at University teaching hospitals in the US was done. Results: Nine consecutive patients underwent AA for IAS during the study period. The median age was 9 months (IQR 3- 16.5). The male to female ratio was 1.25. All patients had > 70% compression by flexible bronchoscopy. 2 patients had previous surgeries. The follow-up was a median of 6 (IQR 4- 8.5) months. The indications for the operation were: reflex apnea (4/9 patients), recurrent intubation (4/9 patients), and severe stridor (1/9). IAS was a technical success (defined as ≤ 20 % residual stenosis) in 78 % (7/9) of the patients. Complete symptom resolution after an AA was seen in 71% (5/7) of the patients. 2 patients had an unsuccessful AA, requiring a tracheal resection and an innominate artery reimplantation, respectively. Conclusion: An upper partial sternotomy approach provides a very versatile approach to an AA for IAS. Besides facilitating an adequate AA, it provides options for direct tracheal surgery or an innominate artery reimplantation in case an optimal result is not obtained by an AA.

Background: Synovial sarcoma is a rare soft-tissue malignant tumor most commonly occurring in the extremities and head and neck region, and rarely occurring in the pericardium. Case presentation: We report a 7-year-old boy was admitted to the hospital with recurrent fever and chest pain over the past four months. A cardiac magnetic resonance imaging (MRI) revealed a tumor beneath the heart in the pericardial, and we surgical resection it completely. The postoperative histopathological examination resulted in a diagnosis of monophasic spindle cell type synovial sarcoma. After two weeks of hospitalization, the patient was discharged. Three months after discharge, the positron emission tomography (PET/CT) scans did not show any signs of recurrence. Conclusion: Pericardial synovial sarcoma is a rare disease that is detected early, and complete resection improves patient survival. We recommend CT be performed in patients with recurrent fever and sizeable pericardial effusion to rule out possible pericardial synovial sarcoma considering the echocardiography limitations.

Catheter Ablation of Ventricular Arrhythmias in patients with Prior Mitral Valve Surgery: Challenging, but Feasible and Effective!Amrish Deshmukh, MD; Frank Bogun, MD; Jackson J. Liang, DOElectrophysiology Section, Division of Cardiology; University of Michigan, Ann Arbor, MIFunding: NoneDisclosures: None

Plant phenology is manifested in the seasonal timing of vegetative and reproductive processes, but also has ontogenetic aspects. The adaptive basis of seasonal phenology has been considered mainly in terms of climatic drivers. However, some biotic factors as likely evolutionary influences on plants’ phenology appear to have been under-researched. Several specific cases of putative biotic factors driving plant phenology are outlined, involving both herbivores and pathogens. These illustrate the diversity of likely interactions rather than any systematic coverage or review. Emphasis is on woody perennials, in which phenology is often most multi-faceted and complicated by the ontogenetic aspect. The complete seasonal leaf fall that characterises deciduous plants may be a very important defence against some pathogens. Whether biotic influences drive acquisition or long-term persistence of deciduousness is considered. In one case; of leaf rusts in poplars, countervailing influences of the rusts and climate suggest persistence. Often, however, biotic and environmental influences likely reinforce each other. The timing and duration of shoot flushing may in at least some cases contribute to defences against herbivores, largely through brief periods of ‘predator satiation’ when plant tissues have highest food value. Wide re-examination of plant phenology, accommodating the roles of biotic factors and their interplays with environments as additional adaptive drivers, is advocated, towards developing and applying hypotheses that are observationally or experimentally testable.

Background: CRISPR-cpf1 is a single RNA-guided endonuclease system, becoming a promising tool in both prokaryotic and eukaryotic genome engineering. The editing efficiency of Cpf1 based engineering still requires improvements. However, limited information regarding the relationship between guide RNA sequence and on-target activity is available. To address these challenges, we developed a screening platform based on the association of Acidaminococcus sp. Cpf1(AsCpf1) DNA cleavage with cellular lethality. Major results: In total, we measured the activities of 12,544 guide RNAs, and observed a substantial variation of the editing efficiency depending on the design of the sequence. Based on this large-scale dataset, we designed and implemented a comprehensive computational model to predict activities of guide RNAs. Through comparison using simulated and experimental data, our approach outperformed existing algorithms, enabling selection of efficient guide RNAs. Conclusions: We refine on-target design rules and isolate the important sequence features that contribute to DNA cleavage, that is, AH dimers at position1-8 of protospacer promoting Cas12a activity while TK, GB dimer playing an inhibitory role. We validate guide RNA affinities designed by our optimized rules in both E.coli and 293T cells.

Introduction: Opinion is divided about optimal early timing of the Fontan Operation (FO). While some studies have suggested 3 years-of-age, others have shown good outcomes below 2 years-of -age. We analyzed the impact of age ≤2-years as compared age >2-years on short-term outcome of the FO using a large national database. Methods: A retrospective analysis of the Kids Inpatient Database (2009-16) for the FO was done. The groups were divided into those who underwent FO at age ≤2-years (EF) as compared to age >2-years (LF). The data was abstracted for demographics, clinical characteristics, and operative outcomes. Standard statistical tests were used. Results: 3381 patients underwent FO during this period of which 1482 (44%) were EF. The mean ages of the EF and LF were 1.6 and 4.3, respectively (p< 0.001). LF were more likely to be non-White, female, and have Heterotaxy syndrome. HLHS was more common in EF. There was no difference in the discharge mortality, length of stay, disposition (majority went home), and mean total charges incurred. The overall discharge mortality was low at 0.7% (24/3381). In multivariate analysis: cardiac arrest, acute kidney injury, mechanical ventilation >96 hours, endocardial cushion defect and non-White ethnicity were predictors of a mortality and not age. Conclusion: Contemporary outcomes for FO are excellent with equivalent short-term outcomes in both the age groups. Occurrence of postoperative complications, non-white ethnicity and endocardial cushion defect diagnosis were predictive of a negative outcome.

A 54-year old male developed unexpectedy a severe penicillin allergy after 5 standard erysipelas treatments by intravenous benzylpenicillin and/or oral phenoxymethylpenicillin without any clinical symptoms of allergy during 16 years. During the 6th erysipelas treatment by intravenous benzylpenicillin, the patient experienced an anaphylactic reaction within 30 minutes.

In this paper, a comparative study of the very-high-cycle fatigue (VHCF) behavior of railway wheel steel under axial loading and rolling contact loading was conducted. Fatigue tests were performed with an ultrasonic fatigue test machine under axial loading, and the fracture surfaces from the fatigue tests and shattered rims taken from the failed railway wheels were observed. The wheel steel under axial loading presents a VHCF behavior with Mode I crack, and that under rolling contact loading is a VHCF behavior with mix Mode II-III crack. For the VHCF behavior with Mode I crack ,surface and interior crack initiation occurred with equal probability at both low and high stress levels and produced a dual linear S-N curve since the value of fatigue limits for the surface and interior crack initiation are close. For the VHCF behavior with mix Mode II-III crack, cracks were initiated from the interior Al 2O 3 inclusion and the fatigue life was beyond 10 7 cycles. Fatigue bands were observed on the fracture surface under rolling contact loading. The ferrite nanograins formed due to the stress state of shear plastic strain with a large compressive stress. The formed nanograins were softer than the matrix caused by the redistribution of the carbon.

In this paper we consider a one-dimensional swelling porous-elastic system with second sound and delay term acting on the porous equation. Under suitable assumptions on the weight of delay, we establish the well-posedness of the system by using semigroup theory and we prove that the unique dissipation due to the delay time is strong enough to exponentially stabilize the system when the speeds of wave propagation are equal.

Background: Catheter ablation is an effective treatment for ventricular tachycardia (VT), albeit the decision to undergo this procedure is often influenced by underlying comorbidities. The present study aims at evaluating the effects of chronic kidney disease (CKD) on clinical outcomes of VT ablation. Methods: We identified 7,212 patients who presented between 2016-2018 and underwent catheter ablation for VT. Their clinical data were retrospectively accrued from the national readmission database (NRD) using the corresponding diagnosis codes. We compared clinical outcomes between patients with chronic kidney disease (CKD-group) and patients without. Odds ratios (OR) for the primary and secondary outcomes were calculated, and multivariable regression analysis was utilized to adjust for confounding variables. Results: Compared with patients without CKD, patients in CKD-group were older (mean age 67.9 vs. 60.5 years, P <0.01), had a longer mean length of stay (8.73 vs. 5.69 days, P <0.01), and higher in-hospital mortality (OR 2.24, 95% confidence interval (CI) (1.29-3.88), P<0.01). CKD-group patients had increased risk of developing acute kidney injury (10% vs. 8.6%, P<0.01) and 30-day readmission rate due to VT (OR 1.77, 95% CI (1.17-2.69), P<0.01). Conclusion: In patients with CKD, VT ablation is associated with worse clinical outcomes in-hospital mortality and 30-day readmission rate. This significantly influences the decision-making prior to performing this procedure.

Impact of prior sternotomy on survival and allograft function after heart transplantation: a single-center matched analysisPrior sternotomy versus primary heart transplantEditorialE. Potapov, J. SteinIn the presented study, the authors showed that prior sternotomy in heart transplant candidates does not impact survival after heart transplantation (reference). The analysis was performed between 106 propensity score-matched pairs (212 patients).The results of published studies are contradictory and confusing. The small, single-center study published by Sert D, 2020, showed an increased early mortality in HTx recipients with prior sternotomy1, with no increased bleeding risk and a similar 4-year survival. In contrast, yet another single-center study with a similar design –no sternotomy vs. VAD-supported vs. prior sternotomy other than for VAD– published by Gaffey in 2015 showed no differences regarding early and long-term mortality, but a significantly higher risk of postoperative bleeding and a greater use of blood products2. A further single-center study with a comparable number of patients published in 2018 by Still S yet again showed that HTx recipients with prior sternotomy required more blood transfusions and showed an increased incidence in postoperative pneumonia, wound infection, and longer hospital stays. A stepwise multivariable regression model identified prior sternotomy as a predictor of primary graft dysfunction with a subsequently higher short-term and 1-year mortality3. However, in these studies the impact of confounding variables was not eliminated.Having said that, the presented study attempts to overcome imbalances in confounding variables by comparing survival and complications between propensity score-matched patient groups. The matching procedure was based on established risk factors including recipients’ baseline characteristics, donor age, sex mismatch, risk scores, ECLS, PVR, serum creatinine, and serum bilirubin, and ultimately produced 106 matched pairs. However, the benefit of balanced confounders is achieved at the cost of a reduced number of patients and therefore less power to detect differences between patient groups. The lack of significant differences in this study cannot merely be explained by a low power, but is instead due to the similarity of effects: Authors report a 30-day mortality of 5.7 % for prior sternotomy vs. 7.5 % for first-time sternotomy and no impact of prior sternotomy on long-term survival with an HR of 0.87 [95% CI: 0.57, 1.56]. Contradicting the above-mentioned studies, these results do not even come close to indicating a trend towards worse long- and short-term survival for patients with prior sternotomy. This also holds true for long-term survival in the unmatched population of 131 patients with and 381 patients without redo surgery.Now how about a larger registry-based analysis? An analysis based on the UNOS database comprising 11,266 patients showed that prior sternotomy was associated with an excess 3.3 % mortality and higher morbidity within the first 60 days after heart transplantation, as measured by the frequency of dialysis, drug-treated infections, and strokes. Conditional 5-year survival after 60 days is unaffected by prior sternotomy4. Five years later, another group performed an analysis of the same UNOS database (meanwhile comprising 14,730 patients) and showed again that prior sternotomy is a risk factor for worse survival after cardiac transplantation, mainly due to an increased early postoperative mortality5.Why are we interested in knowing the effect of prior sternotomy on post-transplant outcomes? Since a prospective, randomized study is not possible due to ethical reasons, we have to rely on retrospective analyses. From a practical perspective, a comparison is meaningless – patients with prior sternotomy would never be refused for HTx due to this fact alone, even if we knew that morbidity and mortality in these patients may be higher.In our opinion, such an analysis may be performed to identify and support the advantages of less invasive LVAD implantation regarding the outcome of later HTx, as was performed in a first analysis of 46 patients (sic!, the lowest number of patients among the discussed studies) published by Riebandt J, 20216. The study showed that patients supported with LVAD implanted via full sternotomy required more packed red blood cells with no increased risk of bleeding, and subsequently developed more donor-specific antibodies, however, without any impact on short- and long-term survival, similar to the studies discussed above2,3.However, the virgin chest is not comparable to that of patients supported with an LVAD implanted via a less invasive approach, even if no7 or partial sternotomy8 is performed. In either of the groups the pericardium remains intact. Regardless of the technique used, the left pleura is opened, as is the pericardium around the ascending aorta and the apex of the right and left ventricles, and the graft is placed into the pericardial space, causing adhesions making any efforts to suggest, that the HTx in the “virgin chest”is similar to that after less invasive LVAD implantation not appropriate.Finally, the authors should nonetheless be congratulated on their outstanding surgical experience and the resulting very good outcomes in HTx – better than in the majority of centers worldwide.References1. Sert DE, Kervan Ü, Kocabeyoğlu SS, et al. Early and long-term results of heart transplantation with reoperative sternotomy. Turk gogus kalp damar cerrahisi dergisi 2020;28:120-6.2. Gaffey AC, Phillips EC, Howard J, et al. Prior Sternotomy and Ventricular Assist Device Implantation Do Not Adversely Impact Survival or Allograft Function After Heart Transplantation. The Annals of thoracic surgery 2015;100:542-9.3. Still S, Shaikh AF, Qin H, et al. Reoperative sternotomy is associated with primary graft dysfunction following heart transplantation. Interactive cardiovascular and thoracic surgery 2018;27:343-9.4. Kansara P, Czer L, Awad M, et al. Heart transplantation with and without prior sternotomy: analysis of the United Network for Organ Sharing database. Transplantation proceedings 2014;46:249-55.5. Axtell AL, Fiedler AG, Lewis G, et al. Reoperative sternotomy is associated with increased early mortality after cardiac transplantation. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2019;55:1136-43.6. Riebandt J, Wiedemann D, Sandner S, et al. Impact of Less Invasive Left Ventricular Assist Device Implantation on Heart Transplant Outcomes. Seminars in thoracic and cardiovascular surgery 2021.7. Potapov EV, Kukucka M, Falk V, Krabatsch T. Off-pump implantation of the HeartMate 3 left ventricular assist device through a bilateral thoracotomy approach. The Journal of thoracic and cardiovascular surgery 2017;153:104-5.8. Nersesian G, Potapov E, Starck CT, et al. Surgical Implantation Techniques of Modern Continuous Flow Ventricular Assist Devices. Surgical technology international 2021;37:263-9.

Rationale, aims and objectives 39 Evidence-based medicine (EBM) holds that estimates of effects of health interventions based on 40 high-certainty evidence (CoE) are expected to change less frequently than the effects generated 41 in low CoE studies. However, this foundational principle of EBM has never been empirically 42 tested. 43 Methods 44 We reviewed all systematic reviews and meta-analyses in Cochrane Database of Systematic 45 Reviews from January 2016 through May 2021 (n=3,323). We identified 414(207x2) and 384 46 (192x2) pairs of original and updated Cochrane reviews that assessed CoE and pooled 47 treatment effect estimates. We appraised CoE using the Grading of Recommendations 48 Assessment, Development and Evaluation (GRADE) method. We assessed the difference in 49 effect sizes between the original versus updated reviews as a function of change in CoE, which 50 we report as a ratio of odds ratio (ROR). We compared ROR generated in the studies that 51 changed CoE from very low/low (VL/L) to moderate/high (M/H) vs. MH/H VL/L. We also 52 assessed the heterogeneity and inconsistency (using the tau and I2 statistic), the change in 53 precision of effect estimates (by calculating the ratio of standard errors) (seR), and the absolute 54 deviation in estimates of treatment effects (aROR). 55 Results 56 57 We found that CoE originally appraised as VL/L had 2.1 (95%CI: 1.19 to 4.12; p=0.0091) times 58 higher odds to be changed in the future studies than M/H CoE. However, the effect size was not 59 different when CoE changed from VL/L M/H vs. M/H VL/L [ROR=1.02 (95%CI: 0.74 to 1.39) 60 vs. 1.02 (95%CI: 0.44 to 2.37); p=1 for the between subgroup differences]. aROR was similar 61 between the subgroups [median (IQR):1.12 (1.07 to 1.57) vs 1.21 (1.12 to 2.43)]. We observed 62 large inconsistency (I 2=99%) and imprecision in treatment effects (seR=1.09). 63 Conclusions 64 We provide the first empirical support for a foundational principle of EBM showing that low65 quality evidence changes more often than high CoE. However, the effect size was not different 66 between studies with low vs high CoE. The finding that the effect size did not differ between low 67 and high CoE indicate urgent need to refine current EBM critical appraisal methods

Around 3-4 children born with congenital heart diseases have univentricular hearts, where the prognosis of univentricular hearts is poor in the past, with a survival rate of less than 50% during the first year and 10% during the first ten years of life. Based on a literature search, current advances in perioperative management of neonates with complex congenital heart diseases have increased their survival rate by 85%. To aid cardiothoracic surgeons worldwide, this comprehensive literature review will focus on the perioperative management of staged palliation surgery for functional univentricular hearts, considering current trends as well as how we do it in our centre. Our review article specifially discusses perioperative strategies regarding surgical considerations, current techniques, to deal with overshunting and undershunting during the first stage of palliation surgery. This article also gives an overview on when a patient is suitable to go through with the next stage of the procedure, which is the implementation of a bidirectional cavopulmonary shunt or the Hemi-Fontan procedure. Lastly, this article gives a comprehensive approach regarding perioperative strategies of the Fontan procedure, which include patient criteria, current surgical techniques, postoperative management, as well as the use of anticoagulants after the Fontan procedure.

In the present work, we define a new anomaly, $\Psi$, termed semifocal anomaly. It is determined by the mean between the true anomaly, $f$, and the antifocal anomaly, $f^{\prime}$; Fukushima defined $f^{\prime}$ as the angle between the periapsis and the secondary around the empty focus. In this first part of the paper, we take an approach to the study of the semifocal anomaly in the hyperbolic motion and in the limit case correspoding to the parabolic movement. From here we find a relation beetween the semifocal anomaly and the true anomaly that holds independently of the movement type. We focus on the study of the two-body problem when this new anomaly is used as the temporal variable.\\ In the second part, we show the use of this anomaly —combined with numerical integration methods— to improve integration errors in one revolution. Finally, we analyze the errors committed in the integration process —depending on several values of the eccentricity— for the elliptic, parabolic and hyperbolic cases in the apsidal region.

We aim to report a patient with vertebral brown tumor in the context of primary hyperparathyroidism presented with shoulder pain. This is the first report of C5 involvement by Brown tumor in a primary hyperparathyroid patient and emphasizes the consideration of cervical vertebral evaluation in patients with persistent shoulder pain.

Various clinical forms of cutaneous leishmaniasis can be encountered such as: ulcerated, lupoïd, sporotrichoïd and other rare forms (eczematiform, erysipeloid, psoriasiform, verrucous, and pseudotumoral). We report an atypical presentation. Dermatologists should be aware when facing a verrucous mass, especially if the patient comes from an endemic country.

Giant Tumor of the perineal regionKey clinical message: Giant condyloma acuminatum, also known as, Buschke-Lowenstein tumour is a very rare, sexually transmitted disease. It is a slow-growing, destructive lesion that affects the anogenital region. The HPV has been identified as an important contributory factor in the development of this tumor.Key words: Dermatology, oncology, Giant condyloma acuminatum , HPV.A 48-year old man presented with a giant lesion of the perineal region which appeared 10 years before and gradually increased in size. Clinical examination revealed a lobulated, exophytic, non-painful, non-bleeding, cauliflower-shaped lesion on the penis and the scrotum, measuring approximately 8 x 7 cm suggestive of a giant condyloma acuminatum (Figure 1). There were no enlarged inguinal nodes. Magnetic resonance imaging of the pelvis and the abdomen revealed no regional lymph node involvement or evidence of distant metastasis. A skin biopsy confirmed the diagnosis of papillary condyloma acuminatum secondary to human papillomavirus (HPV). Radical excision of the entire lesion showed no signs of invasion. Blood tests for detecting Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C virus (HCV) and syphilis were negative. Giant condyloma acuminatum, also known as, Buschke-Lowenstein tumour is a very rare, sexually transmitted disease.1,2 It is a slow-growing, expansive, cauliflower-like, destructive lesion that affects the anogenital region.1,2 The HPV has been identified as an important contributory factor in the development of this tumor.1,2

Neural Tube Defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to cerebral folate deficiency by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased risk for NTDs by depressing embryonic folate concentrations. In this study, we examined CIC variants from whole genome sequencing (WGS) data of 140 isolated spina bifida cases and identified 8 missense variants of CIC gene. We tested the pathogenicity of the observed variants through multiple in vitro experiments. We determined that CIC variants decreased FOLR1 protein level and planar cell polarity (PCP) pathway signaling in a human cell line (HeLa). In a murine cell line (NIH3T3), CIC loss of function variants down regulated PCP signaling. Taken together, this study provides evidence supporting CIC as a risk gene for human NTD.

The generalized finite difference method is a meshless method for solving partial differential equations that allows arbitrary discretizations of points. Typically, the discretizations have the same density of points in the domain. We propose a technique to get adapted discretizations for the solution of partial differential equations. This strategy allows using a smaller number of points and a lower computational cost to achieve the same accuracy that would be obtained with a regular discretization.