A document by Luca Pecoraro. Click on the document to view its contents.

Background: Toxic Epidermal Necrolysis (TEN) is a rare, drug induced life-threatening mucocutaneous condition caused by immune system activation. TEN is associated with widespread keratinocyte death causing full-thickness denudation of the skin and mucosa, resulting in sepsis and a mortality rate of 30%. Case Description: A 32-year-old female patient was precribed cefoperazone/sulbactam for sore throat. One day later she experienced an itchy rash on her hands. She was given IM dexamethazone for 4 days with no improvement. She presented to the emergency department 6 days later with severe itchy rash. On examination, there was a generalized symmetrical, desquamating erythematous rash distributed on the face, chest and back, with buccal ulceration and violaceous discoloration of the hands and feet. Vital signs were normal. Routine laboratory investigations were significant for high C-reactive protein and low serum albumin. Serology for HIV was negative. A diagnosis of cefoperazone/sulbactam-induced-TEN was made and the drug was discontinued. Evaluation of the SCORE of TEN (SCORTEN) on day one was 1. The patient was admitted to the intensive care unit where she received supportive treatment and intravenous immunoglobulin (IVIG) at a dose of 2 gm/kg over 5 days with gradual improvement. Discussion: Cefoperazone/Sulbactam-induced-TEN is an idiosyncratic, dose independent adverse event. IvIG was used 7 days after appearance of the desquamation with considerable recovery. Keywords: Cefoperazone/Sulbactam Stevens - Johnson syndrome, Toxic Epidermal Necrolysis.

Objectives: The large-scale adoption of transcatheter aortic valve implantation (TAVI) and aging of the population in Japan have led to an increase in the number of TAVI procedures among elderly patients. However, the clinical outcomes of TAVI for nonagenarians in Japan are unclear. The aim of this study was to clarify the outcomes of TAVI in nonagenarians with severe aortic stenosis in a real-world Japanese setting. Methods: This study retrospectively assessed the early and mid-term clinical outcomes after TAVI in nonagenarians (group N; n=23) in comparison to those of younger patients (group Y; n=117). Results: There were no postoperative deaths in either group. Although patients in group N required longer hospital stays (19±32.1 days vs. 12.1±9.3 days, p=0.04), all other early outcomes were equivalent in the two groups. The overall survival at 5 years tended to be lower in group N but the difference was not statistically significant (29.5% vs. 51.1%, p=0.26). The freedom from cardiac events at 5 years rate was equivalent in both groups (69.5% vs. 66.0%, p=0.68). There were no late cardiac deaths in group N. The freedom from late cardiac death rate at 5 years was 100% in group N and 84.6% in group Y. Conclusions: The early and mid-term clinical outcomes of TAVI in nonagenarians were comparable to those in younger patients. These results indicate that TAVI is effective for aortic stenosis in Japanese nonagenarians and may help prevent cardiac deaths.

Background Pediatric anticancer drug development has numerous challenges. The PREA and the BPCA were passed to address the deficiency in pediatric drug development in general. Until recently, the requirement for pediatric evaluation of most oncology products has been waived, because children typically do not have the same type of cancers which occur commonly in adults or the indication or drug had been granted orphan designation. PREA therefore had no impact. Pediatric studies for labeling updates are largely done through BPCA by a Written Request, issued by FDA. Because pediatric and adult populations do not share the same biology, natural history, or disease progression, there are limited opportunities to extrapolate adult efficacy and safety to the pediatric population. The requirements for the pediatric studies have varied greatly over time. Procedure In this study, we searched WRs that were issued by the FDA since 2001. We found 40 such requests issued for oncology drugs and biologics which had been accepted by sponsors. Results Clinical trials included in 23 of the WRs have been concluded, 19 have resulted in exclusivity, and 3 drugs that were studied have been approved for use in pediatric populations. Herein we present the spectrum of WRs from a regulatory, study design, dosing, formulation, analysis plan, evidential standard of efficacy and safety perspective. Conclusions This provides information on requests in the past nearly 20 years and studies completed. As WRs are the anchor of pediatric cancer development for the time being, this can potentially provide insight on how pediatric cancer drug development may change in the future.

Background: Prophylaxis with posaconazole (PP) has shown to be effective in the prevention of invasive fungal infections in immunocompromised adult patients. However, evaluation of its effectiveness and safety in children is limited. The aim of the study was to describe the use of posaconazole as antifungal prophylaxis in children. Methods: We reviewed the medical records of immunocompromised patients under 13 years of age with hematological diseases and post hematopoietic stem cell transplantation (HSCT) who received antifungal PP at the Instituto Nacional de Salud del Niño San Borja (Perú) from January 2014 to December 2018. Results: Fifty-six antifungal prophylaxis events were identified in 47 patients with a median age of 7.5 years (interquartile range [IQR] 4-10), 51.6% (n=24) of whom were female. The main underlying medical conditions were aplastic anemia (n=19, 33.9%), acute lymphoblastic leukemia (n=18, 32.1%), acute myeloid leukemia (n=14, 25.0%), and 34.1% had undergone HSCT. The median dose of posaconazole was 13.62 mg/kg/day (IQR: 12.0-16.8), and the median duration of PP was 24 days (IQR: 16-82). Gastrointestinal symptoms included abdominal pain (17.9%), nausea (16.1%), diarrhea (7.1%) and vomiting (3.6%). Elevated alanine aminotransferase and aspartate aminotransferase levels were observed in 9/35 patients (25.7%) and 10/51 (19.6%) patients, respectively. Five cases of breakthrough fungal infection were identified (8.9%). Conclusions: Breakthrough fungal infection, increased transaminase levels and gastrointestinal symptoms were observed during PP in children under 13 years of age.

Infertility secondary to chemotherapy and/or myeloablative conditioning regimens prior to stem cell transplantation is an important cause of morbidity and psychosocial distress among pediatric cancer patients. Known options exist for fertility preservation; however, knowledge among providers varies. We conducted a pilot study with an educational intervention over one-hour for hematology-oncology faculty, fellows, and advanced practice providers. Participants completed pre-/post-test assessment on fertility preservation knowledge. Participants’ pre-test mean (SD) score was 53% (17%), which significantly increased to 72% (11%) in the post-test (P=0.0004). We demonstrated that a fertility education intervention could improve knowledge regarding infertility risk assessment and fertility preservation options.

Glanzmann Thrombasthenia (GT) is a rare bleeding disorder causing life-threatening bleeding at menarche in the adolescent female. We describe a 12-year-old menarchial female with persistent vaginal bleeding despite multiple treatment modalities including aminocaproic acid, recombinant factor VIIa (rFVIIa), intravenous estrogen, and gonadotropin receptor hormone agonists. Although the standard treatment of bleeding in patients with GT is primarily rFVIIa, new-onset menstrual bleeding in conjunction with an immature hypothalamus-pituitary-ovarian axis often requires expanding treatment to include multiple drug modalities. In our case, a two-step approach was necessary. First, targeting the cessation of menses. Secondly, optimizing long-term control of heavy menstrual bleeding.

Background: Accurate and swift tissue diagnosis is extremely important for the timely initiation of treatment in pediatric oncology. In our department, ultrasound guided core needle biopsy (US guided CNB) is used for tissue diagnosis. In 2016, we added on-site cytology, allowing for an immediate primary diagnosis. We retrospectively reviewed our performance in terms of safety and accuracy for CNBs and on-site cytology Procedure: All pediatric biopsies performed in our hospital between February 2016, and December 2019 were included. Patient clinical, procedural and follow up data were collected. CNB pathology and cytology results were compared to final pathologic diagnosis. Results: We included 185 patients for which 210 biopsies were performed; Median latency time to biopsy was one day. Altogether, we had 164 tumors, (148 malignant,16 benign) and 46 other lesions. 159 tumors were correctly diagnosed by CNB; five malignant tumors were misdiagnosed as benign. The sensitivity of our US guided CNB is 96.7%, specificity 100%, and accuracy 97.6%. On-site cytology was performed in 41 cases; 36 malignant tumors, 2 benign tumors and 3 reactive lymph nodes. The cytologist correctly differentiated tumor from inflammation in all cases, and diagnosed the precise tumor type in 38 cases, with accuracy of 93% for final diagnosis. We had no complications related to the procedure or sedation. Conclusions: US guided CNB with on-site TI cytology for suspected malignancy in the pediatric population highly available, safe and accurate, with real time diagnosis in most cases. The accelerated diagnostic root has huge impact on patient care.

Poor graft function (PGF) is a major obstacle to successful allogeneic stem cell transplantation after achieving normal bone marrow function. We report a successful treatment of domino DLI for poor graft function in younger brother with hyper IgM syndrome from HLA-identical elder brother with the same disorder with a history of HLA-mismatched unrelated bone marrow transplantation using same donor. Immunological profiling revealed that DLI-induced T-regulatory cells could correct skewed immune responses in the BM microenvironment due to secondary PGF pathogenesis. Immunological tolerized domino DLI can be a new therapeutic option for secondary PGF in HLA-identical sibling pairs with congenital immunodeficiency.

Primary Undifferentiated pleomorphic sarcomas (UPS) of the heart extremely rare but aggressive tumors in the pediatric age group with an extremely poor prognosis and no clear guidelines available for best management. Diagnosis is often delayed, as they may be insidious and masquerade as other cardiac benign tumors. We present a rare case of cardiac UPS in a 13 year old with 40 months disease free survival following a combination of early gross total surgical resection followed by adjuvant chemotherapy and radiation therapy. The case highlights the importance of a timely diagnosis and multimodal multidisciplinary aggressive approach for improved survival.

Congestive heart failure is highly prevalent in the elderly population and left ventricular assist device has been increasingly used in this population. LVAD therapy is more costly than medical treatment but it increases the survival and quality of life of the elderly patients with low disease acuity. Therefore careful selection of candidates and implementation of LVAD therapy earlier in the course of the disease is crucial to improve outcomes. With the technical advances and improvement in clinical management, the financial burden of LVAD therapy in the elderly will become less, making this therapy more economically feasible.

Aortopulmonary window (APW) is a rare but serious congenital cardiac malformation, most patients with APW will die from congestive heart failure a few months after birth. However, in this case we presented is an extremely rare condition that consist of a type III APW and a ductus arteriosus originated left pulmonary artery. Preoperative diagnosis included echocardiography and chest computerized tomography revealed anatomical structure of the heart and great vessel clearly, cardiac catheterization indicated that the pulmonary resistances indices were 2.92 wood U⁄m^2 in LPA and 3.35 wood U⁄m^2 in RPA, Qp:Qs was 3.26. This patient underwent surgical correction at the age of 9 and successfully survived.

Background: Extracorporeal membrane oxygenation (ECMO) provides circulatory support in children with congenital heart disease, particularly in the setting of cardiopulmonary failure and inability to wean from cardiopulmonary bypass. This study summarized the clinical application of ECMO in treatment of heart failure after cardiac surgery in neonates. Methods: Clinical data of 23 neonates who received ECMO support in our center from January 2017 to June 2019 were retrospectively analyzed. Results: Twenty-three neonates, aged from 0 to 25 days and weight between 2300 to 4500 g, with heart failure post-cardiotomy were supported with ECMO. The successful weaning rate was 78.26% and discharge rate was 52.17%. Bleeding and residual malformation were the most common complications. The univariate analysis showed that non-survivors were related to the factors such as higher lactate value of ECMO 12h, 24h (P=0.008, 0.001, respectively), longer time to lactate normalization (P=0.001), lactate>10 mmol/L before ECMO (P=0.01), lower weight (P=0.01), longer ECMO duration (P=0.005), lower platelet count (P=0.001), more surgical site bleeding (P=0.001) and surgical residual malformation (P=0.04). Further logistic regression analysis revealed that higher lactate value of ECMO 24h (P=0.003), longer ECMO duration (P=0.015) and surgical site bleeding (P=0.025) were independent risk factors. Conclusions: ECMO was an effective technology to support the neonates with cardiopulmonary failure after open-heart surgery. Control the lactate acidosis and surgical site bleeding event may be helpful for patients’ recovery.

Left ventricular free wall rupture (LVFWR) can occur after myocardial infarction. Sometimes LVFWR can be contained by a pericardium leading to the formation of the pseudoaneurysm. In view of the high tendency to expand and rupture an urgent surgery is indicated. We experienced a rare case of giant left ventricular apical pseudoaneurysm which was successfully managed with surgical intervention.

The authors in this manuscript have reported an increase in the number of vascular emergencies seen during the early phase of the COVID-19 pandemic in the Lombardy region of Italy. A significant increase in the number of acute limb ischaemia was seen during this phase along with other vascular emergencies. In this review, we have tried to examine this association between increase in vascular emergencies and COVID-19 infection. We have also described the differences in presentations, prognosis and procedural outcomes following operative interventions in these patients compared to the non-COVID patients. An attempt has been made to assess the role of adjunctive measures like intravenous heparin to improve outcomes.

We report a rare case of interventricular septal dissecting aneurysm, that resulting from ruptured sinus of Valsalva aneurysm and paravalvular aortic root pseudoaneurysm. A 60-year-old man presented with chest pain and palpitation, the diagnosis was confirmed using multimodality imaging, including transthoracic echocardiography, computer tomography angiogram and coronary angiogram. The patient underwent the modified Cabrol procedure, repaired ruptured sinus of Valsalva aneurysm and closured the communication of the pseudoaneurysm in the department of cardiac surgery. In this case report, we provide information for clinicians diagnostic thought, and highlight the role of multimodality cardiac imaging.

Aim: To assess the feasibility of converting electronic medical records (EMR) into the Observational Medical Outcomes Partnership-Common Data Model (OMOP-CDM) schema and potential for subsequent analyses relating to drug safety. Methods: The EMRs belonging to a tertiary care facility from 2013 to 2016 were mapped onto the OMOP-CDM schema. Vocabulary mappings were applied to translate source data values into OMOP-CDM terminologies. Existing analytic codes from a previous study were modified and applied to conduct an illustrative analysis involving oral anticoagulants (OACs) to mimic analyses that may be part of a typical benefit-risk assessment. A novel visualization is proposed to represent comparative efficacy, safety and utilization in one chart. Results: Records of 245,561 unique patients were mapped onto the OMOP-CDM. The CDM and analytic code templates simplified the data analysis for the illustrative example. Of 132 patients identified, a majority were warfarin users (76.5%), followed by rivaroxaban (19.7%) and apixaban (3.8%). Following six months of follow up, differences in cumulative incidence of bleeding and thromboembolic events were observable. The proposed visualization may facilitate collective evaluation of differences relating to utilization, efficacy and safety of drugs of interest. Conclusion: OMOP-CDM conversion of RWD may be useful for gleaning insights on comparative drug utilization, efficacy and safety for risk-benefit assessments in post-market regulatory settings.

Health and specifically Medication Literacy is important in patient empowerment and in empowering patients and families as effective partners in ensuring optimal health outcomes. While there has is a reasonable body of evidence on this for adults, there has been very little work on medication literacy for children, specifically in terms of effective interventions. Adopting agreed upon nomenclature and developing and validating children's specific instruments -- such as infographics - will be important in moving forward, especially when these instruments can be actively incorporated into eHealth initiatives.

Malignant ventricular arrhythmic storm and sudden cardiac death (SCD) following coronary vasospasm (CVS) are relatively uncommon. On another note, a specific pattern, the QRS-ST-T “shark fin” pattern on ECG, is known to be a high-risk pattern and is associated with a very poor prognosis in the context of coronary artery occlusion. Data reporting the association of CVS-induced SCD and specific high-risk ECG patterns is scant. Herein we present a case of a patient with right coronary artery (RCA) spasm who presented in sudden cardiac death and a “shark fin” pattern on ECG. Primary stenting of the residual lesion after intra-coronary nitroglycerin was performed. The patient received optimal medical therapy and an intracardiac defibrillator. Lowering the threshold for defibrillator implantation may be reasonable in CVS-induced ventricular arrhythmias particularly in the presence during vasospasm of high-risk ECG features such as the “shark fin” pattern.

Aims: Children are high risk groups of valproate (VPA) mediated hepatotoxicity, and oxidative stress plays an important role in the process. This study aimed to determine the association between key genetic polymorphisms of antioxidant pathway GSTP1 rs1695, PON1 rs662, CAT rs769217 and VPA mediated abnormal AST elevation. Methods: A total of 194 eligible children with newly diagnosed epilepsy who aged 1 to 16 years old were selected and treated with valproate. According to the AST abnormalities at the maximum AST during the treatment, the subjects were divided into AST normal group and AST elevation group. SNPscan was used for genotyping. Results: In this study, 25.8% of the patients had AST elevation during VPA treatment. The maximum value of AST in patients with AA genotype of GSTP1 rs1695 during VPA monotherapy was significantly higher than that of patients carrying G alleles (36.50 ±14.89 vs 32.88±10.69, P=0.003). The maximum value of AST in CAT rs769217 genotypes were significantly different (P=0.011, P= 0.045, respectively). The risk of GSTP1 rs1695 AG＋GG genotype of AST elevation was reduced (adjusted OR=0.37, 95% CI:0.16-0.84, P=0.017). And the risk of CAT rs769217 CT genotype or CT＋TT genotype of AST elevation was reduced (adjusted OR=0.30, 95% CI:0.13-0.68, P=0.004 and adjusted OR=0.41, 95% CI:0.20-0.82,P=0.012, respectively). Conclusion: GSTP1 rs1695 and CAT rs769217 are related to VPA-induced AST abnormalities in children. Carriers of GSTP1 rs1695 G allele have a reduced risk of AST abnormalities. CAT rs769217 CC genotype is a risk factor for abnormal AST.

Objective: To determine trends in real-world utilization and in-hospital adverse events from Watchman implantation since its approval by the Food and Drug Administration in 2015. Background: The risk of embolic stroke caused by atrial fibrillation is reduced by oral anticoagulants, but not all patients can tolerate long-term anticoagulation. Left atrial appendage occlusion with the Watchman device has emerged as an alternative therapy. Methods: This was a retrospective cohort study utilizing data from National Inpatient Sample for calendar years 2015-2017. The outcomes assessed in this study were associated complications, in-hospital mortality, and resource utilization trends after Watchman implantation. Trends analysis were performed using analysis of variance. Multivariable adjusted logistic regression analysis was performed to determine predictors of mortality. Results: A total of 17,700 patients underwent Watchman implantation during the study period. There was a significantly increased trend in the number of Watchman procedures performed over the study years (from 1,195 in 2015 to 11,165 devices in 2017, p < 0.01). A significant decline in the rate of complications (from 26.4% in 2015 to 7.9% in 2017, p < 0.01) and inpatient mortality (from 1.3% in 2015 to 0.1% in 2017, p < 0.01) were noted. Predictors of in-hospital mortality included a higher CHA₂DS₂-VASc score (OR 2.61 per 1-point increase, 95% CI 1.91-3.57), chronic blood loss anemia (OR 3.63, 95% CI 1.37-9.61) and coagulopathy (OR 4.90, 95% CI 2.32-10.35). Conclusion: In contemporary United States clinical practice, Watchman utilization has increased significantly since approval in 2015, while complications and in-patient mortality have declined.

Aims: it is generally accepted that bundle branch block (BBB) may be corrected simply by pacing (P) the His bundle (HB) distal to site of block. This hypothesis, based on observations with percutaneous catheters, assumes that conduction block is in proximal HB. However, these postulations have not been systematically studied following active fixation of HB pacing lead. We analyzed role of pacing voltage and capture thresholds in selective (S) and non-selective (NS) HBP in patients with right (R) BBB. Methods: In thirty-nine patients with RBBB, 4 showed S-HBP, 18 showed NS-HBP, and 17 showed NS-HBP at >2.40.8 V and S-HBP at lower voltage (NS-S HBP group). Results 1. During S-HBP there was no correction of RBBB. 2. NS-HBP either completely or partially corrected RBBB along with with a decrease in QRS activation time (919ms from 986ms). 3. NS-HBP group with capture threshold of 1.30.5V completely resolved RBBB in 9/14 vs 3/11 patients in NS-S HBP group with higher capture threshold of 2.40.8V. 4. During NS-HBP higher voltage caused complete resolution of RBBB in 22/39 patients vs 10/39 at lower voltage. Conclusions: 1.) Lack of correction with S-HBP suggests that RBBB was distal to site of HBP and yet was corrected with NS-HBP. 2.) Voltage dependent properties in NS-HBP suggests that conduction via a specialized parallel pathway maintains normal ventricular activation time. 3.) Correction of RBBB in all patients with NS-HBP, suggests that conduction block was either bypassed or right ventricular free wall pre-excited by conduction via a parallel pathway.

The subcutaneous implantable cardioverter-defibrillator (S-ICD) is a well-established method for the prevention of sudden cardiac arrest and an alternative to the transvenous implantable cardioverter-defibrillator (TV-ICD). It is preferred mainly for young patients with long life expectancy, high risk of transvenous lead complications or history of previous endocarditis, or device infections. For both S-ICD and TV-ICD, inappropriate therapies are possible. For S-ICD, the most common cause of inappropriate shocks is T wave oversensing (TWOS), while in TV-ICD – supraventricular tachycardia. We present the case of a 38-year-old patient who reported a shock during physical exercise - crunches.

Background: Increasing numbers of patients have recovered from severe coronavirus disease 2019 (COVID-19) in Wuhan, China. This study aimed to evaluate the association of psychological distress with resting palpitations in those recovered patients. Methods: In this prospective cohort study, consecutive patients who recovered from severe COVID-19 and complained of resting palpitations were included. Dynamic electrocardiogram (ECG) was continuously monitored for 2 hours while patients were at rest. A survey using palpitation frequency scale and the Hospital Anxiety and Depression Scale (HADS) was administrated to all participants. Results: Of the 289 consecutive patients recovering from severe COVID-19, 24 patients (8.3%) suffered resting palpitations symptoms, and 22 patients were finally included. Dynamic ECG monitoring showed that 18 (81.8%) patients had tachyarrhythmias, of which, the most common was sinus tachycardia (17/22, 77.3%). However, patients with sinus tachycardia showed a similar frequency of palpitations episodes compared to those without sinus tachycardia. Anxiety (68.2%) and depression (59.1%) were prevalent among these recovered patients. Patients with anxiety or depression symptoms were respectively associated with a higher frequency of palpitations episodes than those without. In addition, both HADS-anxiety score (r =0.609, P<0.01) and HADS-depression score (r =0.516, P=0.01) were positively related to the frequency of palpitations episodes, respectively. Conclusion: Symptom of resting palpitations, manifested mainly by sinus tachycardia, is not uncommon in patients recovering from severe COVID-19. Psychological distress (anxiety and depression) may be responsible, at least in part, for the resting palpitations symptoms.