Indeterminate Etiology Research Articles

Etiology, Characteristics, and Outcomes of Neonatal Liver Failure: Lessons Learned Over the Last 3 Decades

To evaluate trends in etiology and outcomes of neonatal liver failure (NLF) over 30years retrospectively at a single institution. Inclusion criteria for this retrospective cohort study were babies presenting at a chronological age of ≤28days between 1991 and 2020 with prothrombin time≥20seconds and biochemical liver injury. Demographics, etiology, laboratory investigations, need for extrahepatic organ support, acute kidney injury, and intervention with liver transplant (LT) were recorded. Survival outcomes were measured as discharge from the hospital alive with native liver or LT. The study period was stratified into 3 10-year blocks. Trends were analyzed for hospital admissions, etiology, and survival outcomes. One hundred twenty-six babies met the NLF criteria. Admissions to the hospital increased from 21 in 1991-2000 to 65 in 2011-2020. An increasing trend in infectious and metabolic causes, while a decreasing trend in indeterminate etiology, was noted. Survival with native liver improved from 23.8% in 1991-2000 to 55.4% in 2011-20 (P=.021), and mortality reduced from 52.4% to 35.4% during the same periods (P=.213). Twenty-three (18.2%) neonates received LT. Post-LT survival outcomes were 100% for gestational alloimmune liver disease, 66.6% in the indeterminate group, and 25% for herpes simplex virus. Specific etiologies (gestational alloimmune liver disease, OR=0.07 [0-0.77, P=.048]), presence of acute kidney injury (OR=6.22 [1.45, 29.38, P=.015]) and need for inotropes (OR=6.22 [1.45, 29.38, P=.028]) influenced mortality in multivariable logistic regression analysis. In the last 30years, advances in diagnosis, treatment, and increasing experience with LT have improved survival in NLF.

Pegivirus Detection in Cerebrospinal Fluid from Patients with Central Nervous System Infections of Unknown Etiology in Brazil by Viral Metagenomics.

Metagenomic next-generation sequencing (mNGS) methodology serves as an excellent supplement in cases where diagnosis is challenging to establish through conventional laboratory tests, and its usage is increasingly prevalent. Examining the causes of infectious diseases in the central nervous system (CNS) is vital for understanding their spread, managing outbreaks, and effective patient care. In a study conducted in the state of São Paulo, Brazil, cerebrospinal fluid (CSF) samples from 500 patients with CNS diseases of indeterminate etiology, collected between 2017 and 2021, were analyzed. Employing a mNGS approach, we obtained the complete coding sequence of Pegivirus hominis (HPgV) genotype 2 in a sample from a patient with encephalitis (named IAL-425/BRA/SP/2019); no other pathogen was detected. Subsequently, to determine the extent of this virus's presence, both polymerase chain reaction (PCR) and/or real-time PCR assays were utilized on the entire collection. The presence of the virus was identified in 4.0% of the samples analyzed. This research constitutes the first report of HPgV detection in CSF samples in South America. Analysis of the IAL-425 genome (9107 nt) revealed a 90% nucleotide identity with HPgV strains from various countries. Evolutionary analyses suggest that HPgV is both endemic and extensively distributed. The direct involvement of HPgV in CNS infections in these patients remains uncertain.

Clinical characteristics and outcome of amaurosis fugax due to transient retinal ischemia: Results from a contemporary cohort

BackgroundWhether presenting an episode of amaurosis fugax (AFx) increases the risk of ischemic stroke is controversial and there is a lack of consensus in the following management. We aimed to describe the clinical characteristics and prognosis of patients with AFx due to suspected transient retinal ischemia. MethodsObservational, retrospective study of patients admitted in a Comprehensive Stroke Center with diagnosis of AFx due to suspected transient retinal ischemia between 2015 and 2020. Clinical characteristics and diagnostic-therapeutic data were collected, as well as recurrences (new episodes of amaurosis and/or ischemic strokes). Multivariable Cox regression analyses were performed to study factors associated with the risk of recurrence. ResultsWe included 91 patients with a mean age of 67.9±14.8 years, 43(47.3%) were women. After the diagnostic workup 14(15.4%) AFx were attributed to an atherothrombotic etiology, 4(4.4%) cardioembolic source, 10(11%) other determined cause (TOAST-OC) and 63(69,2%) indeterminate etiology. 71(78%) patients started antiplatelet therapy and 2(2.2%) anticoagulant therapy. After a median follow-up of 3.5 years (IQR 1.8-5.2), at least one recurrence was recorded in eight (8.8%) patients (four new AFx and four cerebral infarctions). TOAST-OC (HR=9.66, 95% CI 2.41-38.70; p=0.001) and prior history of ischemic stroke (HR=4.21. 95% CI 1.01-17.66; p=0.049) were both independently associated with the risk of recurrence. ConclusionsIn two out of three patients, AFx due to transient retinal ischemia was of undetermined cause. The risk of stroke recurrence after a first episode of AFx in our cohort was 8.8%. Patients with TOAST-OC etiology identified were at highest risk of recurrence.

Indeterminate etiology of acute liver failure in North America: Less common, still grave prognosis.

The etiology of acute liver failure (ALF) remains one of the most important factors in determining prognosis and predicting outcomes. In a significant proportion of ALF cases, however, the etiology remains unknown and is categorized as indeterminate ALF (IND-ALF). In this study, we summarize findings from patients with IND-ALF from 32 transplant centers across the United States, and we compare laboratory, prognostic, and outcome data for patients with IND-ALF. Between 1998 and 2019, 3364 adult patients with ALF or acute liver injury (ALI) from 32 liver transplant centers were enrolled in the ALFSG registry. The primary clinical outcome of interest was 21-day transplant-free survival (TFS). Of the 3364 patients enrolled in the ALFSG registry, 3.4 % (n=114) were adjudicated as true indeterminate. On multivariate analysis, patients with a lower bilirubin, lower INR, lack of use of mechanical ventilation and no clinical features of coma at baseline had a higher odds ratio of transplant free survival. The number of deaths were similar between patients withtrue-INDALF versus patients withindeterminableALF (29.8%vs. 27.2%), with almost half of the patients requiring liver transplant (42.1%vs. 45.7%). We illustrate the poor prognoses that true-IND-ALF and indeterminable ALF carry and the need for emergency liver transplantation in most cases.

LICHEN PLANUS SCLEROSUS: CASE REPORT

Lichen planus sclerosus is a rare chronic inflammatory disease with mucocutaneous manifestation and indeterminate etiology, more common in postmenopausal women. It usually affects the anogenital region in conjunction with oral lesions. Isolated oral lesions are rare. A 57-year-old female patient was referred to a dental care center due to painful lesions located in the palate, gingiva, and oral mucosa, evolving for 6 months. Clinical examination showed: whitish, circumscribed, non-scrapable, firm lesions, in various sizes, scattered around the mucosa. Incisional biopsy revealed a saw-tooth pattern on the epithelium, showing areas of atrophy and others with a thick paraceratin layer. The connective tissue displayed diffuse chronic inflammatory infiltrate, close to the epithelium-connective junction. A sclerotic appearance, with an expressive collagen presence, was observed. The patient was thus diagnosed with lichen planus sclerosus and was referred to the dermatology service, where she has been undergoing treatment for 5 months, showing signs of improvement. Lichen planus sclerosus is a rare chronic inflammatory disease with mucocutaneous manifestation and indeterminate etiology, more common in postmenopausal women. It usually affects the anogenital region in conjunction with oral lesions. Isolated oral lesions are rare. A 57-year-old female patient was referred to a dental care center due to painful lesions located in the palate, gingiva, and oral mucosa, evolving for 6 months. Clinical examination showed: whitish, circumscribed, non-scrapable, firm lesions, in various sizes, scattered around the mucosa. Incisional biopsy revealed a saw-tooth pattern on the epithelium, showing areas of atrophy and others with a thick paraceratin layer. The connective tissue displayed diffuse chronic inflammatory infiltrate, close to the epithelium-connective junction. A sclerotic appearance, with an expressive collagen presence, was observed. The patient was thus diagnosed with lichen planus sclerosus and was referred to the dermatology service, where she has been undergoing treatment for 5 months, showing signs of improvement.

Insights Through Detailed Immunophenotyping into The Immune Etiology Of Indeterminate Pediatric Acute Liver Failure (IND-PALF): An Immune Dysregulatory Disease

Approximately one-third of acute pediatric liver failure may be due to indeterminate etiology (IND-PALF). Liver histopathology has shown dense infiltrates of CD8+CD103+ (tissue-resident memory T cell phenotype) Perforin+ T cells in most of these patients suggesting underlying immune dysregulation, which may concurrently evolve to severe aplastic anemia (SAA). A viral etiology has been postulated, and management may require liver transplant and/or HCT. Given the high likelihood of immune dysregulation contributing to the severity of the disease and lack of detailed immunological investigation, we undertook cellular and molecular studies in a small cohort of IND-PALF patients. Four patients (3–8y, 3 males, 1 female) presented with PALF and histopathology consistent with IND-PALF. We performed detailed blood immunophenotyping on 3 of the 4 patients (Table). Key immune anomalies included pan-lymphopenia in 2/3 patients, expansion of activated, exhausted and senescent CD8+ T cells, decreased switched memory B cells and CD19+27+ (total memory + plasmablasts) B cells. To facilitate selection of immunomodulatory therapy best suited for disease control, the ability of FOXP3+Tregs to upregulate CTLA4 on activation was assessed and significantly reduced in 2 of the 3 patients. All patients displayed increased sIL-2R, CXCL9, IL-18 and IL-6 levels compared to healthy controls, with CXCL9 higher than IL-18 indicating T cell activation. Genomic analyses including bulk RNA-seq and pathogen-seeking metagenomics was performed on liver tissue and PBMCs on all 3 patients with appropriate controls. A preliminary analysis of metagenomics data did not reveal evidence of viral RNA in tissue. A monogenic immune etiology was not identified in any of the patients. One patient was initiated on abatacept (P1) and has remained clinically stable without liver transplant or HCT and evidence of normalization of bone marrow cellularity; one patient required a liver transplant (P3) and two patients required allogeneic HCT (P2 and P4). All patients are currently on immunosuppressive therapy. In summary, severe CD8+ T cell dysregulation exemplifies patients diagnosed with IND-PALF, and detailed blood immunophenotyping performed early in the disease course can help identify these patients and enable prompt initiation of targeted immunomodulation, which can mitigate end-stage liver and bone marrow failure.TableImmune Profile of IND-PALF patients at diagnosisP1P2P3Reference Interval/Cut-offAge at Presentation/Dx3 yrs.8 yrs.3 yrs.SexFMMCD45+ALC (cells/µL)23219248191695–5226 cells/µLCD3+Tcell (cells/µL)1281523746969–3471 cells/µLCD4+Tcell (cells/µL)7143121513–2081 cells/µLCD8+Tcell (cells/µL)1071066568336–1355 cells/µLCD19+20+ B cell (cells/µL)487249165–1154 cells/µLCD16/56+ NK cell (cells/µL)632217116–1075 cells/µLT cell Activation MarkersCD4+ HLA DR+ (%CD4)40.1420.676.3610.67%CD8+ HLA DR+ (%CD8)47.4254.5038.3814.60%CD4+CD38+DR+ (%CD4)30.3812.604.245.50%CD8+CD38+DR+ (%CD8)42.9350.3436.347.21%T cell Senescence/Exhaustion MarkersCD4+CD57+ (%CD4)51.3724.054.445.55%CD4+CD28-(%CD4)28.8514.443.402.49%CD8+CD57+ (%CD8)76.6246.4522.9622.43%CD8+CD28-(%CD8)56.1312.4811.7018.53%CD4+PD-1+DR+ (%CD4)24.077.780.651.10%CD8+PD-1+DR+ (%CD8)26.7425.0423.782.28%CTLA4 expression on Activated Tregs (ratio of stimulated/unstimulated)1.111.775.624.22%B cell SubsetsCD19+CD27+ Total memory + plasmablasts (%CD19)6.084.588.356–34%CD19+27+IgM-IgD- (sm B cells) (%CD19)4.120.983.102–18%CD19+CD24++CD38++Transitional B cells (%CD19)39.1937.387.413–23%Cytokines (pg/mL)sIL-2R5987.502986.253741.5144–1329 pg/mLCXCL913926.506224.083582<647 pg/mLIL-181968.041152.733819.5089–540 pg/mLIL-621.03106.7021.8<10 pg/mLFeatures of aplastic anemia were observed in all 4 patients though only 2 required HCT. Abnormal values indicated in red font.

New Guidelines for Idiopathic Pulmonary Fibrosis and Progressive Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common and fatal idiopathic interstitial pneumonia and is characterized by chronic progressive pulmonary fibrosis of indeterminate etiology. In 2018, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society published joint clinical practice guidelines for IPF. The guidelines require exclusion of known causes of interstitial lung disease and identification of a radiological and/or pathologic pattern of usual interstitial pneumonia (UIP). The diagnosis of IPF is a multidisciplinary process, involving pulmonologists, radiologists, pathologists and, if necessary, experts in other medical fields. The 2022 guidelines for IPF revisit and clarify the radiological and pathological features of UIP. In addition, recommendations regarding transbronchial lung cryobiopsy, antacid medication, and antireflux surgery are revised or established based on up-to-date evidence in the 2022 guidelines. The new guidelines also encompass the definition and treatment of progressive pulmonary fibrosis (PPF). PPF comprises diverse fibrotic interstitial lung diseases other than IPF, which progress despite standard treatment. The diagnosis of PPF is based on symptoms, physiologic evidence, and radiologic evidence of progression. The use of nintedanib was suggested for patients with PPF other than IPF who are unresponsive to standard treatment. This review introduces and discusses the recommendations for the diagnosis and treatment of IPF and PPF in the new international guidelines.

High yield on aetiology using a systematic diagnostic approach to paediatric acute liver failure, analysis of a nationwide cohort.

Paediatric acute liver failure (P-ALF) is a rare and devastating condition that leads to death or liver transplantation (LTx) in 40%-60% of cases. Determining the aetiology can enable disease-specific treatment, aid in prognostication for hepatic recovery and guide the decision-making for liver transplantation. This study aimed to retrospectively evaluate a systematic diagnostic approach to P-ALF in Denmark and to collect epidemiological nationwide data. All Danish children aged 0-16 years with P-ALF diagnosed between 2005 and 2018, and who were evaluated using a standardised diagnostic assessment programme, were eligible for retrospective analysis of clinical data. A total of 102 children with P-ALF were included (presentation at 0 days to 16.6 years of age, 57 females). Aetiological diagnosis was established in 82% of cases, the remainder were indeterminate. Fifty percent of children with P-ALF of indeterminate aetiology died or underwent LTx within 6 months after their P-ALF diagnosis, compared to 24% of children with an aetiological diagnosis, p= 0.04. Following a systematic diagnostic evaluation programme, made it possible to identify the aetiology of P-ALF in 82% of cases which is associated with improved outcomes. The diagnostic workup should never be considered complete but rather adapt to ongoing diagnostic advances.

Etiology and Outcome of Adult and Pediatric Acute Liver Failure in Europe.

Acute liver failure (ALF) is rare but life-threatening. Common causes include intoxications, infections, and metabolic disorders. Indeterminate etiology is still frequent. No systematic data on incidence, causes, and outcome of ALF across Europe are available. Via an online survey we reached out to European Reference Network Centers on rare liver diseases. Numbers and etiology of ALF cases during 2020 were retrieved and diagnostic and treatment availabilities assessed. In total, 455 cases (306 adult, 149 pediatric) were reported from 36 centers from 20 countries. Intoxication was the most common cause in adult and pediatric care. The number of cases with indeterminate etiology is low. Diagnostic tools and specific treatment options are broadly available within this network. This is the first approach to report on etiology and outcome of ALF in the pediatric and adult population in Europe. High diagnostic yield and standard of care reflects the expert status of involved centers.

Symptomatic fractured iliac venous stent in a young patient.

A 30-year-old man, avidly athletic (jogging, swimming), presented with a 2-year history of recurrent, lifestyle-limiting left lower extremity exertional fatigue. He consented to this publication. Symptoms initially resolved for 6 months after left iliofemoral vein stenting (16 × 100 mm Venovo) elsewhere for occlusion of indeterminate etiology. Physical examination revealed tightness, increased left lower extremity circumference without signs of chronic venous stasis, and normal arterial pulses. He denied history of venous thromboembolism.

Outcomes Analyses of Pediatric Acute Liver Failure Subjects Listed for Liver Transplantation.

We characterized recent outcomes in US pediatric acute liver failure (PALF) subjects listed for liver transplantation (LT) using the Scientific Registry of Transplant Recipients (SRTR) database. Pediatric subjects listed for LT from 2002 to 2015 were assigned to the "PALF" group based on status 1/1A listing, INR >2, no hepatic artery thrombosis, and no primary graft nonfunction (N = 397). Subjects were assigned to the "non-PALF" group if listed with any status other than 1/1A (N = 4509). The PALF group had more infants <3 months of age and males at listing for LT compared to the non-PALF group. Two-thirds of PALF subjects had an indeterminate etiology. LT waitlist survival was significantly worse in the PALF group compared to the non-PALF group. Likelihood of removal from the LT waitlist for being "too sick" was higher, while that of removal for "spontaneous recovery" was lower in PALF subjects. Post-LT short-term (30 days) and long-term (60 months) outcomes were also significantly worse in PALF versus non-PALF subjects. PALF subjects who underwent living-donor-liver-transplant (LDLT) had similar LT waitlist times and post-LT survival compared to those undergoing deceased-donor-liver-transplant (DDLT). Over the study period, we observed a decreased number of liver transplants, and increase in LT waitlist- and short-term post-LT-survival in PALF subjects. LT waitlist and post-LT outcomes are worse in PALF subjects compared to non-PALF subjects. PALF subjects who undergo LDLT have similar waitlist times and post-LT outcomes compared to those undergoing DDLT.

VARICEAL VERSUS NON-VARICEAL ETIOLOGY OF GASTROINTESTINAL BLEEDING IN PATIENTS WITH CIRRHOSIS AND RELATED SECONDARY COMPLICATIONS

Liver cirrhosis is a highly prevalent worldwide disease and in the last decade, there has been an increase of 13%. Patients with advanced liver disease are at higher risk of developing life-threatening decompensations; one of these main complications is the presence of upper gastrointestinal bleeding, representing a frequent cause of hospital admission and mortality. Broad knowledge of these complications is essential to improve the diagnostic and therapeutic approach in these patients. To compare the different complications related to upper gastrointestinal bleeding of variceal vs. non-variceal origin and the characteristics of these patients. Case-control study conducted in a cohort. The cohort was made up of cirrhotic patients due to any etiology who were admitted for hospitalization at our unit in a period from January 2017 to May 2021; two groups were extracted, those with variceal bleeding formed the cases group and, those with non-variceal hemorrhage the control group and a comparison between groups was made using X2 or Fisher's exact test or Student's test accordingly to the type and distribution of each variable, considering significant a value of p <0.01 A total of 294 cirrhotic patients with gastrointestinal bleeding were included, 169 men (57.5%); mean age 54.6 ± 11.9 years; mean days of hospital stay 2.19 ± 2.74. Regarding the etiology of liver cirrhosis, the main etiology was alcohol in 39.7% (117), followed by viral etiology in 6.4% (18), NASH in 5.8% (17) and, less frequently due to autoimmune causes in 3.4% (10), however, up to 44.7% remained with indeterminate etiology. Regarding the origin of gastrointestinal bleeding, 209 (71.1%) were of variceal origin and 85 (28-9%) were of non-variceal origin. A total of 94 (32%) developed acute kidney injury (AKI), and only the variceal origin was related to a higher risk of developing AKI 57/209 vs. 37/85, p <0.01 (OR = 1.6; 95% CI: 1.2-2.2) but there was no difference regarding the etiology of gastrointestinal bleeding and development of other complications such as encephalopathy, ascites, jaundice, infections, need a transfusion, severe hypovolemic shock, death. See table. The etiology (variceal vs. non-variceal) of the gastrointestinal bleeding has no impact on the development of other complications in cirrhosis; therefore, therapeutic prophylaxis and surveillance strategies should be prioritized in the patient with cirrhosis, regardless of the origin of bleeding. The risk of AKI should always be considered and monitored when the origin of the bleeding is variceal since this study shows the closest relationship between these two complications. The authors declare that there is no conflict of interest

Diagnostic utility of closed needle pleural biopsy in exudative pleural effusions

Abstract Background Exudative pleural effusions are often challenging, and on many occasions remain undiagnosed. Hence, a blind closed needle pleural biopsy (CNPB) is extremely relevant against this background. Methods We conducted a prospective study, in which a CNPB using a Cope’s needle was done in patients with exudative pleural effusion. Data were analysed using SPSS software. Results Our study included 250 patients, of which 140 (56%) were males and 110 (44%) female. 218 (87.2%) had tubercular effusion 22 (8.8%) had effusion secondary to malignancy, 8 (3.2%) had synpneumonic effusions, and 1 (0.4%) each had effusion secondary to pancreatitis and rheumatoid arthritis (RA). AFB culture was positive in 50 (22.4%) on pleural fluid, as compared to 209 (87%) on pleural biopsy. CBNAAT detected MTB in 34 (14%) on pleural fluid as compared to 72 (28.8%) on pleural biopsy. Caseous granuloma was found in 184 (73.6%). The sensitivity for AFB culture using CNPB tissue and pleural fluid was 95.8% and 22.5%, respectively (P &lt; 0.05). Drug susceptibility testing (DST) done on pleural tissue divided our patients as drug sensitive 182 (87%), MDR 13 (6.2%), preXDR 12 (5.7%), and XDR TB 2 (0.9%). For malignancy, sensitivity of pleural fluid and pleural biopsy was 9% and 63%, respectively (P &lt; 0.05). Major complications of the procedure were pain in 25 (10%), pneumothorax in 15 (6%), and haematoma in 8 (3%). Of the patients who developed pneumothorax, only one patient required intervention with an intercostal drain, and the rest resolved spontaneously. Conclusion CNPB is an easy, quick, cost-effective, and reliable method that can be used for diagnosing exudative pleural effusions of indeterminate aetiology in the out-patient setting.

Demographics, aetiology and outcome of paediatric acute liver failure in Singapore.

The aetiology of paediatric acute liver failure (PALF) varies widely according to age, and geographic and socioeconomic factors. This study aimed to examine the epidemiology, aetiology and outcome of PALF in Singapore at a single centre. A retrospective review was performed of patients aged 0-18 years who were diagnosed with PALF from 2007 to 2019. PALF was defined by: absence of chronic liver disease; biochemical evidence of acute liver injury; and coagulopathy, non-correctible by vitamin K, defined as prothrombin time (PT) ≥20 seconds or international normalised ratio (INR) ≥2.0 regardless of hepatic encephalopathy (HE) or PT ≥15 seconds or INR ≥1.5 in the presence of HE. 34 patients were included. Median age at diagnosis was 10 months (range 7 days to 156 months). The top three causes of PALF were indeterminate (41.2%), metabolic (26.5%) and infectious (26.5%) aetiologies. A metabolic disorder was the most frequent aetiology in infants <12 months (38.9%), whereas an indeterminate cause was the most common in children >12 months (50%). No cases of viral hepatitis A or B presenting with PALF were detected. Overall spontaneous recovery rate (survival without liver transplantation [LT]) was 38.2%, and overall mortality rate was 47.1%. Six patients underwent living-donor LT, and the post-transplant survival at one year was 83.3%. The aetiologic spectrum of PALF in Singapore is similar to that in developed Western countries, with indeterminate aetiology accounting for the majority. PALF is associated with poor overall survival; hence, timely LT for suitable candidates is critical to improve survival outcomes.

Effect of Guiera senegalensis and Natron on Serum Indices of Cardiac Function of Postpartum Rats

Peripartum cardiomyopathy (PPCM) is a rare but devastating cardiac failure of indeterminate etiology occurring in late pregnancy or early puerperium. The prevalence of PPCM in Northern Nigeria could be attributed to the unique customary puerperal practices of prolonged consumption oflarge quantities of Guiera senegalensis and Natron. This study investigated the effect of decoction of G. senegalensis with and without Natron on cardiac markers, lipid profile and histology ofheart in postpartum female albino rats using standard methods.Thirty-five (35)female albino rats of body weights 190-200 g of five month were randomly grouped into seven (7) of five rats each. Group 2, 3 and 4 were orally administered with 100, 200 and 300 mg/kg body weight of G. senegalensis. Group 5, 6 and 7 were orally administered with 100, 200 and 300 mg/kg body weight (1:1) of G. senegalensis and Natron by gavage, whereas group 1 received distilled water. The study revealed significant (p&lt; 0.05) decrease in triglyceride(TG) in group 2 to VII, high density lipoproteincholesterol (HDL-c) in group 2, 5 and 6, very low density lipoprotein- cholesterol (VLDL-c) in group 3 to V, couples with significant (p&lt; 0.05) increase in low density lipoprotein cholesterol (LDL-c) in group 2, 3, 5 and 7, and for (AIX) in group 2, total cholesterol(TC) in group 2, 3 and 7 when compared with control. Significant (p&lt; 0.05) increase in Lactate dehydrogenase (LDH) in group 3 to 7, and Myoglobin (MB) in group 3 was observed. Significant (p&lt; 0.05) decrease in Troponin I (TnI) in group 2 and 4 was seen. There were no significant (p&gt;0.05) changes in Troponin T (Tn T), aspartate amino transferase (AST) and Creatine Kinase(CK-NAC) of the treatment group when compared to control group. Histopathological examination of section of the heart revealed ventricular dilatation, hypertrophied with enlarged nuclei, stretched, and irregular and mural thrombi in group 2 to 4 and 7. Inflammation in group 5 and 7, Pigment deposited in group 4 to 7 and Mild fibrosis in group 3 were observed. The study demonstrates that consumption of G. senegalensis and Natron for 28 days’induces dyslipidemia and causes changes in the heart of postpartum rats and thus may contribute to the pathogenesis of PPCM.

The Role of Transthoracic Echocardiography in the Evaluation of Patients With Ischemic Stroke

Background: Ischemic stroke can be classified into five etiological types, according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and its adequate investigation and characterization can aid in its clinical management and in preventing new events. Transthoracic echocardiography (TTE) plays a key role in investigating its etiology; approximately one-third of the patients remain without an adequate definition of the etiology or are classified as the undetermined TOAST type.Objectives: To evaluate if the percentage of patients with indeterminate etiology according to the TOAST classification decreased after transthoracic echocardiography, to determine whether or not the prognosis after ischemic stroke is worse among patients classified as the undetermined TOAST type, and to verify the predictive capacity of echocardiography on the prognosis after ischemic stroke.Methods: In this retrospective cohort study, clinical, neurological, and echocardiographic examinations were conducted when the patient was hospitalized for stroke. In-hospital mortality and functional capacity were evaluated at hospital discharge and 90 days thereafter. Multiple linear regression and multiple logistic regression models were adjusted for confounding factors. The level of significance was 5%.Results: A total of 1,100 patients (men = 606; 55.09%), with a mean age of 68.1 ± 13.3 years, were included in this study. Using TTE, 977 patients (88.82%) were evaluated and 448 patients (40.7%) were classified as the undetermined TOAST type. The patients who underwent TTE were 3.1 times less likely to classified as the undetermined TOAST type (OR = 0.32; p < 0.001). Echocardiography during hospitalization was a protective factor against poor prognosis, and reduced the odds of in-hospital death by 11.1 times (OR: 0.090; p < 0.001). However, the presence of the undetermined TOAST classification elevated the chance of mortality during hospitalization by 2.0 times (OR: 2.00; p = 0.013).Conclusions: Echocardiography during hospitalization for ischemic stroke reduces the chances of an undetermined TOAST classification and the risk of in-hospital mortality. However, being classified as the undetermined TOAST type increases the chance of mortality during hospitalization, suggesting that evaluating patients using echocardiography during hospitalization for acute ischemic stroke is important.

Study of Acute Liver Failure in Children Using Next Generation Sequencing Technology

To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology. We identified 148 under 10years of age admitted to King's College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and/or metabolic liver disease was constructed. Targeted sequencing was carried out on 41 children in whom DNA samples were available. Trio exome sequencing was performed on 4 children admitted during 2019. A comparison of the clinical characteristics of those identified with biallelic variants against those without biallelic variants was then made. Homozygous and compound heterozygous variants were identified in 8 out of 41 children (20%) and 4 out of 4 children (100%) in whom targeted and exome sequencing were carried out, respectively. The genes involved were NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). The 12 children who were identified with biallelic variants were younger at presentation and more likely to die in comparison with those who did not: median age at presentation of 3months and 30months and survival rate 75% and 97%, respectively. NGS was successful in identifying several specific etiologies of ALF. Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings. In the future, a rapid sequencing NGS workflow could help in reaching a timely diagnosis and facilitate clinical decision making in children with ALF.

Abstract No. 29 Percutaneous mesocaval shunt creation: a retrospective review of 5 patients with midterm outcomes

To evaluate the indication, approach, safety, and outcomes of percutaneous mesocaval shunt placement Institutional review board-approved retrospective review of the electronic medical records of patients with percutaneous mesocaval shunts was performed from January 2001 through March 2020 (n = 5). Indication for mesocaval shunt placement was refractory variceal hemorrhage in all 5 patients. All patients had extensive portal vein thrombosis (PVT) (1 intrahepatic, 4 extrahepatic) precluding transjugular intrahepatic portosystemic shunt placement. The underlying etiologies for PVT were non-alcoholic cirrhosis, primary sclerosing cholangitis, pancreatic cancer, post-surgical, and during pregnancy of indeterminate etiology. Post-procedurally, patients were followed for up to 10 years with clinical and laboratory assessment as well as CT or MRI imaging. Technical success was defined as placement of a stent from the superior mesenteric vein to the inferior vena cava. Clinical success was defined as cessation of refractory bleeding. Patient demographics, technical approach for placement, pre-procedure and post-procedure MELD scores, shunt patency, and complications were recorded. Technical and clinical success was achieved in 100% (5 of 5) of patients. Procedural imaging was available for 4/5 patients. To perform the inferior vena cava to superior mesenteric vein puncture, a combination of fluoroscopy and intravascular ultrasound was used in 25% (1/4), fluoroscopy and transabdominal ultrasonography was used in 25% (1/4), and fluoroscopy and intracardiac echocardiography was used in 50% (2/4). MELD scores (9 – 29) did not significantly deviate from pre-procedure to 30 days post-procedure in any patient. Mesocaval shunt primary unassisted patency was 5/5 (100%) at 6 months, 4/4 (100%) at 12 and 18 months, and 2/3 (67%) at 24 months. After 32 months, one patient underwent intentional mesocaval shunt closure for chronic, refractory hepatic encephalopathy (HE). The final patient maintained mesocaval shunt patency for greater than 10 years. No immediate complications occurred peri-procedurally. Two patients (40%) suffered HE, one of which resolved with medical optimization and the second required eventual shunt closure. Mesocaval shunt placement is an uncommonly performed procedure to treat complications of portal hypertension when a TIPS cannot be placed. In this cohort, outcomes were comparable to TIPS as it was safe, well tolerated, and remained patent in a majority of patients at 24 months.

Four Biomarkers Linked to Activation of Cluster of Differentiation 8-Positive Lymphocytes Predict Clinical Outcomes in Pediatric Acute Liver Failure.

Immune dysregulation contributes to the pathogenesis of pediatric acute liver failure (PALF). Our aim was to identify immune activation markers (IAMs) in PALF that are associated with a distinct clinical phenotype and outcome. Among 47 PALF study participants, 12 IAMs collected ≤6days after enrollment were measured by flow cytometry and IMMULITE assay on blood natural killer and cluster of differentiation 8-positive (CD8+ ) lymphocytes and subjected to unsupervised hierarchical analyses. A derivation cohort using 4 of 12 IAMs which were available in all participants (percent perforin-positive and percent granzyme-positive CD8 cells, absolute number of CD8 cells, soluble interleukin-2 receptor level) were sufficient to define high (n=10), medium (n=15), and low IAM (n=22) cohorts. High IAM was more frequent among those with indeterminate etiology than those with defined diagnoses (80% versus 20%, P<0.001). High IAM was associated with higher peak serum total bilirubin levels than low IAM (median peak 21.7 versus 4.8mg/dL, P<0.001) and peak coma grades. The 21-day outcomes differed between groups, with liver transplantation more frequent in high IAM participants (62.5%) than those with medium (28.2%) or low IAM (4.8%) (P=0.002); no deaths were reported. In an independent validation cohort (n=71) enrolled in a prior study, segregation of IAM groups by etiology, initial biochemistries, and short-term outcomes was similar, although not statistically significant. High serum aminotransferases, total bilirubin levels, and leukopenia at study entry predicted a high immune activation profile. Four circulating T-lymphocyte activation markers identify a subgroup of PALF participants with evidence of immune activation associated with a distinct clinical phenotype and liver transplantation; these biomarkers may identify PALF participants eligible for future clinical trials of early targeted immunosuppression.

1363. Assessment and Quantification of Nasopharyngeal Streptococcus pneumoniae Colonization Does Not Discriminate Between Children with Viral and Bacterial Respiratory Infection

BackgroundPediatric uncomplicated pneumonia can be caused by viruses, bacteria, and atypical pathogens. Unfortunately, readily-available diagnostics do not reliably identify which cases of uncomplicated pneumonia have a bacterial etiology. It has been suggested that measuring pneumococcal nasopharyngeal carriage can discriminate between viral and bacterial disease. The objective of this study was to determine if nasopharyngeal pneumococcal carriage differed between children with definite viral disease, definite bacterial disease, and respiratory disease of indeterminate etiology.MethodsThree cohorts were recruited. Cohort 1 consisted of children with acute respiratory illness admitted to the pediatric intensive care unit; Cohort 2 consisted of previously healthy children with acute respiratory illness admitted to the general pediatric ward; and Cohort 3 consisted of previously healthy children diagnosed with non-severe community-acquired pneumonia in the emergency department. Children were categorized into the following disease categories: a) viral infection syndrome, b) pneumonia complicated by effusion/empyema, or c) ‘indeterminate’ pneumonia. Study subjects’ nasopharyngeal swabs (NPS) underwent quantitative PCR testing for S. pneumoniae.ResultsThere were 206 children in Cohort 1, 122 children in Cohort 2, and 179 children in Cohort 3. The median subject age was 2.5 y (25-75%ile 1.3-4.9 y). Only a minority (227/507, 45%) had pneumococcal carriage detected; in those participants, there was no association of quantitative genomic load with age, cohort, or disease category. In multivariate logistic regression, NPS pneumococcal carriage (positivity >3 log copies/mL) was associated with younger age and cohort of recruitment, but not with disease category (all those with indeterminate non-severe pneumonia were from Cohort 3).Table 1. Comparison of subjects in different cohorts Table 2. Comparison of subjects in different disease categories Table 3. Associations with nasopharyngeal pneumococcal colonization >3 log copies/mL. ConclusionThe nasopharyngeal S. pneumoniae carriage patterns of subjects with definite viral infection were very similar to those with definite bacterial infection and to those with indeterminate pneumonia. It would therefore appear that assessment and quantification of nasopharyngeal pneumococcal colonization is not useful to discriminate between acute viral and bacterial respiratory disease in children in North America.Disclosures All Authors: No reported disclosures