Systemic Multiple Organ Dysfunction Research Articles

Association of frailty with nutritional parameters in patients with chronic kidney disease

Objectives: Frailty is a significant clinical syndrome characterized by greater susceptibility to stressors due to the dysfunction of multiple organ systems, which increases in prevalence with age. This study was performed to investigate relations between frailty and nutritional parameters in patients with chronic kidney disease (CKD). Methods: This cross-sectional study involved 100 CKD patients aged 50 years or older. Frailty was assessed using the Edmonton Frailty Scale (EFS) and Fried’s Frailty Scale (FFS). The patients nutritional status was assessed using the Mini Nutritional Assessment (MNA) and the routine laboratory tests. Results: The study included 100 patients, consisting of 41 females and 59 males. The mean age of the participants was 65.3±9.3 years. The median glomerular filtration rate (GFR) of the patients was 23 mL/min/1.73 m2) (min: 3-max: 65). According to the MNA, 15 patients had normal nutritional status, 63 were at risk of malnutrition, and 22 were malnourished. According to the EFS score, four patients were categorized as not frail, 11 as vulnerable, 25 with mild frailty, 21 with moderate frailty, and 39 with severe frailty. According to the FFS score, six patients were non-frail, 30 were classified as pre-frail, and 64 were considered frail. Conclusions: Frailty and malnutrition in patients with CKD were independently related to all other factors examined in this study. Screening for malnutrition at the early stages in patients with CKD and the appropriate treatment may prevent the development of frailty.

The impact of COVID-19 on pulmonary, neurological, and cardiac outcomes: evidence from a Mendelian randomization study.

Long COVID is a clinical entity characterized by persistent health problems or development of new diseases, without an alternative diagnosis, following SARS-CoV-2 infection that affects a significant proportion of individuals globally. It can manifest with a wide range of symptoms due to dysfunction of multiple organ systems including but not limited to cardiovascular, hematologic, neurological, gastrointestinal, and renal organs, revealed by observational studies. However, a causal association between the genetic predisposition to COVID-19 and many post-infective abnormalities in long COVID remain unclear. Here we employed Mendelian randomization (MR), a robust genetic epidemiological approach, to investigate the potential causal associations between genetic predisposition to COVID-19 and long COVID symptoms, namely pulmonary (pneumonia and airway infections including bronchitis, emphysema, asthma, and rhinitis), neurological (headache, depression, and Parkinson's disease), cardiac (heart failure and chest pain) diseases, and chronic fatigue. Using two-sample MR, we leveraged genetic data from a large COVID-19 genome-wide association study and various disorder-specific datasets. This analysis revealed that a genetic predisposition to COVID-19 was significantly causally linked to an increased risk of developing pneumonia, airway infections, headache, and heart failure. It also showed a strong positive correlation with chronic fatigue, a frequently observed symptom in long COVID patients. However, our findings on Parkinson's disease, depression, and chest pain were inconclusive. Overall, these findings provide valuable insights into the genetic underpinnings of long COVID and its diverse range of symptoms. Understanding these causal associations may aid in better management and treatment of long COVID patients, thereby alleviating the substantial burden it poses on global health and socioeconomic systems.

No Critical Ultrasound, No Life: The Value of Point-of Care Critical Ultrasound in the Rescue of Critically Ill Infants.

Point-of-care critical ultrasound (POC-CUS) screening plays an increasingly important role in the treatment of critically ill infants. Without POC-CUS, the lives of many infants would not be saved in time and correctly. A premature infant with systemic multiple organ system dysfunction caused by fungal sepsis was treated and nursed under the guidance of POC-CUS monitoring, and the infant was ultimately cured. This premature infant had systemic multiple organ system dysfunction and disseminated intravascular coagulation (DIC) caused by fungal sepsis. In the hypercoagulable state of early-stage DIC, cardiac thrombosis could be found using ultrasound screening. For this case, right renal artery thrombosis was found via renal artery Doppler ultrasound examination. Due to the severity of this disease, ultrasound-guided peripherally inserted central catheter (PICC) insertion and ultrasound checks of the PICC tip's position were performed, which ensured the success of this one-time catheterization and shortened the catheterization time. Lung ultrasound is used for the diagnosis and differential diagnosis of pulmonary diseases, and to guide the application of mechanical ventilation. Because the abdominal circumference of the patient's markedly enlarged abdominal circumference, bloody stool, and absence of bowel sounds, abdominal ultrasonography was performed, which revealed a markedly enlarged liver, significant peritoneal effusion, and necrotizing enterocolitis. Guided by POC-CUS monitoring, we had the opportunity to implement timely and effective treatment that ultimately saved this critically ill patient's life. The successful treatment of this newborn infant fully reflects the importance of carrying out POC-CUS screening.

Genetic and Clinical Characterization of Patients with HNF1B-Related MODY in Croatia.

Mutation of the gene encoding Hepatocyte Nuclear transcription Factor-1 Beta (HNF1B) causes a rare monogenetic subtype of Maturity-Onset Diabetes of the Young (MODY). HNF1B-related MODY results in the dysfunction of multiple organ systems. However, genetic analysis enables personalized medicine for patients and families. To understand the clinical characteristics and explore the gene mutations in Croatian patients. This was a retrospective observational study of individuals (and their relatives) who were, due to the clinical suspicion of MODY, referred to the Department of Laboratory Diagnostics at the University Hospital Centre Zagreb for genetic testing. A total of 118 participants, 56% females, were screened. Seven patients (three females) from five families were identified to have HNF1B-related MODY. The median age at diagnosis was 31 (11-45) years, the median c-peptide was 0.8 (0.55-1.39) nmol/L, the median HbA1c was 9.1 (5.7-18.4)%, and the median BMI was 22.9 kg/m2 (17-24.6). Patients had a variety of clinical manifestations; kidney disease was not as frequent as liver lesions, neuropsychiatric symptoms, hyperlipidemia, hyperuricemia, and hypomagnesemia. We identified two new pathogenic mutations (c.1006C > G protein p.His336Asp on exon 4 and c.1373T > G p protein Val458Gly on exon 7). In a study involving Croatian patients, new genetic (two previously unknown mutations) and clinical (diverse range of clinical presentations) aspects of HNF1B-related MODY were found.

WS10.02 Pharmacological effects of CFTR-modulation in cystic fibrosis patients after lung transplantation: interim results of the multicenter KOALA study

Objectives: Cystic Fibrosis leads to dysfunction of multiple organ systems, lung transplant (LTx) patients experience extrapulmonary symptoms even after lung transplantation, and might benefit from CFTR modulator therapy. The multicenter KOALA study aims to assess the extrapulmonary effect of CFTR modulators in LTx patients with CF. Here, we report the short-term interim results of a single site.

The Impact of Restrictive Transfusion Practices on Hemodynamically Stable Critically Ill Children Without Heart Disease: A Secondary Analysis of the Age of Blood in Children in the PICU Trial.

Guidelines recommend against RBC transfusion in hemodynamically stable (HDS) children without cardiac disease, if hemoglobin is greater than or equal to 7 g/dL. We sought to assess the clinical and economic impact of compliance with RBC transfusion guidelines. A nonprespecified secondary analysis of noncardiac, HDS patients in the randomized trial Age of Blood in Children (NCT01977547) in PICUs. Costs analyzed included ICU stay and physician fees. Stabilized inverse propensity for treatment weighting was used to create a cohort balanced with respect to potential confounding variables. Weighted regression models were fit to evaluate outcomes based on guideline compliance. Fifty international tertiary care centers. Critically ill children 3 days to 16 years old transfused RBCs at less than or equal to 7 days of ICU admission. Six-hundred eighty-seven subjects who met eligibility criteria were included in the analysis. Initial RBC transfusions administered when hemoglobin was less than 7 g/dL were considered "compliant" or "non-compliant" if hemoglobin was greater than or equal to 7 g/dL. Frequency of new or progressive multiple organ system dysfunction (NPMODS), ICU survival, and associated costs. The hypothesis was formulated after data collection but exposure groups were masked until completion of planned analyses. Forty-nine percent of patients (338/687) received a noncompliant initial transfusion. Weighted cohorts were balanced with respect to confounding variables (absolute standardized differences < 0.1). No differences were noted in NPMODS frequency (relative risk, 0.86; 95% CI, 0.61-1.22; p = 0.4). Patients receiving compliant transfusions had more ICU-free days (mean difference, 1.73; 95% CI, 0.57-2.88; p = 0.003). Compliance reduced mean costs in ICU by $38,845 U.S. dollars per patient (95% CI, $65,048-$12,641). Deferring transfusion until hemoglobin is less than 7 g/dL is not associated with increased organ dysfunction in this population but is independently associated with increased likelihood of live ICU discharge and lower ICU costs.

Autologous Stem Cell Transplantation (ASCT) for Refractory Juvenile-Onset Systemic Sclerosis (jSSc) Is Safe and Well Tolerated and Improves Clinical and Patient-Reported Outcomes

Introduction: jSSc is a rare autoimmune disease that leads to inflammation, fibrosis, and dysfunction of multiple organ systems which can cause skin sclerosis, interstitial lung disease (ILD), myositis, fasciitis, gastrointestinal and vascular disease. Severe SSc is often refractory to immunomodulatory medications including newer targeted agents. ASCT has demonstrated success in adults with SSc, but experience and data in pediatric patients is limited. Methods: We report our first four consecutive adolescent and young adult ASCT patients. All patients were referred to our scleroderma center at UPMC Children's Hospital of Pittsburgh where they were evaluated by our multidisciplinary team. Baseline patient characteristics are summarized in Table 1. Patients met criteria for ASCT by severity of lung or skin disease, or both. The first 3 patients had severe ILD or musculoskeletal chest wall weakness resulting in pulmonary function tests (PFTs) below traditional cut offs for adult SSc ASCT trials. All four patients had refractory disease and had previously received 3-8 immunomodulatory medications. Autologous stem cells were mobilized with cyclophosphamide and filgrastim and collected via pheresis. Following this, conditioning chemoradiation was administered per an IRB-approved individual treatment plan (Patients 1-3) or on our clinical trial NCT03630211 (Patient 4) with rituximab, anti-thymocyte globulin (ATG), TBI 600 cGy with lung and kidney shielding, and cyclophosphamide or thiotepa +/- alemtuzumab. A CD34+ selected cryopreserved autologous peripheral blood stem cell graft was infused on day 0. Antimicrobial prophylaxis was given per institutional standard and PCRs for EBV, CMV and adenovirus were closely monitored. Steroids were weaned off by 5 weeks post-ASCT. Results: The median cell dose was 5.9 e6 CD34/kg. All patients engrafted, with median neutrophil engraftment on day 11 (range 11-15), and median platelet engraftment (>50K) on day 18.5 (range 16-20). There were infusion-related side effects with equine ATG, but none with rabbit ATG. There were no cases of sinusoidal obstructive syndrome, thrombotic microangiopathy or clinically significant bleeding. No patients required a PCA for pain and received minimal (median=3) doses of narcotics. Patients were discharged from the hospital a median of 19 days after transplant (range 17-21). Only one patient was readmitted, and had a negative 48 hour infectious rule out. Two patients acquired COVID-19 infections at 5 and 19.5 months post-ASCT; both remained outpatient with quick improvement after treatment with best available therapy. There were no viral reactivations, bacterial or fungal infections. There has been no evidence of organ toxicity and there are objective improvements in clinical parameters as well as patient reported outcomes (PROs) over the follow-up visits (Table 2). All patients demonstrated an improvement in their skin involvement, as measured by the modified Rodnan Skin Score (mRSS). There was an improvement in clinical symptoms and exam findings of Raynaud's. The lower esophageal sphincter became less hypotensive; objective measures and symptoms of gastroesophageal reflux were much improved. Despite severely reduced values of forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) prior to ASCT, all subjects regained pre-ASCT values. All patients demonstrated an improvement in their PROs and report improvement in fatigue, pain, and the ability to participate in activities of daily living. All patients are off immunomodulatory medications. Tandem serial skin biopsies of the forearm support decreased collagen burden and disappearance of a myofibroblasts population with single cell RNA sequencing (n=3, timepoints 0, 6, 12 mos; data not shown), which correlates with an improvement in the skin score. Conclusions: In refractory jSSc patients, ASCT is well tolerated, even in patients with severe disease who would otherwise not be eligible for clinical trials based on exclusion criteria that were developed for adults with SSc. ASCT can serve as a hard reset to the immune system for patients with this refractory autoimmune disease, with improvements in clinical parameters that reflect disease modification involving the skin, musculoskeletal, vascular, and gastrointestinal systems. Further clinical research treating patients with this rare disease is of great need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Myocardial protective effect of sivelestat sodium in rat models with sepsis-induced myocarditis.

The incidence of sepsis has been steadily increasing worldwide, and the heart is one of the target organs that can be easily damaged by sepsis. At present, antibiotics and organ function support are the main treatment options for sepsis and multiple system organ dysfunction, but are still under investigation. Fifty rats were randomly divided into the sham operation group, sepsis group, sivelestat sodium low-dose (L) group (administered with sivelestat sodium 1.6 mg/kg), sivelestat sodium middle-dose (M) group (administered with sivelestat sodium 4.8 mg/kg), and sivelestat sodium high-dose (H) group (administered with sivelestat sodium 10 mg/kg). Morphological changes of myocardial cells and the distribution of extracellular signal-regulated kinase (ERK)1/2 proteins were observed by light microscope. Serum troponin-T, creatine kinase isoenzyme MB, brain natriuretic peptide, interleukin (IL)-6, tumor necrosis factor-α, and IL-1β levels and changes in cardiac function indicators were measured. The protein expressions of Bax, Bcl-2, and ERK1/2 were detected by Western blotting. Compared with the sham operation group, the release of inflammatory factors in the sepsis group increased; the protein expressions of Bax, Bcl-2, and ERK1/2 increased; left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximum rate of LVP rise (+dp/dtmax) level decreased, whereas -dp/dtmax increased. In the sivelestat sodium groups, the release of inflammatory factors decreased; Bax expression decreased, whereas Bcl-2 and ERK1/2 protein expressions increased; LVSP, LVEDP, and +dp/dtmax increased, whereas -dp/dtmax decreased. In addition, all of these changes occurred in a dose-dependent manner. Sivelestat sodium can effectively lower the expressions of inflammatory factors and improve cardiac function. It can act on the ERK1/2 signaling pathway to exert its cardiomyocyte-protective effect, and the activation of this signaling pathway can offer potential treatment sites for septic myocarditis.

Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies.

Ciliopathies are a class of genetic diseases resulting in cilia dysfunction in multiple organ systems, including the olfactory system. Currently, there are no available curative treatments for olfactory dysfunction and other symptoms in ciliopathies. The loss or shortening of olfactory cilia, as seen in multiple mouse models of the ciliopathy Bardet–Biedl syndrome (BBS), results in olfactory dysfunction. However, the underlying mechanism of the olfactory cilia reduction is unknown, thus limiting the development of therapeutic approaches for BBS and other ciliopathies. Here, we demonstrated that phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], a phosphoinositide typically excluded from olfactory cilia, aberrantly redistributed into the residual cilia of BBS mouse models, which caused F-actin ciliary infiltration. Importantly, PI(4,5)P2 and F-actin were necessary for olfactory cilia shortening. Using a gene therapeutic approach, the hydrolyzation of PI(4,5)P2 by overexpression of inositol polyphosphate-5-phosphatase E (INPP5E) restored cilia length and rescued odor detection and odor perception in BBS. Together, our data indicate that PI(4,5)P2/F-actin–dependent cilia disassembly is a common mechanism contributing to the loss of olfactory cilia in BBS and provide valuable pan-therapeutic intervention targets for the treatment of ciliopathies.

Spectrum of Genetic T-Cell Disorders from 22q11.2DS to CHARGE.

Improved genetic testing has led to recognition of a diverse group of disorders of inborn errors of immunity that present as primarily T-cell defects. These disorders present with variable degrees of immunodeficiency, autoimmunity, multiple organ system dysfunction, and neurocognitive defects. 22q11.2 deletion syndrome, commonly known as DiGeorge syndrome, represents the most common disorder on this spectrum. In most individuals, a 3Mb deletion of 22q11 results in haploinsufficiency of 90 known genes and clinical complications of varying severity. These include cardiac, endocrine, gastrointestinal, renal, palatal, genitourinary, and neurocognitive anomalies. Multidisciplinary treatment also includes pediatrics/general practitioners, genetic counseling, surgery, interventional therapy, and psychology/psychiatry. Chromosome 10p deletion, TBX1 mutation, CHD7 mutation, Jacobsen syndrome, and FOXN1 deficiency manifest with similar overlapping clinical presentations and T-cell defects. Recognition of the underlying disorder and pathogenesis is essential for improved outcomes. Diagnosing and treating these heterogenous conditions are a challenge and rapidly improving with new diagnostic tools. Collectively, these disorders are an example of the complex penetrance and severity of genetic disorders, importance of translational diagnostics, and a guide for multidisciplinary treatment.

Ethanol Consumption and Sepsis: Mechanisms of Organ Damage

Sepsis is highly prevalent, and is one of the main causes of mortality among hospitalized patients. Ethanol consumption in large quantities compromises the normal functioning of the body, leading to dysfunction of multiple different organ systems.

Red Blood Cell Morphological Changes and Enlarged Platelets Found in Idiopathic Multicentric Castleman Disease

BACKGROUNDIdiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disorder characterized by systemic inflammatory symptoms, cytopenias, generalized lymphadenopathy, and multiple organ system dysfunction. iMCD is subclassified into iMCD-TAFRO, with thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis/renal failure, and organomegaly, and iMCD-NOS (not otherwise specified), with high platelet counts and hypergammaglobulinemia. Despite recent diagnostic guidelines, iMCD diagnosis remains challenging because many of the histopathologic features and clinical/laboratory abnormalities are non-specific. Characterization of easily measurable findings from minimally invasive procedures, such as peripheral blood smear, could help to improve the accuracy of diagnosis as well as potentially providing insights into disease pathogenesis. Peripheral blood smears are often performed during routine clinical evaluation and enable morphologic evaluation of red blood cells (RBCs) and white blood cells (WBCs). In this study, we systematically characterized peripheral blood smear morphologic findings in iMCD for the first time.METHODSPeripheral blood smear morphologic findings in medical records from 68 iMCD patients, who were enrolled in an international registry for CD patients and had been confirmed to meet iMCD criteria by an expert panel, were reviewed and analyzed. Patients were also categorized into iMCD-TAFRO (N=39) or iMCD-NOS (N=29) based on clinical and laboratory data. Two-sample proportion tests were used to compare the frequency of features between iMCD-TAFRO and iMCD-NOS, when the abnormality was present in ≥ 5 subjects in both subtypes. P-value correction was not performed as findings are preliminary and hypothesis generating.RESULTSAmong the 68 iMCD patients, average age was 35.8 years (14-61); 46% were female, 54% were male; racial distribution was 62% white; 10% Black; 15% Asian; 13% other. The most common peripheral blood smear findings across all iMCD patients included abnormalities in RBC size and color, with anisocytosis (58.8%), polychromasia (57.4%), hypochromia (55.9%), and microcytosis (50.0%) being the most prevalent findings in the overall cohort (Table 1). Other RBC abnormalities were observed but less frequently, including abnormalities in shape such as poikilocytosis (44.1%). Giant or large platelets were found in 47% of iMCD cases. Abnormalities in WBCs, including toxic granulation, atypical lymphocytes, and toxic vacuolization, were detected less frequently. When comparing the two clinical subtypes, patients with iMCD-TAFRO had more frequent anisocytosis (p=0.043), hypochromia (p=0.002), polychromasia (p=0.022), and giant/large platelets (p<0.001) versus iMCD-NOS.DISCUSSIONHere, we have characterized peripheral blood morphologic abnormalities in iMCD for the first time. The most common findings in this cohort included abnormalities in RBC size and color. These abnormalities can be found in a number of conditions, including myelofibrosis, autoimmune diseases, and other inflammatory conditions. In iMCD, they are likely related to cytokine-driven anemia of chronic inflammation. The presence of large or giant platelets in nearly half of iMCD patients, with significantly more in iMCD-TAFRO than iMCD-NOS, is particularly notable since this has not been described in iMCD. These enlarged platelets, which can be found in immune thrombocytopenic purpura, myeloproliferative disorders, pseudothrombocytopenia, and inherited platelet disorders, may reflect hyperactivity of megakaryocytes and/or early release from the bone marrow in response to peripheral platelet sequestration. Though less common in this cohort, there are additional changes in RBC shape and WBC features that may be more specific to iMCD and potentially informative in increasing the index of suspicion for iMCD. These findings suggest that the peripheral blood smear may be able to support the diagnosis of iMCD and result in faster treatment administration. Future work is needed to determine whether the constellation of findings in the peripheral blood identified herein is unique to iMCD or seen in various other infectious, malignant, and autoimmune diseases. [Display omitted] DisclosuresFajgenbaum: Pfizer: Other: Study drug for clinical trial of sirolimus; EUSA Pharma: Research Funding; N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’.

MP27-06 SEXUAL FUNCTION AND DYSFUNCTION IN INDIVIDUALS WITH SPINA BIFIDA: A SYSTEMATIC REVIEW

You have accessJournal of UrologySexual Function/Dysfunction: Evaluation I (MP27)1 Sep 2021MP27-06 SEXUAL FUNCTION AND DYSFUNCTION IN INDIVIDUALS WITH SPINA BIFIDA: A SYSTEMATIC REVIEW Taylor L. Hughes, Kirsten Simmons, Rohit Tejwani, Kevin T. Hobbs, Karen Barton, John S. Wiener, J. Todd Purves, and Jonathan C. Routh Taylor L. HughesTaylor L. Hughes More articles by this author , Kirsten SimmonsKirsten Simmons More articles by this author , Rohit TejwaniRohit Tejwani More articles by this author , Kevin T. HobbsKevin T. Hobbs More articles by this author , Karen BartonKaren Barton More articles by this author , John S. WienerJohn S. Wiener More articles by this author , J. Todd PurvesJ. Todd Purves More articles by this author , and Jonathan C. RouthJonathan C. Routh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002024.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Survival to adulthood is now expected among most individuals with spina bifida (SB); consequently, issues involving transition to adult life are increasingly important, including sexual function and dysfunction. Gaps in knowledge surrounding sexual function in this population impede SB-specific sexual health counseling and treatment. Our objective was to review the literature for self-reported experiences of sexual function and dysfunction in individuals with SB. METHODS: Published studies, sourced from Medline, Embase, and Web of Science, included self-reported data from SB patients on one or more sexual function domains: genital sensitivity, orgasm, erectile function, ejaculation, lubrication, and/or dyspareunia. The protocol was registered in PROSPERO (#CRD42020189811), an international prospective register of systematic reviews. Two authors independently assessed eligibility, extracted data, and cross-checked results, with disagreements resolved by a third independent reviewer. RESULTS: Systematic search yielded 23 studies representing 1,441 patients (816 males, 625 females). Validated questionnaires in the SB population were lacking. Eight studies utilized questionnaires validated in non-SB adults; the remainder used semi-structured interviews and non-validated instruments. Eleven assessed dysfunction in both sexes, ten in males, and two in females. Most studies were >10 years old, and quantitative meta-analysis was impractical due to study heterogeneity. Erectile function and orgasm were the most commonly assessed outcomes in males and females, respectively. 7-91% (median 31%) of males experienced erectile dysfunction; 0-71% (median 35.5%) reported abnormal ejaculatory function. A considerable number of females (28-63%) and males (5-77%) experienced abnormal or impaired orgasms. 23-33% of males and 14-84% of females experienced impaired genital sensation. Higher SB lesion levels and hydrocephalus were associated with increased sexual impairment. CONCLUSIONS: The limited literature on sexual dysfunction in adults with SB noted significant male erectile and ejaculatory dysfunction and impaired orgasms and genital sensitivity in both sexes. SB-specific instruments assessing sexual dysfunction are lacking and would improve multidisciplinary care for this population. Ideal instruments would assess the needs of both men and women with SB, be applicable and accessible to patients of varying ages and abilities, and account for differing degrees of SB-related dysfunction of sexual and multiple other organ systems. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e473-e474 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Taylor L. Hughes More articles by this author Kirsten Simmons More articles by this author Rohit Tejwani More articles by this author Kevin T. Hobbs More articles by this author Karen Barton More articles by this author John S. Wiener More articles by this author J. Todd Purves More articles by this author Jonathan C. Routh More articles by this author Expand All Advertisement Loading ...

Fontan circulation has improved life expectancy for infants born with complex heart disease over the last 50 years but has also resulted in significant morbidity.

The prognosis for infants born with complex heart disease improved dramatically with the introduction of the Fontan circulation 50years ago. With today's carefully designed and staged operations to a Fontan circulation, life expectancy has increased and most children will survive into adult life. The Fontan circulation entails an unphysiological circulation with high risk for multiple organ system dysfunction. Neurodevelopmental disabilities with adverse psychosocial effects are prevalent. The Fontan circulation may eventually fail and necessitate heart transplantation. CONCLUSION: Fifty years development of the Fontan circulation to today's staged surgical procedures has improved survival but also revealed the burden of a high morbidity for a growing number of patients.

Case reports of cerebral sinus venous thrombosis in COVID-19 patients

BackgroundCoronavirus disease 2019 (COVID-19) pandemic has started in December 2019 and still ongoing. The disease has been expanding rapidly with a high variety of phenotypes from asymptomatic, mild respiratory tract infection, multiple organ system dysfunction, and death. Neurological manifestations also appear in patients with COVID-19, such as headache, seizures, a decrease of consciousness, and paralysis. The hypercoagulable state in patients with COVID-19 is associated with the thromboembolic incident including ischemic strokes, venous thromboembolism, pulmonary artery embolism, and many further. Cerebral sinus venous thrombosis (CSVT) is a rare neurovascular emergency that is often found in critically ill patients. We report two cases of CSVT with different onsets, neurologic manifestations, and prognoses.Case presentationTwo cases of cerebral sinus venous thrombosis in COVID-19 patients were reported, following respiratory, hematology, and coagulation disarrangements, which was triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The first patient, which was presented with a seizure, had hypertension and diabetes mellitus as comorbidities. The latter case had no comorbidity but showed more severe presentations of COVID-19 such as brain and lung thrombosis, although already had several days of intravenous anticoagulant administrations. These two cases also have a different course of disease and outcomes, which were interesting topics to study.ConclusionsCSVT is one of the neurological complications of the COVID-19 when the brainstem venous drainage is involved. Despite successful alteration to the negative result of SARS-CoV-2 through the rt-PCR test, thrombogenesis and coagulation cascade continuing. Therefore, a high level of neutrophil to lymphocyte ratio (NLR), D-dimer, fibrinogen, and C-reactive protein (CRP) are paramount indicators of poor prognosis.

Preliminary Results from Accelerate, an International, Web-Based, Natural History Registry of Castleman Disease

Introduction: Castleman disease (CD) describes a heterogeneous group of disorders that share characteristic histopathological lymph node features. Unicentric CD (UCD) involves localized lymphadenopathy whereas multicentric CD (MCD) involves generalized lymphadenopathy, cytokine-driven systemic inflammatory symptoms, and life-threatening multiple organ system dysfunction. Uncontrolled Human Herpesvirus 8 (HHV-8) infection causes approximately half of MCD cases (HHV-8-associated MCD). The etiology of HHV-8-negative MCD is unknown or idiopathic (iMCD). Currently, there is a lack of clinical and laboratory data describing the 3 subtypes of CD and their natural histories. Further, a systematic analysis of treatments for each subtype has not been performed. Acknowledging these gaps, the field prioritized the development of a natural history study of CD, ACCELERATE, which began enrollment in 2016. The primary objective of ACCELERATE is to collect real world data on the natural history and treatment of patients with CD.Methods: ACCELERATE employs a unique two-armed approach to enroll individuals, who have had a lymph node pathology report suggesting “Castleman disease.” The “physician-directed arm” (PDA) consists of 10 study sites located in 6 European countries, a traditional paper-based patient consent, and physician data entry via a web-based portal. In contrast, the “patient-powered arm” (PPA) involves a web-based platform through which participants located anywhere outside of Europe can enroll directly at www.CDCN.org/ACCELERATE. Once enrolled in the PPA, medical records, including pathology images, are obtained and data is extracted into the web-based portal by the ACCELERATE Registry Team (ART). Analyses of demographic, select clinical and laboratory, and treatment data were performed in cases with complete extracted records. A Certification & Access Subcommittee will review all cases to grade the quality of data that exist in favor of a CD diagnosis. iMCD diagnosis is based on recently-published consensus criteria.Results: Since launching in August 2016, 51 subjects have consented, satisfied inclusion criteria, and completed all enrollment forms. The ART has completed extraction of medical records into the database for 15 patients, including 9 iMCD participants and 6 UCD participants. There were 4 females with iMCD and 3 with UCD. The median age at diagnosis was 31 (range: 14-58) for iMCD and 38.5 (range: 10-52) for UCD. Six iMCD patients demonstrated hyaline vascular or hypervascular histopathological features, 2 had mixed features, and 1 had plasmacytic features. All 6 UCD patients demonstrated hyaline vascular features. A greater number of clinical and laboratory abnormalities were observed in iMCD patients compared to UCD patients (Table 1). Four of the UCD patients received surgical excision as the sole therapy, and 2 were treated with surgical excision plus medical therapy with a corticosteroid or rituximab. Twenty-two different medications, including 4 different corticosteroids, were used to treat iMCD patients. Medications used simultaneously were classified as regimens. Twenty unique regimens were used, 7 of which included the anti-IL-6 monoclonal antibody, siltuximab, which is the only FDA-approved iMCD treatment. On average, each iMCD patient was treated with approximately 4.3 different regimens after diagnosis (mean time: 3.3 years). Regimens administered more than once to the iMCD cohort included: corticosteroid (CS) monotherapy (n=5), siltuximab+CS (n=5), rituximab monotherapy (n=4), tocilizumab+CS (n=4), siltuximab monotherapy (n=3), rituximab+CS (n=3), and rituximab+cyclophosphamide+CS (n=2).Conclusions: The ACCELERATE Registry is a powerful tool for gathering international clinical and laboratory data for CD. It will allow investigators to describe the natural history of CD and provide a database for testing new hypotheses. Information gathered from the registry may lead to refinements in the diagnostic criteria and improved insights into disease management. Based on this preliminary analysis, it is evident that CD is a heterogeneous disease that is treated with a variety of therapeutic strategies. As sample size increases, we will gain critical insights into treatment effectiveness. We are actively seeking increased enrollment of participants around the world at www.CDCN.org/ACCELERATE. [Display omitted] DisclosuresFajgenbaum:Janssen Pharmaceuticals: Research Funding. Liu:Evercore ISI: Employment. Lukac:PAREXEL International Czech Republic s.r.o, on behalf of Janssen Pharmaceuticals: Employment. Guilfoyle:Janssen: Employment, Equity Ownership. Tendler:Janssen Pharmaceuticals: Employment, Equity Ownership. Uldrick:National Institutes of Health: Patents & Royalties: immunomodulatory compound for KSHV malignancies (Inst); Merck: Research Funding; Celgene: Research Funding; Roche: Research Funding.

Virome Capture Sequencing in Castleman Disease Identifies Associations with Herpesviridae Family Members but No Novel Viruses

Castleman disease (CD) describes multiple distinct and heterogeneous disorders defined by common lymph node histopathology, including atrophic or hyperplastic germinal centers, prominent follicular dendritic cells, hypervascularization, polyclonal lymphoproliferation, and/or polytypic plasmacytosis. Unicentric CD (UCD) involves a solitary lymph node station that displays CD histopathology, whereas multicentric CD (MCD) involves multiple regions of enlarged nodes. Most UCD patients do not experience systemic symptoms and are successfully treated by removal of the enlarged node. In contrast, MCD involves constitutional symptoms, cytopenia, hepatosplenomegaly, fluid accumulation, cytokine storm-associated multiple organ system dysfunction, and is often fatal. In 1994, Kaposi sarcoma-associated herpesvirus/human herpesvirus-8 (HHV-8) was identified as the etiological driver of MCD in immunocompromised individuals. However, approximately 50% of MCD patients are HHV-8 negative (idiopathic MCD (iMCD)). Its idiopathic nature limits targeted treatment for iMCD patients who do not respond to anti-Interleukin-6 therapy. iMCD is itself heterogeneous, and recent work has identified at least one distinct sub-population of iMCD patients with a severe clinical presentation featuring thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO). Several hypotheses have been proposed to explain the pathophysiology of iMCD and UCD, all of which remain untested. One notable hypothesis entertains that iMCD and UCD are in fact driven by viral infection–either HHV-8 that is not detected by current diagnostic methods, a novel virus, or a known but unanticipated virus. In support of the last possibility, there are several case reports of associations with Epstein-Barr virus (EBV), HHV-6 and Hepatitis B virus (HBV); however, neither a systematic study of known viruses, nor a search for novel viruses in CD has been reported.To this end, we employed Virome Capture Sequencing for Vertebrate Viruses (VirCapSeq-VERT),-a RNA-hybrid capture, deep sequencing and bioinformatics pipeline designed for viral discovery. In accordance with the Treaty of Helsinki, we obtained freshly frozen lymph node tissue from patients with iMCD (n=11) and UCD (n=12) as experimental conditions. HHV-8-positive MCD (n=2) was included as a positive control for HHV-8 infection. Lymph nodes from patients with lymphoma without clinical suspicion of HHV-8 infection (n=6) and an additional reactive lymph node were included as a negative control. HHV-8 was only detected in HHV-8-positive MCD and not in iMCD or UCD, consistent with prior clinical testing. Additionally, we did not identify any previously unknown viruses in iMCD or UCD lymph node tissue. Members of the herpesviridae family, including EBV, HHV-6 and HHV-7, were found in all conditions. Interestingly, in iMCD, the identification of herpesviridae family members was associated with relapsing disease and the more clinically severe iMCD-TAFRO variant. Additional numerous associations of unclear significance were made with viruses such as Human Endogenous Retrovirus Type K (HERV-K), transfusion transmitted virus/Torque teno virus (TTV), and Pegivirus.To investigate the significance of the EBV infection, we analyzed the number of EBV positive cells by in situ hybridization on lymph node tissue from a separate cohort of patients with CD and related disorders. The mean number of Epstein-Barr virus-encoded small RNAs (EBER) positive cells/high-powered fields (HPF) across 10 HPF was significantly lower in UCD (2 ± 2.3; n=9) and iMCD (1.7 ± 2.8; n=12) than in HHV-8 positive MCD (106.5 ± 75.6; n=2) and EBV-associated lymphoproliferation (63.5 ± 54.4; n=2) (p < 0.005 for all comparisons). The only iMCD-TAFRO case in this cohort had 4 EBER-positive cells/HPF. Further study is needed with larger cohorts of patients to validate the prognostic and potentially pathogenic significance of these associations, and in particular, the association of EBV and other herpesviridae family members with iMCD-TAFRO. DisclosuresFajgenbaum:Janssen Pharmaceuticals: Research Funding.

Refinement of an open-microcavity optical biosensor for bacterial endotoxin test

The Limulus Amebocyte Lysate (LAL) test is an in vitro assay widely used in the pharmaceutical and biotechnology industries to detect bacterial endotoxins. Endotoxin is a structural component of the cell wall of Gram-negative bacteria, which has serious pathogenic effects in the body and may cause dysfunction of multiple organ systems and increased risk of mortality. To address the growing need for LAL assays due to the increased demand from drug and vaccine manufacturers, we have developed a new LAL assay approach. Our detection mechanism is different and improved from those currently used in the industry, leading to increased test sensitivity and reduced assay time. Our study utilizes an open-microcavity photonic-crystal biosensor to quantify endotoxin concentrations. It has demonstrated an improved LAL assay sensitivity by 10 fold compared to the commercial standard methods and reduced the time needed for the assay by more than half. In addition, this approach requires as little as 5 μL of LAL reagent per test, thereby decreasing costs and conserving horseshoe crabs. The results reported in this paper indicate the possibility of using the photonic-crystal biosensor based approach for significant enhancements of endotoxin testing.

ATTR amyloidosis during the COVID-19 pandemic: insights from a global medical roundtable

BackgroundThe global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing the ongoing coronavirus disease 2019 (COVID-19) pandemic has raised serious concern for patients with chronic disease. A correlation has been identified between the severity of COVID-19 and a patient’s preexisting comorbidities. Although COVID-19 primarily involves the respiratory system, dysfunction in multiple organ systems is common, particularly in the cardiovascular, gastrointestinal, immune, renal, and nervous systems. Patients with amyloid transthyretin (ATTR) amyloidosis represent a population particularly vulnerable to COVID-19 morbidity due to the multisystem nature of ATTR amyloidosis.Main bodyATTR amyloidosis is a clinically heterogeneous progressive disease, resulting from the accumulation of amyloid fibrils in various organs and tissues. Amyloid deposition causes multisystem clinical manifestations, including cardiomyopathy and polyneuropathy, along with gastrointestinal symptoms and renal dysfunction. Given the potential for exacerbation of organ dysfunction, physicians note possible unique challenges in the management of patients with ATTR amyloidosis who develop multiorgan complications from COVID-19. While the interplay between COVID-19 and ATTR amyloidosis is still being evaluated, physicians should consider that the heightened susceptibility of patients with ATTR amyloidosis to multiorgan complications might increase their risk for poor outcomes with COVID-19.ConclusionPatients with ATTR amyloidosis are suspected to have a higher risk of morbidity and mortality due to age and underlying ATTR amyloidosis-related organ dysfunction. While further research is needed to characterize this risk and management implications, ATTR amyloidosis patients might require specialized management if they develop COVID-19. The risks of delaying diagnosis or interrupting treatment for patients with ATTR amyloidosis should be balanced with the risk of exposure in the health care setting. Both physicians and patients must adapt to a new construct for care during and possibly after the pandemic to ensure optimal health for patients with ATTR amyloidosis, minimizing treatment interruptions.

English

With a continuous increase in Covid-19 cases, patients infected with SARS-CoV-2 have shown a wide variety of symptoms including fever, shortness of breath, cough, myalgia, dizziness, headache, impaired consciousness, abdominal pain and diarrhoea. Lab studies have shown higher leukocyte counts and neutrophil-lymphocyte ratio (NLR), decreased lymphocytes, increased prothrombin time and a partial thromboplastin time, increased serum lactate dehydrogenase, ferritin and various other markers, indicating multiple organ system dysfunction including respiratory system, immune system, nervous system and gastrointestinal tract. Apart from these, heart and kidneys are also found to be affected in some patients. Patients presenting with previous history of diseases such as cardiovascular diseases, kidney diseases, pregnant females, neonates, immunosuppressed patients, and aged people have shown poor prognosis of disease. Various studies suggest possible reasons of multiple organ dysfunctions including wide distribution of angiotensin-converting enzyme 2 (ACE-2) receptors, cytokine storm and hypercoagulability of blood. We have listed the various organ systems affected by the virus and possible explanations as to why and how these organ systems are affected. SARS-CoV-2 outbreak has caused a global pandemic, with more than 33,400,000 confirmed cases of Covid-19, including more than 1,000,000 deaths, reported to World Health Organization (WHO) globally till 30 September 2020. 1 with a basic reproductive number estimated to be 2.2 (1.4 - 3.9) the virus spread is very fast affecting many individuals across the globe. 2 One of the major causes of efficient spread of SARS-CoV-2 in humans is the angiotensin-converting enzyme 2 receptors, used by the virus to enter the cells. 3 Hence, wide distribution of angiotensin-converting enzyme 2 receptors in body including lungs, kidney, bladder, gastrointestinal tract, heart, central nervous system and peripheral nervous system4 and even placenta5 is one of the reasons the virus is found to affect these organs. Two closely related viruses causing Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) were also found to affect multiple organ systems. SARS‐CoV-1 was found in the respiratory pathway (trachea, bronchus, lung), gastrointestinal tract (stomach, small intestines), glands (sweat gland, liver, pancreas, parathyroid, pituitary, adrenal gland), renal system (convoluted renal tubules) and brain tissue (cerebrum) in the autopsy samples of patients who died because of severe acute respiratory syndrome. 6 Respiratory, circulatory, gastrointestinal, haematological, renal and hepatological symptoms were also found to be affected in patients with Middle East respiratory syndrome infection. 7 Though the virus is found to affect multiple organ systems, the underlying mechanisms are not clearly understood.