Operative Volume of Newborn Surgery in German University Hospitals: High Volume Versus Low Volume Centers

Introduction Adequate patient volume is essential for the maintenance of quality, meaningful research, and training of the next generation of pediatric surgeons. The role of university hospitals is to fulfill these tasks at the highest possible level. Due to decentralization of pediatric surgical care during the last decades, there is a trend toward reduction of operative caseloads. The aim of this study was to assess the operative volume of the most relevant congenital malformations at German academic pediatric surgical institutions over the past years. Methods Nineteen chairpersons representing university-chairs in pediatric surgery in Germany submitted data on 10 index procedures regarding congenital malformations or neonatal abdominal emergencies over a 3-year period (2015 through 2017). All institutions were categorized according to the total number of respective cases into “high,” “medium,” and “low” volume centers by terciles. Some operative numbers were verified using data from health insurance companies, when available. Finally, the ratio of cumulative case load versus prevalence of the particular malformation was calculated for the study period. Results From 2015 through 2017, a total 2,162 newborns underwent surgery for congenital malformations and neonatal abdominal emergencies at German academic medical centers, representing 51% of all expected newborn cases nationwide. The median of cases per center within the study period was 101 (range 18–258). Four institutions (21%) were classified as “high volume” centers, four (21%) as “medium volume” centers, and 11 (58%) as “low volume” centers. The proportion of patients operated on in high-volume centers varied per disease category: esophageal atresia/tracheoesophageal fistula: 40%, duodenal atresia: 40%, small and large bowel atresia: 39%, anorectal malformations: 40%, congenital diaphragmatic hernia: 56%, gastroschisis: 39%, omphalocele: 41%, Hirschsprung disease: 45%, posterior urethral valves: 39%, and necrotizing enterocolitis (NEC)/focal intestinal perforation (FIP)/gastric perforation (GP): 45%. Conclusion This study provides a national benchmark for neonatal surgery performed in German university hospitals. The rarity of these cases highlights the difficulties for individual pediatric surgeons to gain adequate clinical and surgical experience and research capabilities. Therefore, a discussion on the centralization of care for these rare entities is necessary.

Mendelian gene identification through mouse embryo viability screening

The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease. Based on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.

Lipid Profile Abnormalities and Their Association with Covid-19 Severity among Patients Admitted at Covid-19 Center in Ethiopia

Background: Current studies have presented and analyzed epidemiological, clinical and clinical laboratory features COVID-19 Patients. Studies suggests that patients with severe COVID-19 shows unregulated lipid metabolism and profile but adequate information is not available concerning the association of lipid parameter features with severity of disease its outcome in Ethiopia. Objective: This study aims to determine the magnitude of lipid profile abnormalities and association of COVID-19 outcome among admitted patients at Millennium COVID-19 care center in Ethiopia. Methods: A prospective observational cohort study was conducted among COVID-19 admitted patients to investigate lipid profile parameters from January 2021- June 2021. A total of 500 patients confirmed with COVID-19 infection by RT-PCR were included. Dynamic alteration in lipid profiles were recorded and tracked. Data were analyzed using SPSS version 25. P value <0.05 was considered significantly associated. Result: The median age of the 500 study participants was 55.58+7.707 years, and from these 71.3% of patients were males. This study found that high-density Lipoprotein cholesterol (HDL-C) and Total Cholesterol levels were significantly higher in the severe and Critical disease category. The total cholesterol results showed that significantly higher 25 (5.38%) in severe infection cases than that, (17 (3.4%), 12(2.4%) and 5 (1%) in moderate, mild and critical cases consecutively (P<0.000). Whereas, patients with severe infection had slightly lower of HDL than Mild and moderate infection cases (P=0.000 and P=0.000) respectively. Moreover, a significant decrement in the level of TG was detected in severe infection cases compared to mild and moderate cases (P=0.0001). Hence, the higher TG/HDL-C ratio (3.754) was found in severe infection cases, compared with mild and moderate infection (P=0.001 and P=0.002) respectively. Conclusion: Lipid function biomarkers like CHO, TG and LDL serum value was found elevated among severe than other patients. Lipid Metabolism biomarkers are a candidate for predicting COVID-19 disease severity in order to guide clinical care and general Public

Results on patient-reported outcomes are underreported in summaries of product characteristics for new drugs

Background Summaries of product characteristics (SmPCs) are regulatory documents published upon drug approval. They should report all relevant study data and advise how to use drugs safely and effectively. Patient-reported outcomes (PROs) are increasingly used in clinical trials to incorporate the patient perspective—SmPCs should thus adequately report PROs. In Germany, new drugs undergo mandatory early benefit assessment. Pharmaceutical companies submit dossiers containing all evidence; the subsequent dossier assessments focus on patient-relevant outcomes and comprehensively report PROs. Objective The primary aim was to investigate to what extent PROs recorded as outcomes in clinical trials of new drugs are reported in SmPCs. Methods We analysed dossier assessments with randomized controlled trials (RCTs) of new drugs entering the market between 01/2014 and 07/2018 and the corresponding SmPCs, and compared PRO reporting in both document types. For this purpose, we evaluated dossier assessment characteristics (e.g. drug name, indication, disease category) and study characteristics (e.g. evaluable PROs available?). PROs were divided into symptoms and health-related quality of life (HRQoL). SmPCs were screened to identify RCTs. We conducted 3 main evaluation steps: (1) Did the RCT included in the dossier assessment contain evaluable PROs? (2) If yes, was the RCT included in the SmPC? (3) If yes, were the PROs reported in the SmPC? Results are presented descriptively. Results 88 dossier assessments including 143 RCTs on 72 drugs were considered: 109 (76.2%) RCTs included evaluable PROs, of which 89 were included in SmPCs. 38 RCTs (42.7%) investigated oncologics, 18 (20.2%) anti-infectives, and 33 (37.1%) other drugs. The RCTs considered symptoms more often than HRQoL (82 vs. 66 RCTs). In SmPCs, PROs were reported for 41 RCTs (46.1%), with a slightly higher reporting rate for RCTs considering HRQoL (43.9%) than for RCTs considering symptoms (41.5%). In oncologic indications, PROs were reported for 36.7% of RCTs considering HRQoL and 33.3% of RCTs considering symptoms. In infectious diseases, the rates were 21.4% (symptoms) and 0% (HRQoL), and for other diseases about 60% (symptoms) to 70% (HRQoL). Conclusion Even though a large amount of PRO data on new drugs is available from clinical trials included in SmPCs, the corresponding results are underreported.

Variables Affecting Outcomes After Allogeneic Hematopoietic Stem Cell Transplant for Cerebral Adrenoleukodystrophy

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in early cerebral adrenoleukodystrophy (CALD) can stabilize neurologic function and improve survival but has associated risks including transplant related mortality (TRM), graft failure, and graft-versus-host disease (GVHD). An observational study of 59 patients with median age at allo-HSCT of 8 years addressed impact of donor source, donor match, conditioning regimen, and cerebral disease stage on first allo-HSCT outcomes. Efficacy analyses included 53 patients stratified by disease category: advanced disease (AD; n=16) with Loes score &gt;9 or neurological function score (NFS) &gt;1 and two early disease (ED) cohorts (ED1 [Loes ≤4 and NFS ≤1; n=24] and ED2 [Loes &gt;4-9 and NFS ≤1; n=13]). Survival free of major functional disabilities and without second allo-HSCT at 4 years was significantly higher in the ED (66%) versus AD (41%) cohort (p=0.015) and comparable between ED1 and ED2 cohorts (p=0.991). The stabilization of neurologic function post-transplant was greater in the ED versus AD cohort, with a median change from baseline at 24 months post-allo-HSCT in NFS and Loes score, respectively, of 0 and 0.5 in ED1 (n=13), 0.5 and 0 in ED2 (n=6), and 2.5 and 3.0 (n=4) in AD cohort. TRM was lower in the ED (7%) compared with AD (22%) cohort, however the difference was not significant (p=0.094). Transplant-related safety outcomes were also impacted by transplant-related characteristics: graft failure incidence was significantly higher with unrelated umbilical cord grafts versus matched related donors (MRD) (p=0.039), and acute GVHD and graft failure incidences varied by conditioning regimen. The study is registered to https://clinicaltrials.gov as NCT02204904.

Reference Standards for Cardiorespiratory Fitness by Cardiovascular Disease Category and Testing Modality: Data From FRIEND

Background The importance of cardiorespiratory fitness for stratifying risk and guiding clinical decisions in patients with cardiovascular disease is well‐established. To optimize the clinical value of cardiorespiratory fitness, normative reference standards are essential. The purpose of this report is to extend previous cardiorespiratory fitness normative standards by providing updated cardiorespiratory fitness reference standards according to cardiovascular disease category and testing modality. Methods and Results The analysis included 15 045 tests (8079 treadmill, 6966 cycle) from FRIEND (Fitness Registry and the Importance of Exercise National Database). Using data from tests conducted January 1, 1974, through March 1, 2021, percentiles of directly measured peak oxygen consumption (VO 2peak ) were determined for each decade from 30 through 89 years of age for men and women with a diagnosis of coronary artery bypass surgery, myocardial infarction, percutaneous coronary intervention, or heart failure. There were significant differences between sex and age groups for VO 2peak ( P <0.001). The mean VO 2peak was 23% higher for men compared with women and VO 2peak decreased by a mean of 7% per decade for both sexes. Among each decade, the mean VO 2peak from treadmill tests was 21% higher than the VO 2peak from cycle tests. Differences in VO 2peak were observed among the age groups in both sexes according to cardiovascular disease category. Conclusions This report provides normative reference standards by cardiovascular disease category for both men and women performing cardiopulmonary exercise testing on a treadmill or cycle ergometer. These updated and enhanced reference standards can assist with patient risk stratification and guide clinical care.

82. Blood Gene Expression Profiles in Neonates with Herpes Simplex Virus (HSV) Infection

Background Neonatal HSV infection is associated with significant morbidity and mortality. Neonates with HSV infection can present with skin, eye, and mouth (SEM), central nervous system disease (CNS), and disseminated disease (DIS). We hypothesize that host immune responses may contribute to differences in disease presentation and outcomes. To address this knowledge gap, we analyzed host transcriptional immune profiles of neonates with HSV infection. Methods Infants &lt; 6 weeks of age (24 (86%) &lt; 4 weeks; 4 (14%) 4-6 weeks old) with neonatal HSV, and healthy infant controls (HC) were enrolled at Children’s Medical Center (Dallas, TX), and Nationwide Children’s Hospital (Columbus, OH) from 2007-2018. Whole blood samples were analyzed by RNA-seq. Modular analyses were performed to identify the immune pathways that were activated or suppressed according to each HSV disease category. Results Of the 28 infants with HSV infection, 9 had SEM (median [IQR] age: 14 [14-28] days), 10 CNS (age: 18 [15-29] days), and 9 DIS (age: 10 [7-10] days). Three infants with DIS died within 5 days of diagnosis. Statistical group comparisons between 13 HC and 18 infants with HSV disease (training set) identified 1,322 differentially expressed genes (neonatal HSV biosignature). This biosignature was validated in the remaining 10 infants with HSV disease (test set), and was characterized by significant overexpression of interferon (INF), inflammation, neutrophils, and monocyte genes and under-expression of T-cell genes. Further analysis according to HSV disease category confirmed overexpression of neutrophil and inflammation genes in infants with SEM, CNS and DIS (Fig 1). On the other hand, overexpression of INF and plasma cell genes, and further suppression of monocytes, cytotoxic/NK cells, and T-cell genes were only evident in children with DIS. Fig 1: Modular immune pathways according to HSV disease category Modules are groups of genes that shared a similar function. Each dot represents a transcriptional module with red indicating overexpression and blue underexpression in relation to healthy controls. The number and color intensity on the dot indicate the percentage of differentially expressed transcripts within a module. SEM: skin, eye mouth; CNS: central nervous system; DIS: disseminated HSV disease. Conclusion Transcriptional profiles of infants with HSV infection exhibited marked activation of the innate immune response irrespective of disease classification. Children with DIS showed more profound dysregulation and suppression of cellular immune responses. Transcriptional profiling may aid unravel mechanisms associated with clinical outcomes in neonatal HSV and inform future therapeutic and preventive strategies. Disclosures Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)

Ethnopharmacological Study of Medicinal Plants in Bajwat Wildlife Sanctuary, District Sialkot, Punjab Province of Pakistan

Bajwat Wildlife Sanctuary is a complex riverine ecosystem and is unique because of the presence of river Chenab, various seasonal streams, lakes, and Head Marala barrage. These ecogeographic conditions provide diverse natural habitats for various plant and animal species to grow uninterrupted and have undocumented ethnopharmacologically important medicinal flora. The present study involves the first-ever extensive investigation to document the ethnopharmacological knowledge on medicinal plants of local healers and inhabitants of the Bajwat Wildlife Sanctuary to treat ailments. The unstructured and semistructured interviews of the local healers and inhabitants were conducted that included 130 individuals. The ethnomedicinal formulations, their method of preparation, mode of administration, parts of the plant used, diseases cured, and their categorization along with species use report (UR) were analyzed. The ethnopharmacological study led to the enlisting of 114 medicinal plant species belonging to 97 genera and distributed among 47 plant families. 2029 URs were collected with 42 general disease categories. Each plant species was reported 18 times to cure various diseases (∼18 UR), while ∼48 URs were collected on each disease category by local informants. Digestive issues (290 URs, ∼14.29%) and skin infections (279 URs, ∼13.75%) were found most commonly among the occupants of the area. The oral administration (69%) of herbal drugs and the preparation of plant extracts (32%) were the most common ethnopharmacological strategies. Inhabitants of the area were well aware of the limited use of poisonous plants. 8 (∼7%) out of the total 114 medicinal plant species were listed in the IUCN Red List of Threatened Species as Least Concern, while Eucalyptus camaldulensis Dehnh. was enlisted as near-threatened. The results of the present investigation show that the occupants of the Bajwat have sound information about the ethnopharmacological consumption of medicinal plants, and some of the novel ethnomedicinal formulations were reported which provide the basic data for further pharmacological research.