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BackgroundAlthough coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics.MethodsA panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion.ResultsGiven the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available.ConclusionsAntiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.

Background: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia. Methods: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians)

Objective: There are urinary tract infection (UTI) guidelines for treatment of patients Study Design: Retrospective study from December 1st, 2015 to May 31st, 2016.Results: The study population included 903 children (70.1% female) with a median age of 11 years, evaluated in an outpatient clinic (n = 780, 86.4%) or school health site (n = 123, 13.6%). E. coli was the most common urinary pathogen (50.9%) and 92.6% of E. coli isolates were susceptible to cephalexin. However, cephalexin was prescribed empirically for only 12.8% of patients. In contrast, sulfamethoxazole-trimethoprim was commonly prescribed, but only 79% of E. coli isolates were susceptible. Antibiotics were discontinued in only three of 48 children who had negative urine cultures.Conclusions: Cephalexin may be the most appropriate first-line choice for management of outpatient UTI for our patient population. Antibiotics were rarely discontinued for those with negative urine cultures. Antibiotic stewardship in the outpatient setting could reduce unnecessary antibiotic exposure in the management of pediatric UTI.

1. Gail F. Shust, MD* 2. Vijaya L. Soma, MD* 3. Philip Kahn, MD† 4. Adam J. Ratner, MD, MPH*,‡ 1. *Division of Pediatric Infectious Diseases 2. †Division of Pediatric Rheumatology, Department of Pediatrics 3. ‡Department of Microbiology, New York University Grossman School of Medicine, New York, NY Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain asymptomatic or develop only mild symptoms. However, rare severe cases occur. During spring 2020, a new pediatric syndrome, likely a postinfectious complication of coronavirus disease 2019 (COVID-19), was described. The seminal report discussed 8 children with signs of hyperinflammation and shock and features consistent with Kawasaki disease (KD) or toxic shock syndrome. Initially named pediatric inflammatory multisystem syndrome, it is now commonly called multisystem inflammatory syndrome in children (MIS-C). Alarmingly, patients with MIS-C generally experience more severe disease than children with acute COVID-19, frequently requiring hospitalization and, at times, critical care. Cases of MIS-C have now been reported from many countries. The United States alone has had more than 2,000 cases and 30 deaths meeting the Centers for Disease Control and Prevention (CDC) MIS-C definition (Table). View this table: Table. CDC Case Definition for MIS-C An individual younger than 21 years presenting with fever (temperature ≥100.4°F [≥38.0°C] for ≥24 hours, or report of subjective fever lasting ≥24 hours), laboratory evidence of inflammation (including, but not limited to, ≥1 of the following: elevated C-reactive protein level, erythrocyte sedimentation rate, fibrinogen level, procalcitonin level, D-dimer level, ferritin level, lactic acid dehydrogenase level, interleukin [IL]-6 level, and neutrophil count; reduced lymphocyte count; and low albumin level), and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement; AND no alternative plausible diagnoses; AND positive for current or recent SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR), serologic testing, or antigen testing; OR exposure to a suspected or confirmed COVID-19 case within the 4 weeks before the onset of symptoms. Clinical signs and symptoms of MIS-C vary and may include fever, gastrointestinal symptoms, mucocutaneous lesions, hypotension, and shock. Given the clinical overlap among MIS-C, COVID-19, KD, and toxic shock syndrome, and the …

Background The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. Methods We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. Results A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score–matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score–matched analysis. Conclusions Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.)

IMPORTANCE: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. OBJECTIVE: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). SETTING, DESIGN, AND PARTICIPANTS: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase–polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. EXPOSURE: SARS-CoV-2. MAIN OUTCOMES AND MEASURES: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. RESULTS: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P

Purpose of review Here we summarize current knowledge about multisystem inflammatory syndrome in children (MIS-C), a presumed postinfectious inflammatory condition that has emerged as an important COVID-19-associated complication, to help clinicians identify and manage cases. Recent findings Clinical presentation of MIS-C is dominated by significant inflammation. Fever, gastrointestinal symptoms, cardiac dysfunction, and hypotension are common features. Kawasaki disease-like findings are common, but epidemiologic data and recent mechanistic studies suggest that distinct inflammatory pathways mediate Kawasaki disease and MIS-C. A broad diagnostic approach is recommended, given overlapping presentations between MIS-C and many other disease processes. Current management of MIS-C is highly variable, depending on illness severity, and can range from supportive care to aggressive immune modulation. A multidisciplinary approach with early involvement of multiple pediatric subspecialists is recommended for complicated cases. Summary Several studies have described the clinical manifestations of MIS-C, but definitive diagnosis remains challenging. Robust information about long-term outcomes awaits further study, as do immunologic data to refine diagnostic and therapeutic strategies.

Background: Gut microbial diversity and composition play important roles in health. This cross-sectional study was designed to test the hypothesis that hospitalized children who may be relatively immunocompromised (IC), defined as those with cancer, sickle cell disease (SCD), transplantation, or receiving immunosuppressive therapy) would have decreased microbial diversity, increased Clostridioides difficile colonization and different species composition compared to non-immunocompromised (Non-IC) children admitted to the same pediatric unit. Methods: A stool sample was obtained within 72 h of admission to a single unit at The Children's Hospital at Montefiore, Bronx, NY from March 2016 to February 2017 and the microbiome assessed by 16S rRNA sequencing. C. difficile colonization was assessed by glutamate dehydrogenase antigen and toxin polymerase chain reaction assays. Results: Stool samples were obtained from 69 IC (32 SCD, 19 cancer, 9 transplantation and 9 other) and 37 Non-IC patients. There were no significant differences in microbial alpha diversity and C. difficile colonization comparing IC vs. non-IC patients. Lower alpha diversity, however, was independently associated with the use of proton pump inhibitors or antibiotics, including prophylactic penicillin in patients with SCD. Differences in specific species abundances were observed when comparing IC vs. non-IC patients, particularly children with SCD. Non-IC patients had increased abundance of commensals associated with health including Alistipes putredinis, Alistipes ihumii, Roseburia inulinivorans, Roseburia intestinalis, and Ruminococcus albus (p < 0.005). Conclusions: Antibiotics and proton pump inhibitors, which were more commonly used in IC children, were identified as risk factors for lower microbial diversity. Non-IC patients had higher abundance of several bacterial species associated with health. Longitudinal studies are needed to determine the clinical significance of these differences in gut microbiome.

Background Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7). Patients homozygous for the minor allele (CC) in the UGT2B7 -161 promoter polymorphism have lower clearance and significantly higher rates of leukopenia compared to wild-type homozygote (TT) or heterozygote (CT) patients. This study was designed to determine if TT and CT genotype patients could tolerate a higher epirubicin dose compared to CC genotype patients. Patients and Methods We studied women with histologically confirmed non-metastatic, invasive breast cancer who were scheduled to receive at least three cycles of FE100C in the (neo)adjuvant setting. Patients received standard-dose FE100C during the first 21-day cycle. Based on genotype, the epirubicin dose was escalated in the second and third cycles to 115 and 130 mg/m2 or to 120 and 140 mg/m2 for CT and TT genotype patients, respectively. The main outcome measurements were myelosuppression and dose-limiting toxicity. These were analyzed for relationships with the three genotypes. Results Forty-five patients were enrolled (10 CC, 21 CT, and 14 TT genotypes) and received 100 mg/m2 of epirubicin in the first cycle. Twelve and 10 TT patients were dose escalated at the second and third cycles, respectively; 16 CT patients were dose escalated at the second and third cycles. Leukopenia, but not febrile neutropenia, was genotype and dose dependent and increased in patients with CT and TT genotypes as their dose was increased. However, the third-cycle leukopenia rates were comparable to patients with the CC genotype receiving standard-dose epirubicin. Conclusion Pharmacogenetically guided epirubicin dosing is well tolerated and allowed dose escalation without increased toxicity.

Summary Background & aims Pre-clinical studies suggest that 16:4(n-3) in purified form or as a component of fish oil might induce platinum-based chemotherapy resistance. Our aim was to determine plasma total and free 16:4(n-3) before and during platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients supplemented with fish oil or provided standard care, and to explore relationships between plasma 16:4(n-3) levels and tumor response to treatment. Methods In a retrospective, secondary data analysis of a prior clinical trial, plasma from patients with NSCLC (n = 21) who underwent platinum-based chemotherapy and were assigned to 2.2 g/day of eicosapentaenoic (EPA) plus 1.1 g DHA/day as fish oil (FO; n = 12) or received no intervention (standard care; SC; n = 9). Plasma 16:4(n-3) was quantified as free and esterified (total) fatty acid using HPLC-MS/MS. Plasma 16:4(n-3) levels were evaluated over time in relation to fish oil supplementation and response to platinum-based therapy, and compared with a group of healthy subjects (REF; n = 11). Results Plasma 16:4(n-3) was detected in all samples. The percentage change/day in plasma esterified (total) 16:4(n-3) was higher for FO versus SC group (2.7 versus −1.8%/d, U = 20, p = 0.02), but change in plasma free 16:4(n-3) was not different between FO and SC. Median plasma free and esterified 16:4(n-3) were similar between responders and non-responders to platinum-based chemotherapy. Total and free plasma 16:4(n-3) fatty acids were similar between NSCLC patients and REF (NSCLC vs REF: total 16:4(n-3): 122.9 vs. 95.2 nM and free 16:4(n-3) 23.9 vs. 27.6 nM). Conclusions This first of its kind study that evaluated plasma 16:4(n-3) in NSCLC patients showed that 16:4 (n-3) was elevated during FO supplementation, independent of fish oil supplementation or platinum-based chemotherapy.

Literature is limited on pediatric anti-infective medication errors. There is a pressing need for additional research, as studies suggest high rates of overall pediatric medication errors and known harmful side effect profiles for anti-infective medications with narrow dosing ranges. This study aimed to identify risk factors related to harmful anti-infective medication errors in pediatric patients.A retrospective chart review of all voluntary error reports involving anti-infective medication errors and pediatric patients (0 to 22 years old) reported June 2014-December 2015 was conducted. Error reports were generated using the hospital's general error reporting system and a pharmacy-based patient surveillance reporting system and were stratified based on the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) Medication Error Index. Harmful errors were compared to nonharmful errors using Fisher's exact test.Of 338 anti-infective medication-related error reports, 13.6% of voluntarily reported errors reached the patient and 1.5% resulted in harm to the patient and required additional monitoring, interventions, and/or prolonged hospitalization. Antibacterials comprised 93.8% of all error reports, with beta-lactams (63.0%), macrolides (6.5%) and glycopeptides (6.2%) the most common classes. When using Fisher's exact test to compare harmful and nonharmful medication errors, the risk factor significantly associated with harmful errors was anti-infective class (p = 0.001).Voluntarily reported anti-infective medication errors within the pediatric patient population often reached the patient, and specific anti-infective medications are potentially of higher risk. Further investigation and additional quality and patient safety strategies may be needed for these higher-risk profile medications.

Background Blocking of lymphocyte trafficking to bile ducts is a potential mechanism to alter the disease course of patients with primary sclerosing cholangitis (PSC). Aim To describe the effect of the α4 β7 integrin antibody, vedolizumab, on liver biochemistry and disease activity in patients with PSC and inflammatory bowel disease (IBD). Methods This is a retrospective multi-centre study of adult patients with a diagnosis of both IBD and PSC. The primary outcome was change in serum alkaline phosphatase level at weeks 14 and 30. Secondary outcomes included changes in other liver biochemistries and in clinical outcomes for the bowel disease. A safety analysis for adverse events was performed. Results Thirty-four patients (16 Crohn's disease, 18 ulcerative colitis) were included. Nine (26%) had a history of liver transplant. Median follow-up on vedolizumab was 9 months (IQR: 7-16). There was no overall change in serum alkaline phosphatase level with vedolizumab therapy (median 268 [IQR: 105-551] IU/L at baseline versus 249 [IQR: 183-634] IU/L, P = 0.99 at week 30). No significant changes in other liver biochemistries or the Mayo PSC Risk Score were demonstrated at week 30. Clinical remission was achieved at week 30 in 55% of Crohn's disease and 29% of ulcerative colitis patients. Seven (21%) patients ceased vedolizumab; six patients stopped therapy due to persistent IBD activity and one for worsening of liver biochemistries. Conclusion Vedolizumab treatment in patients with PSC and IBD did not improve liver biochemistry but was associated with improvement in bowel disease and a favourable safety profile.

Aim Imbalances in cytochrome P450 (CYP)-dependent eicosanoid formation may play a central role in ischemic acute kidney injury (AKI). We reported previously that inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) action ameliorated ischemia/reperfusion (I/R)-induced AKI in rats. Now we tested the hypothesis that enhancement of epoxyeicosatrienoic acid (EET) actions may counteract the detrimental effects of 20-HETE and prevent the initiation of AKI. Methods Male Lewis rats underwent right nephrectomy and ischemia was induced by 45 min clamping of the left renal pedicle followed by up to 48 h of reperfusion. Circulating CYP-eicosanoid profiles were compared in patients who underwent cardiac surgery with (n = 21) and without (n = 38) developing postoperative AKI. Results Ischemia induced an about eightfold increase of renal 20-HETE levels, whereas free EETs were not accumulated. To compensate for this imbalance, a synthetic 14,15-EET analogue was administered by intrarenal infusion before ischemia. The EET analogue improved renal reoxygenation as monitored by in vivo parametric MRI during the initial 2 h reperfusion phase. The EET analogue improved PI3K- as well as mTORC2-dependent rephosphorylation of Akt, induced inactivation of GSK-3β, reduced the development of tubular apoptosis and attenuated inflammatory cell infiltration. The EET analogue also significantly alleviated the I/R-induced drop in creatinine clearance. Patients developing postoperative AKI featured increased preoperative 20-HETE and 8,9-EET levels. Conclusions Pharmacological interventions targeting the CYP-eicosanoid pathway could offer promising new options for AKI prevention. Individual differences in CYP-eicosanoid formation may contribute to the risk of developing AKI in clinical settings.

Celiac disease (CD) is an immune-mediated enteropathy that occurs in genetically susceptible hosts with the ingestion of gluten-containing products. Ongoing gluten consumption leads to intestinal damage, characterized by villous blunting and increased intraepithelial lymphocytes, resulting in malabsorption. Pertinent to the development of bone disease, malabsorption of calcium and vitamin D leads to secondary hyperparathyroidism and metabolic bone disease among individuals with CD. In this article, we review the pathogenesis of CD and the effects of malabsorption on bone health. Imbalances in bone resorption and formation particularly in individuals with CD and persistent disease activity ultimately lead to a state of bone loss and impaired mineralization. Initiation of a gluten-free diet is critical in the management of CD-related metabolic bone disease, demonstrating improvements in bone mineral density within the first year of dietary adherence.

Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases, and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g. KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the RNA induced silencing complex (RISC)—physically interacts with KRAS and stabilizes it at the protein level. In multiple cell lines, AGO2 knockdown reduces KRAS protein level and attenuates cell proliferation. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the clara cell-specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation in tumor nodules, indicating impaired KRAS signaling. Furthermore, RNA-seq analysis of KPC nodules demonstrated broadly reduced expression of Kras-related genes. Taken together, our data demonstrate a novel pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work has future translational relevance. Citation Format: Jean C. Tien, Seema Chugh, Andrew E. Goodrum, Yunhui Cheng, Lisha Wang, Rahul Mannan, Xiaoming Wang, Vijaya L. Dommeti, Yuping Zhang, Alice Xu, Fengyu Su, Xuhong Cao, Sunita Shankar, Arul M. Chinnaiyan. Ago2 induces Kras signaling and promotes tumor progression in mouse models of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2936.

Background and Aims This study aims to assess current practices and perspectives of gastroenterologists on approaches to code status before inpatient endoscopy. Methods Self-reported data were obtained through a voluntary, anonymous survey of gastroenterologists and gastroenterology trainees in the United States (U.S.). The survey assessed respondents’ approach to, beliefs, and knowledge regarding inpatient periprocedural code status discussions. Results Four hundred thirty-six gastroenterologists and 83 trainees completed the survey. In patients with an existing do not resuscitate (DNR) order, respondents reversed the code status before endoscopy either all (40.8%, n = 212) or most of the time (18.3%, n = 95). When asked their personal opinion, 32.6% (n =169) supported automatic DNR reversal to full resuscitation attempt during a procedure, 18.5% (n = 96) supported that DNR orders could be sustained, and 48.7% (n = 253) supported offering limited resuscitation. Many gastroenterologists were unaware of institutional (40.7%, n = 211) or national (80.7%, n = 419) policies and a majority reported that a gastroenterology-specific guideline would be helpful (88.6%, n = 460). Conclusions Although the majority of gastroenterologists reverse DNR orders more than 75% of the time before endoscopy, many also believe patients should be allowed to remain DNR during a procedure and supported a third option for limited resuscitation. Most gastroenterologists were unaware of institutional policies or existing national guidelines. These findings suggest considerable variation in knowledge and current approaches regarding periendoscopic code status reversal.

Introduction Serum creatinine concentration in health is essentially a function of muscle mass. We designed a prospective study to know the influence of gestational age and birth weight on creatinine in the first week of life. Materials and methods A total of 218 neonates were enrolled during a 2-year study period (May 2014—April 2016) at Kamineni Hospitals, Hyderabad, India. The study group was categorized based on gestational age [very preterm (VPT), preterm (PT), and term] and birth weight [very low birth weight (VLBW), low birth weight (LBW), and normal birth weight (NBW)]. The serum creatinine was assayed on the day of delivery in the mother and on days 0, 3, 5, and 7 in the neonates. The method of estimation of serum creatinine was by the modified kinetic Jaffe's reaction. Results Serum creatinine was high in the VPT neonates (28—33 weeks of gestational age) and VLBW neonates ( Conclusion The serum creatinine in the first week of a newborn should be interpreted cautiously as the kidneys are in the process of maturation. High serum creatinine in neonates with insignificant muscle mass is a reflection of maternal serum creatinine coupled with an immature kidney. How to cite this article Ayyala VL, Devabathina N, Gurappagari P. Effect of Gestational Age and Birth Weight on Serum Creatinine in the First Week of Newborn Life. Indian J Med Biochem 2017;21(2):131-135.

Background: Vernal keratoconjunctivitis (VKC) is an allergic eye disease that especially affects young boys. Both olopatadine and bepotestine are dual acting drugs that provide rapid symptomatic relief coupled with the long-term disease-modifying benefit. The present study is conducted to compare the efficacy and safety of olopatadine eye drops and bepotastine eye drops in patients of vernal keratoconjunctivitis.Methods: A prospective, randomized, parallel-group, comparative study is conducted over a period of 4 weeks on paediatric patients with VKC. 50 patients are recruited and randomized into two treatment groups. They received the assigned drugs for 4 weeks and are called for follow up at the end of 1st week, 4th week and 12th week. At each follow-up, patients are examined and the clinical parameters are graded.Results: This study shows that both olopatadine and bepotastine are equally efficacious. Bepotastine provided quicker relief to symptoms of watering, ocular discomfort and conjunctival hyperaemia. Number of responders are also more in the bepotastine group. Absolute eosinophilic count improved with both the drugs but there is no statistically significant difference between them. Both drugs showed good safety profile. However, 24% patients reported aversion to bitter taste with bepotastine. There is no treatment related severe adverse effects in both the groups.Conclusions: Both olopatadine and bepotastine are effective in treating vernal keratoconjunctivitis. However, bepotastine performed better in reducing tearing, ocular discomfort and conjunctival hyperaemia.

IntroductionA small bowel source is suspected when evaluation of overt gastrointestinal (GI) bleeding with upper and lower endoscopy is negative. Video capsule endoscopy (VCE) is the recommended next diagnostic test for small bowel bleeding sources. However, clinical or endoscopic predictive factors for small bowel bleeding in the setting of an overt bleeding presentation are unknown. We aimed to define predictive factors for positive VCE among individuals presenting with overt bleeding and a suspected small bowel source.MethodsWe included consecutive inpatient VCE performed between September 1, 2012 to September 1, 2015 for melena or hematochezia at two tertiary centers. All patients had EGD and colonoscopy performed prior to VCE. Patient demographics, medication use, and endoscopic findings were retrospectively recorded. VCE findings were graded based on the P0-P2 grading system. The primary outcome of interest was a positive (P2) VCE. The secondary outcome of interest was the performance of a therapeutic intervention. Data were analyzed with the Fisher exact test for dichotomous variables and logistic regression.ResultsTwo hundred forty-three VCE were reviewed, and 117 were included in the final analysis. A positive VCE (P2) was identified in 35 (29.9%) cases. In univariate analysis, a positive VCE was inversely associated with presence of diverticula on preceding colonoscopy (OR: 0.44, 95% CI: 0.2-0.99), while identification of blood on terminal ileal examination was associated with a positive VCE (OR: 5.18, 95% CI: 1.51-17.76). In multivariate analysis, only blood identified on terminal ileal examination remained a significant risk factor for positive VCE (OR: 6.13, 95% CI: 1.57-23.81). Blood on terminal ileal examination was also predictive of therapeutic intervention in both univariate (OR: 4.46, 95% CI: 1.3-15.2) and multivariate analysis (OR: 5.04, 95% CI: 1.25-20.32).ConclusionAmong patients presenting with overt bleeding but negative upper and lower endoscopy, the presence of blood on examination of the terminal ileum is strongly associated with a small bowel bleeding source as well as with small bowel therapeutic intervention. Presence of diverticula on colonoscopy is inversely associated with a positive VCE and therapeutic intervention in univariate analysis.

The original version of the article unfortunately contained an error in a percentage value in Results section of Abstract.

Background Children with sickle cell disease (SCD) have numerous risk factors for intestinal dysbiosis, including frequent hospitalization, iron overload, antibiotic exposure including penicillin prophylaxis, hypoxia, and altered gut permeability. Many of these conditions are also established risk factors for C. difficile infection (CDI); however, the incidence of CDI in children with SCD has not been characterized. Methods We performed a 10-year retrospective review from 1/2008–December 2017. Patients who qualified with CDI were either admitted or within 2 weeks of discharge from our site and had a positive test. A positive test was defined as a positive glutamate dehydrogenase 1 test in conjunction with either a positive ELISA or a positive PCR for toxin. Three investigators independently reviewed if patients had active diarrhea during the time of their positivity. Patients excluded were Results Over a 10-year period (2008–2017), there were 5666 admissions for children with SCD, corresponding to 25,915 hospitalization days and 957 unique patients. The average age of this cohort at the time of admission was 10.6 ± 6.7 years; 51.7% were male. One patient qualified; a 12-year-old who developed diarrhea and abdominal pain after recent hospitalization for pneumonia (Figure 1). This yielded a CDI incidence of 0.39/10,000 patient-days or 0.18 cases per 1000 admissions (Table 1). There were 208 cases of CDI in non-SCD children, with an incidence of 5.53/10,000 patient-days (P < 0.001) or 2.77 cases per 1000 admissions (P < 0.001) (Table 2) during the study period. In 2015–2017, there were no cases of CDI in 957 SCD patients, of which 218 were on penicillin prophylaxis. Conclusion There is a very low incidence of CDI in children with SCD despite significant antibiotic exposure and other risk factors for intestinal dysbiosis. These findings are consistent with recent studies in adults (N Engl J Med 2019; 380:887–888) and suggest that sickle cell patients are somehow protected against CDI. Additional studies are needed to define the host and biome factors that confer this protection. Disclosures All authors: No reported disclosures.

Objective The aim of this study was to describe the multiphase multi-detector row computed tomography (MDCT) imaging findings of large (>5 cm) focal hepatocellular carcinoma (HCC). Methods Following review of the medical records of 321 patients with newly diagnosed HCC who underwent MDCT within the radiology database from January 2007 to November 2014, 27 patients (20 men and 7 women; mean age, 69 [SD, 10.1] years [range, 49-87 years]) with histologically confirmed HCC greater than 5 cm were included in this institutional review board-approved study. Multiphase, dedicated liver MDCT images of these cases were retrospectively reviewed by 2 radiologists in consensus to describe the enhancement characteristics of these lesions. Results Mean tumor diameter was 8.4 (SD, 2.4) cm (range, 5.2-13.5 cm). Cirrhosis was present in 16 (59%) of 27 patients. Seventeen (85%) of 20 patients with available laboratory data presented with elevated alpha-fetoprotein (median, 97 ng/mL). Twenty-three (85%) of 27 demonstrated either heterogeneous enhancement with gradual fill-in (14/27 [52%]) or peripheral enhancement with centripetal fill-in (9/27 [33%]). Twenty-two (81%) of 27 lacked washout on delayed phase images, and 21 (78%) of 27 demonstrated a pseudocapsule. Twenty-seven of 27 lesions were well defined, 8 (30%) of 27 were exophytic, 15 (56%) of 27 were unifocal, 5 (25%) of 20 cases demonstrated vascular invasion, and 7 (26%) of 27 cases presented with extrahepatic metastases. Conclusions Large (>5 cm) focal HCC may present as a dominant mass with a pseudocapsule and initial heterogeneous or peripheral enhancement with gradual or centripetal fill-in without washout on multiphase MDCT. Awareness of this variant is important to allow distinction from other benign (eg, hemangioma) and malignant (eg, cholangiocarcinoma) focal liver lesions.

Neuromyelitis optica (NMO) or devics disease was considered as a variant of Multiple sclerosis, w ith recent advances in investigations and with better understanding of etiopathogenesis, NMO is a distinct immune mediated, largely relapsing, inflammatory , demyelinating disease of central nervous system. NMO most commonly i nvolves the optic nerves and spinal cord. Relapsing and monophasic are two var iants of NMO , as relapsing NMO is a rapidly disabling disease, prompt diagnosis of the type from the monophasic, helps in the management as well as decreasing the motor and visual morbidity

Many laboratories use polymerase chain reaction (PCR)-based assays to detect the Clostridium difficile toxin B gene (tcdB) in stool. However, PCR testing experience in pediatric patients is limited. We compared the detection of C. difficile by PCR in hospitalized children with and without diarrhea.Stool samples from patients aged 1-18 years with diarrhea (symptomatic) and from patients without diarrhea (asymptomatic) were tested for C. difficile tcdB using a commercial PCR assay. Samples were cultured for C. difficile using standard techniques with tcdB PCR and cytotoxicity assays performed on C. difficile isolates. Demographic, clinical and laboratory data were abstracted. Categorical and continuous variables were compared between the 2 groups using Fisher Exact test and the Mann-Whitney test, respectively.Thirty-five of 188 (19%) stool samples from symptomatic patients and 18 of 74 (24%) samples from asymptomatic patients were positive by PCR (P=0.31). Among PCR-positive patients, symptomatic patients had a significantly higher proportion of subjects who received antimicrobials in the preceding 30 days (P=0.04) and a greater number of preceding antimicrobial days than did asymptomatic patients (P=0.02) but were comparable with respect to the other variables analyzed.C. difficile PCR assays are frequently positive in hospitalized children both with and without diarrhea. As we observed a high level of toxigenic C. difficile colonization in children, our findings suggest that a positive C. difficile PCR result in a child with diarrhea should be interpreted with caution.

In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)-derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetes-mediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.

Appropriate metrics for performance analysis is an active topic of debate within the transplant community. This study explores current proposals on metric expansion as well as potential metrics and prospective collaborations that have not received widespread discussion within the transplant community. The premature introduction of additional, nonvalidated metrics risks behaviors that may undermine donor utilization and patient access to transplantation.

The purpose of this chapter is to examine how gender positively influences processes and procedures of faculty-led groups within higher educational institutions. A closer inspection of the gender makeup of these faculty-led groups may shed light on the role gender plays in shaping the policies pursued. There will be a section on the effectiveness of using an online platform in terms of efficiency and communication dynamics. The authors, who served as faculty senate leaders, will use a case study approach, plus their own reflections, to explore ways to improve institutional effectiveness within faculty governance.

Single-agent tyrosine kinase inhibitors (TKIs) have significantly improved patient outcomes across multiple tumor subtypes. However, TKI therapy is rarely curative. Early optimism of combining TKIs with cytotoxic chemotherapy failed to produce substantial results in numerous randomized studies. This article highlights potential missteps and improvements in combination therapy thus far, while shedding light on potential improvements for future combinations.

Clostridium difficile is the most commonly isolated stool pathogen in inflammatory bowel disease (IBD). Traditional risk factors for C. difficile may not exist in patients with IBD, and no prior studies have assessed the risk factors for the isolation of C. difficile in both symptomatic and asymptomatic IBD outpatients. We prospectively recruited consecutive IBD patients presenting to our outpatient clinic between April 2015 and February 2016. We excluded patients with a diverting ostomy or ileoanal pouch. Demographics, healthcare exposures, medical therapies and disease activity were recorded from medical charts or surveys. A rectal swab was performed from which toxigenic culture and PCR analysis for the presence of toxin and fluorescent PCR ribotyping were performed. The primary outcome of interest was isolation of toxigenic C. difficile. A total of 190 patients were enrolled in this prospective study including 137 (72%) with Crohn’s disease and 53 (28%) with ulcerative colitis. At the time of enrollment, 69 (36%) had clinically active disease. Sixteen (8.4%) patients had toxigenic C. difficile isolated on rectal swab at enrollment and four (2.1%) patients had non-toxigenic C. difficile cultured. Mixed infection with more than one toxigenic isolate was present in 5/16 (33.3%) individuals. Patients with CD with a toxin positive isolate were more likely to have a history of CDI in the past 12 months (40 vs. 11.02%, p = 0.027) and an emergency department visit in the past 12 weeks (50 vs. 20.63%, p = 0.048). In UC, individuals with isolation of C. difficile were more likely to be hospitalized within the past 12 months (66.6 vs. 8.51%, p = 0.003). C. difficile isolation at the time of presentation was not associated with a subsequent disease relapse over a 6-month period in CD (p = 0.557) or UC (p = 0.131). Healthcare exposures remain a significant risk factor for C. difficile isolation in the IBD population; however, this was not associated with relapse of disease. Further studies assessing the clinical significance of C. difficile isolation is warranted in IBD.

Case description The case highlights a $1.4 billion fraud committed by the founder of a NYSE listed, Information Technology Services firm in India. In response to the crisis, the Indian government appointed an interim board to find a strategic investor in the company. The case traces the events leading to the fall of the company. Students are asked to analyze the governance and intermediation failures, assess the financial position of the company and to estimate the intrinsic value of the company from an acquirer's perspective.

Background The IDSA recommends the use of sulfamethoxazole-trimethoprim (SXT) as empiric therapy (E/T) for uncomplicated urinary tract infections (UTI) in areas where the resistance rate is

Background Our institution revealed Enterobacteriaceae with discordant cefazolin (CEF)-resistant / ampicillin-sulbactam (SAM) susceptible patterns (CRASS-P). This discordance could be from the multiple MIC cephalosporin breakpoint adjustments from CLSI. SAM has higher resistance for gram-negative bacteria compared with cephalosporins such as CEF which is confirmed by our antibiogram. We sought to understand if narrow-spectrum antibiotic choices for CRASS-P urinary tract infections (UTIs) led to clinical cure (CC). Methods We conducted a retrospective review from January 2018 to February 2019 of all CRASS-P Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae isolates from urine cultures. Patients with any symptom related to a UTI, urinalysis with >10 white blood cells/high-powered field, urine culture with >10,000 colony-forming units/mL, and receipt of an antibiotic were included. CC was defined as symptom resolution within 48 hours with no return to care within 28 days of the positive urinary culture. “Group A” included patients prescribed narrow-spectrum antibiotics such SAM, CEF, or an oral cephalosporin (OC) vs. broad-spectrum antibiotics such as ceftriaxone, quinolones or sulfa-medications (“Group B”). Results There were 960/1356 (70.8%) CRASS-P urinary isolates and 244 patients met inclusion criteria. Of 244 patients, 72 were in Group A and 172 were in Group B. There was no difference in the diversity of the 3 uropathogens, P = 0.34 (Table 1). Median age was 69±20.3 and 67.5±23.9 years for Group A and Group B, respectively, P = 0.23. Females accounted for 73.6% and 77.9% in Group A and B, respectively, P = 0.51. Overall, patients reached CC in 98.6% (71/72) of Group A patients, compared with 92.4% (159/172) of Group B patients, P = 0.07. Antibiotics used in treatment are outlined in Figure 1. UTI was associated with bacteremia for 2 patients in Group A and 4 patients in Group B (P = 0.84). Both patients in Group A reached CC and used AMC for treatment. However, 1 out of 4 patients did not achieve CC in Group B. Conclusion The use of SAM or OC can spare the broad-spectrum antibiotics use for CRASS-P UTIs as there was no statistical difference in CC between the two groups. The use of SAM with CRASS-P bacteremia secondary to UTI is possible; however, future studies are needed. Disclosures All authors: No reported disclosures.

Summary Coagulation factor IX (FIX) is a serine protease that plays a pivotal role in the blood coagulation cascade. FIX deficiency leads to a blood clotting disorder known as haemophilia B. FIX, synthesized as a prepro-peptide of 461 amino acids, is processed and secreted into plasma. The protein undergoes numerous modifications, including, but not limited to glycosylation, γ-carboxylation and disulphide bond formation. Upon processing and limited proteolysis, the protein is converted into an active protease. Under physiological conditions, the FIX zymogen is a monomer. The purpose of this work was to analyse the conditions that may affect FIX monomeric state and promote and/or reduce oligomerization. Using native gel electrophoresis and size exclusion chromatography, we found that under decreased pH and ionic strength conditions, the FIX zymogen can oligomerize, resulting in the formation of higher molecular weight species, with a concomitant reduction in specific activity. Similarly, FIX oligomers formed readily with low bovine serum albumin (BSA) concentrations; however, increased BSA concentrations impeded FIX oligomerization. We hypothesize that normal blood physiological conditions are critical for maintaining active FIX monomers. Under conditions of stress associated with acidosis, electrolyte imbalance and low albumin levels, FIX oligomerization is expected to take place thus leading to compromised activity. Furthermore, albumin, which is commonly used as a drug stabilizer, may enhance the efficacy of FIX biological drugs by reducing oligomerization.

Purpose: Combinations of tyrosine kinase inhibitors (TKI) with gemcitabine have been attempted with little added benefit to patients. We hypothesized that TKIs designed to bind to ATP-binding pockets of growth factor receptors also bind to transporter proteins that recognize nucleosides. Experimental Design: TKI inhibition of uridine transport was studied with recombinant human (h) equilibrative (E) and concentrative (C) nucleoside transporters (hENT, hCNT) produced individually in yeast. TKIs effects on uridine transport, gemcitabine accumulation, regulation of hENT1 activity, and cell viability in the presence or absence of gemcitabine were evaluated in human pancreatic and lung cancer cell lines. Results: Erlotinib, gefitinib and vandetanib inhibited [3H]uridine transport in yeast and [3H]uridine and [3H]gemcitabine uptake in the four cell lines. Treatment of cell lines with erlotinib, gefitinib, or vandetanib for 24 hours reduced hENT1 activity which was reversed by subsequent incubation in drug-free media for 24 hours. Greater cytotoxicity was observed when gemcitabine was administered before erlotinib, gefitinib, or vandetanib than when administered together and synergy, evaluated using the CalcuSyn Software, was observed in three cell lines resulting in combination indices under 0.6 at 50% reduction of cell growth. Conclusions: Vandetanib inhibited hENT1, hENT2, hCNT1, hCNT2, and hCNT3, whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1. The potential for reduced accumulation of nucleoside chemotherapy drugs in tumor tissues due to inhibition of hENTs and/or hCNTs by TKIs indicates that pharmacokinetic properties of these agents must be considered when scheduling TKIs and nucleoside chemotherapy in combination. Clin Cancer Res; 20(1); 176–86. ©2013 AACR.

Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing) product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016).

Traditional welding techniques result in the creation of large heat affected zones (HAZ) as well as several filler materials need to be used. In addition, evolution of several unwanted gases into the atmosphere as well as solidification of some unwanted phases in the materials being welded demands for the alternate welding routes by which all these problems could be avoided. As an attempt in this direction, friction stir welding has been carried out on 6 mm thick reduced activation ferritic martensitic steel at various rotational speeds. The resultant microstructures and the observed properties are discussed in this paper.

Gastrointestinal disorders often present to the primary care setting where initial preventive, diagnostic, and treatment strategies are implemented. This article reviews the presentation and diagnosis of common gastrointestinal disorders, including colorectal cancer, irritable bowel syndrome, peptic ulcer disease, gallbladder disorders, inflammatory bowel disease, gastroesophageal reflux, and Barrett's esophagus. We focus on the evaluation and management of these diseases in women.

Background The intestinal microbiome modulates local and systemic immune responses and may impact clinical outcomes. However, there are few studies in pediatric patients. We conducted a cross-sectional study of fecal microbiomes in hospitalized children on a single inpatient unit at Children’s Hospital at Montefiore, Bronx, New York in 2016–2017 to test the hypothesis that “high-risk” children with chronic illnesses (cancer, transplant and sickle cell disease [SCD]) have decreased microbial diversity and higher rates of asymptomatic colonization with C. difficile compared with children hospitalized on the same ward but without similar risk factors. Methods Stool was collected within 72 hours of admission from patients who provided consent and assayed for C. difficile colonization by glutamate dehydrogenase (GDH); microbiome analysis was performed by 16S rRNA sequencing. Clinical and demographic data were obtained from the EMR. Results One hundred and six unique patients provided a sample for analysis. Sixty-nine were categorized as high-risk, including 32 SCD patients. C. difficile colonization rates were 22% and 19% in the high-risk and low-risk groups, respectively, but highest in the subset of SCD patients on penicillin prophylaxis (33%). The high-risk group had a trend toward lower microbial diversity than controls, and SCD patients exhibited a diversity index greater than other high-risk patients. Antibiotic use in the last 3 months and PPI use were associated with decreased microbial diversity across the entire study population (P = 0.004, P = 0.007, respectively). Among children with SCD, those on penicillin prophylaxis had a trend toward decreased alpha diversity while folic acid was associated with increased diversity (P = 0.02). SCD patients had greater quantities of Bacteroides and Parabacteroides and fewer Escherichia and Shigella than the other cohorts. Conclusion SCD and penicillin prophylaxis might be risk factors for C. difficile colonization and intestinal dysbiosis. The implications of these findings require further, longitudinal study. Disclosures All authors: No reported disclosures.

Substance P is involved in mediating a number of biological effects such as emesis, pain, inflammation, bronchoconstriction, antitumor activity, and regulation of gastrointestinal and CNS function by binding to the neurokinin-1 (NK1) receptor. Antagonists of this receptor have the potential to be useful in the treatment of various disease conditions.More than 300 patents have been filed by nearly 20 companies and 2 academic institutions in the past 2 decades. This review provides an overview of the patenting activity in the NK1 antagonist field over the last 20 years.Chemically diverse non-peptide NK1 receptor antagonists have been identified since the discovery of CP-96,345 by Pfizer in 1991. Representative examples of patented ligands and their biological activities are presented in a company-wise approach.The NK1 receptor research has led to the clinical introduction of aprepitant in 2003 and its water soluble injectable form, fosaprepitant dimeglumine, in 2009 by Merck for the prevention of postoperative nausea and vomiting and for inhibiting chemotherapy-induced nausea and vomiting. In addition, maropitant citrate received approval in 2007 for veterinary use.