Improved survival in COVID-19 related sepsis and ARDS treated with a unique "triple therapy" including therapeutic plasma exchange: A single center retrospective analysis.

BACKGROUND: Throughout the COVID-19 pandemic, the mortality of critically ill patients remained high. Our group developed a treatment regimen targeting sepsis and ARDS which we labeled "triple therapy" consisting of (1) corticosteroids, (2) therapeutic plasma exchange (TPE), and (3) timely intubation with lung protective ventilation. Our propensity analysis assesses the impact of triple therapy on survival in COVID-19 patients with sepsis and ARDS. METHODS: Retrospective propensity analysis comparing triple therapy to no triple therapy in adult critically ill COVID-19 patients admitted to the Intensive Care Unit at Lexington Medical Center from 1 March 2020 through 31 October 2021. RESULTS: Eight hundred and fifty-one patients were admitted with COVID-19 and 53 clinical and laboratory variables were analyzed. Multivariable analysis revealed that triple therapy was associated with increased survival (OR: 1.91; P = .008). Two propensity score-adjusted models demonstrated an increased likelihood of survival in patients receiving triple therapy. Patients with thrombocytopenia were among those most likely to experience increased survival if they received early triple therapy. Decreased survival was observed with endotracheal intubation ≥7 days from hospital admission (P < .001) and there was a trend toward decreased survival if TPE was initiated ≥6 days from hospital admission (P = .091). CONCLUSION: Our analysis shows that early triple therapy, defined as high-dose methylprednisolone, TPE, and timely invasive mechanical ventilation within the first 96 hours of admission, may improve survival in critically ill septic patients with ARDS secondary to COVID-19 infection. Further studies are needed to define specific phenotypes and characteristics that will identify those patients most likely to benefit.

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis.

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

Effect of supplementation of cryoprotectant solution with hydroxypropyl cellulose for vitrification of bovine oocytes.

BACKGROUND: Successful cryopreservation of bovine oocytes is very important for research and commercial applications. However, the survival and development rate of vitrified-thawed (VT) oocytes are lower than those of non-vitrified-thawed (non-VT) oocytes. OBJECTIVE: To investigate the effect of adding hydroxypropyl cellulose (HPC) to the vitrification solution for bovine oocytes. MATERIALS AND METHODS: For vitrification, bovine metaphase II oocytes were pretreated with a solution containing 10% ethylene glycol supplemented with 0, 10, 50, or 100 ug/mL HPC for 5 min, exposed to a solution containing 30% ethylene glycol supplemented with 0, 10, 50, or 100 ug/mL HPC for 30 s, and then directly plunged into liquid nitrogen. RESULTS: The survival rate of oocytes was significantly higher in the 50 HPC group than in the 0, 10, and 100 HPC groups. The reactive oxygen species level was lower in the non-VT and 50 HPC groups than in the other groups. The mRNA levels of proapoptotic genes (Bax) were lower in the non-VT, 0, and 50 HPC groups than in the other groups. The mRNA levels of antiapoptotic genes (BCl2) were higher in the non-VT than in the other groups. The development rates of embryos (day 8) obtained via parthenogenetic activation (PA) were determined in the non-VT, 0 HPC, and 50 HPC groups. The cleavage rate was significantly higher in the non-VT group. CONCLUSION: Supplementation of vitrification solution with HPC improves the survival of VT bovine oocytes and the development capacity of embryos derived from these oocytes via PA. doi.org/10.54680/fr23110110212.

Association between body mass index and stroke severity in acute ischaemic stroke with non-valvular atrial fibrillation.

BACKGROUND AND PURPOSE: The objective of this study was to investigate the association between body mass index (BMI) and both initial stroke severity at presentation and functional outcomes after acute ischaemic stroke (AIS) in patients with non-valvular atrial fibrillation (NVAF). METHODS: Patients were categorized on the basis of their BMI into underweight (BMI <18.5, n = 111), normal (18.5 ≤ BMI <25, n = 1036) and overweight to obese (BMI ≥25, n = 472) groups. Initial stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score and functional outcomes were assessed using the modified Rankin Scale score at discharge. The differences in stroke severity and functional outcomes were compared between groups using robust log-linear regression with a Poisson distribution and binary logistic regression analysis. RESULTS: A total of 1619 AIS patients with NVAF from six hospitals were included. Compared with the NIHSS scores [median 5, interquartile range (IQR) 2-14] of normal-weight patients, the NIHSS scores (median 9, IQR 4-19) of underweight patients were more likely to be higher, whereas those of overweight to obese patients were lower (median 4, IQR 1-12) (P < 0.001). In terms of functional outcomes after stroke, underweight patients had a higher risk of poor functional outcomes (odds ratio 1.78, 95% confidence interval 1.09-2.56, P = 0.01) but overweight to obese patients had no significant difference in functional outcomes compared with normal-weight patients. CONCLUSION: An inverse association was found between BMI and stroke severity in AIS patients with NVAF. This suggests the presence of an obesity paradox for short-term outcomes in patients with NVAF.

Targetoid hepatic observations on gadoxetic acid-enhanced MRI using LI-RADS version 2018: emphasis on hepatocellular carcinomas assigned to the LR-M category.

AIM: To determine useful imaging features for differentiating hepatocellular carcinoma (HCC) categorised as LR-M from non-HCC malignancies in using the Liver Imaging-Reporting and Data System (LI-RADS) version 2018 on gadoxetic acid-enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: Patients at high-risk for HCC with surgically confirmed HCCs (n=131) and non-HCC malignancies (n=90) and who had undergone gadoxetic acid-enhanced MRI were included. LI-RADS categories were assigned to identify hepatic observations defined as LR-M by two radiologists. Major and ancillary imaging features of hepatic observation with targetoid appearance including intratumoural septa were compared between HCCs and non-HCC malignancies. A classification tree analysis (CTA) was applied to differentiate high-risk HCCs from non-HCC malignancies in the LR-M category. RESULTS: A total of 36 HCCs (27.5%) and 70 non-HCC malignancies (77.8%) were assigned as LR-M. An enhancing capsule (p=0.0293), blood products in the mass (p=0.0393), non-targetoid restriction (p=0.018), and a septum (p=0.0053) were significantly predictive of HCC. On CTA, the presence of a septum was an initial predictor for a high probability of HCC followed by non-targetoid restriction. The CTA model has a sensitivity of 63.9%, specificity of 90%, and accuracy of 81.1% for differentiating HCC assigned LR-M from non-HCC malignancy. CONCLUSION: A considerable proportion of HCCs could have been categorised as LR-M as they had a targetoid appearance on gadoxetic acid-enhanced MRI. An intratumoural septum and non-targetoid restriction as well as enhancing capsule and blood products in the mass may be useful for differentiating HCC assigned to LR-M from non-HCC malignancy on gadoxetic acid-enhanced MRI.

Comparison of the diagnostic performance of the 2017 and 2018 versions of LI-RADS for hepatocellular carcinoma on gadoxetic acid enhanced MRI.

AIM: To compare the diagnostic performance of the 2017 (v2017) and 2018 versions (v2018) of the Liver Imaging-Reporting and Data System (LI-RADS) for hepatocellular carcinoma (HCC) using gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) and to evaluate the effect in v2018. MATERIALS AND METHODS: Treatment-naive patients at high-risk for HCC who underwent Gd-EOB-MRI were included. The LI-RADS categories were assigned according to v2017 and v2018. The diagnostic performances were compared between v2017 and v2018 according to the size and combination of imaging features. RESULTS: A total of 117 patients with 137 observations were identified, including 89 HCCs; 76.2% (64/84) of observations with threshold growth were re-classified as subthreshold growth when using v2018 instead of v2017. The final categories changed in nine (14%) cases. For the combination of LR-5/LR-5V, there were no significant differences in sensitivity and specificity between the two versions (sensitivity, 64% versus 58.4%; specificity, 87.5% versus 85.4%; all p>0.05). For the combination of LR-4 and LR-5/5V, the diagnostic performance of v2018 was inferior to that of v2017 when considering only major features (accuracy, 86.1% versus 80.3%, respectively; p=0.013), particularly in observations measuring 10-20 mm, but was comparable after adding the ancillary features (accuracy, 86.9% versus 86.1%, respectively; p=1.00). CONCLUSION: In LI-RADS v2018, although a considerable number of observations re-classified subthreshold growth, changes in the assigned categories were insignificant; overall diagnostic performance was comparable to that of v2017, but v2018 might emphasise the value of ancillary features in combination with major features for determining the probability of HCC.

101 Dothideomycetes genomes: A test case for predicting lifestyles and emergence of pathogens.

Dothideomycetes is the largest class of kingdom Fungi and comprises an incredible diversity of lifestyles, many of which have evolved multiple times. Plant pathogens represent a major ecological niche of the class Dothideomycetes and they are known to infect most major food crops and feedstocks for biomass and biofuel production. Studying the ecology and evolution of Dothideomycetes has significant implications for our fundamental understanding of fungal evolution, their adaptation to stress and host specificity, and practical implications with regard to the effects of climate change and on the food, feed, and livestock elements of the agro-economy. In this study, we present the first large-scale, whole-genome comparison of 101 Dothideomycetes introducing 55 newly sequenced species. The availability of whole-genome data produced a high-confidence phylogeny leading to reclassification of 25 organisms, provided a clearer picture of the relationships among the various families, and indicated that pathogenicity evolved multiple times within this class. We also identified gene family expansions and contractions across the Dothideomycetes phylogeny linked to ecological niches providing insights into genome evolution and adaptation across this group. Using machine-learning methods we classified fungi into lifestyle classes with >95 % accuracy and identified a small number of gene families that positively correlated with these distinctions. This can become a valuable tool for genome-based prediction of species lifestyle, especially for rarely seen and poorly studied species.

Non-melanoma skin cancer as a clinical marker for internal malignancies: a nationwide population-based cohort study.

INTRODUCTION: Non-melanoma skin cancers (NMSCs) are the most common cancers in the world, but the risk of internal malignancy in patients with NMSC has not been well investigated. OBJECTIVES: We aimed to assess the risk of internal malignancy in patients with NMSC compared with controls without NMSC in Korean population. METHODS: This nationwide cohort study, compared 27 259 NMSC patients with 54 518 matched controls without NMSC, 40 years or older using the data from Korea Health Insurance Review and Assessment Service from 2007 to 2016. The first 2 years were washout period, and we followed the patients for 8 years to observe the development of any internal malignancies after a diagnosis of NMSC. The Cox proportional hazard model was used to determine the hazard ratios (HRs) for developing internal malignancies. RESULTS: The overall risk of internal malignancies at all sites was 2727.7 and 1392.4 per 100 000 person-years for the patients with NMSC and controls, respectively. The risk was significantly higher in the patients with NMSC (HR 1.866, 95% confidence interval [CI] 1.768-1.970). Bone cancer showed the highest risk (HR 12.745, 95% CI 6.288-25.834), followed by nasal cavity and larynx (HR 10.279, 95% CI 6.178-7.103), oral cavity and pharynx (HR 10.211, 95% CI 7.375-14.137), anus and anal canal (HR 8.147, 95% CI 3.893-17.051) and cervical (HR 5.900, 95% CI 3.694-9.423) cancers with risks greater than fivefold higher in NMSC patients compared with the controls. The risks of cancers of the thorax, oesophagus, breast, lung, stomach, thyroid gland and non-Hodgkin's lymphoma were also statistically higher in the patients with NMSC. In contrast, the risks of cancers of the colon and rectum were found to be significantly decreased in the patients with NMSC (HR 0.765, 95% CI 0.657-0.890). CONCLUSION: Patients with NMSC require careful screening and follow-up for internal malignancy.

The effect of low body mass index on the development of chronic obstructive pulmonary disease and mortality.

BACKGROUND: Sarcopenia may worsen disease progression and lead to poor outcomes in chronic obstructive pulmonary disease (COPD). OBJECTIVES: We aimed to determine the effect of BMI on the development of COPD and mortality. METHODS: We enrolled 437 584 participants registered in the physical health check-up cohort database of the Korean National Health Interview Survey from 2002 to 2003, and we defined COPD diagnosis based on the ICD-10 code and prescribed medication. BMI (kg m-2 ) classified them to five groups (low BMI < 18.5, normal BMI 18.5-23, overweight 23-25, obesity 25-30, severe obesity ≥30) at baseline. RESULTS: Participants in the low BMI group had a significantly higher rate of COPD development for 13 years (7.6%) than those in other groups (3.4-4.1%, P < 0.0001). Amongst never or light smokers, COPD development in the low BMI group (5.6-6.7%) was significantly higher than that in other groups (2.8-4.7%). Similarly, amongst participants with a smoking history of ≥30 years, COPD development in the low BMI group (20.1%) was higher than those in other groups (8.4-12.4%). On multivariable analysis, normal or higher than normal body weight was significantly protective against the development of COPD (hazard ratio [HR], 0.609-0.739,) compared to low BMI. COPD-free-survival (HR, 0.491-0.622) and overall survival (HR, 0.440-0.585) were also better in them compared to those with low BMI (all P < 0.0001). CONCLUSIONS: Low BMI is an important risk factor for COPD development and mortality. Maintaining adequate body weight may reduce the risk for COPD development and mortality.

Evolution and persistence of resistance-associated substitutions of hepatitis C virus after direct-acting antiviral treatment failures.

Daclatasvir plus asunaprevir (DCV+ASV) treatment is an all-oral direct-acting antiviral (DAA) therapy for the genotype 1b HCV-infected patients. In this study, we investigated how resistance-associated substitutions (RASs) evolved after treatment failures and assessed the effect of those substitutions on viral fitness. Sequencing of NS5A and NS3 revealed typical RASs after treatment failures. Interestingly, the RASs of NS3 reverted to the wild-type amino acid within 1 year after treatment failures. However, the RASs of NS5A were stable and did not change. The effect of NS5A and NS3 RASs on viral RNA replication was assessed after mutagenic substitution in the genotype 1b HCV RNA. Among single substitutions, the effect of D168V was more substantial than the others and the effect of the triple mutant combination (D168V+L31V+Y93H) was the most severe. The RAS at NS5A Y93 affected both viral RNA replication and virus production. Finally, the effect of trans-complementation of NS5A was demonstrated in our co-transfection experiments and these results suggest that such a trans-complementation effect of NS5A may help maintain the NS5A RASs for a long time even after cessation of the DAA treatment. In conclusion, the results from this investigation would help understand the emergence and persistence of RASs.

Magnetic resonance tumour regression grade and pathological correlates in patients with rectal cancer.

BACKGROUND: Evidence to support the specific use of magnetic resonance tumour regression grade (mrTRG) is inadequate. The aim of this study was to investigate the pathological characteristics of mrTRG after chemoradiotherapy (CRT) for rectal cancer and the implications for surgery. METHODS: Patients undergoing long-course CRT (45-50 Gy plus a booster dose of 4-6 Gy) for mid or low rectal cancer (cT3-4 or cN+ without metastasis) between 2011 and 2015 who had post-CRT rectal MRI before surgery were included retrospectively. Three board-certified experienced radiologists assessed mrTRG. mrTRG was correlated with pathological tumour regression grade (pTRG), ypT and ypN. In a subgroup of patients with mrTRG1-2 and no tumour spread (such as nodal metastasis) on MRI, the projected rate of completion total mesorectal excision (TME) if they underwent transanal excision (TAE) and had a ypT status of ypT2 or higher was estimated, and recurrence-free survival was calculated according to the operation (TME or TAE) that patients had actually received. RESULTS: Some 439 patients (290 men and 149 women of mean(s.d.) age 62·2(11·4) years) were analysed. The accuracy of mrTRG1 for predicting pTRG1 was 61 per cent (40 of 66), and that for ypT1 or less was 74 per cent (49 of 66). For mrTRG2, these values were 22·3 per cent (25 of 112) and 36·6 per cent (41 of 112) respectively. Patients with mrTRG1 and mrTRG2 without tumour spread were ypN+ in 3 per cent (1 of 29) and 16 per cent (8 of 50) respectively. Assuming mrTRG1 or mrTRG1-2 with no tumour spread on post-CRT MRI as the criteria for TAE, the projected completion TME rate was 26 per cent (11 of 43) and 41·0 per cent (41 of 100) respectively. For the 100 patients with mrTRG1-2 and no tumour spread, recurrence-free survival did not differ significantly between TME (79 patients) and TAE (21) (adjusted hazard ratio 1·86, 95 per cent c.i. 0·42 to 8·18). CONCLUSION: Patients with mrTRG1 without tumour spread may be suitable for TAE.

Incidence of cephalosporin-induced anaphylaxis and clinical efficacy of screening intradermal tests with cephalosporins: A large multicenter retrospective cohort study.

BACKGROUND: Few studies have investigated the incidence of anaphylaxis induced by individual or structurally similar cephalosporins. The aims of the study were to assess the incidence of cephalosporin-induced anaphylaxis and evaluate the clinical efficacy of screening skin tests. METHODS: In this retrospective cohort study, we obtained information on total cephalosporin use and cephalosporin-induced anaphylaxis in intravenous cephalosporin recipients in 12 general hospitals between 2013 and 2015. Cephalosporins were divided into 4 groups according to similar side-chain structures. The incidence of cephalosporin-induced anaphylaxis was assessed for each cephalosporin, cephalosporin generation, and side-chain group. To verify the efficacy of screening intradermal tests (IDT) with cephalosporin, the 12 hospitals were assigned to the intervention or control group depending on whether they performed screening IDT before the administration of cephalosporins. RESULTS: We identified 76 cases of cephalosporin-induced anaphylaxis with 1 123 345 exposures to intravenous cephalosporins (6.8 per 100 000 exposures), and the incidence of fatal anaphylaxis by cephalosporin was 0.1 cases per 100 000 exposures. The highest incidences of anaphylaxis occurred in the ceftizoxime (13.0 cases per 100 000 exposures) and side-chain group 1 (cefepime, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime; 9.3 per 100 000). There was no case of anaphylaxis induced by cefoxitin, cefmetazole, cefminox, and cefotiam. The clinical effectiveness of routine screening IDT was not significant (P = .06). CONCLUSIONS: The incidence of cephalosporin-induced anaphylaxis differed according to individual drugs and side-chain structure. Screening IDT showed no clinical efficacy at a population level.

Polyamine patterns in plasma of patients with systemic lupus erythematosus and fever.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations and serologic markers. In this study, we analyzed nine polyamine (PA) profiles of plasma from patients with SLE and healthy controls (HCs), and the relationship between the PA profiles and disease activity. PA alterations in plasma of 44 patients with SLE and fever were investigated using gas chromatography mass spectrometry (GC-MS) in selected ion monitoring mode using N-ethoxycarbonyl/ N-pentafluoropropionyl derivatives, and compared with those of 43 HCs. Patients with SLE and HCs showed differences in five of nine PA profiles. Among five changed PA levels, four PAs, namely N1-acetylcadaverine, spermidine, N1-acetylspermidine, and spermine, were dramatically decreased. However, the level of cadaverine was increased in patients with SLE. In the partial correlation with PA profiles and disease activity markers of SLE, several disease activity markers and nutritional markers were correlated with cadaverine, spermidine, and N 8-acetylspermidine. Thus, our results provide a comprehensive understanding of the relationship between PA metabolomics and disease activity markers in patients with SLE.

Repeated Measurement of Fractional Exhaled Nitric Oxide Is Not Essential for Asthma Screening.

BACKGROUND AND OBJETIVE: Older guidelines recommend that fractional exhaled nitric oxide (FeNO) should be checked more than twice during the same session to confirm an asthma diagnosis. Recent studies show the excellent reproducibility of FeNO measurements. Objetive: We aimed to determine whether repeated FeNO measurements during the same session are necessary for asthma screening. MATERIAL AND METHODS: We retrospectively reviewed the electronic medical records of adult outpatients who visited the respiratory medicine department for diagnosis of asthma and assessed FeNO measurements obtained from June 2016 to July 2017. RESULTS: Of the 132 patients enrolled, 79 (59.8%) were diagnosed with asthma. Repeated FeNO measurements taken during the same session showed high reproducibility (intraclass correlation coefficient >0.9; P<.001) and a strong correlation (Pearson coefficient >0.9; P<.001), although reproducibility and correlation were slightly weaker in patients with low FeNO values. The value of repeated measurement was not significant; however, the second FeNO measurement was significantly higher than the first measurement in patients with the worst and best lung function. The predictive power of the first measurement of FeNO (sensitivity, 80.5%; specificity, 85.1%) was not inferior to the second (sensitivity, 76.6%; specificity 85.1%). The same was true of the geometric mean of the two. CONCLUSIONS: Repeated FeNO measurement during the same session is not essential for asthma screening in cases where the first acceptable FeNO measurement is performed using the proper method.

Anakinra Protects Against Serum Deprivation-Induced Inflammation and Functional Derangement in Islets Isolated From Nonhuman Primates.

We investigated whether serum deprivation induces islet amyloid polypeptide (IAPP) oligomer accumulation and/or a proinflammatory response and, if so, whether the addition of interleukin (IL)-1 receptor antagonist to the culture medium can relieve the proinflammatory response during serum-deprived culture of nonhuman primate (NHP) islets. After culture in medium with and without Ana under serum-deprived culture conditions, IAPP oligomer/amyloid accumulation, in vitro viability, islet function, cytokine secretion, and posttransplantation outcome in streptozotocin-induced diabetic nude mice were determined in islets isolated from heterozygote human IAPP transgenic (hIAPP+/- ) mice and/or NHP islets. Serum deprivation induced accumulation of IAPP oligomer, but not amyloid, in NHP islets. Anakinra (Ana) protected islets from the serum deprivation-induced impairment of in vitro viability and glucose-stimulated insulin secretion and attenuated serum deprivation-induced caspase-1 activation, transcription, and secretion of IL-1ß, IL-6, and tumor necrosis factor-α in hIAPP+/- mice and NHP islets. Supplementation of medium with Ana during serum-deprived culture also improved posttransplantation in vivo outcomes of NHP islets. In conclusion, serum deprivation induced accumulation of IAPP oligomers and proinflammatory responses in cultured isolated islets. Supplementation of the culture medium with Ana attenuated the functional impairment and proinflammatory responses induced by serum deprivation in ex vivo culture of NHP islets.

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

BACKGROUND: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). METHODS: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. RESULTS: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. CONCLUSIONS: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform.

Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3 polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMETTM Plus microarray in 42 healthy males. Aside from CYP3A5*3, the rs3814055 polymorphism in the NR1I2 gene was associated with the tacrolimus pharmacokinetics based on false discovery rate-corrected multiple tests and the least absolute shrinkage and selection operator analysis. The area under the concentration-time curve to the last quantifiable time point (AUClast) was 3.42 times greater in subjects with homozygous mutations in both genes (CYP3A5*3/*3 and NR1I2 T/T) than in wild-type subjects. The two variants explained the 54% variability in the tacrolimus AUClast. An in vitro luciferase reporter assay indicated that downregulation of PXR expression is the likely molecular mechanism responsible for the increased exposure to tacrolimus in subjects carrying the rs3814055 C>T variant.

Varied incidence of immediate adverse reactions to low-osmolar non-ionic iodide radiocontrast media used in computed tomography.

BACKGROUND: Low-osmolar non-ionic radiocontrast media (RCMs) are commonly used throughout hospitals. However, the incidence of immediate adverse drug reactions (ADRs) to various low-osmolar non-ionic RCMs is not well studied. We compared the incidence of immediate ADRs among different low-osmolar non-ionic RCMs used in computed tomography (CT). METHODS: Severance Hospital has collected data for adverse reactions occurring in-hospital using an internally developed system. Using this data, we reviewed 1969 immediate ADRs from 286 087 RCM-contrasted CT examinations of 142 099 patients and compared the immediate ADRs of iobitridol, iohexol, iopamidol, and iopromide. We analysed the incidence of immediate ADRs to different RCMs, as well as the effect of single or multiple CT examinations per day. RESULTS: Iopromide showed the highest incidence of immediate ADRs (1.03%) and was followed by iopamidol (0.67%), iohexol (0.64%), and iobitridol (0.34%). In cases of anaphylaxis, iopromide also showed the highest incidence (0.041%), followed by iopamidol (0.023%), iohexol (0.018%), and iobitridol (0.012%). Risk of immediate ADR due to multiple CT examinations (1.19%) was significantly higher than the risk due to a single CT examination (0.63%). Risk of anaphylaxis was also higher for multiple CT examinations (0.052%) than for a single CT examination (0.020%). CONCLUSIONS AND CLINICAL RELEVANCE: The incidence of immediate ADRs varied according to the low-osmolar non-ionic RCM used. Iopromide-induced immediate ADRs were more frequent, while iobitridol was associated with fewer immediate ADRs than other RCMs. Multiple CT examinations per day resulted in a higher incidence of immediate ADRs and anaphylaxis than a single CT examination. Clinicians should consider these risk differences of immediate ADRs when prescribing contrasted CT examinations.

Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders.

Inherited muscular disorders (IMDs) are clinically and genetically heterogeneous genetic disorders. We investigated the mutational spectrum and genotype-phenotype correlations in Korean patients with IMD. We developed a targeted panel of 69 known IMD genes and recruited a total of 209 Korean patients with IMD. Targeted capture sequencing identified 994 different variants. Among them, 98 variants were classified as pathogenic/likely pathogenic variants; 38 were novel variations. A total of 39 patients had the pathogenic/likely pathogenic variants. Among them, 75 (36%) patients were genetically confirmed, and 18 (9%) patients had one heterozygous variant of recessive myopathy. However, two genetically confirmed patients had an additional heterozygous variant of another recessive myopathy. Four patients with one heterozygous variant of a recessive myopathy showed different phenotypes, compared with the known phenotype of the identified gene. The major causative genes of Korean patients with IMDs were DMD (19 patients), COL6A1 (9), DYSF (9), GNE (7), LMNA (7), CAPN3 (6), and RYR1 (5). This study showed the mutational and clinical spectra in Korean patients with IMD and confirmed the usefulness of strategies utilizing targeted sequencing.