Morpho-Phylogenetic Evidence Reveals Novel Species and New Records of Botryosphaeriaceae in China and Thailand.

Species in the Botryosphaeriaceae are common plant pathogens, endophytes, and saprobes found on a variety of mainly woody hosts. Botryosphaeriaceae is a high-profile fungal family whose genera have been subjected to continuous revisions in recent years. Surveys conducted during 2019 and 2020 on several decaying woody hosts (from dead arial twigs, branches, stems, bark, and seed pods) in China and Thailand revealed a high diversity of Botryosphaeriaceae fungi. Identification of 16 Botryosphaeriaceae isolates was carried out based on both morphological characteristics and phylogenetic analyses of combined ITS, LSU, tef1-α, and tub2 sequence data. Four novel species (Dothiorella ovata, Do. rosacearum, Do. septata, and Lasiodiplodia delonicis) and seven previously known species (Botryosphaeria fujianensis, Diplodia mutila, Di. seriata, L. crassispora, L. mahajangana, Macrophomina euphorbiicola and Sphaeropsis eucalypticola) were identified while new hosts and geographical records were reported. This study indicates that the fungal family Botryosphaeriaceae seems to be common and widespread on a broad range of hosts in China and Thailand.

Botryosphaerialean fungi associated with woody oil plants cultivated in Sichuan Province, China.

Woody oil plants are important economic trees which are widely cultivated and distributed throughout China. Surveys conducted during 2020 and 2021 on several woody oil plantations from five regions of Sichuan Province, China, revealed a high diversity of Botryosphaerialean fungi. The identification of 50 botryosphaeriaceous isolates was carried out based on both morphology and multi-gene phylogenetic analysis of internal transcribed spacer region (ITS), translation elongation factor 1-alpha gene (tef1) and ß-tubulin gene (tub2). This allowed the identification of twelve previously known Botryosphaeriales species: Aplosporellaprunicola, A.ginkgonis, Barriopsistectonae, Botryosphaeriadothidea, Bo.fabicerciana, Diplodiamutila, Di.seriata, Dothiorellasarmentorum, Neofusicoccumparvum, Sardiniellaguizhouensis, Sphaeropsiscitrigena, and Sp.guizhouensis, and four novel species belonging to the genera Diplodia and Dothiorella, viz. Di.acerigena, Di.pistaciicola, Do.camelliae and Do.zanthoxyli. The dominant species isolated across the surveyed regions were Botryosphaeriadothidea, Sardiniellaguizhouensis and Diplodiamutila, representing 20%, 14% and 12% of the total isolates, respectively. In addition, most isolates were obtained from Pistaciachinensis (14 isolates), followed by Camelliaoleifera (10 isolates). The present study enhances the understanding of Botryosphaeriales species diversity on woody oil plants in Sichuan Province, China.

Comparison of platelet indices in dengue fever patients based on platelet transfusion: A prospective observational study in a tertiary care center.

CONTEXT: Dengue fever is the most prevalent mosquito-borne viral disease in humans. Platelet indices (PIs) are given by the cell counters but are often not reported which is possibly due to under-recognition of the utility of these parameters. AIMS: This study aimed to compare PIs in patients with dengue fever to assess their role in the outcome such as hospital stay and platelet transfusion requirements. SETTINGS AND DESIGN: Prospective observational study in a tertiary care center, Thrissur, Kerala. SUBJECTS AND METHODS: A group of 250 dengue patients was studied over a period of 18 months. The platelet parameters (platelet count, mean platelet volume [MPV], platelet distribution width [PDW], platelet large cell ratio [PLCR], plateletcrit [PCT] and immature platelet fraction [IPF]) were measured with Sysmex XN-1000 and followed up every 24 h. The clinical features, duration of hospital stay and platelet transfusion requirements details were collected. STATISTICAL ANALYSIS USED: Independent t-test, Chi-square test, Karl Pearson correlation coefficient. RESULTS: A total of sample size was 250. The study showed normal PDW and MPV, low platelet count and PCT, and high PLCR and IPF in dengue patients. There were significant differences in PIs (lower platelet count and PCT, higher MPV, PDW, PLCR, and IPF) in comparison between dengue patients based on platelet transfusion. CONCLUSIONS: PIs may act as a predictive tool in the diagnosis and predicting outcomes in dengue fever. Low platelet count and PCT, high PDW, MPV, PLCR, and IPF in transfused dengue patients were found to be statistically significant. Clinicians need to be sensitized about the utility and limitations of these indices and rationalize the need for red cell and platelet transfusions in dengue.

Identification and Pathogenicity of Pestalotiod Fungi Associated with Woody Oil Plants in Sichuan Province, China.

Pestalotiod fungi are associated with a wide variety of plants worldwide and occur as endophytes, pathogens, and saprobes. The present study provides an updated phylogeny for genera Neopestalotiopsis, Pestalotiopsis, and Seiridium using fresh collections from woody oil plants (Camellia oleifera, Olea europaea, Paeonia suffruticosa, Sapium sebiferum, and Vernicia fordii) in Sichuan Province, China. We coupled morphology and combined sequence data analyses of ITS, tub2, and tef1-α for Neopestalotiopsis and Pestalotiopsis, with ITS, LSU, tub2, tef1-α, and rpb2 for Seiridium. Three novel species of Neopestalotiopsis (N. mianyangensis, N. paeonia-suffruticosa, N. terricola) and three of Seiridium (S. guangyuanum, S. vernicola, S. oleae), were found. Three other species, Pestalotiopsis kenyana, Seiridium ceratosporum, and S. rosarum were identified and reported as new records. All isolated species are fully described and illustrated. Additionally, the sexual morph of Pestalotiopsis kenyana is described for the first time. Pathogenicity tests revealed that Neopestalotiopsis mianyangensis, N. paeonia-suffruticosa, N. terricola, Pestalotiopsis kenyana, Seiridium guangyuanum, S. vernicola, and S. oleae are pathogenic on detached olive leaves.

Therapeutic Drug Monitoring of Subcutaneous Infliximab in Inflammatory Bowel Disease-Understanding Pharmacokinetics and Exposure Response Relationships in a New Era of Subcutaneous Biologics.

CT-P13 is the first subcutaneous infliximab molecule approved for the management of inflammatory bowel disease (IBD). Compared to intravenous therapy, SC infliximab offers a range of practical, micro- and macroeconomic advantages. Data from the rheumatological literature suggest that subcutaneous CT-P13 may lead to superior disease outcomes in comparison to intravenous infliximab. Existing studies in IBD have focussed on pharmacokinetic comparisons and are inadequately powered to evaluate efficacy and safety differences between the two modes of administration. However, emerging clinical trial and real-world data support comparable clinical, biochemical, endoscopic and safety outcomes between subcutaneous and intravenous infliximab in both luminal Crohn's disease and ulcerative colitis. Across the available data, subcutaneous CT-P13 provides relative pharmacokinetic stability and higher trough drug levels when compared to intravenous administration. The clinical impact of this observation on immunogenicity and treatment persistence is yet to be determined. Trough levels between the two methods of administration should not be compared in isolation as any subcutaneous advantage must be considered in the context of comparable total drug exposure and the theoretical disadvantage of lower peak concentrations compared to intravenous therapy. Furthermore, target drug levels for subcutaneous CT-P13 associated with remission are not known. In this review, we present the available literature surrounding the pharmacokinetics of subcutaneous CT-P13 in the context of therapeutic drug monitoring and highlight the potential significance of these observations on the clinical management of patients with IBD.

Impact of exclusive breast feeding until six months of age on common illnesses: A prospective observational study.

Objectives: The WHO recommends exclusive breast feeding (EBF) for all infants for the first six months of life. National Family Health Survey-4 (2015-16) shows EBF rates of only 54.9%. We conducted a prospective study to assess prevalence of EBF and incidences of illnesses in infants from birth till six months of age. Methods: Healthy term infants born in our hospital between December 2017 and November 2018 were recruited at birth. Structured diary cards were given to mothers to record feeding patterns, occurrence and severity of illnesses. Mothers were interviewed at 6, 10, 14 and 26 weeks or contacted by telephone at 18 and 22 weeks. Data were analyzed using SPSS IBM Statistics 22. Results: The prevalence of EBF among 450 infants (M:F = 1.3:1) who completed the study was 47% at 6 months. 185 (69 EBF + 116 non-EBF) of 450 infants reported a total of 242 illnesses, most commonly respiratory (82.6%) followed by gastrointestinal (11.6%). Number of illnesses per infant was 0.45 and 0.6 in EBF group and non-EBF group respectively (p = 0.015). Illness incidences in EBF infants were significantly lower during all successive time intervals after 10 weeks of age. Logistic regression analysis confirmed significantly lower illness incidences in EBF infants at 10-14 weeks [OR = 0.27 (CI 0.12-0.64)] and 18-22 weeks [OR = 0.50 (CI 0.27-0.90)]. Conclusions: The prevalence of EBF is suboptimal in our setting, with illness incidences significantly higher in non-EBF children. Appropriate intervention strategies need to be tailored to reinforce early initiation and continuation of EBF throughout the first six months of life.

Occurrence and Morpho-Molecular Identification of Botryosphaeriales Species from Guizhou Province, China.

Botryosphaeriales is an important order of diverse fungal pathogens, saprobes, and endophytes distributed worldwide. Recent studies of Botryosphaeriales in China have discovered a broad range of species, some of which have not been formerly described. In this study, 60 saprobic isolates were obtained from decaying woody hosts in southwestern China. The isolates were compared with other species using morphological characteristics, and available DNA sequence data was used to infer phylogenetic analyses based on the internal transcribed spacer (ITS), large subunit rRNA gene (LSU), and translation elongation factor 1-α (tef) loci. Three novel species were illustrated and described as Botryobambusa guizhouensis, Sardiniella elliptica, and Sphaeropsis guizhouensis, which belong to rarely identified genera within Botryosphaeriaceae. Botryobambusa guizhouensis is the second species identified from the respective monotypic genus. The previously known species were identified as Aplosporella hesperidica, Barriopsis tectonae, Botryosphaeria dothidea, Diplodia mutila, Di. neojuniperi, Di. pseudoseriata, Di. sapinea, Di. seriata, Dothiorella sarmentorum, Do. yunnana, Lasiodiplodia pseudotheobromae, Neofusicoccum parvum, Sardiniella celtidis, Sa. guizhouensis, and Sphaeropsis citrigena. The results of this study indicate that numerous species of Botryosphaeriales are yet to be revealed in southwestern China.

Prevalence and Relevance of Multiple Renal Arteries: A Radioanatomical Perspective.

BACKGROUND: A single renal artery supplies the kidney in 70% of the population but variation exists in the remaining 30%. Multiple renal arteries (MRA) in different permutations and combinations are one of the many forms of variants. Lack of awareness of multiplicity could have detrimental effects on the outcome of renal surgery. The present study aims at identifying the variants of renal artery based on its origin, multiplicity, and portal of entry in a cohort of people belonging to Southern India and its clinical implications thereof. METHODS: Multi-detector CT (MDCT) images of renal vasculature of 100 kidneys from 50 live kidney donors who attended the Department of Nephrology of our institution, from 2016 to 2018 were collected and studied for variations in renal arterial anatomy. RESULTS: Out of the 18% of kidneys observed with multiple renal arteries, 88.8% had double renal arteries (DRA) and 11.1% had triple renal arteries (TRA). Common types of the double renal arteries were - two hilar arteries (31.3%) and one hilar with one inferior polar artery (IPA, 31.3%). Triple renal arteries types - 50% with one hilar, one superior polar, and one inferior polar; 50% with two hilar and one inferior polar artery. No statistically significant association was noted between the incidence of multiple renal arteries and its laterality (p-value=0.193). CONCLUSION: A thorough understanding of the renal artery variants is crucial for safe and efficacious uro-radiological interventional procedures.

https://botryosphaeriales.org/, an online platform for up-to-date classification and account of taxa of Botryosphaeriales.

Fungi are eukaryotes that inhabit various ecosystems worldwide and have a decomposing effect that other organisms cannot replace. Fungi are divided into two main groups depending on how their sexual spores are formed, viz. Ascomycota and Basidiomycota. The members of Botryosphaeriales (Dothideomycetes, Ascomycota) are ubiquitous. They are pathogenic on a wide range of hosts, causing diverse diseases including dieback, canker, leaf spots and root rots and are also reported as saprobes and endophytes worldwide. As an important fungal group, of which most are plant pathogens, it is necessary to organize data and information on Botryosphaeriales so that scientific literature can be used effectively. For this purpose, a new website, https://botryosphaeriales.org is established to gather all published data together with updates on the present taxonomy of Botryosphaeriales. The website consists of an easy-to-operate searching system and provides an up-to-date classification together with accounts of Botryosphaeriales taxa, including colour illustrations, descriptions, notes and numbers of species in each genus, as well as their classification. Thus, readers will be able to obtain information on botryosphaerialean taxa through this platform. Database URL: https://botryosphaeriales.org/.

Evidence-Based Guidelines for Drug Interaction Studies: Model-Informed Time Course of Intestinal and Hepatic CYP3A4 Inhibition by Clarithromycin.

Drug-drug interaction (DDI) studies are mandated in drug development; however, protocols for evaluating the impact of cytochrome P450 (CYP) inhibition on new molecular entities are currently inconsistent. This study utilised validated physiologically based pharmacokinetic (PBPK) software to define the optimal dose, frequency, and duration of clarithromycin to achieve optimal characterisation of CYP3A4 inhibition in a study population. The Simcyp® Simulator (Version 19.0) was used to simulate clarithromycin-mediated CYP3A4 inhibition in healthy virtual cohorts. Between trial variability in magnitude and time course of CYP3A4 activity was assessed following clarithromycin dosing strategies obtained from the University of Washington Drug Interaction Database. Heterogeneity in CYP3A4 inhibition was evaluated across sex, race, and age. Literature review identified 500 mg twice daily for 5 days as the most common clarithromycin dosing protocol for CYP3A4 inhibition studies. On simulation, clarithromycin 500 mg twice daily resulted in the largest steady-state inhibition of hepatic (percent mean inhibition [95%CI] = 80 [77-83]) and small intestine (94 [94-95]) CYP3A4 activity (as compared to 500 mg once daily, 400 mg once/twice daily, or 250 mg once/twice daily). Additionally, 500 mg twice daily was associated with the shortest time for 90% of individuals to reach 90% of their minimum hepatic (4 days) and small intestine (1 days) CYP3A4 activity. The study presented herein supports that clarithromycin dosing protocol of 500 mg twice daily for 5 days is sufficient to achieve maximal hepatic and small intestine CYP3A4 inhibition. These findings were consistent between sex, race, and age differences.

Exploring the Use of Serum-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides.

Liver-derived small extracellular vesicles (sEVs), prepared from small sets of banked serum samples using a novel two-step protocol, were deployed as liquid biopsy to study the induction of cytochromes P450 (CYP3A4, CYP3A5, and CYP2D6) and organic anion transporting polypeptides (OATP1B1 and OATP1B3) during pregnancy (nonpregnant (T0), first, second, and third (T3) trimester women; N = 3 each) and after administration of rifampicin (RIF) to healthy male subjects. Proteomic analysis revealed induction (mean fold-increase, 90% confidence interval) of sEV CYP3A4 after RIF 300 mg × 7 days (3.5, 95% CI = 2.5-4.5, N = 4, P = 0.029) and 600 mg × 14 days (3.7, 95% CI = 2.1-6.0, N = 5, P = 0.018) consistent with the mean oral midazolam area under the plasma concentration time curve (AUC) ratio in the same subjects (0.28, 95% CI = 0.22-0.34, P < 0.0001; and 0.17, 95% CI = 0.13-0.22, P < 0.0001). Compared with CYP3A4, liver sEV CYP3A5 protein (subjects genotyped CYP3A5*1/*3) was weakly induced (≤ 1.5-fold). It was also possible to measure liver sEV-catalyzed dextromethorphan (DEX) O-demethylation to dextrorphan (DXO), correlated with sEV CYP2D6 expression (r = 0.917, P = 0.0001; N = 10) and 3-hour plasma DXO-to-DEX concentration ratio (r = 0.843, P = 0.002, N = 10), and show that CYP2D6 was not induced by RIF. Nonparametric analysis of liver sEV revealed significantly higher CYP3A4 (3.2-fold, P = 0.003) and CYP2D6 (3.7-fold, P = 0.03) protein expression in T3 vs. T0 women. In contrast, expression of both OATPs in liver sEV was unaltered by RIF administration and pregnancy.

An Outbreak of Covid-19 on an Aircraft Carrier.

BACKGROUND: An outbreak of coronavirus disease 2019 (Covid-19) occurred on the U.S.S. Theodore Roosevelt, a nuclear-powered aircraft carrier with a crew of 4779 personnel. METHODS: We obtained clinical and demographic data for all crew members, including results of testing by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR). All crew members were followed up for a minimum of 10 weeks, regardless of test results or the absence of symptoms. RESULTS: The crew was predominantly young (mean age, 27 years) and was in general good health, meeting U.S. Navy standards for sea duty. Over the course of the outbreak, 1271 crew members (26.6% of the crew) tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by rRT-PCR testing, and more than 1000 infections were identified within 5 weeks after the first laboratory-confirmed infection. An additional 60 crew members had suspected Covid-19 (i.e., illness that met Council of State and Territorial Epidemiologists clinical criteria for Covid-19 without a positive test result). Among the crew members with laboratory-confirmed infection, 76.9% (978 of 1271) had no symptoms at the time that they tested positive and 55.0% had symptoms develop at any time during the clinical course. Among the 1331 crew members with suspected or confirmed Covid-19, 23 (1.7%) were hospitalized, 4 (0.3%) received intensive care, and 1 died. Crew members who worked in confined spaces appeared more likely to become infected. CONCLUSIONS: SARS-CoV-2 spread quickly among the crew of the U.S.S. Theodore Roosevelt. Transmission was facilitated by close-quarters conditions and by asymptomatic and presymptomatic infected crew members. Nearly half of those who tested positive for the virus never had symptoms.

Unravelling Diaporthe Species Associated with Woody Hosts from Karst Formations (Guizhou) in China.

Though several Diaporthe species have been reported in China, little is known about the species associated with nature reserves in Guizhou province. During a survey of fungi in six nature reserves in Guizhou province of China, thirty-one Diaporthe isolates were collected from different woody hosts. Based on morphology, culture characteristics and molecular phylogenetic analysis, these isolates were characterized and identified. Phylogenetic analysis of internal transcribed spacer region (ITS), combined with translation elongation factor 1-alpha (tef), ß-tubulin (tub), calmodulin (cal) and histone H3 (his) gene regions identified five known Diaporthe species and seven distinct lineages representing novel Diaporthe species. The details of five known species: Diaporthe cercidis, D. cinnamomi, D. conica, D. nobilis and D. sackstonii are given and the seven new species D. constrictospora, D. ellipsospora, D. guttulata, D. irregularis, D. lenispora, D. minima, and D. minusculata are introduced with detailed descriptions and illustrations. This study revealed a high diversity of previously undescribed Diaporthe species associated with woody hosts in various nature reserves of Guizhou province, indicating that there is a potential of Diaporthe species remains to be discovered in this unique landform (Karst formations) in China. Interestingly, the five known Diaporthe species have been reported as pathogens of various hosts, and this could indicate that those newly introduced species in this study could be potentially pathogenic pending further studies to confirm.

Endophytic Diaporthe Associated With Citrus grandis cv. Tomentosa in China.

Diaporthe species are associated with Citrus as endophytes, pathogens, and saprobes worldwide. However, little is known about Diaporthe as endophytes in Citrus grandis in China. In this study, 24 endophytic Diaporthe isolates were obtained from cultivated C. grandis cv. "Tomentosa" in Huazhou, Guangdong Province in 2019. The nuclear ribosomal internal transcribed spacer (ITS), partial sequences of translation elongation factor 1-α (tef1), ß-tubulin (tub2), and partial calmodulin (cal) gene regions were sequenced and employed to construct phylogenetic trees. Based on morphology and combined multigene phylogeny, eleven Diaporthe species were identified including two new species, Diaporthe endocitricola and D. guangdongensis. These are the first report of D. apiculata, D. aquatica, D. arecae, D. biconispora, D. limonicola, D. masirevicii, D. passifloricola, D. perseae, and D. sennae on C. grandis. This study provides the first intensive study of endophytic Diaporthe species on C. grandis cv. tomentosa in China. These results will improve the current knowledge of Diaporthe species associated with C. grandis. The results obtained in this study will also help to understand the potential pathogens and biocontrol agents and to develop a platform in disease management.

Profile and outcome of patients with upper gastrointestinal bleeding presenting to urban emergency departments of tertiary hospitals in Tanzania.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a common emergency department (ED) presentation with high morbidity and mortality. There is a paucity of data on the profile and outcome of patients who present with UGIB to EDs, especially within limited resource settings where emergency medicine is a new specialty. We aim to describe the patient profile, clinical severity and outcomes of the patients who present with UGIB to the ED of tertiary referral hospitals in Tanzania. METHODS: This was a prospective cohort study of consecutive adult (≥18 years) patients presenting to the EDs of Muhimbili National Hospital (ED-MNH) and MUHAS Academic Medical Centre (ED-MAMC), in Tanzania with non-traumatic upper gastrointestinal bleeding (UGIB) from July 2018 to December 2018. Patient demographic data, clinical presentation, and ED and hospital management provided were recorded. We used the clinical Rockall score to assess disease severity. The primary outcome of 7- day mortality was summarized using descriptive statistics. Regression analysis was performed to identify predictors of mortality. RESULTS: During the study period, 123 patients presented to one of the two EDs with an UGIB. The median age was 42 years (Interquartile range (IQR) 32-64 years), and 87 (70.7%) were male. Hematemesis with melena was the most frequently encountered ED complaint 39 (31.7%). Within 7 days, 23 (18.7%) patients died and one-third 8 (34.8%) of these died within 24 h. There were no ED deaths. About 65.1% of the patients had severe anemia but only 60 (48.8%) received blood transfusion in the ED. Amongst those with history of (h/o) esophageal varices 7(41.2%) did not receive octreotide. Upper GI endoscopy, was performed on 46 (37.4%) patients, of whom only 8 (17.4%) received endoscopy within 24 h (early UGI endoscopy). All patients who received early UGI endoscopy had a low or moderate clinical Rockall score i.e. < 3 and 3-4. No patient with scores of > 4 received early UGI endoscopy. Age > 40 years was a significant independent predictor of mortality (OR = 7.00 (95% CI 1.7-29.2). Having a high clinical Rockall score of ≥ 4 was a significant independent predictor of mortality (OR = 6.4 (95% CI 1.8-22.8). CONCLUSIONS: In this urban ED in Sub-Saharan Africa, UGIB carried a high mortality rate. Age > 40 years and clinical Rockall score ≥ 4 were independent predictors of higher mortality. Future studies should focus on evaluating how to improve access to UGI endoscopy so as to improve outcomes.

Validation of a 3-h Sampling Interval to Assess Variability in Cytochrome P450 3A Phenotype and the Impact of Induction and Mechanism-Based Inhibition Using Midazolam as a Probe Substrate.

Background: Drug probe phenotyping is used extensively in academic and industry research to evaluate cytochrome P450 (CYP) phenotype in order to account for sources of between- and within- subject variability in metabolic clearance. In terms of application, CYP3A is the most important drug metabolizing enzyme the most frequently studied. Currently, phenotyping studies for CYP3A involve the administration of midazolam and collection of timed blood samples up to 24-48 hours in order to determine an area under the plasma concentration time curve (AUC). The key challenge that limits the use of midazolam-based phenotyping for CYP3A in academic research settings and preclude the use of this approach in a clinical setting is the logistical burden of collecting frequent blood samples for up to 48 h post dose following the administration of a probe drug ± an interacting drug. Aim: The current study sought to validate if a reduced sampling interval could be used to accurately define both between-subject variability in CYP3A phenotype and the magnitude of changes in CYP3A activity due to either induction or mechanism-based inhibition. Methods: The area under the curve (AUC) for midazolam was assessed under baseline, induction (7 days rifampin, 300 mg daily) and, following a washout period of 4 days, mechanism based inhibition (3 days clarithromycin, 250 mg daily) conditions in a cohort of 30 health males. The capacity of normalized reduced sampling interval AUCs measured over 0 to 1, 0 to 2, 0 to 3, and 0 to 4 h to accurately define the AUC0-6 was evaluated with respect to precision (R2 for correlation), bias (slope of normalized correlation), agreement (Bland Altman analysis) and proportional bias (linear regression of Bland Altman parameters). Results: Robust concordance was observed between the AUC calculated from PK collection intervals of 0 to 3 and 0 to 6 h in terms of both the measurement of between-subject variability in midazolam AUC and changes in midazolam AUC due to induction and mechanism-based inhibition of CYP3A4. Conclusion: On this basis, it is proposed that a 3-h assessment of midazolam AUC (AUC0-3) represents a viable strategy to reduce the logistical burden associated with the assessment of CYP3A phenotype.

High Genetic Diversity and Species Complexity of Diaporthe Associated With Grapevine Dieback in China.

Grapevine trunk diseases have become one of the main threats to grape production worldwide, with Diaporthe species as an emerging group of pathogens in China. At present, relatively little is known about the taxonomy and genetic diversity of Chinese Diaporthe populations, including their relationships to other populations worldwide. Here, we conducted an extensive field survey in six provinces in China to identify and characterize Diaporthe species in grape vineyards. Ninety-four isolates were identified and analyzed using multi-locus phylogeny. The isolates belonged to eight species, including three novel taxa, Diaporthe guangxiensis (D. guangxiensis), Diaporthe hubeiensis (D. hubeiensis), Diaporthe viniferae (D. viniferae), and three new host records, Diaporthe gulyae (D. gulyae), Diaporthe pescicola (D. pescicola), and Diaporthe unshiuensis (D. unshiuensis). The most commonly isolated species was Diaporthe eres (D. eres). In addition, high genetic diversity was observed for D. eres in Chinese vineyards. Haplotype network analysis of D. eres isolates from China and Europe showed a close relationship between samples from the two geographical locations and evidence for recombination. In comparative pathogenicity testing, D. gulyae was the most aggressive taxon, whereas D. hubeiensis was the least aggressive. This study provides new insights into the Diaporthe species associated with grapevines in China, and our results can be used to develop effective disease management strategies.

Guidance for Rifampin and Midazolam Dosing Protocols To Study Intestinal and Hepatic Cytochrome P450 (CYP) 3A4 Induction and De-induction.

Cytochrome P450 3A4 (CYP3A4) catalyses the metabolism of > 30% of clinically used small molecule drugs. Induction of CYP3A4 is often associated with clinically important metabolic drug-drug interactions (DDIs). To collate published data regarding induction of CYP3A4 expression by rifampin and identify an optimal protocol to study DDIs using physiologically based pharmacokinetic (PBPK) modelling. The University of Washington Drug Interaction Database was searched for published data regarding induction of CYP3A4 by rifampin. A verified PBPK model was used to define the optimal dose, duration, timing and route of administration of rifampin and midazolam to assess induction of intestinal and hepatic CYP3A4 by rifampin. Sensitivity analysis was performed to evaluate the impact of participant characteristics including sex, race and age. The maximal induction of intestinal CYP3A4 (9.5-fold) was almost double that of hepatic CYP3A4 (5.5-fold). Maximal induction of intestinal and hepatic CYP3A4 was achieved in > 90% of participants within 5 and 10 days, respectively. Intestinal CYP3A4 expression returned to baseline in > 90% of participants within 7 days of rifampin cessation, whereas induction of hepatic CYP3A4 persisted for greater than 7 days in > 50% of participants. There was a significant difference in magnitude, but not time course, of CYP3A4 induction between males and females. Age and race did not significantly affect either the magnitude or time course of CYP3A4 induction. Maximal induction of intestinal CYP3A4 is achieved faster than hepatic CYP3A4. To assess maximal hepatic CYP3A4 induction, oral rifampin (600 mg daily) should be dosed for > 10 days.

The strong correlation between neonatal early-onset Group B Streptococcal disease and necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a leading cause of newborn gastrointestinal emergencies, affecting 1-3 per 1000 live births. Although NEC has been linked to a microbial etiology, associations with maternal intrapartum and resultant newborn early-onset invasive Group B streptococcus (EO-GBS) have been weakly defined. OBJECTIVE: The study aim was to determine the relationship between EO-GBS and NEC. STUDY DESIGN: Data from 2008 to 2015 were collected from pediatric records with ICD diagnosis codes consistent with all stages of NEC, with the exception of neonatal EO-GBS data (only available 2011-2015). RESULTS: For the 131 newborns meeting inclusion criteria, the mean gestational age (GA) and birthweight at delivery was 30.2 weeks and 1449 g. Maternal comorbidities were not associated with a more advanced stage of NEC, however male gender (OR 3.2, p < .001), lower mean 1 (OR = 0.89, p = .045) and 5 min Apgar scores (OR = 0.84, p = .009) were significantly associated with higher NEC stage, after controlling for GA. Infectious morbidities including chorioamnionitis (OR = 1.5, p = .553) and intrapartum antibiotic administration (OR = 1.3, p = .524) were not significantly associated with higher NEC stage. Neither neonatal sepsis workup (OR = 0.27, p = .060) nor positive blood culture (OR = 0.97, p = .942) prior to NEC diagnosis were statistically significant. Type of feed prior to diagnosis (p = .530) was not significantly associated with NEC stage, however, expressed breast milk tended to be protective against higher stage of NEC (OR = 0.49, p = .055). Type of feed included total parenteral nutrition, mother's or donor expressed breast milk, trophic, full and high calorie feeds. Of the 579 newborns admitted from 2011 to 2015, 13 (2%) were diagnosed with EO-GBS and 64 met diagnostic criteria for NEC. GBS positive newborns had significantly higher odds of NEC (OR = 5.37, p = .009). NEC stage was not significantly different for patients with GBS positive vs. GBS negative mothers (p = .732), nor was there a significant difference in GA (p = .161). CONCLUSION: Our study is the first to describe a strong correlation between neonatal EO- GBS disease and NEC, with more than a five-fold increase in the odds of developing NEC in newborns of GBS positive mothers. PURPOSE: To investigate a possible relationship between EO-GBS disease and the neonatal diagnosis of NEC. Secondary analysis will determine if maternal antepartum and intrapartum factors along with neonatal variables contribute to a more advanced stage of NEC by retrospective chart review of patient data collected at Children's Hospital: New Orleans.