Suillus hypogaeus: First record of a truffle Suillus.

Suillus (order Boletales) is a diverse genus of epigeous, mushroom-forming fungi native to temperate forests across the Northern Hemisphere; however, some species are also present in areas where Pinaceae has been introduced in the Southern Hemisphere. Unlike the closely related genus Rhizopogon, there are no described hypogeous, sequestrate species of Suillus. Here, we describe Suillus hypogaeus, the first known species of the genus with hypogeous, sequestrate sporocarps. Collections were made on Marys Peak in Benton County, Oregon, USA, at an elevation of 800 m in forests dominated by Pseudotsuga menziesii var. menziesii. The peridium is white, quickly staining pink to purple-reddish where bruised or cut. The gleba is pale yellow when young, becoming purple with maturity, and the basidiospores are obovoid, light yellow in KOH, and amyloid in Melzer's reagent. Multilocus molecular phylogenetic analyses support the placement of S. hypogaeus among the Larix specialists in the spectabilis group of Suillus. Although Larix and Pseudotsuga are sister genera, Larix does not occur on Marys Peak or elsewhere in western Oregon. Suillus hypogaeus, therefore, represents both an independent origin of the hypogeous, sequestrate sporocarp within the Boletales and an independent host shift between Larix and Pseudotsuga within the genus Suillus.

A physiological approach to renal clearance: From premature neonates to adults.

AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). CONCLUSIONS: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

Joint longitudinal model-based meta-analysis of FEV1 and exacerbation rate in randomized COPD trials.

Model-based meta-analysis (MBMA) is an approach that integrates relevant summary level data from heterogeneously designed randomized controlled trials (RCTs). This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV1) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the predictive performance of the published MBMA using goodness-of-fit plots for assessment. Furthermore, the model was extended including drugs that were not available before July 2013, estimating a new set of parameters. The legacy MBMA model predicted the post-2013 FEV1 data well, and new estimated parameters were similar to those of drugs in the same class. However, the exacerbation model overpredicted the post-2013 mean annual exacerbation rate data. Inclusion of year when the study started on the pre-treatment placebo rate improved the model predictive performance perhaps explaining potential improvements in the disease management over time. The addition of new data to the legacy COPD MBMA enabled a more robust model with increased predictability performance for both endpoints FEV1 and mean annual exacerbation rate.

Improved Confidence in a Confirmatory Stage by Application of Item-Based Pharmacometrics Model: Illustration with a Phase III Active Comparator-Controlled Trial in COPD Patients.

PURPOSE: The current study aimed to illustrate how a non-linear mixed effect (NLME) model-based analysis may improve confidence in a Phase III trial through more precise estimates of the drug effect. METHODS: The FULFIL clinical trial was a Phase III study that compared 24 weeks of once daily inhaled triple therapy with twice daily inhaled dual therapy in patients with chronic obstructive pulmonary disease (COPD). Patient reported outcome data, obtained by using The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) questionnaire, from the FULFIL study were analyzed using an NLME item-based response theory model (IRT). The change from baseline (CFB) in E-RS:COPD total score over 4-week intervals for each treatment arm was obtained using the IRT and compared with published results obtained with a mixed model repeated measures (MMRM) analysis. RESULTS: The IRT included a graded response model characterizing item parameters and a Weibull function combined with an offset function to describe the COPD symptoms-time course in patients receiving either triple therapy (n = 907) or dual therapy (n = 894). The IRT improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of at least 3.64 times larger for the MMRM analysis to achieve the IRT precision in the CFB estimate. CONCLUSION: This study shows the advantage of IRT over MMRM with a direct comparison of the same primary endpoint for the two analyses using the same observed clinical trial data, resulting in an increased confidence in Phase III.

Greetings from belowground: two new species of truffles in the genus Pachyphlodes (Pezizaceae, Pezizales) from México.

Pachyphlodes is a lineage of ectomycorrhizal, hypogeous, sequestrate ascomycete fungi native to temperate and subtropical forests in the Northern Hemisphere. Pachyphlodes species form ectomycorrhizae mainly with Fagales hosts. Here we describe two new species of Pachyphlodes, P.brunnea, and P.coalescens, based on morphological and phylogenetic analysis. Pachyphlodesbrunnea is distributed in the states of Tamaulipas and Nuevo León in northern México, occurring with Quercus and Juglans species. It is characterized by its dark brown peridium, white gleba, and spores with capitate columns. Pachyphlodescoalescens is distributed in the states of Michoacán and Tlaxcala in central and southwestern México co-occurring with Quercus and is distinguished by its reddish-brown peridium, light yellow gleba, and spore ornamentation. Both species, along with P.marronina, constitute the Marronina clade. This clade contains North American species characterized by a brown peridium and spores ornamented with capitate spines to coalesced spine tips that form a partial perispore.

Improved Decision-Making Confidence Using Item-Based Pharmacometric Model: Illustration with a Phase II Placebo-Controlled Trial.

This study aimed to illustrate how a new methodology to assess clinical trial outcome measures using a longitudinal item response theory-based model (IRM) could serve as an alternative to mixed model repeated measures (MMRM). Data from the EXACT (Exacerbation of chronic pulmonary disease tool) which is used to capture frequency, severity, and duration of exacerbations in COPD were analyzed using an IRM. The IRM included a graded response model characterizing item parameters and functions describing symptom-time course. Total scores were simulated (month 12) using uncertainty in parameter estimates. The 50th (2.5th, 97.5th) percentiles of the resulting simulated differences in average total score (drug minus placebo) represented the estimated drug effect (95%CI), which was compared with published MMRM results. Furthermore, differences in sample size, sensitivity, specificity, and type I and II errors between approaches were explored. Patients received either oral danirixin 75 mg twice daily (n = 45) or placebo (n = 48) on top of standard of care over 52 weeks. A step function best described the COPD symptoms-time course in both trial arms. The IRM improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of 2.5 times larger for the MMRM analysis to achieve the IRM precision. The IRM showed a higher probability of a positive predictive value (34%) than MMRM (22%). An item model-based analysis data gave more precise estimates of drug effect than MMRM analysis for the same endpoint in this one case study.

Prognostic Value of MMP-9 -1562 C/T Gene Polymorphism in Patients With Sepsis.

INTRODUCTION: Matrix metalloproteinase-9 (MMP-9) plays an important role in the pathophysiology of sepsis. A single-nucleotide polymorphism (SNP) at position -1562 (C/T) in the MMP-9 gene has been associated with differential MMP-9 expression, being higher when the -1562 T allele is present. We evaluated the association of the SNP MMP9 -1562 C/T with severity and mortality in patients with sepsis to establish whether the prognosis of the disease is affected. MATERIALS AND METHODS: A case-control study exploratory was carried out in a cohort of infected patients. 540 individuals were selected in total, 270 patients with sepsis and 270 controls (infected but non-septic), classified according to the 2016 consensus (Sepsis-3). The presence of the single-nucleotide polymorphism (SNP; allele T and/or allele C) was determined through analyses of restriction fragment length polymorphism and plasma levels of MMP-9 were determined through enzyme-linked immunosorbent assay immunoassay. RESULTS: SNP MMP-9 -1562 has two known alleles (T and C), with predominance of the C over the T allele; in the group of patients with sepsis, T allele was found in 7.2% of cases, while C allele in the rest (92.8%); in comparison, in the group of infected but non-septic patients, frequencies were 9.4% for T allele and 90.6% for the C allele (P = .33). Also, the presence of the polymorphic T allele was not related to the levels of MMP-9 in patients with sepsis in comparison with infected but non-septic patients 780 (397-1375) ng/mL vs 646 (172-1249) ng/mL (P = .64). There was also no association between the SNP and sepsis mortality (P = .78). CONCLUSIONS: We concluded that there was no association between the SNP MMP9 -1562 C/T and sepsis or between the SNP MMP9 -1562 C/T and sepsis mortality in the Northeastern Colombian septic patient cohort. Further research is needed to clarify the correlation among sepsis, genetic factors with allele T and MMP-9 plasma concentration.

Description and distribution of Tuberincognitum sp. nov. and Tuberanniae in the Transmexican Volcanic Belt.

The genus Tuber is a lineage of diverse ectomycorrhizal, hypogeous, sequestrate ascomycete fungi that are native to temperate forests in the Northern Hemisphere. Recently, many new species of Tuber have been described in North America and Asia, based on morphological characteristics and molecular data. Here we describe and illustrate a new species, Tuberincognitum, based upon phylogenetic analysis and morphological description. We also present a new record for Tuberanniae in México. These two Tuber species are distributed in the Transmexican Volcanic Belt in the states of México, Michoacán, Guanajuato, Querétaro and Tlaxcala at altitudes between 2,000 and 3,200 meters. These species are associated with Pinus (T.anniae) and Quercus forests (T.incognitum).

Harvest rates and foraging strategy of Carollia perspicillata (Chiroptera: Phyllostomidae) in an artificial food patch.

An organism's foraging strategy depends on its ability to acquire and use information from food patches. A forager that does not obtain information from a food patch should remain there for a fixed time or a fixed amount of harvest. Foragers that obtain partial or complete information from the patch should be able to estimate costs and benefits from its exploitation. The foraging strategy used by a forager can be determined using the giving-up density (GUD) technique. The GUD is the amount of food left by a forager after feeding in a patch with diminishing returns. We constructed an artificial feeder to examine the foraging strategy of the short-tailed fruit bat Carollia perspicillata (Chiroptera: Phyllostomidae). In this feeder, the bat's harvest rate declined with time, i.e., they experienced diminishing returns. When offered feeders with different initial food densities, bats consumed proportionately more from rich patches than from poor ones, but they equalized GUDs. When offered feeders with different concentrations of sugar (i.e., different energy content), the higher the sugar concentration in the food, the more they consumed. Altogether, the evidence indicates that these fruit bats used complete, unbiased information to decide how much time to stay in a food patch.

Comparison of methods to estimate glomerular filtration rate in paediatric oncology patients.

AIMS: Glomerular filtration rate (GFR) is estimated daily in paediatric oncology patients; however, few equations, particularly ones that do not include serum creatinine, have been evaluated in this population. We aimed to compare the predictive performance of different equations available to estimate GFR in paediatric oncology patients. METHODS: GFR was measured (mGFR) in paediatric oncology patients based on a chromium 51-labeled ethylene diamine tetraacetic acid excretion test. GFR was estimated (eGFR) in these same patients using equations identified from the literature. mGFR and eGFR values were compared, and the predictive performance of various eGFR equations was assessed in terms of their bias, precision and accuracy. RESULTS: In total, 124 mGFR values ranging from 7 to 146 mL/min were available for analysis from 73 children. Twenty-two equations were identified from the literature. The Flanders metadata equation displayed the lowest absolute bias (mean error of 0.9 mL/min) and the greatest precision (root mean square error of 13.1 mL/min). The univariate Schwartz equation predicted the highest percentage (81.5%) of eGFR values within 30% of mGFR values, and the Rhodin fat-free mass equation predicted the highest percentage (37.1%) of eGFR values within 10% of mGFR values. CONCLUSIONS: A number of equations were identified that could be used to estimate renal function in paediatric oncology patients; however, none was found to be highly accurate. The Flanders metadata equation and univariate Schwartz performed the best in this study, and we would suggest that these two equations may be used cautiously in paediatric oncology patients for clinical decision making, understanding their limitations.

Antimicrobial stewardship in paediatric oncology: Impact on optimising gentamicin use in febrile neutropenia.

OBJECTIVES: To evaluate the impact of an antimicrobial stewardship (AMS) intervention, involving introduction of new guidelines on the treatment of febrile neutropenia (FN), on improving the use of gentamicin in paediatric oncology patients. DESIGN AND INTERVENTION: Updated guidelines for gentamicin usage in paediatrics with FN were implemented at a tertiary children's teaching hospital, in Brisbane, Australia. Data on gentamicin usage before and after the guideline change were collected retrospectively from children with cancer admitted to hospital with FN between January 2012 and December 2013. Gentamicin use, duration of gentamicin therapy and therapeutic monitoring practice were compared against bacterial culture status for admissions before and after the guideline change to assess the impact on practice. RESULTS: Data were collected from 227 children corresponding to 453 separate admissions, 195 preguideline and 257 post-guideline change. Following guideline change, the proportion of admissions in which gentamicin was administered reduced from 79.0 to 20.9% (P-value < 0.001) and administrations not associated with a cultured Gram-negative organism dropped from 87.2 to 58.2% (P-value < 0.001), indicating a change in practice according to the new guideline. Following guideline change, admissions in which gentamicin was used for >48 hr despite the absence of a confirmed Gram-negative infection decreased from 85.6 to 46.9% (P-value < 0.001). CONCLUSIONS: Guideline changes driven through an AMS initiative involving paediatric oncology patients significantly improved targeted- and nontargeted-antimicrobial use potentially reducing the risk of emergence of resistance against gentamicin in this cohort.

Balancing Antibacterial Efficacy and Reduction in Renal Function to Optimise Initial Gentamicin Dosing in Paediatric Oncology Patients.

This study aimed to determine the optimal starting dose of gentamicin in paediatric oncology patients. A population pharmacokinetic model describing drug exposure, a semi-mechanistic model describing bacterial killing and an Emax model describing renal cortex accumulation were linked in a utility function using NONMEM®. The optimal gentamicin starting dose was estimated in patients aged from 0.1 to 18.2 years, by balancing the probability of efficacy on day 1 against relative renal function reduction on day 7 with continued dosing. Using achievement of a gentamicin area under the concentration time curve to bacterial minimum inhibitor concentration (MIC) ratio of ≥ 100 and maximum concentration to MIC ratio of ≥ 10 as the efficacy endpoints, a starting dose of 7.1, 9.5, 10.8 and 14.6 mg/kg/q24h was optimal at a MIC of 0.5, 1, 2 and 4 mg/L respectively, with ≥ 75% probability of obtainment. Using achievement of a 2-log10 bacterial count reduction at 24-h post-dose as the efficacy endpoint, a starting dose of 12.8 mg/kg/q24h was optimal, with 85.6% probability of obtainment. Under these different dosing scenarios, relative reduction in renal function ranged on average from 6.9 to 14.5% on day 7. The current recommended starting dose of gentamicin of 7.5 mg/kg/q24h may not be sufficient to achieve efficacy on day 1 if bacterial MIC is > 0.5 mg/L. A higher initial dose (up to 14.6 mg/kg/q24h), in less sensitive microorganisms, would likely cause only a relatively small reduction in renal function at day 7. Close monitoring is crucial if high doses are given, especially for longer than 7 days.

Endothelial nitric oxide synthase gene polymorphism is associated with systemic lupus erythematosus.

OBJECTIVE: In systemic lupus erythematosus (SLE), endothelial nitric oxide synthase (eNOS) gene locus has been found to be suggestive of linkage with disease, nitric oxide (NO) is produced in significant amounts, and endothelial cell dysfunction is observed. eNOS gene polymorphism may affect both the synthesis of eNOS protein and its enzymatic activity. We examined the influence of eNOS gene polymorphisms on susceptibility to SLE. METHODS: Genomic DNA from 88 Northwestern Colombian women with SLE, as well as 199 controls matched for sex, age, and ethnicity, was genotyped for the -786T -- > C polymorphism in the promoter region, the intron 4 variable number of tandem repeats, and the Glu298Asp polymorphism in exon 7 of the eNOS gene by polymerase chain reaction and restriction fragment length polymorphism techniques. Haplotype and allele frequency comparisons, a Hardy-Weinberg equilibrium test, and linkage disequilibrium (LD) analysis were performed. RESULTS: The intron 4b allele was associated with SLE (OR 2.2, 95% CI 1.29-3.60, pc = 0.005) as was the 4bb genotype (OR 2.9, 95% CI 1.61-5.33, pc = 0.0009), while the 4a allele was protective (OR 0.4, 95% CI 0.26-0.76, pc = 0.005), as was the 4ab genotype (OR 0.29, 95% CI 0.15-0.56, pc < 0.0001). In controls, all loci were in linkage disequilibrium (p < 0.02). In patients, intron 4 was in Hardy-Weinberg disequilibrium, due to an excess of homozygotes (p = 0.01). CONCLUSION: eNOS polymorphism influences SLE predisposition. Since intron 4bb genotype is responsible for higher levels of eNOS synthesis and intron 4 ab genotype is associated with lower synthesis, our results might provide insight into the elevated levels of NO observed in SLE patients.

Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study.

Polymorphisms in the endothelial NO synthase (eNOS) gene have been evaluated as risk factors for preeclampsia. However, data from small studies are conflicting. We assessed whether eNOS genotypes alter the risk of preeclampsia in a population in which the incidence of this disorder is high. A total of 844 young pregnant women (322 preeclamptic and 522 controls) were recruited from 5 cities. Genotyping for the Glu298Asp, intron-4 and -786T-->C polymorphisms in the eNOS gene was conducted. Multivariate odds ratios (ORs) were obtained to estimate the association of individual polymorphisms and haplotypes with preeclampsia risk. No increase in the risk of preeclampsia for the intron-4 or -786T-->C polymorphisms was observed under any model of inheritance. In contrast, in women homozygous for the Asp298 allele, the adjusted OR for preeclampsia was 4.60 (95% confidence interval [CI], 1.73 to 12.22) compared with carriers of the Glu298 allele. After a multivariate analysis, carriage of the "Asp298-786C-4b" haplotype was also associated with increased risk of preeclampsia (OR, 2.11 [95% CI, 1.33 to 3.34]) compared with carriers of the "Glu298-786T-4b" haplotype. The eNOS Glu298Asp polymorphism and the Asp298-786C-4b haplotype are risk factors for preeclampsia.