CHARMM GUI Membrane Builder for oxidized phospholipid membrane modeling and simulation.

Oxidative stress leads to the production of oxidized phospholipids (oxPLs) that modulate the biophysical properties of phospholipid monolayers and bilayers. As many immune cells are responsible for surveilling cells and tissues for the presence of oxPLs, oxPL-dependent mechanisms have been suggested as targets for treating chronic kidney disease, atherosclerosis, diabetes, and cancer metastasis. This review details recent experimental and computational studies that characterize oxPLs' behaviors in various monolayers and bilayers. These studies investigate how the tail length and polar functional groups of OxPLs impact membrane properties, how oxidized membranes can be stabilized, and how membrane integrity is generally affected by oxidized lipids. In addition, for oxPL-containing membrane modeling and simulation, CHARMM-GUI Membrane Builder has been extended to support a variety of oxPLs, accelerating the simulation system building process for these biologically relevant lipid bilayers.

Emergency treatment of peri-operative anaphylaxis: Resuscitation Council UK algorithm for anaesthetists.

Peri-operative anaphylaxis is a rare but potentially catastrophic event which must be considered whenever unexpected and significant cardiovascular or respiratory compromise occurs during anaesthesia. The Resuscitation Council UK algorithm for peri-operative anaphylaxis highlights the importance of early intravenous adrenaline and fluid resuscitation and provides guidance on the treatment of refractory anaphylaxis and immediate follow-up. This algorithm is endorsed by the Royal College of Anaesthetists, Association of Anaesthetists, British Society of Allergy and Clinical Immunology and Clinical Immunology Professional Network of the British Society for Immunology. This document was produced by the Perioperative Allergy Network steering committee in collaboration with the Resuscitation Council UK.

A potential biomarker of radiosensitivity in metastatic hormone sensitive prostate cancer patients treated with combination external beam radiotherapy and radium-223.

PURPOSE: The ADRRAD trial reported the safety and feasibility of the combination of external beam radiotherapy and radium-223 in the treatment of de novo bone metastatic prostate. This study aimed to determine if any biomarkers predictive of response to these treatments could be identified. EXPERIMENTAL DESIGN: 30 patients with newly diagnosed bone metastatic hormone sensitive prostate cancer were recruited to the ADRRAD trial. Blood samples were taken pre-treatment, before cycles 2 to 6 of radium-223, and 8 weeks and 6 months after treatment. Mononuclear cells were isolated and DNA damage was assessed at all timepoints. RESULTS: DNA damage was increased in all patients during treatment, with bigger increases in foci observed in patients who relapsed late compared to those who relapsed early. Increases in DNA damage during the radium-223 only cycles of treatment were specifically related to response in these patients. Analysis of hematology counts also showed bigger decreases in red blood cell and hemoglobin counts in patients who experienced later biochemical relapse. CONCLUSIONS: While some patients responded to this combination treatment, others relapsed within one year of treatment initiation. This study identifies a biomarker based approach that may be useful in predicting which patients will respond to treatment, by monitoring both increases in DNA damage above baseline levels in circulating lymphocytes and decreases in red blood cell and hemoglobin counts during treatment.

Beluga whale and bottlenose dolphin ACE2 proteins allow cell entry mediated by spike protein from three variants of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses infect numerous non-human species. Spillover of SARS-CoV-2 into novel animal reservoirs may present a danger to host individuals of these species, particularly worrisome in populations already endangered or threatened by extinction. In addition, emergence in new reservoirs could pose spillback threats to humans, especially in the form of virus variants that further mutate when infecting other animal hosts. Previous work suggests beluga whales (Delphinapterus leucas) and bottlenose dolphins (Tursiops truncatus) may be at risk owing to their formation of social groups, contact with humans, exposure to contaminated wastewater, and structure of their angiotensin-converting enzyme 2 (ACE2) proteins, which SARS-CoV-2 uses as a cellular receptor. We examined marine-mammal susceptibility to virus infection by challenging 293T cells expressing beluga or dolphin ACE2 with pseudovirions bearing the SARS-CoV-2 spike protein. Beluga and dolphin ACE2 were sufficient to allow cell entry by an early pandemic isolate (Wuhan-Hu-1) and two evolved variants (Delta B.1.617.2 and Omicron BA.1 strains). We conclude that SARS-CoV-2 poses a potential threat to marine mammal reservoirs that should be considered in surveillance efforts.

Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial.

Importance: Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen. Objective: To determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin. Design, Setting, and Participants: This phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands. Interventions: The single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher. Main Outcomes and Measures: Outcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers. Results: Among 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed. Conclusion: Muvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT04472676.

Abemaciclib does not increase the corrected QT interval in healthy participants.

Abemaciclib is an orally administered, potent, and selective small molecule inhibitor of cyclin-dependent kinases 4 and 6, approved for advanced or metastatic breast cancer. This study aimed to use an exposure-response approach to investigate the effect of abemaciclib and its active metabolites (M2 and M20) on QTc interval and delay in cardiac repolarization at clinically relevant exposures. This was a single-blind, randomized, and placebo-controlled study of ascending doses of abemaciclib. Thirty-five healthy participants were administered a single dose of 200-600 mg abemaciclib. Twelve-lead electrocardiogram tracings and pharmacokinetic samples were collected serially pre- and post-dose. The primary objective was to study the relationship between abemaciclib and its active metabolites (M2 and M20) and QTc interval following ascending oral doses of abemaciclib. The secondary objective included evaluating the safety and tolerability of single ascending doses of abemaciclib in healthy participants. Exposure-response analysis demonstrated that there was no significant relationship between placebo-corrected change from baseline QTcF (ΔΔQTcF), abemaciclib, and metabolite plasma concentrations. Additionally, the ΔΔQTcF slopes of abemaciclib, its metabolites, and total analyte concentrations were not statistically different from zero. Single doses of abemaciclib, up to 400 mg, were well-tolerated by healthy participants; however, at the 600 mg dose (three times the highest registered dose), the frequency and severity of treatment-related gastrointestinal events (primarily diarrhea, nausea, and vomiting) increased. In conclusion, single doses of abemaciclib, up to 400 mg, had no statistically or clinically relevant effects on QTc, and abemaciclib was well tolerated up to a dose of 400 mg in this study.

W. Matthews Grant's Dual Sources Account and Ultimate Responsibility.

A number of philosophers and theologians have recently challenged the common assumption that it would be impossible for God to cause humans actions which are free in the libertarian or incompatibilist sense. Perhaps the most sophisticated version of this challenge is due to W. Matthews Grant. By offering a detailed account of divine causation, Grant argues that divine universal causation does not preclude humans from being ultimately responsible for their actions, nor free according to typical libertarian accounts. Here, we argue that the kind of divine universal causation that Grant proposes is incompatible with a plausible interpretation of Robert Kane's influential conception of ultimate responsibility. This conclusion is significant since Grant seeks to harmonize his divine causal account with Kane's articulation of ultimate responsibility.

Efficacy of three different cervical dislocation methods for on-farm killing of layer chicks.

Unfit chicks with low viability are often euthanized in the layer industry. An effective euthanasia protocol is characterized by rapid, irreversible insensibility, followed by prompt death. This study was conducted to evaluate the efficacy of three cervical dislocation methods for killing layer chicks (2-3-day-old, avg BW ± SD; 44 ± 3 g, n = 40): manual cervical dislocation (CD), assisted manual cervical dislocation (ACD; the bird's ventral neck is placed on a blunt table edge and the back of the neck pressed firmly), and mechanical cervical dislocation by Koechner Euthanizing Device (KED-model-S). All three killing methods were assessed on anesthetized chicks (intramuscular injections of medetomidine [0.3 mg/kg BW] and ketamine [30 mg/kg BW] were used to induce clinical anesthesia). CD and ACD were also evaluated using conscious chicks to compare the killing methods and to determine the effect of anesthesia on response variables. There were no differences in time to loss of pupillary light reflex, cessation of heartbeat, or duration of gasping between conscious chicks killed with CD and ACD, but these values were all longer for conscious compared to anesthetized chicks. KED resulted in longer latencies to loss of pupillary light reflex, cessation of heartbeat, and duration of gasping. Radiographs revealed that both CD and ACD resulted in cervical luxation, mainly below the C4 vertebra, whereas KED did not cause luxation in any of the 8 chicks tested. Chicks killed by CD and ACD presented more subdural hemorrhage (SDH) at the site of cervical dislocation than those killed by KED. None of the killing methods resulted in brain trauma. Compared to CD and ACD, KED resulted in longer latency to brain death and less anatomical pathology indicating a lower efficacy of KED as an on-farm killing method.

Changing characteristics of post-COVID-19 syndrome: Cross-sectional findings from 458 consultations using the Stanford Hall remote rehabilitation assessment tool.

BACKGROUND: In the UK, there have been multiple waves of COVID-19, with a five-tier alert system created to describe the transmission rate and appropriate restrictions. While acute mortality decreased, there continued to be a significant morbidity, with individuals suffering from persistent, life-restricting symptoms for months to years afterwards. A remote rehabilitation tool was created at the Defence Medical Rehabilitation Centre (DMRC) Stanford Hall to assess post-COVID-19 symptoms and their impact on the UK military.This study aims to understand changes in post-COVID-19 syndrome between wave 1 and wave 2, identify interactions between alert level and symptoms and investigate any predictive nature of acute symptoms for postacute symptomology in a young, physically active population. METHODS: Cross-sectional study of 458 consecutive remote rehabilitation assessments performed at DMRC Stanford Hall between 2 April 2020 and 29 July 2021. Consultations were coded, anonymised, and statistical analysis was performed to determine associations between acute and postacute symptoms, and between symptoms, alert levels and waves. RESULTS: 435 assessments were eligible; 174 in wave 1 and 261 in wave 2. Post-COVID-19 syndrome prevalence reduced from 43% to 2% between the waves. Acutely, widespread pain was more prevalent in wave 2 (p<0.001). Postacutely, there was increased anxiety (p=0.10) in wave 1 and increased sleep disturbance (p<0.001), memory/concentration issues (p<0.001) and shortness of breath/cough (p=0.017) in wave 2. Increasing alert level was associated with increased postacute symptom prevalence (p=0.046), with sleep disturbance increasing at higher alert level (p=0.016). Acute symptoms, including fatigue, sleep disturbance and myalgia, were associated with multiple postacute symptoms. CONCLUSIONS: This study reports the overall prevalence and symptom burden in the UK military in the first two waves of COVID-19. By reporting differences in COVID-19 in different waves and alert level, this study highlights the importance of careful assessment and contextual understanding of acute and postacute illnesses for individual management plans.

International links between Streptococcus pneumoniae vaccine serotype 4 sequence type (ST) 801 in Northern European shipyard outbreaks of invasive pneumococcal disease.

BACKGROUND: Pneumococcal disease outbreaks of vaccine preventable serotype 4 sequence type (ST)801 in shipyards have been reported in several countries. We aimed to use genomics to establish any international links between them. METHODS: Sequence data from ST801-related outbreak isolates from Norway (n = 17), Finland (n = 11) and Northern Ireland (n = 2) were combined with invasive pneumococcal disease surveillance from the respective countries, and ST801-related genomes from an international collection (n = 41 of > 40,000), totalling 106 genomes. Raw data were mapped and recombination excluded before phylogenetic dating. RESULTS: Outbreak isolates were relatively diverse, with up to 100 SNPs (single nucleotide polymorphisms) and a common ancestor estimated around the year 2000. However, 19 Norwegian and Finnish isolates were nearly indistinguishable (0-2 SNPs) with the common ancestor dated around 2017. CONCLUSION: The total diversity of ST801 within the outbreaks could not be explained by recent transmission alone, suggesting that harsh environmental and associated living conditions reported in the shipyards may facilitate invasion of colonising pneumococci. However, near identical strains in the Norwegian and Finnish outbreaks does suggest that transmission between international shipyards also contributed to those outbreaks. This indicates the need for improved preventative measures in this working population including pneumococcal vaccination.

Assembly and Annotation of the Complete Genome Sequence of T4-Like Bacteriophage 132.

Here, we describe the complete sequence of bacteriophage 132, a T4-like Escherichia coli phage. Phage 132 has a genome of 166,922-bp length, with 286 predicted genes.

The efficacy of three on-farm euthanasia methods for broiler chickens throughout the production cycle.

1. There is a need to humanely kill moribund or injured broiler birds on-farm with no reasonable chance of recovery. Two experiments evaluated the efficacy of three commercially applicable killing methods; manual cervical dislocation (CD), mechanical cervical dislocation with the Koechner Euthanising Device (KED) and a non-penetrative captive bolt device (Zephyr-EXL; ZEXL), at 7, 21 or 35 d of age, on their ability to induce insensibility (unconsciousness and loss of brain stem reflexes) and death.2. Experiment one assessed the damage to the cranial-cervical region resulting from the methods applied to cadavers of cull birds (n = 180) by radiography and gross pathology observation.3. Experiment two evaluated the latency to insensibility and death when cull broiler birds (n = 240) were killed by CD, KED or ZEXL, using behavioural and reflexive indicators. Insensibility and death were measured by the absence of pupillary light, palpebral blink and nictitating membrane reflexes and cessation of rhythmic breathing, cloacal winking and convulsions. Analysis of variance for the main effect of the method was performed to determine the differences.4. In experiment one, only the Zephyr resulted in skull fractures. A higher number of vertebral fractures occurred with KED application compared to CD, at 21 and 35 d.5. In experiment two, indicators of sensibility were absent earliest with the ZEXL (µ < 2 s); then,CD (µ = 28 s) and were longest with KED (µ = 47 s), at 21 and 35 d. Cloacal winking and convulsions ceased earlier after CD (88 s), compared to either KED (124 s) or Zephyr (118 s). Death after a single application occurred 100%, 100% and 98% of time for CD, KED and ZEXL, respectively.6. Overall, all methods were efficacious at inducing insensibility and death. Insensibility occurred earliest with ZEXL, whilst death occurred earliest with CD. KED resulted in the longest time to insensibility and death.

Abemaciclib in combination with endocrine therapy for East Asian patients with HR+, HER2- advanced breast cancer: MONARCH 2 & 3 trials.

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double-blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression-free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P < .001; median: 21.2 vs 11.6 months) and MONARCH 3 (HR, 0.326; 95% CI, 0.200 to 0.531, P < .001; median: not reached vs 12.82 months). Diarrhea (MONARCH 2: 90%; MONARCH 3: 88%) and neutropenia (MONARCH 2: 68%; MONARCH 3: 58%) were the most frequent adverse events observed in the East Asian populations. Abemaciclib exposures and PK were similar in East Asians and the non-East Asian populations of both trials. Abemaciclib in combination with ET in the East Asian populations of MONARCH 2 and MONARCH 3 provided consistent results with the ITT populations, demonstrating improvements in efficacy with generally tolerable safety profiles for patients with HR+, HER2- advanced breast cancer.

Pre-existing influenza-specific nasal IgA or nasal viral infection does not affect live attenuated influenza vaccine immunogenicity in children.

The United Kingdom has a national immunization programme which includes annual influenza vaccination in school-aged children, using live attenuated influenza vaccine (LAIV). LAIV is given annually, and it is unclear whether repeat administration can affect immunogenicity. Because LAIV is delivered intranasally, pre-existing local antibody might be important. In this study, we analysed banked samples from a study performed during the 2017/18 influenza season to investigate the role of pre-existing influenza-specific nasal immunoglobulin (Ig)A in children aged 6-14 years. Nasopharyngeal swabs were collected prior to LAIV immunization to measure pre-existing IgA levels and test for concurrent upper respiratory tract viral infections (URTI). Oral fluid samples were taken at baseline and 21-28 days after LAIV to measure IgG as a surrogate of immunogenicity. Antibody levels at baseline were compared with a pre-existing data set of LAIV shedding from the same individuals, measured by reverse transcription-polymerase chain reaction. There was detectable nasal IgA specific to all four strains in the vaccine at baseline. However, baseline nasal IgA did not correlate with the fold change in IgG response to the vaccine. Baseline nasal IgA also did not have an impact upon whether vaccine virus RNA was detectable after immunization. There was no difference in fold change of antibody between individuals with and without an URTI at the time of immunization. Overall, we observed no effect of pre-existing influenza-specific nasal antibody levels on immunogenicity, supporting annual immunization with LAIV in children.

Assessing the effect of water deprivation on the efficacy of on-farm euthanasia methods for broiler chickens.

1. Moribund or diseased poultry requiring euthanasia are often dehydrated. To understand how dehydration influences the efficacy of various killing methods, this experiment investigated the effect of water deprivation (WD) on times to unconsciousness and death.2. Broiler chickens (n = 179) were water-deprived for 0, 24, 48 or 72 hours to mimic dehydration, then killed via manual cervical dislocation, mechanical cervical dislocation (Koechner Euthanising Device (KED)), or non-penetrating captive bolt (Zephyr-EXL), at 8, 22, 36 or 50 d of age. Degree of WD was confirmed by skin turgor, packed cell volume and body weight loss. Method efficacy was evaluated by the time to unconsciousness and death using pupillary light (PUP), palpebral blink (PAL) and nictitating membrane (NIC) reflexes, feather erection (FE), cloacal winking (CW) and convulsions (CN). The extent of damage caused by each method was examined via radiography, gross pathology and histopathology. The main effects of WD time and euthanasia method were analysed by two-way analyses of variance (CRD, PROC MIXED, SAS 9.4) with a-priori contrasts to compare water-deprived versus non-water-deprived (NON) birds.3. Skin turgor, packed cell volume and body weight loss had a quadratic relationship with WD, with highest values for those birds which were water-deprived for 72 h. WD level did not affect time to unconsciousness. Time to death was longer for WD birds than NON, with longer latencies to FE, CW and CN for water-deprived birds. WD only affected radiography or gross pathology scores on d 8, with the extent of subcutaneous haemorrhage within the neck decreasing as WD increased.4. The shortest latency to PUP loss, at all ages, and to PAL and NIC loss, at 22 d, was with the Zephyr-EXL. KED had the longest time to unconsciousness (PUP, PAL and NIC), at all ages, and to death, at 36 and 50 d.5. Overall, WD increased time to death, but did not affect the onset of unconsciousness, with no interaction between methods and WD level.

Defining characteristics of immersion carbon dioxide gas for successful euthanasia of neonatal and young broilers.

This study investigated how the carbon dioxide (CO2) concentration within a chamber affects the efficacy of CO2 euthanasia and how the efficacy of CO2 induction methods changes as birds age. In experiment 1, pairs of broiler chicks (n = 192; 0, 3, and 6 D of age) were immersed into a chamber prefilled with 70, 80, 90, or 100% CO2. For experiment 2, 3- and 6-day-old broiler chicks (n = 88) were immersed in pairs into 100% CO2 or exposed to CO2 gradual fill in a chamber with a displacement rate of 28% chamber volume per minute. Latency to performance of headshaking (HS) and gasping (GS) as potential indicators of distress, loss of posture indicative of insensibility, and the cessation of rhythmic breathing (CRB) and cessation of movement (COM) as the indicators of death were monitored (live focal sampling/video recordings). The duration and frequency of HS and GS were assessed. For both experiments, behavior data were analyzed for CO2 method and age (4 × 3 factorial). Age and CO2 concentration interacted for latency to CRB and COM, with longer latencies for 0-day-old chicks immersed into 70% CO2 than other concentrations and ages. CO2 concentration did not affect latency to HS, GS, or loss of posture but affected CRB and COM, with latencies longest for 70% and shortest for 90 and 100% CO2. Newly hatched chicks had a longer latency to CRB and COM and longer duration and frequency of distress behaviors than older chicks. At all ages, initiation of all behaviors occurred later with gradual fill compared to immersion. There was an increased duration and frequency of distress behaviors with gradual induction compared with immersion. Overall, immersion into 90 to 100% CO2 resulted in the shortest time to insensibility and death, with a decreased duration and frequency of distress behaviors. Chicks immersed into 70% CO2 had the longest duration of GS and time to death. Age affects the efficacy of CO2 euthanasia, with increasing age decreasing time to death and the duration and frequency of distress behaviors.

A novel tool for improving the interpretation of isotope bone scans in metastatic prostate cancer.

OBJECTIVES: The isotope bone scan (IBS) is the gold-standard imaging modality for detecting skeletal metastases as part of prostate cancer staging. However, its clinical utility for assessing skeletal metastatic burden is limited due to the need for subjective interpretation. We designed and tested a novel custom software tool, the Metastatic Bone Scan Tool (MetsBST), aimed at improving interpretation of IBSs, and compared its performance with that of an established software programme. METHODS: We used IBS images from 62 patients diagnosed with prostate cancer and suspected bone metastases to design and implement MetsBST in MATLAB by defining thresholds used to identify the texture and size of metastatic bone lesions. The results of MetsBST were compared with those of the commercially available automated Bone Scan Index (aBSI) with regression analysis. RESULTS: There was strong agreement between the MetsBST and aBSI results (R2 = 0.9189). In a subregional analysis, MetsBST quantified the extent of metastatic disease in multiple bone sites in patients receiving multimodality therapy (radium-223 and external beam radiotherapy) to illustrate the differences in bone metastatic response to different treatments. CONCLUSION: The results of MetsBST and the commercial software aBSI were highly consistent. MetsBST introduces novel clinical utility by its ability to differentiate between the responses of different bone metastases to multimodality therapies. ADVANCES IN KNOWLEDGE: MetsBST reduces the variability in assessment of tumour burden caused by subjective interpretation. Therefore, it is a useful aid to physicians reporting nuclear medicine scans, and may improve decision-making in the treatment of metastatic prostate cancer.

Burkholderia pseudomallei multi-centre study to establish EUCAST MIC and zone diameter distributions and epidemiological cut-off values.

OBJECTIVES: Melioidosis, caused by Burkholderia pseudomallei, requires intensive antimicrobial treatment. However, standardized antimicrobial susceptibility testing (AST) methodology based on modern principles for determining breakpoints and ascertaining performance of methods are lacking for B. pseudomallei. This study aimed to establish MIC and zone diameter distributions on which to set epidemiological cut-off (ECOFF) values for B. pseudomallei using standard EUCAST methodology for non-fastidious organisms. METHODS: Non-consecutive, non-duplicate clinical B. pseudomallei isolates (9-70 per centre) were tested at eight study centres against eight antimicrobials by broth microdilution (BMD) and the EUCAST disc diffusion method. Isolates without and with suspected resistance mechanisms were deliberately selected. The EUCAST Development Laboratory ensured the quality of study materials, and provided guidance on performance of the tests and interpretation of results. Aggregated results were analysed according to EUCAST recommendations to determine ECOFFs. RESULTS: MIC and zone diameter distributions were generated using BMD and disc diffusion results obtained for 361 B. pseudomallei isolates. MIC and zone diameter ECOFFs (mg/L; mm) were determined for amoxicillin-clavulanic acid (8; 22), ceftazidime (8; 22), imipenem (2; 29), meropenem (2; 26), doxycycline (2; none), tetracycline (8; 23), chloramphenicol (8; 22) and trimethoprim-sulfamethoxazole (4; 28). CONCLUSIONS: We have validated the use of standard BMD and disc diffusion methodology for AST of B. pseudomallei. The MIC and zone diameter distributions generated in this study allowed us to establish MIC and zone diameter ECOFFs for the antimicrobials studied. These ECOFFs served as background data for EUCAST to set clinical MIC and zone diameter breakpoints for B. pseudomallei.

Development and Application of a Mechanistic Population Modeling Approach to Describe Abemaciclib Pharmacokinetics.

Abemaciclib is an oral anticancer drug that inhibits cyclin dependent kinases 4 and 6 and is metabolized by cytochrome P450 3A in the intestines and liver to active metabolites. The objectives were (1) to develop a mechanistic model to characterize the pharmacokinetics (PK) of the active moieties and investigate the effect of patient factors and (2) apply the model to dat from two phase III breast cancer trials of abemaciclib in combination with endocrine therapy. To develop the model, data from seven phase I studies and two phase II studies including 421 patients with cancer and 65 healthy individuals were pooled for nonlinear mixed effects modeling. The PK was similar between patients and healthy subjects, and the effects of diarrhea, formulation, race, and patient covariates on exposure were negligible. Application of the model confirmed its predictive performance and that abemaciclib PK did not change when coadministered with endocrine therapy.