Osimertinib after definitive chemoradiotherapy in unresectable stage III epidermal growth factor receptor-mutated non-small-cell lung cancer: analyses of central nervous system efficacy and distant progression from the phase III LAURA study.

BACKGROUND: Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here. PATIENTS AND METHODS: Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints. RESULTS: Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo. CONCLUSIONS: Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC.

Blood lactate clearance after maximal exercise depends on active recovery intensity.

AIM: High-intensity exercise is time-limited by onset of fatigue, marked by accumulation of blood lactate. This is accentuated at maximal, all-out exercise that rapidly accumulates high blood lactate. The optimal active recovery intensity for clearing lactate after such maximal, all-out exercise remains unknown. Thus, we studied the intensity-dependence of lactate clearance during active recovery after maximal exercise. METHODS: We constructed a standardized maximal, all-out treadmill exercise protocol that predictably lead to voluntary exhaustion and blood lactate concentration>10 mM. Next, subjects ran series of all-out bouts that increased blood lactate concentration to 11.5±0.2 mM, followed by recovery exercises ranging 0% (passive)-100% of the lactate threshold. RESULTS: Repeated measurements showed faster lactate clearance during active versus passive recovery (P<0.01), and that active recovery at 60-100% of lactate threshold was more efficient for lactate clearance than lower intensity recovery (P<0.05). Active recovery at 80% of lactate threshold had the highest rate of and shortest time constant for lactate clearance (P<0.05), whereas the response during the other intensities was graded (100%=60%>40%>passive recovery, P<0.05). CONCLUSION: Active recovery after maximal all-out exercise clears accumulated blood lactate faster than passive recovery in an intensity-dependent manner, with maximum clearance occurring at active recovery of 80% of lactate threshold.

Progressive multifocal leukoencephalopathy with gastrointestinal disease in a pediatric kidney transplant recipient.

PML is a demyelinating disease of the central nervous system caused by infection with JCV. Several cases of PML in bone marrow and solid organ transplant recipients have been reported in recent years. JCV has been isolated from the gastrointestinal mucosa of immunocompromised patients, but there are no published reports of PML associated with symptomatic gastrointestinal involvement in kidney transplant recipients. We report a case of a nine-yr-old girl with a kidney transplant who developed a severe gastrointestinal illness causing pseudo-obstruction in association with PML. JCV was suspected as the causative agent in this patient by the detection of high JCV titer through PCR analysis of the cerebrospinal fluid and blood and positive staining for simian virus 40 in the colon. JCV intestinal infection should be considered in kidney transplant recipients presenting with intestinal pseudo-obstruction.

Patient need at the heart of workforce planning: the use of supply and demand analysis in a large teaching hospital's acute medical unit.

Timely medical assessment is integral to the safety and quality of healthcare delivery in acute medicine. Medical staff are an expensive resource. This study aimed to develop a modelling system that facilitated efficient workforce planning according to patient need on the acute medical unit. A realistic 24-hour 'supply' of junior doctors was calculated by adjusting the theoretical numbers on the rota for leave allowances, natural breaks and other ward duties by a combination of direct observation of working practice and junior doctor interviews. 'Demand' was analysed using detailed admission data. Supply and demand were then integrated with data from a survey of the time spent on the process of clerking and assessment of medical admissions. A robust modelling system that predicted the number of unclerked patients was developed. The utility of the model was assessed by demonstrating the impact of a regulation-compliant redesign of the rota using existing staff and by predicting the most efficient use of an additional shift. This simple modelling system has the potential to enhance quality of care and efficiency by linking workforce planning to patient need.

Conversion of a peroxiredoxin into a disulfide reductase by a triplet repeat expansion.

Pathways for the reduction of protein disulfide bonds are found in all organisms and are required for the reductive recycling of certain enzymes including the essential protein ribonucleotide reductase. An Escherichia coli strain that lacks both thioredoxin reductase and glutathione reductase grows extremely poorly. Here, we show that a mutation occurring at high frequencies in the gene ahpC, encoding a peroxiredoxin, restores normal growth to this strain. This mutation is the result of a reversible expansion of a triplet nucleotide repeat sequence, leading to the addition of one amino acid that converts the AhpC protein from a peroxidase to a disulfide reductase. The ready mutational interconversion between the two activities could provide an evolutionary advantage to E. coli.

The potential for ozone depletion in the arctic polar stratosphere.

The nature of the Arctic polar stratosphere is observed to be similar in many respects to that of the Antarctic polar stratosphere, where an ozone hole has been identified. Most of the available chlorine (HCl and ClONO(2)) was converted by reactions on polar stratospheric clouds to reactive ClO and Cl(2)O(2) throughout the Arctic polar vortex before midwinter. Reactive nitrogen was converted to HNO(3), and some, with spatial inhomogeneity, fell out of the stratosphere. These chemical changes ensured characteristic ozone losses of 10 to 15% at altitudes inside the polar vortex where polar stratospheric clouds had occurred. These local losses can translate into 5 to 8% losses in the vertical column abundance of ozone. As the amount of stratospheric chlorine inevitably increases by 50% over the next two decades, ozone losses recognizable as an ozone hole may well appear.

In situ observations of aerosol and chlorine monoxide after the 1991 eruption of mount pinatubo: effect of reactions on sulfate aerosol.

Highly resolved aerosol size distributions measured from high-altitude aircraft can be used to describe the effect of the 1991 eruption of Mount Pinatubo on the stratospheric aerosol. In some air masses, aerosol mass mixing ratios increased by factors exceeding 100 and aerosol surface area concentrations increased by factors of 30 or more. Increases in aerosol surface area concentration were accompanied by increases in chlorine monoxide at mid-latitudes when confounding factors were controlled. This observation supports the assertion that reactions occurring on the aerosol can increase the fraction of stratospheric chlorine that occurs in ozone-destroying forms.

Chronic liver injury drives non-traditional intrahepatic fibrin(ogen) crosslinking via tissue transglutaminase.

Essentials Fibrin clots are often implicated in the progression of liver fibrosis. Liver fibrosis was induced in transgenic mice with defects in clot formation or stabilization. Liver fibrosis and fibrin(ogen) deposition do not require fibrin polymerization or factor XIIIa. Fibrin(ogen) is an in vivo substrate of tissue transglutaminase in experimental liver fibrosis. SUMMARY: Background Intravascular fibrin clots and extravascular fibrin deposits are often implicated in the progression of liver fibrosis. However, evidence supporting a pathological role of fibrin in hepatic fibrosis is indirect and based largely on studies using anticoagulant drugs that inhibit activation of the coagulation protease thrombin, which has other downstream targets that promote fibrosis. Therefore, the goal of this study was to determine the precise role of fibrin deposits in experimental hepatic fibrosis. Methods Liver fibrosis was induced in mice expressing mutant fibrinogen insensitive to thrombin-mediated proteolysis (i.e. locked in the monomeric form), termed FibAEK mice, and factor XIII A2 subunit-deficient (FXIII-/- ) mice. Female wild-type mice, FXIII-/- mice and homozygous FibAEK mice were challenged with carbon tetrachloride (CCl4 ) twice weekly for 4 weeks or 6 weeks (1 mL kg-1 , intraperitoneal). Results Hepatic injury and fibrosis induced by CCl4 challenge were unaffected by FXIII deficiency or inhibition of thrombin-catalyzed fibrin polymer formation (in FibAEK mice). Surprisingly, hepatic deposition of crosslinked fibrin(ogen) was not reduced in CCl4 -challenged FXIII-/- mice or FibAEK mice as compared with wild-type mice. Rather, deposition of crosslinked hepatic fibrin(ogen) following CCl4 challenge was dramatically reduced in tissue transglutaminase-2 (TGM2)-deficient (TGM2-/- ) mice. However, the reduction in crosslinked fibrin(ogen) in TGM2-/- mice did not affect CCl4 -induced liver fibrosis. Conclusions These results indicate that neither traditional fibrin clots, formed by the thrombin-activated FXIII pathway nor atypical TGM2-crosslinked fibrin(ogen) contribute to experimental CCl4 -induced liver fibrosis. Collectively, the results indicate that liver fibrosis occurs independently of intrahepatic fibrin(ogen) deposition.

Prevalence of oral disease among adults with primary HIV infection.

OBJECTIVE: To explore the type and prevalence of oral mucosal lesions among adults with primary HIV infection (PHI) compared with HIV-negative adults at high risk for HIV disease, and in relation to HIV viral load. METHODS: We conducted standardized oral examinations to identify specific oral mucosal lesions among adults with PHI, both pre-seroconversion and post- seroconversion-recently infected, compared with HIV-negative adults. We compared the group with oral lesions to those without oral lesions with respect to HIV-RNA load and CD4 + T-cell count. RESULTS: Among 115 adults (predominantly men), pseudomembranous candidiasis was the most common oral lesion among those with PHI, and was found in 4% of the 23 participants in pre-seroconversion and in 9% of 69 participants with post-seroconversion recent infection, compared with none found among 23 HIV negatives. Among those with PHI, the median viral load was higher and the median CD4 + T-cell count lower among the 15 participants with an oral lesion of any type than among the 77 participants without oral lesions (P = 0.02 and 0.04, respectively). CONCLUSION: This finding suggests that individuals with PHI who have oral lesions may be more likely to transmit HIV because of their higher viral load.

Genetic interactions between a pep7 mutation and the PEP12 and VPS45 genes: evidence for a novel SNARE component in transport between the Saccharomyces cerevisiae Golgi complex and endosome.

The PEP7 gene from Saccharomyces cerevisiae encodes a 59-kD hydrophilic polypeptide that is required for transport of soluble vacuolar hydrolase precursors from the TGN to the endosome. This study presents the results of a high-copy suppression analysis of pep7-20 mutant phenotypes. This analysis demonstrated that both VPS45 and PEP12 are allele-specific high-copy suppressors of pep7-20 mutant phenotypes. Overexpression of VPS45 was able to completely suppress the Zn2+ sensitivity and partially suppress the carboxypeptidase Y deficiency. Overexpression of PEP12 was able to do the same, but to a lesser extent. Vps45p and Pep12p are Sec1p and syntaxin (t-SNARE) homologues, respectively, and are also thought to function in transport between the TGN and endosome. Two additional vacuole pathway SNARE complex homologues, Vps33p (Sec1p) and Pth1p (syntaxin), when overexpressed, were unable to suppress pep7-20 or any other pep7 allele, further supporting the specificity of the interactions of pep7-20 with PEP12 and VPS45. Because several other vesicle docking/fusion reactions take place in the cell without discernible participation of Pep7p homologues, we suggest that Pep7p is a step-specific regulator of docking and/or fusion of TGN-derived transport vesicles onto the endosome.

Managing acute central nervous system infections in the UK adult intensive care unit in the wake of UK encephalitis guidelines.

The acute central nervous system infections meningitis and encephalitis commonly require management on intensive care units. The clinical features often overlap and in the acute phase-altered consciousness and seizures may also need to be managed. In April 2012, the first UK national guideline for the management of suspected viral encephalitis was published by the British Infection Association and Association of British Neurologists, and other key stakeholders, and included a simple management algorithm. The new guideline results from evidence demonstrating a number of common oversights in the standard management of suspected viral encephalitis in many settings. In combination with British Infection Association meningitis guidelines, evidence-based approaches now exist to facilitate the non-expert managing patients with suspected central nervous system infections. Here we bring together these guidelines and the supporting evidence applicable for intensivists into a single resource.

Randomised clinical trial: the 5-HT4 agonist revexepride in patients with gastro-oesophageal reflux disease who have persistent symptoms despite PPI therapy.

BACKGROUND: A substantial proportion of patients with gastro-oesophageal reflux disease (GERD) have only a partial response to proton pump inhibitor (PPI) therapy. Prokinetic drugs may improve reflux symptoms by enhancing oesophageal motility and gastric emptying. AIM: To evaluate the effect of revexepride, a novel prokinetic 5-hydroxytryptamine type 4 (5-HT4 ) receptor agonist, compared with placebo, in patients with GERD who have a partial response to PPIs. METHODS: A phase 2b, double-blind, parallel-group study was conducted, in which patients were randomised to one of three revexepride treatment groups (0.1, 0.5 and 2.0 mg three times daily) or placebo (1:1:1:1 ratio). Daily e-diary data captured patients' symptoms over an 8-week treatment period. The primary efficacy outcome was the weekly percentage of regurgitation-free days in the second half of the study (weeks 5-8). RESULTS: In total, 480 patients were randomised and 477 received treatment (mean age 47.9 years; 61% women). The mean percentage of regurgitation-free days increased from baseline (range, 15.0-18.8%) to week 8 (62.3-70.5%) in all four study arms; however, there were no statistically significant differences in this change between placebo and the three treatment arms. No dose-dependent relationship in treatment effect was observed for any of the study endpoints. The incidence of treatment-emergent adverse events (TEAEs) was revexepride dose-dependent. Only one serious TEAE occurred and none resulted in death. CONCLUSIONS: Revexepride was no more effective than placebo in controlling regurgitation in patients with GERD symptoms partially responsive to PPIs. Revexepride was well tolerated. ClinicalTrials.gov Identifier: NCT01472939.

Novel organizational features, captured cellular genes, and strain variability within the genome of KSHV/HHV8.

Strong serologic and molecular probe correlations indicate that the newly discovered gamma herpesvirus KSHV or HHV8 is the likely etiologic agent of all forms of Kaposi's sarcoma as well as BCBL/PEL and MCD in patients with acquired immunodeficiency syndrome (AIDS). Two large segments of HHV8 DNA from an AIDS-associated BCBL tumor covering genomic positions 0-52 kilobase [kb] and 108-140 kb have been cloned, mapped, and partially sequenced. Our studies have focused on novel viral proteins encoded within a 13-kb divergent locus (DL-B) by nine captured homologues of cellular genes, including vIL-6, vDHFR, vTS, vBcl-2, three C-C beta chemokines (vMIP-1A, vMIP-1B, and vBCK), and two LAP/PHD subclass zinc finger proteins (IE1A and IE1B). The HHV-8 vIL-6, vDHFR, vTS, and vBcl-2 proteins have all been shown to be active in a variety of appropriate functional assays, and transcripts from vIL-6, vMIP-1B, vIE1-A, vIE1-B, and vDHFR genes are all expressed as abundant single messenger RNA species after butyrate or phorbol ester (TPA) induction of the lytic cycle in HHV8-positive BCBL cell lines. All of these genes lie within a divergent transcriptional domain that contains a single central enhancer and associated untranslated leader region plus seven distinct proximal promoters, some of which are negatively regulated through AP-1 and ZRE motifs by the EBV ZTA transactivator. This region also encompasses a predicted complex oriLyt domain of 1050 bp that is duplicated in inverted orientation adjacent to the T0.7 latency RNA in another large divergent locus (DL-E). We have previously described three distinct subtypes of the HHV8 genome that differ by 1.0%-1.5% at the nucleotide level within the ORF26 and ORF75 genes. Certain strains or clades appear to have preferential geographic distributions, but it is not known as yet whether there are any specific disease associations. Interestingly, the A, B, and C subtypes of HHV-8 also proved to differ dramatically in coding content at both the extreme left and right ends of the unique segment of the genome as well as in the positions of the junctions with the terminal repeats. On the left-hand side, the receptor-like ORF-K1 protein is highly variable with A-strain subtypes displaying 15% amino acid differences from C strains and up to 30% differences from B strains. On the right-hand side, two unrelated alternative types of the putative multiple membrane spanning ORF-K15 protein are found.

Streptococcus mutans H2O2-forming NADH oxidase is an alkyl hydroperoxide reductase protein.

Nox-1 from Streptococcus mutans, the bacteria which cause dental caries, was previously identified as an H2O2-forming reduced nicotinamide adenine dinucleotide (NADH) oxidase. Nox-1 is homologous with the flavoprotein component, AhpF, of Salmonella typhimurium alkyl hydroperoxide reductase. A partial open reading frame upstream of nox1, homologous with the other (peroxidase) component, ahpC, from the S. typhimurium system, was also identified. We report here the complete sequence of S. mutans ahpC. Analyses of purified AhpC together with Nox-1 have verified that these proteins act as a cysteine-based peroxidase system in S. mutans, catalyzing the NADH-dependent reduction of organic hydroperoxides or H2O2 to their respective alcohols and/or H2O. These proteins also catalyze the four-electron reduction of O2 to H2O2, clarifying the role of Nox-1 as a protective protein against oxygen toxicity. Major differences between Nox-1 and AhpF include: (i) the absolute specificity of Nox-1 for NADH; (ii) lower amounts of flavin semiquinone and a more prominent FADH2 to NAD+ charge transfer absorbance band stabilized by Nox-1; and (iii) even higher redox potentials of disulfide centers relative to flavin for Nox-1. Although Nox-1 and AhpC from S. mutans were shown to play a protective role against oxidative stress in vitro and in vivo in Escherichia coli, the lack of a significant effect on deletion of these genes from S. mutans suggests the presence of additional antioxidant proteins in these bacteria.

Peroxidase activity of a TSA-like antioxidant protein from a pathogenic amoeba.

The 29 kDa surface protein of Entamoeba histolytica is an abundant antigenic protein expressed by pathogenic strains of this organism. The protein is a member of a widely-dispersed group of homologues which includes at least two cysteinyl peroxidases, Salmonella typhimurium alkyl hydroperoxidase C-22 protein (AhpC) and Saccharomyces cerevisiae thiol-specific antioxidant protein (TSA). Here, for the first time in a pathogenic eukaryote, we have demonstrated that the amoebic protein also possesses peroxidatic and antioxidant activities in the presence of reductants such as dithiothreitol or thioredoxin reductase plus thioredoxin. Although the S. typhimurium AhpF flavoprotein was not an effective reductant of the amoebic TSA protein, one inhibitory monoclonal antibody directed toward amoebic TSA was also partially inhibitory toward reduced but not oxidized bacterial AhpC. These antioxidant proteins are likely to be important not only in general cell protection, but also in the promotion of infection and invasion by these pathogenic organisms through protection against oxidative attack by activated host phagocytic cells.

Low doses vs. high doses of the angiotensin converting-enzyme inhibitor lisinopril in chronic heart failure: a cost-effectiveness analysis based on the Assessment of Treatment with Lisinopril and Survival (ATLAS) study. The ATLAS Study Group.

OBJECTIVE: A cost-effectiveness analysis of high and low doses of the angiotensin-converting enzyme (ACE) inhibitor lisinopril in the treatment of chronic heart failure. METHODS: A cost-effectiveness analysis using data from a randomized controlled trial, ATLAS, where 3164 patients with chronic heart failure were allocated to a high-dose (daily target dose 32.5-35 mg) or low-dose strategy (daily target dose 2.5-5.0 mg) of lisinopril. Differential costs were based on resource use data collected in the trial costed using UK unit costs. Cost-effectiveness analysis related differential costs to differential life-years during a 4-year trial follow-up. RESULTS: The mean total number of hospital in-patient days per patient was 18. 5 in the high dose group and 22.5 in the low dose group. Over the whole duration of the trial, the mean (S.D.) daily dose of lisinopril in the high-dose group was 22.5 mg (15.7 mg) compared to 3.2 mg (2.5 mg) in the low-dose group. The mean difference in cost per patient was pound sterling 397 lower in the high-dose group [95% CI (high-dose-low-dose) - pound sterling 1263 to pound sterling 436]. Mean life-years per patient were 0.085 years higher in the high-dose group [95% CI (high-dose-low-dose) -0.0074 to 0.1706). Based on mean costs and life-years, high-dose therapy dominates low-dose (less costly and more effective). Allowing for uncertainty in mean costs and life-years, the probability of high-dose therapy being less costly than low dose was 82%. If a decision maker is willing to pay at least pound sterling 3600 per life-year gained, the probability of high-dose being more cost-effective was 92%. CONCLUSIONS: The ATLAS Study showed that the treatment of heart failure with high-doses of lisinopril has a high probability of being more cost-effective than low-dose therapy.

Underutilization of autologous blood donation among eligible elective surgical patients.

In January 1983, blood banks encouraged the use of autologous blood for transfusion in elective surgical patients due to the advent of transfusion-associated AIDS. Since autologous blood does not transmit hepatitis and other viruses and does not cause alloimmunization, it should be utilized whenever possible. To determine whether patients eligible to predeposit autologous blood before elective operation were actually doing so, we studied patients at three hospitals between January 1 and June 30, 1985. Patients considered eligible for autologous predeposit blood donation were adults with preoperative hemoglobin levels of 11 g/dl or more who underwent elective surgical procedures for which blood transfusion was anticipated. Excluded were patients undergoing cardiovascular, intracranial, or renal transplant procedures. Of eligible patients, only 11 percent (32 of 278) predeposited blood; of these, 81 percent (26 of 32) were transfused with only autologous blood. Among eligible patients who did not predeposit blood, all could have benefited from predepositing because transfusion was likely for the procedure. Of those who did not predeposit, 33 percent (83 of 246) received homologous blood and therefore would have benefited from autologous donation. We conclude that autologous donations are underutilized for medically eligible patients undergoing elective operation.

Variable tissue reactions and endocrine responses to a jugular catheter.

Although the use of soft catheter materials allows for safe long-term venous access in humans and animals, a significant percentage of individuals react adversely. We have studied a group of 52 male rats over 30 days (d) for the category and degree of tissue responses to silicone-based catheters implanted in the jugular vein. Included in this evaluation was blood withdrawal at multiple intervals for assay of plasma hormones corticosterone (CORT) and prolactin (PRL) as they were correlated with the immune phenomena associated with early (5-7d) obstruction of the catheter tip. The intravascular portion of all catheters were covered with a transparent sheath which was composed of endothelial cells, smooth muscle cells, fibroblasts and numerous collagen fibers. Early blockage of catheters was the result of large white masses (wm) enclosing the tip which were continuous with the sheath. The wm consisted of: a) an inner zone nearest the catheter in some regions predominantly composed of numerous platelets and in others granulocytes and platelets; b) a middle zone containing numerous neutrophils; c) an outer zone containing a few inflammatory cells and many spaces filled with red blood cells. Rats that developed a wm blockage 7-10d after catheter placement had higher plasma CORT levels (3-5d post implant) when compared to those of animals with catheters remaining open 3-4 weeks. When viewed together, these observations describe a subset of a larger population of rats that have a local intravascular inflammatory reaction to silicone-based catheters. This preparation may be a useful model for investigating reported differences in human reactivity to silicone-based prostheses.

PEPP: collaborating to improve quality.

By collecting and analyzing information about Medicare payment errors, PEPP initiatives are making a contribution to healthcare quality efforts nationwide. Here's how one organization takes a collaborative approach to improving quality.