Finding new bearings: a qualitative study on the transition from inpatient to ambulatory care of patients with acute myeloid leukemia

Purpose

Treatment of adult acute myeloid leukemia (AML) is intensive, with induction treatment initiated in an inpatient setting and subsequent consolidation therapy often conducted in an outpatient setting. The purpose of the present qualitative paper is to provide insight into the experience of patients in the transition from inpatient to ambulatory care.

Methods

Participants were 35 AML patients who were interviewed about their experience of the illness and treatment. Utilizing the grounded theory method, we describe the adjustment of participants to the transition to ambulatory care.

Results

As outpatients, participants described adjusting to the intensity of ambulatory treatment and to the need to assume greater responsibility for their care. They also expressed a growing desire to understand their long-term care plan, compared to their preference to focus on the present prior to discharge, and they were struggling to construct a new sense of identity.

Conclusions

AML patients are now leaving acute care settings sicker and earlier. Considering their perceptions can inform interventions to facilitate adjustment during the transition to outpatient care.     

A meta-analysis of the prognostic significance of cardiopulmonary exercise testing in patients with heart failure

The objective of the study is to assess the role of cardiopulmonary exercise testing (CPX) variables, including peak oxygen consumption (VO₂), which is the most recognized CPX variable, the minute ventilation/carbon dioxide production (VE/VCO₂) slope, the oxygen uptake efficiency slope (OUES), and exercise oscillatory ventilation (EOV) in a current meta-analysis investigating the prognostic value of a broader list of CPX-derived variables for major adverse cardiovascular events in patients with HF. A search for relevant CPX articles was performed using standard meta-analysis methods. Of the initial 890 articles found, 30 met our inclusion criteria and were included in the final analysis. The total subject populations included were as follows: peak VO₂ (7,319), VE/VCO₂ slope (5,044), EOV (1,617), and OUES (584). Peak VO₂, the VE/VCO₂ slope and EOV were all highly significant prognostic markers (diagnostic odds ratios ≥ 4.10). The OUES also demonstrated promise as a prognostic marker (diagnostic odds ratio = 8.08) but only in a limited number of studies (n = 2). No other independent variables (including age, ejection fraction, and beta-blockade) had a significant effect on the meta-analysis results for peak VO₂ and the VE/VCO₂ slope. CPX is an important component in the prognostic assessment of patients with HF. The results of this meta-analysis strongly confirm this and support a multivariate approach to the application of CPX in this patient population.     

Therapeutic Response in Feline Sandhoff Disease Despite Immunity to Intracranial Gene Therapy

Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of β-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 ± 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase α- and β-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 ± 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.     

Structures of ABCB10, a human ATP-binding cassette transporter in apo- and nucleotide-bound states

ABCB10 is one of the three ATP-binding cassette (ABC) transporters found in the inner membrane of mitochondria. In mammals ABCB10 is essential for erythropoiesis, and for protection of mitochondria against oxidative stress. ABCB10 is therefore a potential therapeutic target for diseases in which increased mitochondrial reactive oxygen species production and oxidative stress play a major role. The crystal structure of apo-ABCB10 shows a classic exporter fold ABC transporter structure, in an open-inwards conformation, ready to bind the substrate or nucleotide from the inner mitochondrial matrix or membrane. Unexpectedly, however, ABCB10 adopts an open-inwards conformation when complexed with nonhydrolysable ATP analogs, in contrast to other transporter structures which adopt an open-outwards conformation in complex with ATP. The three complexes of ABCB10/ATP analogs reported here showed varying degrees of opening of the transport substrate binding site, indicating that in this conformation there is some flexibility between the two halves of the protein. These structures suggest that the observed plasticity, together with a portal between two helices in the transmembrane region of ABCB10, assist transport substrate entry into the substrate binding cavity. These structures indicate that ABC transporters may exist in an open-inwards conformation when nucleotide is bound. We discuss ways in which this observation can be aligned with the current views on mechanisms of ABC transporters.     

Flat colorectal neoplasms and the impact of the revised Vienna Classification on their reporting: A case-control study in UK and Japanese patients

Objective. The prevalence and interpretation of flat colorectal neoplasms in the East or West remain highly variable. Several factors may contribute to this variability including differences in reporting techniques between Japanese and Western histopathologists when lesions are classified. The aims of this study were (i) to determine the frequency and characteristics of flat colorectal neoplasms in British and Japanese patients, (ii) to examine whether histopathological discrepancies exist between Western and Japanese-trained pathologists applying conventional classification methods and (iii) to determine the impact of the revised Vienna Classification on any differences observed. Material and methods. One hundred and forty-four patients in the United Kingdom with neoplastic lesions prospectively identified by a colonoscopist, fully-trained in Japan, were age and gender-matched with 144 Japanese patients with neoplastic lesions detected by the same colonoscopist. Two British and two Japanese pathologists were independently asked to assess all neoplasms using both conventional and revised Vienna Classification methods. Results. No significant difference in the frequency of flat neoplasms was found between British and Japanese patients; however, flat neoplasia from Japanese patients tended to contain more advanced pathologies. Discrepancies in histological diagnoses were observed between pathologists but which were reduced with the revised Vienna Classification. Japanese pathologists tended to diagnose higher grades of dysplasia for the same lesion compared to their British counterparts. Conclusions. The frequency of flat neoplasms in British and Japanese patients is similar. However Japanese lesions, especially flat (IIb) and slightly depressed (IIc) neoplasms tend to be more biologically aggressive. The revised Vienna Classification achieves greater consensus.     

Alcohol use variability in a community-based sample of nonstudent emerging adult heavy drinkers

Background: While nonstudent emerging adults are at elevated risk for experiencing alcohol-related problems, there remains a paucity of research devoted specifically to addressing drinking in this group. Objectives: The present study sought to offer unique insights into nonstudent drinking by examining drinking variability across 30 days using a retrospective diary method. Specific aims were to: (1) compare within- and between-person variability in alcohol use across 30 days, and (2) determine the extent to which central social-cognitive between-person factors (i.e., social expectancies, perceived drinking norms, social drinking motivations) predict between-person alcohol use as well as within-person variability in drinking. Methods: Participants were 195 (65.1% men) nonstudent emerging adults recruited from the community with a mean age of 21.9 (SD = 2.1) years. Results: Findings showed that a substantial portion of variation in daily alcohol consumption was attributable to the within-person (83%) rather than between-person (17.2%) level. Social expectancies, perceived drinking norms, and social motives were found to influence variability in daily alcohol consumption. Conclusion: Our findings contribute to knowledge that could guide efforts to design and tailor intervention strategies to minimize the harms experienced by an understudied and at-risk population of drinkers.     

Autophagy and leucine promote chronological longevity and respiration proficiency during calorie restriction in yeast

We have previously shown that autophagy is required for chronological longevity in the budding yeast Saccharomyces cerevisiae. Here we examine the requirements for autophagy during extension of chronological life span (CLS) by calorie restriction (CR). We find that autophagy is upregulated by two CR interventions that extend CLS: water wash CR and low glucose CR. Autophagy is required for full extension of CLS during water wash CR under all growth conditions tested. In contrast, autophagy was not uniformly required for full extension of CLS during low glucose CR, depending on the atg allele and strain genetic background. Leucine status influenced CLS during CR. Eliminating the leucine requirement in yeast strains or adding supplemental leucine to growth media extended CLS during CR. In addition, we observed that both water wash and low glucose CR promote mitochondrial respiration proficiency during aging of autophagy-deficient yeast. In general, the extension of CLS by water wash or low glucose CR was inversely related to respiration deficiency in autophagy-deficient cells. Also, autophagy is required for full extension of CLS under non-CR conditions in buffered media, suggesting that extension of CLS during CR is not solely due to reduced medium acidity. Thus, our findings show that autophagy is: (1) induced by CR, (2) required for full extension of CLS by CR in most cases (depending on atg allele, strain, and leucine availability) and, (3) promotes mitochondrial respiration proficiency during aging under CR conditions.     

Staphylococcus aureus LukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

Staphylococcus aureus causes diseases ranging from superficial wound infections to more invasive manifestations like osteomyelitis and endocarditis. The evasion of host phagocytes recruited to the site of infection is essential to the success of S. aureus as a pathogen. A single S. aureus strain can produce up to five different bicomponent pore-forming leukotoxins that lyse immune cells by forming pores in the cellular plasma membrane. Although these leukotoxins have been considered redundant due to their cytotoxic activity toward human neutrophils, each toxin displays varied species and cell-type specificities. This suggests that cellular factors may influence which cells each toxin targets. Here we describe the identification of CD11b, the α subunit of the αM/β2 integrin (CD11b/CD18), macrophage-1 antigen, or complement receptor 3, as a cellular receptor for leukocidin A/B (LukAB), an important toxin that contributes to S. aureus killing of human neutrophils. We demonstrate that CD11b renders human neutrophils susceptible to LukAB-mediated killing by purified LukAB as well as during S. aureus infection ex vivo. LukAB directly interacts with human CD11b by binding to the I domain, a property that determines the species specificity exhibited by this toxin. Identification of a LukAB cellular target has broad implications for the use of animal models to study the role of LukAB in S. aureus pathogenesis, explains the toxin’s tropism toward human neutrophils and other phagocytes, and provides a cellular therapeutic target to block the effect of LukAB toward human neutrophils.