The Emmaus Project: Aging, Illness, and Dying Among Older Christians-A Qualitative Study.

Older patients have an increased risk of depression, neglect, and abuse. Studies demonstrate that spiritual and religious coping is important at times of personal crisis, but few studies explore the impact of religion on older persons' experiences of aging, illness, and impending death. This study set out to identify recurring spiritual and clinical themes shared by retirement home residents in the context of a Christian faith-based processing group. A qualitative cohort study of residents over the age of 65 was conducted at a retirement home in Chicago, Illinois. The study consisted of 8 hour-long Scripture-based processing group sessions co-led by a study researcher and the onsite chaplain. Questionnaires were administered to each group and handwritten responses were collected and analyzed to identify recurring clinical and spiritual themes. Ten participants enrolled in the group study. The questionnaire completion rate was 35% (49/140). The most recurring clinical themes included 1) events of death or terminal illness and 2) physical limitations. The most recurring spiritual themes included 1) God's presence and 2) prayer and worship. The most recurring coded theme overall was family. This study provided insight into the spiritual experiences of older Christians in one retirement home community. Increased awareness of the spiritual perspectives of the geriatric population may strengthen the doctor-patient relationship and lead to improvements in clinical care.

Breast Cancer Treatment Delays at an Urban Safety Net Hospital Among Women Experiencing Homelessness.

Disparities in outcomes for vulnerable women is an ongoing problem. Homelessness and breast cancer treatment outcomes is understudied. This is a descriptive study exploring types of homelessness and treatment delays at an urban safety net hospital providing care to a vulnerable patient population.This study is a retrospective chart review of homeless female patients diagnosed with breast cancer between January 1, 2000 and December 31, 2014. Data for this study were acquired from the hospital cancer registry and electronic medical record. All demographic characteristics, time to treatment and factors related to delays to treatment were analyzed descriptively, reporting frequencies and proportions. The total number of individuals analyzed was 24. All except two subjects were delayed to treatment (≥ 30 days from diagnosis to treatment). Most women in this cohort were categorized as chronically homeless (46%) with the rest categorized as transitionally (29%) or episodically (12%) homeless. The majority of subjects (70%) were Black, non-Hispanic. All except one subject were publicly insured (71% Medicaid; 12% Medicare) or uninsured (8%). Regardless of type of homelessness, most subjects were either 30-60 or 60-90 days delayed. Those who were chronically homeless experienced significantly more delays to first treatment (56% of those who were delayed 30-60 days and 57% of those who were delayed 60-90 days; p value 0.006) than those who were episodically or transitionally homeless. Significant delays and barriers to breast cancer treatment exist among women experiencing homelessness. Further studies to improve breast cancer care for homeless women are warranted.

Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients With Crohn's Disease.

BACKGROUND & AIMS: Individuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's disease (CD). We tested for associations between mutations in genes encoding reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, neutrophil function, and phenotypes of CD in pediatric patients. METHODS: We performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production. RESULTS: We identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P = .0008) and stricturing complications (P = .002) than children with CD without these mutations. Among patients with CD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P = .0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P = .002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P = .009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and antimicrobial responses. CONCLUSIONS: We identified missense mutations in genes that encode NADPH oxidases in children with CD; these were associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients.

Cyclin-Dependent Kinase 4/6 Inhibitor (Palbociclib) Induced Aplastic Anemia in a Patient with Metastatic Breast Cancer.

Breast cancer is the most common cancer diagnosed in women worldwide. Over the years, breast cancer treatment has undergone revolutionary changes especially for women with hormone receptor positive metastatic disease. As a result, women are living longer with their disease, particularly in developed countries. The use of cyclin-dependent kinase (CDK) 4/6 inhibitors with antiestrogen therapy is a relatively new therapeutic option which has been shown to improve progression-free survival. Hematologic adverse events, most frequently neutropenia, are well-known side effects of CDK 4/6 inhibitors. However, to our knowledge, aplastic anemia has never been reported. We report a case of aplastic anemia in a patient with metastatic breast cancer treated with palbociclib after multiple prior lines of therapy.

Assessing the impact of nurse post-discharge telephone calls on 30-day hospital readmission rates.

BACKGROUND: Several care transition interventions propose that post-discharge phone calls can reduce adverse events and decrease costly return visits to the hospital. However, given the multi-faceted nature of most care transitions interventions, the true relationship between post-discharge phone calls and readmissions in a real world setting is uncertain. OBJECTIVE: To determine the effect of receiving a post-discharge telephone call on all-cause 30-day readmission in a general medicine population. DESIGN: Retrospective observational study. PARTICIPANTS: Patients discharged home from the Medicine Service at a tertiary care academic medical center between November 2010 and May 2012. INTERVENTION: Patients received two telephone call attempts by a nurse within 72 h of discharge. Nurses followed a standard script to address issues associated with readmission. MAIN OUTCOME AND MEASURES: Billing data captured readmissions. We used logistic regression-adjusted patient and clinical covariates as well as a propensity score representing likelihood of being called to determine the association between call receipt and risk for readmission. KEY RESULTS: There were 5,507 eligible patients. In unadjusted analyses, patients who received a call and completed the intervention were significantly less likely to be readmitted compared to those who did not [155 (5.8 %) vs 123 (8.6 %), p < 0.01]. In multivariable models adjusting for socio-demographic and clinical covariates alone, completing a post-discharge telephone call intervention was associated with lower odds for readmission (AOR 0.71; 95 % CI: 0.55-0.91). However, when models adjusted for the likelihood of receiving the phone call using the propensity score, no association between call receipt and readmission was observed (AOR 0.91; 95%CI: 0.69-1.20). CONCLUSIONS: Effectiveness of post-discharge phone call programs may be more related to whether patients are able to answer a phone call than to the care delivered by the phone call. Programs would benefit from improving their ability to perform phone outreach while simultaneously improving on the care delivered during the calls.

An unusual cause of pneumonia: seen but not heard.

A 75-year-old man presented with a non-resolving pneumonia, malaise and weight loss. His medical history included a squamous cell carcinoma of the larynx and a non-small cell carcinoma of the lung. Chest CT showed right lower lobe collapse and consolidation. Bronchoscopy identified a foreign body in the right main bronchus and was subsequently removed with rigid bronchoscope. The removed foreign body was identified as a Blom-Singer speaking valve which had been aspirated 3 months previously. This is a rare complication of a speaking valve aspiration. This case illustrates the potential differential diagnoses of retained foreign bodies in the lung and that the symptoms can mimic neoplastic disease. Once removed, patients can have a dramatic improvement in quality of life and it is important to remember that a speaking valve may be aspirated, even if one present on the initial examination!

Validation of the Caregiver Guilt Questionnaire (CGQ) in a sample of British dementia caregivers.

BACKGROUND: Depression is well documented as a key outcome variable for dementia caregivers; however, guilt has been under-researched, which may be in part due to the lack of an appropriate measure. The Caregiver Guilt Questionnaire (CGQ) was originally developed and piloted with a Spanish population but has not yet been tested in an English-speaking population. METHODS: A cross-sectional postal survey was undertaken with a sample of 221 dementia caregivers in the UK, as part of a larger study of dementia caregiver outcome measures. RESULTS: The five-factor structure identified for the CGQ in the Spanish sample was replicated in this study. The five factors, "guilt about doing wrong by the care recipient," "guilt about failing to meet the challenges of caregiving," 'guilt over experience of negative emotions in relation to caregiving," "guilt about self-care," and "guilt about neglecting other relatives" accounted for 60% of the variance. Internal consistencies for the whole scale and factors were acceptable, and convergent validity was established with the Zarit Burden Interview guilt factor. A higher score on the CGQ was associated with a higher score on the Center for Epidemiological Studies Depression scale (CES-D) and a new cut-off score of 22 was established, which predicted a clinical score on the CES-D with 80.0% sensitivity and 61.5% specificity. CONCLUSIONS: The replication of the five-factor structure suggests that these are relevant themes within the feelings of guilt to both Hispanic and British dementia caregivers. The CGQ has been demonstrated to be a valid measure for use with British dementia caregivers and is likely to be of use in clinical and research settings.

WITHDRAWN: Interventions for preventing ankle ligament injuries.

BACKGROUND: Some sports, for example basketball and soccer, have a very high incidence of ankle injuries, mainly sprains. Consequently, ankle sprains are one of the most commonly treated injuries in acute care. OBJECTIVES: To assess the effects of interventions used for the prevention of ankle ligament injuries or sprains in physically active individuals from adolescence to middle age. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauam Group's specialised register, MEDLINE, PubMed, EMBASE, CINAHL, the National Research Register and bibliographies of study reports. We also contacted colleagues and some trialists. The most recent search was conducted in July 2000. SELECTION CRITERIA: Randomised or quasi-randomised trials of interventions for the prevention of ankle sprains in physically active individuals from adolescence to middle age were included provided that ankle sprains were recorded. Interventions included use of modified footwear, external ankle supports, co-ordination training and health education. These could be applied as a supplement to treatment provided that prevention of re-injury was the primary objective. DATA COLLECTION AND ANALYSIS: At least two reviewers independently assessed methodological quality and extracted data. Wherever possible, results of outcome measures were pooled and sub-grouped by history of previous sprain. Relative risks (RR) and 95% confidence intervals (95% CI) are reported for individual and pooled data. MAIN RESULTS: In this review update, a further nine new trials were included. Overall, 14 randomised trials with data for 8279 participants were included. Twelve trials involved active, predominantly young, adults participating in organised, generally high-risk, activities. The other two trials involved injured patients who had been active in sports before their injury. The prophylactic interventions under test included the application of an external ankle support in the form of a semi-rigid orthosis (three trials), air-cast brace (one trial) or high top shoes (one trial); ankle disk training; taping; muscle stretching; boot inserts; health education programme and controlled rehabilitation.The main finding was a significant reduction in the number of ankle sprains in people allocated external ankle support (RR 0.53, 95% CI 0.40 to 0.69). This reduction was greater for those with a previous history of ankle sprain, but still possible for those without prior sprain. There was no apparent difference in the severity of ankle sprains or any change to the incidence of other leg injuries. The protective effect of 'high-top' shoes remains to be established.There was limited evidence for reduction in ankle sprain for those with previous ankle sprains who did ankle disk training exercises. Various problems with data reporting limited the interpretation of the results for many of the other interventions. AUTHORS' CONCLUSIONS: This review provides good evidence for the beneficial effect of ankle supports in the form of semi-rigid orthoses or air-cast braces to prevent ankle sprains during high-risk sporting activities (e.g. soccer, basketball). Participants with a history of previous sprain can be advised that wearing such supports may reduce the risk of incurring a future sprain. However, any potential prophylactic effect should be balanced against the baseline risk of the activity, the supply and cost of the particular device, and for some, the possible or perceived loss of performance.Further research is indicated principally to investigate other prophylactic interventions, their cost-effectiveness and general applicability.

Older peoples' attitudes to mental illness.

Despite the prevalence of mental health problems in later life, older people markedly underutilize mental health services. A greater awareness of factors influencing older peoples' attitudes to mental illness may therefore improve awareness and treatment of mental disorders in this population. A mixed methodology approach was used to explore and compare older peoples' attitudes to mental illness in a sample of clinical and non-clinical participants. Results indicated that, similar to younger people, older people endorsed a range of positive and negative attitudes to mental illness. However, when attitudes to mental illness were considered within the context of ageing and experience a more complex pattern of results emerged. Although negative attitudes to mental illness were associated with negative attitudes to ageing across the entire sample, clinical participants (and those with prior experience of mental illness) reported more positive attitudes to mental illness and more negative attitudes to ageing than non-clinical participants, for whom the reverse was true. Attitudes were also differentially related to health behaviour outcomes. Results suggest that attitudes to mental illness and ageing may be linked and mediated by personal experience and capacity for psychological self-regulation in the face of age-associated adversity.

Monitoring changes in membrane phosphatidylinositol 4,5-bisphosphate in living cells using a domain from the transcription factor tubby.

Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) is a key component in signal transduction, being a precursor to other signalling molecules and itself associated with roles in signal transduction and cell biology. Tubby is a membrane bound transcription factor whose dysfunction results in obesity in mice. It contains a domain that selectively binds PtdIns(4,5)P(2). We have investigated the use of a fluorescently tagged version of this domain to monitor changes in PtdIns(4,5)P(2) concentration in living cells and compared it to the pleckstrin homology domain of PLCdelta1. Our results show that selected mutants of this domain report receptor-mediated changes in cellular PtdIns(4,5)P(2). In contrast to the pleckstrin homology domain of PLCdelta1 it does not have a significant affinity for inositol 1,4,5-trisphosphate (IP(3)). Using a selected mutant, we examine the regulation of ATP-sensitive K(+) channels via a G(q/11)-coupled receptor. These experiments reveal a correlation between reporter translocation and the onset of current inhibition whilst the recovery of current after agonist removal is delayed when compared to the reporter. Furthermore our studies reveal the importance of Ca(2+) in determining the overall activity of phospholipase C in living cells. This probe may be valuable in examining changes in PtdIns(4,5)P(2) distinct from those of IP(3) in intact cells in a variety of physiological settings.

Issues in conducting cross-cultural research: implementation of an agreed international protocol [corrected] designed by the WHOQOL Group for the conduct of focus groups eliciting the quality of life of older adults.

Multi-centre and cross-cultural research require the use of common protocols if the results are to be either pooled or compared. All too often adherence to protocols is not discussed in reports and where it is reported poor adherence is frequently noted. This paper discusses the use of international guidelines developed by WHOQOL Field Centres to conduct and report focus groups aimed at eliciting key concepts of quality of life among older adults. This was the first step in the development of the WHOQOL-OLD instrument. Although there was overall adherence to the agreed guidelines, there were some differences in the level of reporting, even after participating Field Centres had the opportunity to explain their reports. The reasons for these discrepancies are reported. It is concluded that because of local situations, it is difficult to achieve identical implementation of multi-centre cross-cultural protocols and that the highest standards of auditing are required if findings are to be compared. Suggestions for how such protocols can be improved are given.

Development of the WHOQOL-old module.

This paper describes the development of an add-on module for the WHOQOL measures of quality of life (QoL) for use with older adults. The add-on module, known as the WHOQOL-OLD, was derived following standard WHOQOL methodology. In the pilot phase of the study, 22 centres from around the world carried out focus groups with older adults, with carers, and with professionals working with older adults in order to identify gaps in the coverage of the WHOQOL-100 that were relevant for QoL in older adults. Items generated from the focus groups were then tested in over 7400 respondents from the centres, with items being tested and reduced using both classical and modern psychometric methods. These analyses indicated a further gap in the coverage of the items, so further items were generated that specifically assessed intimate relations in older adults. A field trial study was then carried out in a further approximately 5500 respondents, again with the use of both classical and modern psychometric methods. The outcome of this second round of data collection and analysis is a 24-item 6-facet module which can be used in conjunction with the WHOQOL-BREF or the WHOQOL-100 for assessment of QoL in older adults.

Cross-linguistic equivalence of WHOQOL-100: a study from North India.

The study examined the equivalence between Hindi and English versions of the World Health Organization Quality of Life Assessment (WHOQOL)-100 in North India. Eighty two bilingual subjects were administered the two language versions of WHOQOL-100 in a cross-over design after an interval of 1 week. More than half of item-facet correlations and one-third of Cronbach alpha values for facets were above 0.7 in both language versions. One third of facets and domain scores were significantly different in the two language versions, though these scores had high intraclass correlation coefficients (r > 0.7). Men and women had significantly different scores on < or = 25% and ill and well subjects on > or = 50% of facets and domains in both language versions and the pattern of significant differences in scores was similar in the two language versions. Confirmatory factor analysis suggested a reasonable fit for a four-factor structure (CFI = 0.82) in and across both language versions. Results suggest that Hindi and English versions of WHOQOL-100 have some equivalence but conceptual and scalar concerns remain regarding the application of a language version (of a simultaneously developed test) to subjects from another culture, even if they are proficient in the language of administration.

Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1).

OBJECTIVE: In the hereditary long QT syndromes the commonest defect is in the K+ channel pore forming subunit, KCNQ1. In this study we investigated the role that abnormal KCNQ1 trafficking has in the pathogenesis of the hereditary long QT syndrome (LQT1). METHODS: We introduced nine missense and nonsense mutations occurring in LQT1 into the cDNA encoding KCNQ1 fused in frame to the green fluorescent protein. These mutations occur in syndromes that are inherited in both autosomal dominant and recessive fashions. We used biochemistry, electrophysiology and cell imaging to examine the behaviour of wildtype and mutant channel subunits expressed together with the auxiliary subunit KCNE1 expressed in CHO-K1 and C2C12 cells. RESULTS: We found that a number of mutations in KCNQ1 are retained in the endoplasmic reticulum and unable to translocate to the plasma membrane. Furthermore, some mutations act in a dominant negative fashion and have the ability to suppress the trafficking of wildtype channel. We use fluorescence resonance energy transfer microscopy to show that this occurs because of direct interaction between the mutant subunit and wildtype channel in the endoplasmic reticulum. Finally, a number of specific and nonspecific pharmacological tools are unable to promote the delivery of these mutants to the plasma membrane. CONCLUSIONS: Our data revealed that channel trafficking may contribute to the pathogenesis of LQT1.

Multisite phosphorylation mechanism for protein kinase A activation of the smooth muscle ATP-sensitive K+ channel.

The activation of ATP-sensitive K+ channels by protein kinase A in vascular smooth muscle is an important component of the action of vasodilators. In this study, we examine the molecular mechanisms of regulation of the cloned equivalent of this channel comprising the sulfonylurea receptor 2B and the inward rectifier 6.1 subunit (SUR2B/Kir6.1). Specifically, we focus on whether the channel is directly phosphorylated and the sites at which this occurs in the protein complex. We identify one site in Kir6.1 (S385) and two sites in SUR2B (T633 and S1465) using a combination of biochemical and functional assays. Our work supports a model in which multiple sites in the channel complex have to be phosphorylated before activation occurs.

Do anionic phospholipids serve as cofactors or second messengers for the regulation of activity of cloned ATP-sensitive K+ channels?

The regulation of ion channels by anionic phospholipids is currently very topical. An outstanding issue is whether phosphatidylinositol 4,5-diphosphate and related species act as true second messengers in signaling or behave in a manner analogous to an enzymatic cofactor. This question is especially pertinent regarding ATP-sensitive K+ channels in smooth muscle, for which there is substantial literature supporting inhibitory regulation by hormones. In this study, we have examined regulation of the potential cloned equivalents of the smooth muscle ATP-sensitive K+ channel (SUR2B/Kir6.1 and SUR2B/Kir6.2). We find that both can be inhibited via the Gq/11-coupled muscarinic M3 receptor but that the pathways by which this occurs are different. Our data show that SUR2B/Kir6.1 is inhibited by protein kinase C and binds anionic phospholipids with high affinity, such that potential physiological fluctuations in their levels do not influence channel activity. In contrast, Kir6.2 is not regulated by protein kinase C but binds anionic phospholipids with low affinity. In this case, phosphatidylinositol 4,5-diphosphate and related species have the potential to act as second messengers in signaling. Thus, Kir6.1 and Kir6.2 are regulated by distinct inhibitory mechanisms.

Glutathione regulates the expression of gamma-glutamylcysteine synthetase via the Met4 transcription factor.

Our previous studies have shown that glutathione is an essential metabolite in the yeast Saccharomyces cerevisiae because a mutant deleted for GSH1, encoding the first enzyme in gamma-l-glutamyl-l-cysteinylglycine (GSH) biosynthesis, cannot grow in its absence. In contrast, strains deleted for GSH2, encoding the second step in GSH synthesis, grow poorly as the dipeptide intermediate, gamma-glutamylcysteine, can partially substitute for GSH. In this present study, we identify two high copy suppressors that rescue the poor growth of the gsh2 mutant in the absence of GSH. The first contains GSH1, indicating that gamma-glutamylcysteine can functionally replace GSH if it is present in sufficiently high quantities. The second contains CDC34, encoding a ubiquitin conjugating enzyme, indicating a link between the ubiquitin and GSH stress protective systems. We show that CDC34 rescues the growth of the gsh2 mutant by inducing the Met4-dependent expression of GSH1 and elevating the cellular levels of gamma-glutamylcysteine. Furthermore, this mechanism normally operates to regulate GSH biosynthesis in the cell, as GSH1 promoter activity is induced in a Met4-dependent manner in a gsh1 mutant which is devoid of GSH, and the addition of exogenous GSH represses GSH1 expression. Analysis of a cis2 mutant, which cannot breakdown GSH, confirmed that GSH and not a metabolic product, serves as the regulatory molecule. However, this is not a general mechanism affecting all Met4-regulated genes, as MET16 expression is unaffected in a gsh1 mutant, and GSH acts as a poor repressor of MET16 expression compared with methionine. In summary, GSH biosynthesis is regulated in parallel with sulphate assimilation by activity of the Met4 protein, but GSH1-specific mechanisms exist that respond to GSH availability.

The cytoplasmic C-terminus of the sulfonylurea receptor is important for KATP channel function but is not key for complex assembly or trafficking.

ATP-sensitive K+ channels are an octameric assembly of two proteins, a sulfonylurea receptor (SUR1) and an ion conducting subunit (Kir 6.0). We have examined the role of the C-terminus of SUR1 by expressing a series of truncation mutants together with Kir6.2 stably in HEK293 cells. Biochemical analyses using coimmunoprecipitation indicate that SUR1 deletion mutants and Kir6.2 assemble and that a SUR1 deletion mutant binds glibenclamide with high affinity. Electrophysiological recordings indicate that ATP sensitivity is normal but the response of the mutant channel complexes to tolbutamide, MgADP and diazoxide is disturbed. Quantitative immunofluorescence and cell surface biotinylation supports the idea that there is little disturbance in the efficiency of trafficking. Our data show that deletions of the C-terminal most cytoplasmic domain of SUR1, can result in functional channels at the plasma membrane in mammalian cells that have an abnormal response to physiological and pharmacological agents.