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1.  Decreased Daytime Sleeping is Associated with Improved Cognition Following Hospital Discharge in Older Adults 
The longitudinal association between sleep and cognitive functioning is not well understood in late-life. Examination of the association between a potentially modifiable risk factor such as sleep, and cognitive change in at-risk older adults is of both theoretical and practical importance. We examined the relationship between changes in objectively-assessed sleep and global cognitive functioning from inpatient post-acute rehabilitation to 6-months follow-up.
Secondary analysis of two prospective, longitudinal studies.
Inpatient rehabilitation units at a VA Medical Center.
192 older patients (mean age=73.8±9.4 years) undergoing inpatient rehabilitation.
All participants completed 7 nights/days of ambulatory sleep monitoring via wrist actigraphy (yielding an estimate of nighttime wakefulness and daytime sleep) and the Mini-Mental State Examination (MMSE; global cognitive functioning) during a post-acute inpatient rehabilitation stay and 6-months following discharge. The 5-item Geriatric Depression Scale (GDS5), Geriatric Pain Measure (GPM), and Cumulative Illness Rating Scale for Geriatrics were completed during inpatient rehabilitation.
Growth curve modeling (controlling for baseline age, education, gender, BMI, depression, pain, and comorbidity burden) revealed that individuals whose amount of daytime sleep decreased from inpatient post-acute rehabilitation to 6-month follow-up also experienced improvements in MMSE (β = −0.01, t(80) = β3.22, p<0.01). Change in nighttime wakefulness was not a significant predictor of change in MMSE.
Older adults whose daytime sleeping decreased following hospital discharge also experienced improvements in cognitive functioning at 6-months follow-up. As such, daytime sleep may represent a promising candidate for targeted interventions aimed at promoting cognitive recovery following hospital discharge.
PMCID: PMC4123221  PMID: 25093233
Sleep; Cognition; Longitudinal Change; Inpatient Hospitalization; Older Adults
2.  Patterns of sleep quality during and after postacute rehabilitation in older adults: a latent class analysis approach 
Journal of sleep research  2013;22(6):640-647.
Sleep quality is related to emotional, physical, psychological and cognitive functioning and functional independence in later life. After acute health events, older adults are likely to utilize postacute rehabilitation services to improve functioning and facilitate return to independent living. Patterns of how sleep changes with postacute rehabilitation, and predictors of such patterns, are unknown. The current investigation employed latent class analysis (LCA) methods to classify older adults (n = 233) into groups based on patterns of self-reported sleep quality pre-illness, during postacute rehabilitation and up to 1 year following postacute rehabilitation. Using LCA, older adults were grouped into (1) consistently good sleepers (46%), (2) good sleepers who transitioned into poor sleepers (34%), (3) consistently poor sleepers (14%) and (4) poor sleepers who transitioned into good sleepers (6%). In three planned analyses, pain was an independent predictor of membership in classes 1 or 2 (good pre-illness sleep quality) versus classes 3 or 4 (poor pre-illness sleep quality), and of membership in class 1 (consistently good sleep) versus class 2 (good sleep that transitioned to poor sleep). A lower Mini-Mental State Examination score was a predictor of membership in class 1 versus class 2. There were no statistically significant predictors of membership in class 3 versus class 4. Demographics, comorbidities and depressive symptoms were not significant predictors of class membership. These findings have implications for identification of older adults at risk for developing poor sleep associated with changes in health and postacute rehabilitation. The findings also suggest that pain symptoms should be targeted to improve sleep during postacute rehabilitation.
PMCID: PMC4060888  PMID: 23834036
ageing; latent class analysis; rehabilitation; sleep
3.  Ten Simple Rules to Achieve Conference Speaker Gender Balance 
PLoS Computational Biology  2014;10(11):e1003903.
PMCID: PMC4238945  PMID: 25411977
4.  Diurnal Cortisol and Functional Outcomes in Post-Acute Rehabilitation Patients 
Cortisol is a stress-related hormone with a robust circadian rhythm where levels typically peak in the morning hours and decline across the day. Although acute cortisol increases resulting from stressors are adaptive, chronic elevated cortisol levels are associated with poor functioning. Studies have shown age-related changes in cortisol levels. The present study investigated the relationship between salivary diurnal cortisol and functional outcomes among older adults undergoing inpatient post-acute rehabilitation.
Thirty-two older adults (mean age 78 years; 84% men) in a Veterans Administration inpatient post-acute rehabilitation unit were studied. Functional outcomes were assessed with the motor component of the Functional Independence Measure (mFIM; where mFIM change = discharge − admission score). Saliva samples were collected on 1 day at wake time, 45 minutes later, 11:30 AM, 2 PM, 4:30 PM, and bedtime. We analyzed the relationship between cortisol measures and functional outcomes, demographics, and health measures.
The analyses consistently showed that greater functional improvement (mFIM change) from admission to discharge was associated with lower comorbidity scores and higher cortisol levels at 2 PM, 4:30 PM, and bedtime. A morning cortisol rise was also associated with greater mFIM change.
Measurement of cortisol in saliva may be a useful biological marker for identification of patients who are “at risk” of lower benefits from inpatient rehabilitation services and who may require additional assistance or intervention during their post-acute care stay.
PMCID: PMC3348493  PMID: 22219521
Cortisol; Older adults; Rehabilitation; Inpatient; Functional Status
To explore the unique impact of poor sleep and symptoms of depression on sleep quality for up to one year after inpatient post-acute rehabilitation among older adults.
Prospective longitudinal cohort study.
Two in-patient post-acute rehabilitation facilities
245 individuals over age 65 years (mean age=80 years, 38% female)
Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) during the post-acute care stay twice to evaluate pre-illness sleep quality and sleep quality during the post-acute care stay, and again at 3, 6, 9 and 12-months follow-up. Demographics, symptoms of depression, cognitive functioning, and comorbidities were also assessed.
Across time points, sleep was significantly disturbed for many individuals. Nested regression models predicting PSQI total score at 3, 6, 9 and 12 months showed that variables entered in Block 1 (age, gender, cognitive functioning and comorbidities) were significant predictors of poor sleep at 6-months, but not at 3, 9 or 12 months follow-up. Depression (Block 2) and pre-illness PSQI total score (Block 3) were significant predictors of PSQI total score at all follow-up time points. PSQI total score during post-acute care (Block 4) explained a significant proportion of variance only at the 3-month follow-up.
This study confirms that chronic poor sleep is common among older adults during post-acute rehabilitation, and resolution of sleep disturbance after acute health events may be a lengthy process. Our findings expand understanding of the role of depressive symptoms and pre-existing sleep complaints in predicting poor sleep over time among these vulnerable older adults.
PMCID: PMC3377443  PMID: 22617164
rehabilitation; sleep; aging; depression
6.  Awake at 4 a.m.: Treatment of Insomnia With Early Morning Awakenings Among Older Adults 
Journal of Clinical Psychology  2010;66(11):1161-1174.
Insomnia is a common problem among older adults. In particular, older adults experience insomnia coupled with early morning awakenings due to an interaction between age-related changes in circadian rhythm timing coupled with behavior changes that contribute to sustained poor sleep. Cognitive–behavioral therapy for insomnia (CBT-I), at times coupled with circadian interventions (e.g., timed light exposure), are likely to be most successful in optimizing sleep quality. In delivering CBT-I to older adults, modifications are sometimes necessary to accommodate for medical problems, lifestyle, social factors, and patient preferences. Addition of circadian interventions can ameliorate the negative effects of inappropriately timed sleep as well. These treatment methods can be highly effective and benefits can be long-standing. A case example is used to illustrate these points.
PMCID: PMC3377480  PMID: 20845423
insomnia; circadian rhythms; advanced sleep phase syndrome; aging; cognitive–behavioral therapy; light therapy
7.  Sleep Quality in Residents of Assisted Living Facilities: Effect on Quality of Life, Functional Status, and Depression 
To describe sleep patterns in older adults living in assisted living facilities (ALFs) and to explore the relationship between sleep disturbance and quality of life, functional status, and depression over 6 months of follow-up.
Prospective, observational cohort study. SETTING: Eighteen ALFs in the Los Angeles area. PARTICIPANTS: One hundred twenty-one ALF residents aged 65 and older (mean age 85.3, 86% female, 88% non-Hispanic white).
Data were collected at baseline and 3 and 6 months after enrollment. Data collected were demographics, physical and cognitive functioning, depression, quality of life, comorbidities, medications, and subjective (i.e., questionnaires) and objective (i.e., 3 days and nights of wrist actigraphy) measures of sleep.
Sixty-five percent of participants reported clinically significant sleep disturbance on the Pittsburgh Sleep Quality Index, and objective wrist actigraphy confirmed poor sleep quality. In regression analyses including sleep variables and other predictors, more self-reported sleep disturbance at baseline was associated with worse health-related quality of life (Medical Outcomes Study 12-item Short Form Survey Mental Component Summary score) and worse depressive symptoms five-item Geriatric Depression Scale at follow-up. Worse nighttime sleep (according to actigraphy) at baseline was associated with worse activities of daily living functioning and more depressive symptoms at follow-up.
Sleep disturbance is common in older ALF residents, and poor sleep is associated with declining functional status and quality of life and greater depression over 6 months of follow-up. Studies are needed to determine whether improving sleep in ALF residents will result in improvements in these outcomes. Well-established treatments should be adapted for use in ALFs and systematically evaluated in future research.
PMCID: PMC3377484  PMID: 20722819
sleep; assisted living facilities; depression; quality of life; functional status
8.  Sleep in Assisted Living Facility Residents Versus Home-Dwelling Older Adults 
Sleep problems among assisted living facility (ALF) residents are not well understood, and sleep-related differences between ALF residents and home-dwelling older adults have not been examined.
We compared sleep patterns in 19 ALF residents to sleep patterns in 19 matched home-dwelling older people (age ≥65 years). All were participating in the follow-up portion of a longitudinal study of sleep and functional outcomes following post-acute rehabilitation. Sleep was assessed with the Pittsburgh Sleep Quality Index and 1 week of wrist actigraphy.
By actigraphy, ALF residents awoke earlier in the morning and exhibited more nighttime awakenings compared to home-dwelling participants (06:50 hours ± 1:29 hours vs 07:51 hours ± 1:19 hours and 19.5 ± 8.5 vs 12.9 ± 11.4 awakenings, respectively).
Larger studies are needed to confirm these initial findings that ALF residents have more disrupted sleep than do home-dwelling older persons, and to examine the functional and health consequences of poor sleep among ALF residents.
PMCID: PMC3184036  PMID: 19126856
Sleep; Aging; Circadian rhythms; Assisted living
Clinics in geriatric medicine  2008;24(1):39-vi.
Nighttime sleep disruption is characteristic of long-term care residents, is typically accompanied by daytime sleepiness and may be caused by a multitude of factors. Causal factors include medical and psychiatric illness, medications, circadian rhythm abnormalities, sleep disordered breathing and other primary sleep disorders, environmental factors and lifestyle habits. There is some suggestion that these factors are amenable to treatment; however, further research on the implementation of treatments within the long-term care setting is needed. Additional work is also needed to understand the administrative and policy factors that might lead to systemic changes in how sleep is viewed and sleep problems are addressed in long-term care settings.
A growing number of older adults reside in long-term care facilities. In this setting, residents commonly suffer from nighttime sleep disruption, which is often accompanied by daytime sleepiness and may be caused by a multitude of factors. Importantly, sleep disturbance is associated with negative health outcomes, including risk for falling, and elevated mortality risk among long-term care residents. A number of factors contribute to sleep disturbance in the long-term care setting including medical and psychiatric illness, medications, circadian rhythm abnormalities, sleep disordered breathing and other primary sleep disorders, environmental conditions (e.g., noise and light) and lifestyle habits. Based on research with older adults in the community and work conducted within long-term care settings, there is some suggestion that these factors are amenable to nonpharmacological treatments. Further research on the broad implementation of treatments for sleep problems within the long-term care setting is still needed. Additional work is also needed to understand the administrative and policy factors that might lead to systemic changes in how sleep is viewed and sleep problems are addressed in long-term care settings.
PMCID: PMC2215778  PMID: 18035230
long; term care; dementia; circadian rhythms; sleep disorders
11.  Reconciling the regulatory role of Munc18 proteins in SNARE-complex assembly 
IUCrJ  2014;1(Pt 6):505-513.
Mammalian Munc18 proteins are essential for membrane fusion and human health. Here, we review the literature describing structural and in vitro data, and identify a possible explanation for the conflicting functional roles that have been reported.
Membrane fusion is essential for human health, playing a vital role in processes as diverse as neurotransmission and blood glucose control. Two protein families are key: (1) the Sec1p/Munc18 (SM) and (2) the soluble N-ethylmaleimide-sensitive attachment protein receptor (SNARE) proteins. Whilst the essential nature of these proteins is irrefutable, their exact regulatory roles in membrane fusion remain controversial. In particular, whether SM proteins promote and/or inhibit the SNARE-complex formation required for membrane fusion is not resolved. Crystal structures of SM proteins alone and in complex with their cognate SNARE proteins have provided some insight, however, these structures lack the transmembrane spanning regions of the SNARE proteins and may not accurately reflect the native state. Here, we review the literature surrounding the regulatory role of mammalian Munc18 SM proteins required for exocytosis in eukaryotes. Our analysis suggests that the conflicting roles reported for these SM proteins may reflect differences in experimental design. SNARE proteins appear to require C-terminal immobilization or anchoring, for example through a transmembrane domain, to form a functional fusion complex in the presence of Munc18 proteins.
PMCID: PMC4224468  PMID: 25485130
SM proteins; SNARE proteins; syntaxin; Munc18; membrane trafficking
Sleep disruption is common in the long-term care setting. This paper discusses the available literature on two herbal approaches to sleep problems in long-term care. The largest body of evidence exists for the use of the dietary/herbal supplements valerian and melatonin. While these agents appear to have a modest positive effect on sleep quality among older adults, most studies were small in size and included only subjective assessments of sleep quality. In addition, it is unclear whether these agents pose risks to long-term care residents due to potential drug interactions. Additional research is needed prior to making conclusive recommendations about the use of these interventions for sleep in the long-term care setting.
PMCID: PMC1939981  PMID: 17498609
alternative therapies; elderly; insomnia; sleep
13.  Neuropsychiatric symptoms in Alzheimer’s disease: Past progress and anticipation of the future 
Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer’s first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer’s Association convened a Research Roundtable on the topic of NPS in AD. A major outcome of the Roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer’s Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome specific synthetic reviews and recommendations prepared by NPS-PIA Workgroups on depression, apathy, sleep, agitation, and psychosis.
PMCID: PMC3766403  PMID: 23562430
Neuropsychiatric symptoms; Behavioral and psychological symptoms of dementia; Agitation/aggression; Sleep disorders; Depression; Apathy; Psychosis; Delusions; Hallucinations; Dementia; Alzheimer’s disease; Mild cognitive impairment; Mild Behavioral Impairment
14.  Medical device design for adolescent adherence and developmental goals: a case study of a cystic fibrosis physiotherapy device 
This study investigates the psychosocial aspects of adolescent medical device use and the impact on adolescent adherence and goals for the transitional years between child and adulthood.
Patients and methods
Interviews were carried out with 20 adolescents with cystic fibrosis, investigating adolescent medical device use and experiences in relation to their personal and social lives and development through the adolescent years. The qualitative dataset was thematically examined using a content analysis method.
The results show that adolescent users of medical technologies want their independence and capabilities to be respected. Adolescent adherence to medical device use was associated with short- and long-term motivations, where older adolescents were able to comprehend the longer-term benefits of use against short-term inconvenience more acutely than younger adolescents. It was suggested that medical devices could provide a tool for communication with families and clinicians and could support adolescents as they take responsibility for managing their condition. Themes of “fitting into teenage life” and “use in the community” were associated with adolescents’ needs to form their own identity and have autonomy.
This study shows that adolescent needs regarding medical device use are complex. It provides evidence to suggest that devices designed inclusively for adolescents may lead to improved adherence and also facilitate transition through the adolescent years and achievement of adolescent goals.
PMCID: PMC3962322  PMID: 24669187
young people; teenagers; technologies; compliance; transition; user requirements
15.  Milligram Quantities of Homogeneous Recombinant Full-Length Mouse Munc18c from Escherichia coli Cultures 
PLoS ONE  2013;8(12):e83499.
Vesicle fusion is an indispensable cellular process required for eukaryotic cargo delivery. The Sec/Munc18 protein Munc18c is essential for insulin-regulated trafficking of glucose transporter4 (GLUT4) vesicles to the cell surface in muscle and adipose tissue. Previously, our biophysical and structural studies have used Munc18c expressed in SF9 insect cells. However to maximize efficiency, minimize cost and negate any possible effects of post-translational modifications of Munc18c, we investigated the use of Escherichia coli as an expression host for Munc18c. We were encouraged by previous reports describing Munc18c production in E. coli cultures for use in in vitro fusion assay, pulldown assays and immunoprecipitations. Our approach differs from the previously reported method in that it uses a codon-optimized gene, lower temperature expression and autoinduction media. Three N-terminal His-tagged constructs were engineered, two with a tobacco etch virus (TEV) or thrombin protease cleavage site to enable removal of the fusion tag. The optimized protocol generated 1–2 mg of purified Munc18c per L of culture at much reduced cost compared to Munc18c generated using insect cell culture. The purified recombinant Munc18c protein expressed in bacteria was monodisperse, monomeric, and functional. In summary, we developed methods that decrease the cost and time required to generate functional Munc18c compared with previous insect cell protocols, and which generates sufficient purified protein for structural and biophysical studies.
PMCID: PMC3877047  PMID: 24391775
16.  The α-Proteobacteria Wolbachia pipientis Protein Disulfide Machinery Has a Regulatory Mechanism Absent in γ-Proteobacteria 
PLoS ONE  2013;8(11):e81440.
The α-proteobacterium Wolbachia pipientis infects more than 65% of insect species worldwide and manipulates the host reproductive machinery to enable its own survival. It can live in mutualistic relationships with hosts that cause human disease, including mosquitoes that carry the Dengue virus. Like many other bacteria, Wolbachia contains disulfide bond forming (Dsb) proteins that introduce disulfide bonds into secreted effector proteins. The genome of the Wolbachia strain wMel encodes two DsbA-like proteins sharing just 21% sequence identity to each other, α-DsbA1 and α-DsbA2, and an integral membrane protein, α-DsbB. α-DsbA1 and α-DsbA2 both have a Cys-X-X-Cys active site that, by analogy with Escherichia coli DsbA, would need to be oxidized to the disulfide form to serve as a disulfide bond donor toward substrate proteins. Here we show that the integral membrane protein α-DsbB oxidizes α-DsbA1, but not α-DsbA2. The interaction between α-DsbA1 and α-DsbB is very specific, involving four essential cysteines located in the two periplasmic loops of α-DsbB. In the electron flow cascade, oxidation of α-DsbA1 by α-DsbB is initiated by an oxidizing quinone cofactor that interacts with the cysteine pair in the first periplasmic loop. Oxidizing power is transferred to the second cysteine pair, which directly interacts with α-DsbA1. This reaction is inhibited by a non-catalytic disulfide present in α-DsbA1, conserved in other α-proteobacterial DsbAs but not in γ-proteobacterial DsbAs. This is the first characterization of the integral membrane protein α-DsbB from Wolbachia and reveals that the non-catalytic cysteines of α-DsbA1 regulate the redox relay system in cooperation with α-DsbB.
PMCID: PMC3839904  PMID: 24282596
17.  Comparative Sequence, Structure and Redox Analyses of Klebsiella pneumoniae DsbA Show That Anti-Virulence Target DsbA Enzymes Fall into Distinct Classes 
PLoS ONE  2013;8(11):e80210.
Bacterial DsbA enzymes catalyze oxidative folding of virulence factors, and have been identified as targets for antivirulence drugs. However, DsbA enzymes characterized to date exhibit a wide spectrum of redox properties and divergent structural features compared to the prototypical DsbA enzyme of Escherichia coli DsbA (EcDsbA). Nonetheless, sequence analysis shows that DsbAs are more highly conserved than their known substrate virulence factors, highlighting the potential to inhibit virulence across a range of organisms by targeting DsbA. For example, Salmonella enterica typhimurium (SeDsbA, 86 % sequence identity to EcDsbA) shares almost identical structural, surface and redox properties. Using comparative sequence and structure analysis we predicted that five other bacterial DsbAs would share these properties. To confirm this, we characterized Klebsiella pneumoniae DsbA (KpDsbA, 81 % identity to EcDsbA). As expected, the redox properties, structure and surface features (from crystal and NMR data) of KpDsbA were almost identical to those of EcDsbA and SeDsbA. Moreover, KpDsbA and EcDsbA bind peptides derived from their respective DsbBs with almost equal affinity, supporting the notion that compounds designed to inhibit EcDsbA will also inhibit KpDsbA. Taken together, our data show that DsbAs fall into different classes; that DsbAs within a class may be predicted by sequence analysis of binding loops; that DsbAs within a class are able to complement one another in vivo and that compounds designed to inhibit EcDsbA are likely to inhibit DsbAs within the same class.
PMCID: PMC3828196  PMID: 24244651
18.  The psychosocial impact of home use medical devices on the lives of older people: a qualitative study 
Increased life expectancy and the accompanying prevalence of chronic conditions have led to the focus and delivery of health care migrating from the hospital and into people’s homes. While previous studies have investigated the integration of particular types of medical devices into the home, it was our intention to describe how medical devices are integrated into the lives of older people.
Adopting a qualitative study design, 12 older people, who used medical devices in the home, took part in in-depth, semi structured interviews. In 7 of the interviews participants and their partners were interviewed together. These interviews were recorded, transcribed and analysed thematically.
Two themes were constructed that describe how medical devices that are used in the home present certain challenges to older people and their partners in how the device is adopted and the personal adaptations that they are required to make. The first theme of 'self-esteem’ highlighted the psychological impact on users. The second theme of 'the social device' illustrated the social impact of these devices on the user and the people around them.
We found that these devices had both a positive and negative psychosocial impact on users’ lives. An improved understanding of these psychological and social issues may assist both designers of medical devices and the professionals who issue them to better facilitate the integration of medical devices into the homes and lives of older people.
PMCID: PMC4226280  PMID: 24195757
Home environment; Medical devices; Older people; Psychosocial issues; Qualitative research
19.  A Comparison of Morphological and Molecular-Based Surveys to Estimate the Species Richness of Chaetoceros and Thalassiosira (Bacillariophyta), in the Bay of Fundy 
PLoS ONE  2013;8(10):e73521.
The goal of this study was to compare the ability of morphology and molecular-based surveys to estimate species richness for two species-rich diatom genera, Chaetoceros Ehrenb. and Thalassiosira Cleve, in the Bay of Fundy. Phytoplankton tows were collected from two sites at intervals over two years and subsampled for morphology-based surveys (2010, 2011), a culture-based DNA reference library (DRL; 2010), and a molecular-based survey (2011). The DRL and molecular-based survey utilized the 3′ end of the RUBISCO large subunit (rbcL-3P) to identify genetic species groups (based on 0.1% divergence in rbcL-3P), which were subsequently identified morphologically to allow comparisons to the morphology-based survey. Comparisons were compiled for the year (2011) by site (n = 2) and by season (n = 3). Of the 34 taxa included in the comparisons, 50% of taxa were common to both methods, 35% were unique to the molecular-based survey, and 12% were unique to the morphology-based survey, while the remaining 3% of taxa were unidentified genetic species groups. The morphology-based survey excelled at identifying rare taxa in individual tow subsamples, which were occasionally missed with the molecular approach used here, while the molecular methods (the DRL and molecular-based survey), uncovered nine cryptic species pairs and four previously overlooked species. The last mentioned were typically difficult to identify and were generically assigned to Thalassiosira spp. during the morphology-based survey. Therefore, for now we suggest a combined approach encompassing routine morphology-based surveys accompanied by periodic molecular-based surveys to monitor for cryptic and difficult to identify taxa. As sequencing technologies improve, molecular-based surveys should become routine, leading to a more accurate representation of species composition and richness in monitoring programs.
PMCID: PMC3794052  PMID: 24130665
20.  Rv2969c, essential for optimal growth in Mycobacterium tuberculosis, is a DsbA-like enzyme that interacts with VKOR-derived peptides and has atypical features of DsbA-like disulfide oxidases 
The gene product of M. tuberculosis Rv2969c is shown to be a disulfide oxidase enzyme that has a canonical DsbA-like fold with novel structural and functional characteristics.
The bacterial disulfide machinery is an attractive molecular target for developing new antibacterials because it is required for the production of multiple virulence factors. The archetypal disulfide oxidase proteins in Escherichia coli (Ec) are DsbA and DsbB, which together form a functional unit: DsbA introduces disulfides into folding proteins and DsbB re­oxidizes DsbA to maintain it in the active form. In Mycobacterium tuberculosis (Mtb), no DsbB homologue is encoded but a functionally similar but structurally divergent protein, MtbVKOR, has been identified. Here, the Mtb protein Rv2969c is investigated and it is shown that it is the DsbA-like partner protein of MtbVKOR. It is found that it has the characteristic redox features of a DsbA-like protein: a highly acidic catalytic cysteine, a highly oxidizing potential and a destabilizing active-site disulfide bond. Rv2969c also has peptide-oxidizing activity and recognizes peptide segments derived from the periplasmic loops of MtbVKOR. Unlike the archetypal EcDsbA enzyme, Rv2969c has little or no activity in disulfide-reducing and disulfide-isomerase assays. The crystal structure of Rv2969c reveals a canonical DsbA fold comprising a thioredoxin domain with an embedded helical domain. However, Rv2969c diverges considerably from other DsbAs, including having an additional C-terminal helix (H8) that may restrain the mobility of the catalytic helix H1. The enzyme is also characterized by a very shallow hydrophobic binding surface and a negative electrostatic surface potential surrounding the catalytic cysteine. The structure of Rv2969c was also used to model the structure of a paralogous DsbA-like domain of the Ser/Thr protein kinase PknE. Together, these results show that Rv2969c is a DsbA-like protein with unique properties and a limited substrate-binding specificity.
PMCID: PMC3792642  PMID: 24100317
DsbA; VKOR; DsbB; antibacterial target; oxidative folding; virulence; thioredoxin
21.  Sleep Disturbance Among Older Adults in Assisted Living Facilities 
To evaluate whether objectively- and subjectively-measured sleep disturbances persist among older adults in assisted living facilities (ALFs) and to identify predictors of sleep disturbance in this setting.
Prospective, observational cohort study
Setting and Participants
121 residents, aged ≥ 65 years, in 18 ALFs in the Los Angeles area
Objective (actigraphy) and subjective (Pittsburgh Sleep Quality Index, PSQI) sleep measures were collected at baseline and 3- and 6-month follow-up. Predictors of baseline sleep disturbance tested in bivariate analyses and multiple regression models included demographics, Mini-Mental State Examination score, number of comorbidities, nighttime sedating medication use, functional status (Activities of Daily Living, ADL; Instrumental Activities of Daily Living, IADL), restless legs syndrome, and sleep apnea risk.
Objective and subjective sleep measures were similar at baseline, 3- and 6-month follow-up (objective nighttime total sleep (hours) 6.3, 6.5, and 6.4; objective nighttime percent sleep 77.2, 77.7, and 78.3; and PSQI total score 8.0, 7.8, and 7.7, respectively). The mean baseline nighttime percent sleep decreased by 2% for each additional unit increase in baseline comorbid conditions (measured as number of conditions) and increased by 4.5% for each additional unit increase in baseline ADLs (measured as number of ADLs), in a multiple regression model.
In this study, we found that objectively- and subjectively-measured sleep disturbances are persistent among ALF residents and are related to greater number of comorbidities and poorer functional status at baseline. Interventions are needed to improve sleep in this setting.
PMCID: PMC3358504  PMID: 22531104
sleep; assisted living facilities; long-term care
22.  User needs elicitation via analytic hierarchy process (AHP). A case study on a Computed Tomography (CT) scanner 
The rigorous elicitation of user needs is a crucial step for both medical device design and purchasing. However, user needs elicitation is often based on qualitative methods whose findings can be difficult to integrate into medical decision-making. This paper describes the application of AHP to elicit user needs for a new CT scanner for use in a public hospital.
AHP was used to design a hierarchy of 12 needs for a new CT scanner, grouped into 4 homogenous categories, and to prepare a paper questionnaire to investigate the relative priorities of these. The questionnaire was completed by 5 senior clinicians working in a variety of clinical specialisations and departments in the same Italian public hospital.
Although safety and performance were considered the most important issues, user needs changed according to clinical scenario. For elective surgery, the five most important needs were: spatial resolution, processing software, radiation dose, patient monitoring, and contrast medium. For emergency, the top five most important needs were: patient monitoring, radiation dose, contrast medium control, speed run, spatial resolution.
AHP effectively supported user need elicitation, helping to develop an analytic and intelligible framework of decision-making. User needs varied according to working scenario (elective versus emergency medicine) more than clinical specialization. This method should be considered by practitioners involved in decisions about new medical technology, whether that be during device design or before deciding whether to allocate budgets for new medical devices according to clinical functions or according to hospital department.
PMCID: PMC3545827  PMID: 23289426
User needs elicitation; Analytic hierarchy process; AHP; Medical decision-making; Medical device
23.  Use of the Breathlessness, Cough, and Sputum Scale (BCSS©) in Pulmonary Rehabilitation§ 
In pulmonary rehabilitation (PR) effective measures have been taken while in analyzing a patient’s intervention with the help of entry to exit evaluations. The absence of an objective and quantifiable scale are limitations of PR that allow analyzing of a patient’s self reported symptoms throughout PR. The Breathlessness, Cough and Sputum Scale (BCSS©) is used to predict patient exacerbations by evaluating common symptoms identified in the COPD population. This study used the BCSS© survey to track complex symptom changes throughout the course of PR intervention. The BCSS© tool measured the patient’s self reported symptoms in real time for each visit when patient enrolled in PR.
Thirty-five patients with COPD from three outpatient PR centers were asked to report the severity of breathlessness, cough, and sputum prior to each PR session using the BCSS© survey.
There was a significant decrease in self reported symptoms of the mean BCSS© score from entry 4.6(± 2.9) to exit 2.3 (± 2.5), p < 0.001. The results showed variable decrease in the self reported symptoms with more PR visits. The secondary outcome showed high correlations with quality of life measures using the Pulmonary Function Status Scale (PFSS) on entry and exit to PR.
The BCSS© tool is an effective means for measuring the impact of PR on improving patient tolerance and self-reported symptoms as a result of COPD. More research is needed to better assess the complex symptoms of COPD patients in PR to enhance programmatic outcomes.
PMCID: PMC3594703  PMID: 23494521
Rehabilitation; quality of life; dyspnea; cough; sputum.
24.  Engaging with economic evaluation methods: insights from small and medium enterprises in the UK medical devices industry after training workshops 
With increased governmental interest in value assessment of technologies and where medical device manufacturers are finding it increasingly necessary to become more familiar with economic evaluation methods, the study sought to explore the levels of health economics knowledge within small and medium-sized enterprises (SMEs) and to scope strategies they employ to demonstrate the value of their products to purchasers.
A short questionnaire was completed by participants attending one of five workshops on product development in the medical device sector that took place in England between 2007 and 2011. From all responses obtained, a large proportion of participants were based in SMEs (N = 43), and these responses were used for the analysis. Statistical analysis using non-parametric tests was performed on questions with approximately interval scales. Qualitative data from participant responses were analysed to reveal emerging themes.
The questionnaire results revealed that 60% of SME participants (mostly company directors or managers, including product or project managers) rated themselves as having low or no knowledge of health economics prior to the workshops but the rest professed at least medium knowledge. Clinical trials and cost analyses or cost-effectiveness studies were the most highly cited means by which SMEs aim to demonstrate value of products to purchasers. Purchasers were perceived to place most importance on factors of safety, expert opinion, cost-effectiveness and price. However many companies did not utilise formal decision-making tools to prioritise these factors. There was no significant dependence of the use of decision-making tools in general with respect to professed knowledge of health economics methods. SMEs did not state a preference for any particular aspect of potential value when deciding whether to develop a product. A majority of SMEs stated they would use a health economics tool. Research and development teams or marketing and sales departments would most likely use one.
This study points to the need for further research into the education requirements of SMEs in the area of Health Technology Assessment (HTA) and also for investigation into how SMEs engage with existing HTA processes as required by assessors such as NICE.
PMCID: PMC3507868  PMID: 22943625
25.  The Weak Complex between RhoGAP Protein ARHGAP22 and Signal Regulatory Protein 14-3-3 Has 1∶2 Stoichiometry and a Single Peptide Binding Mode 
PLoS ONE  2012;7(8):e41731.
ARHGAP22 is a RhoGAP protein comprising an N-terminal PH domain, a RhoGAP domain and a C-terminal coiled-coil domain. It has recently been identified as an Akt substrate that binds 14-3-3 proteins in response to treatment with growth factors involved in cell migration. We used a range of biophysical techniques to investigate the weak interaction between 14-3-3 and a truncated form of ARHGAP22 lacking the coiled-coil domain. This weak interaction could be stabilized by chemical cross-linking which we used to show that: a monomer of ARHGAP22 binds a dimer of 14-3-3; the ARHGAP22 PH domain is required for the 14-3-3 interaction; the RhoGAP domain is unlikely to participate in the interaction; Ser16 is the more important of two predicted 14-3-3 binding sites; and, phosphorylation of Ser16 may not be necessary for 14-3-3 interaction under the conditions we used. Small angle X-ray scattering and cross-link information were used to generate solution structures of the isolated proteins and of the cross-linked ARHGAP22:14-3-3 complex, showing that no major rearrangement occurs in either protein upon binding, and supporting a role for the PH domain and N-terminal peptide of ARHGAP22 in the 14-3-3 interaction. Small-angle X-ray scattering measurements of mixtures of ARHGAP22 and 14-3-3 were used to establish that the affinity of the interaction is ∼30 µM.
PMCID: PMC3429473  PMID: 22952583

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