Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer's Disease.

BACKGROUND: Consensus is lacking on what constitutes a meaningful score change for individual patients on clinical outcome assessments (COAs) that are commonly used in clinical trials of Alzheimer's disease. Such thresholds are one important approach to help contextualize trial results and demonstrate meaningful treatment benefit. OBJECTIVES: To estimate meaningful within-patient change thresholds for the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE) among participants with mild cognitive impairment (MCI). DESIGN: Retrospective anchor- and distribution-based analyses of data from the ADC-008 (NCT00000173) study were used to estimate thresholds for meaningful within-patient change on the target measures. SETTING: Analyses were conducted using data from ADC-008 a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study among participants with the amnestic subtype of MCI, which was conducted by the Alzheimer's Disease Cooperative Study (ADCS) between March 1999 and January 2004 in the United States and Canada. PARTICIPANTS: Analyses were based on 769 eligible participants who completed the baseline assessment from 69 ADCS sites in the United States and Canada. MEASUREMENTS: The target outcome measures for this analysis included the CDR-SB, the ADAS-Cog, and the MMSE. The anchor measures for this analysis included the Global Deterioration Scale and the MCI-Clinical Global Impression of Change. RESULTS: Focusing on the 12-month time point, within-patient increases of 1-2.5 points in the CDR-SB and increases of 2-5 points on the 11-item ADAS-Cog and 13-item ADAS-Cog, on average, reflect minimal-to-moderate levels of deterioration, respectively. CONCLUSIONS: These thresholds may be useful to aid the interpretation of Alzheimer's disease clinical trial data by illustrating meaningful within-patient progression over the course of a clinical trial via supplementary progressor analyses, which may in turn be informative for treatment decisions. Estimates generated via these methods are specifically intended to evaluate within-patient change and are not intended to assess the magnitude and meaningfulness of differences between group-level changes over time.

Worst itch numerical rating scale for prurigo nodularis: a psychometric evaluation.

BACKGROUND: Study TR03 evaluated the safety and efficacy of nalbuphine ER for prurigo nodularis (PN; NCT02174419). OBJECTIVE: We conducted supplementary analyses to assess the psychometric properties of the Worst Itch Numeric Rating Scale (WI-NRS), the TR03 primary endpoint. METHODS: Study TR03 was a double-blind, placebo-controlled, phase 2 trial in PN patients with documented scores ≥5 on the WI-NRS (0 [no itch]-10 [worst itch imaginable]) on ≥5 of 7 days before baseline. Using TR03 data, the WI-NRS's psychometric properties, including reliability, validity and ability to detect change, were evaluated. A responder threshold was estimated to facilitate interpretation of WI-NRS score changes. RESULTS: Amongst 62 treated patients, improvements in mean [SD] (median) WI-NRS scores were observed between baseline (8.2 [1.21] (8.1)) and week 10 (5.8 [2.43] (6.0)). The WI-NRS had an intraclass correlation coefficient of 0.96 (95% confidence interval, 0.93-0.98) in 42 patients who had stable Itch verbal rating scale (VRS) scores from week 9-10, supporting strong test-retest reliability. Construct validity was supported, with strong correlations at week 10 with Average Itch NRS (r = 0.87) and Itch VRS single-day/weekly mean scores (r = 0.81/0.89) and moderate correlations with ItchyQoL™ total/domain scores (r = 0.41-0.43). The WI-NRS discriminated between predefined severity subgroups based on the Itch VRS and detected changes in itching severity (effect-size estimate: -2.05; standardized response mean: -1.21). An anchor-based threshold based on a two-category improvement in the single-day Itch VRS suggests a responder threshold of ≥3.8 points (~40% improvement). CONCLUSIONS: The WI-NRS demonstrates good measurement properties, supporting its use in evaluating treatment change in PN.

Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.

Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130F/F knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis. Specifically, exacerbated weight loss, early mortality and reduced muscle and adipose tissue mass were features of the gp130F/F:KrasG12D model, but not parental KrasG12D mice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130F/F:KrasG12D mice revealed the upregulation of IL-6 and STAT3-target genes compared with KrasG12D muscle tissue. These cachectic features of gp130F/F:KrasG12D mice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130F/F:KrasG12D:Stat3-/+ or gp130F/F:KrasG12D:Il6-/- mice, respectively. Furthermore, protein levels of the soluble IL-6 receptor (sIL-6R), which is the central facilitator of IL-6 trans-signalling, were elevated in cachectic muscle from gp130F/F:KrasG12D mice, and the specific blockade of IL-6 trans-signalling, but not classical signalling, with an anti-IL-6R antibody ameliorated cachexia-related characteristics in gp130F/F:KrasG12D mice. Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.

The role of organisational support in teleworker wellbeing: a socio-technical systems approach.

The prevalence of telework and other forms of mobile working enabled by digital technology is increasing markedly. Following a socio-technical systems approach, this study aims to examine the role of organisational social support and specific support for teleworkers in influencing teleworker wellbeing, the mediating role of social isolation, potentially resulting from a person-environment mismatch in these relationships, and possible differences in these relationships between low-intensity and hybrid teleworkers. Teleworkers' (n = 804) perceptions of support and telework outcomes (psychological strain, job satisfaction, and social isolation) were collected using an on-line survey of teleworking employees distributed within 28 New Zealand organisations where knowledge work was undertaken. Organisational social support and teleworker support was associated with increased job satisfaction and reduced psychological strain. Social isolation mediated the relationship between organisational social support and the two outcome variables, and some differences were observed in the structural relationships for hybrid and low-intensity teleworker sub-samples. These findings suggest that providing the necessary organisational and teleworker support is important for enhancing the teleworker-environment fit and thereby ensuring desirable telework outcomes.

Differential involvement of gp130 signalling pathways in modulating tobacco carcinogen-induced lung tumourigenesis.

Interleukin (IL)-6 family cytokines signal exclusively via the gp130 coreceptor, and are implicated in smoking-associated lung cancer, the most lethal cancer worldwide. However, the role of gp130 signalling pathways in transducing the carcinogenic effects of tobacco-related compounds is ill-defined. Here, we report that lung tumourigenesis induced by the potent tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (Nicotine-derived Nitrosamine Ketone; NNK) is suppressed in gp130(F/F) knock-in mice characterized by the contrasting gp130-dependant hypoactivation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) and phosphatidylinositol 3-kinase/Akt, and hyperactivation of signal transducer and activator of transcription (STAT)3 signalling cascades. Specifically, in response to NNK, the absolute number and size of lung lesions in gp130(F/F) mice were significantly reduced compared with gp130(+/+) littermate controls, and associated with lower cellular proliferation without any alteration to the level of apoptosis in gp130(F/F) lung tumours. At the molecular level, reduced activation of ERK MAPK, but not Akt, was observed in lung tumours of gp130(F/F) mice, and corresponded with impaired expression of several tumour suppressor genes (for example, Trp53, Tsc2). Notably, STAT3 was not activated in the lungs of gp130(+/+) mice by NNK, and genetic normalization of STAT3 activation in gp130(F/F):Stat3(-/+) mice had no effect on NNK-induced tumourigenesis. The expression of tumour suppressor genes was reduced in tumours from current versus never-smoking lung cancer patients, and in vitro pharmacological inhibition of ERK MAPK signalling in human lung cancer cells abrogated NNK-induced downmodulation of tumour suppressor gene expression. Among IL-6 cytokine family members, IL-6 gene expression was specifically upregulated by NNK in vitro and in vivo, and inversely correlated with tumour suppressor gene expression. Collectively, our data reveal that a key molecular mechanism by which NNK promotes tumour cell proliferation during tobacco carcinogen-induced lung carcinogenesis is via upregulation of IL-6 and the preferential usage of gp130-dependant ERK MAPK signalling to downmodulate tumour suppressor gene expression.

Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis.

Signalling by the toll-like receptor (TLR) family of pathogen recognition receptors has emerged as a key molecular component in the pathogenesis of an increasing number of inflammatory-related cancers, among which gastric cancer rates as the second most lethal cancer world-wide. The myeloid differentiation factor 88 (MyD88) adapter molecule has a critical role in mediating innate immune signalling by members of the TLR and interleukin (IL)-1 families, and has been associated with either pro- or antitumourigenic responses in various cancer models. However, little is known about the in vivo role of MyD88 adapter-like (Mal)/TIR-domain containing adapter protein (TIRAP), which is restricted to facilitating TLR4 and TLR2 signalling. To interrogate the role of these innate immune signalling components in gastric tumourigenesis, here we have employed the spontaneous gastric cancer gp130(F/F) mouse model, in which TLR2 promotes the growth of gastric tumours. Genetic ablation of Myd88 in gp130(F/F) mice suppressed tumourigenesis and was associated with increased apoptosis and reduced proliferation in the gastric tumour epithelium, comparable to that observed previously upon deletion of Tlr2 in gp130(F/F) mice. By contrast, the tumour burden in gp130(F/F):Mal(-/-) mice was equivalent to their gp130(F/F) littermates. At the molecular level, suppressed tumourigenesis in gp130(F/F):Myd88(-/-) mice correlated with reduced expression and activation of TLR2-regulated protumourigenic genes and signalling pathways, respectively. Consistent with the previously defined non-essential role for TLR2 in gastric tumour inflammation, the extent of inflammatory cell infiltrates in gastric tumours from gp130(F/F):Mal(-/-) and gp130(F/F):Myd88(-/-) mice remained unaltered compared with gp130(F/F) mice. Collectively, our data reveal a differential, but inflammation-independent, requirement for Mal and MyD88 during TLR2-promoted gastric tumourigenesis.

Outcomes of pregnancies in women with suspected antiphospholipid syndrome.

OBJECTIVES: To evaluate maternal and neonatal outcomes in women suspected to have primary antiphospholipid syndrome (PAPS). METHODS: A cohort from the Nova Scotia Atlee Perinatal Database (n = 211034) was studied. A total of 58 women with antiphospholipid antibodies without a clinical diagnosis of rheumatologic disease were evaluated. We compared them to maternal and neonatal outcomes of women without rheumatologic disease or PAPS who delivered in Nova Scotia 1988-2008. RESULTS: With PAPS, mean maternal age was older; mean gestational age and mean neonatal birth weight were less. With bivariate analysis, maternal colonization and urinary tract infection with group B streptococcus, thromboembolic disease, thrombocytopenia and Caesarean birth were more frequent in the suspected PAPS group compared to the control. Among neonates, hyperbilirubinemia, anemia, apnea, intraventricular hemorrhage grade I and II, retinopathy of prematurity, bronchopulmonary dysplasia, neonatal intensive care unit admission, and assisted ventilation occurred more frequently with PAPS. Babies in PAPS group had a longer hospital stay (8.7 vs 3.9 days). Logistic regression analysis identified that PAPS was only associated with increased risks of preeclampsia (Odds Ratio (OR) 2.2; 95% Confidence Interval (CI) 1.1-4.3; P = 0.016), urinary tract infection (OR 2.2; 95% CI 1.1-4.6; P = 0.02), and prematurity (gestational age ≤37) (OR 2.2; 95% CI, 1.07-4.3, P = 0.03). Positive predictive values for pregnancy induced hypertension, urinary tract infection and prematurity in women who had suspected APS were 24.1%, 17.2% and 45.6% respectively. CONCLUSION: With suspected PAPS, risks for preeclampsia, urinary tract infection and prematurity are increased. Outcomes for babies are related to prematurity.

An investigation of cancer incidence in a First Nations community in Alberta, Canada, 1995-2006.

OBJECTIVE: To determine colorectal and overall cancer incidence as part of a three-pronged investigation in response to the concerns of a First Nations community in Alberta, Canada, located close to sulfur-rich natural gas installations, and to determine whether the incidence of cancers observed in this reserve was higher than expected. METHODS: A population dataset with information identifying First Nations status and band affiliation was linked to the Alberta Cancer Registry to determine cancer incidence cases between 1995 and 2006 for on- and off-reserve study populations. Using indirect standardized incidence ratios, observed cancer incidence cases for the study populations were compared with cases expected based on three separate reference populations. RESULTS: Observed colorectal and overall cancer incidence cases within the First Nations community were not higher than expected. Cervical cancer incidence cases, however, were higher than expected for on- and off-reserve populations; public health measures designed to address this risk have been implemented and on-going surveillance of cancer incidence in the community will be maintained.

Women's views regarding participation in a proposed randomized controlled trial of twin delivery.

OBJECTIVE: To determine the views of women regarding participation in a proposed multicentre randomized controlled trial comparing planned vaginal birth to planned Caesarean delivery for twins at 32 or more weeks' gestation, in which the first twin (twin A) is presenting as a vertex. METHODS: Pregnant women with a known twin gestation were recruited from 2 hospital centres. Written information was provided about the proposed Twin Birth Study, and the women were then requested to complete a questionnaire to determine their views regarding participation in the proposed trial. RESULTS: Of the 64 women recruited for the study, 31 (48%) indicated they would be willing to consider participating in the proposed trial (95% CI, 37-60%), 14 (22%) were unsure about trial participation (95% CI, 13-33%), and 19 (30%) indicated they would not be willing to participate in the proposed study (95% CI, 20-42%). The most common reason for agreement to participation was altruism (n = 28). Those who responded "not sure" wished to speak with their partner (n = 5) or their doctor (n = 8) before deciding on participation. Of those who indicated they would not participate in the proposed trial, 12 (63%) indicated they preferred to have a vaginal birth, and 7 (37%) preferred to have a Caesarean section. CONCLUSIONS: Almost half the women in our sample were agreeable to considering their participation in a randomized trial that will compare planned vaginal birth to planned Caesarean section for twins at 32 or more weeks' gestation with twin A presenting as a vertex. Altruism was the most common reason for agreeing to participate, whereas preference for a specific mode of delivery was the most common reason for declining participation.

Responsiveness of the Acne-Specific Quality of Life Questionnaire (Acne-QoL) to treatment for acne vulgaris in placebo-controlled clinical trials.

The Acne-Specific Quality of Life Questionnaire (Acne-QoL) was developed to measure the impact of facial acne across four dimensions of patient quality of life. The main objective of the current study was to evaluate the responsiveness of this instrument. Secondarily, this study provided an opportunity to extend the developer's psychometric validation. The Acne-QoL was utilized in two randomized, double-blind, placebo-controlled studies of the efficacy of Estrostep (norethindrone acetate/ethinyl estradiol) in the treatment of facial acne; a total of 296 Estrostep and 295 placebo patients were evaluated. The Acne-QoL was completed at the beginning, middle (cycle 3), and end (cycle 6) of the 6-month treatment period. The responsiveness of the Acne-QoL was demonstrated through its ability to detect both small (baseline to mid-study) and moderate (baseline to study end) treatment advantages for Estrostep patients. Confirmatory factor analysis supported the subscale structure, and internal consistency estimates were excellent. Convergent and discriminant validity were supported by correlations between Acne-QoL scores and clinical measures that were both in the direction and relative magnitude hypothesized. Finally, item response theory analyses confirmed that each item is highly related to its subscale's latent construct and that each subscale is sensitive across a broad range of the underlying continuum. The results of this evaluation confirm that the Acne-QoL is responsive, internally consistent, and valid.

Needs and experiences of non-English-speaking hospice patients and families in an English-speaking country.

There is increasing evidence that, in practice, hospice care is predominantly accessed by white, middle-class patients, who live in stable home environments with available caregivers and other supports. The present challenge for researchers, administrators, and clinicians is to identify populations of terminally ill patients most in need of hospice care and to direct services to these patients. As a contribution to the development of this area, this paper presents the findings from a recent Australian hospice study that examines the needs and experiences of families from non-English-speaking backgrounds. The findings indicate that it is as important to focus on similarities as it is to highlight differences.

beta-Adrenergic agonists increase phosphorylation of elongation factor 2 in cardiomyocytes without eliciting calcium-independent eEF2 kinase activity.

The beta-adrenergic agonist isoproterenol increased the phosphorylation of elongation factor eEF2 in ventricular cardiomyocytes from adult rats (ARVC). Phosphorylation of eEF2 inhibits its activity, and protein synthesis was inhibited in ARVC concomitantly with increased eEF2 phosphorylation. eEF2 kinase activity in ARVC extracts was completely dependent upon Ca(2+)/calmodulin. In contrast to other cell types, however, treatments designed to raise intracellular cAMP failed to induce Ca(2+)/calmodulin-independent activity. Instead, they increased maximal eEF2 kinase activity. Similar data were obtained when partially purified ARVC eEF2 kinase was treated with cAMP-dependent protein kinase in vitro. These data suggest that ARVC possess a distinct isoform of eEF2 kinase.

Decreasing influenza impact in lodges: 1997-2000 Calgary Regional Health Authority.

Influenza causes high morbidity and hospitalization rates in residents of seniors lodges, I causing increased pressure on emergency departments and hospital beds every winter. This quasi-experimental study assessed the prevention of influenza outbreaks and their consequences in Calgary lodges. A multidisciplinary team worked to improve communication between health professionals, increase resident and staff immunization coverage, obtain weights and creatinines prior to influenza season, and facilitate amantadine prophylaxis during influenza A outbreaks. We had an increase in standing orders for amantadine and up to 56% of residents from one lodge had documented creatinine levels. Amantadine was administered to residents within two days of outbreak notification. Influenza morbidity in lodge outbreaks decreased from a rate of 37% to 9% over the three years and hospitalization rates decreased from 9% to 1%. We recommend that other regions consider a similar approach to decreasing influenza morbidity and hospitalization in lodge residents.

Interparental conflict and adolescent depressed mood: the role of family functioning.

Family functioning was investigated as a mediator between interparental conflict and adolescent depressed mood among adolescents living in two-parent and divorced families. Data were collected three times, with one year intervals. At the initial interview, adolescents were, on the average, 15.5 years old. Two types of interparental conflict were assessed: interparental conflict involving arguments about the adolescent, and arguments focused on the parents' behaviors. The results confirmed that family functioning mediated the effects of parent issue/interparental conflict, but not adolescent issue/interparental conflict. This was most evident for girls than boys. Implications of the findings for research and practice are discussed.

Association of a lower molecular weight protein to the mu-opioid receptor demonstrated by (125)I-beta-endorphin cross-linking studies.

Cross-linking experiments using the (125)I-beta-endorphin revealed the presence of several receptor-related species in cell lines expressing endogenous opioid receptors, including a small molecular mass protein (approximately 22 kDa). Previous reports have suggested that this 22-kDa (125)I-beta-endorphin cross-linked protein could be the degradative product from a higher molecular mass species, i.e., a fragment of the receptor. To determine if this protein is indeed a degraded receptor fragment, (125)I-beta-endorphin was cross-linked to the (His)(6) epitope-tagged mu-opioid receptor (His-mu) stably expressed in the murine neuroblastoma Neuro(2A) cells. Similar to earlier reports with cell lines expressing endogenous receptors, two major bands of 72- and 25-kDa proteins were specifically cross-linked. Initial cross-linking experiments indicated the absolute requirement of the high-affinity (125)I-beta-endorphin binding to the mu-opioid receptor prior to the appearance of the low molecular weight species, suggesting that the 22-kDa protein could be a degraded fragment of the receptor. However, variations in the ratios of these protein bands being cross-linked by several homo- or heterobifunctional cross-linking agents were observed. Although neither the carboxyl terminus mu-opioid receptor-specific antibodies nor the antibodies against the epitope at the amino terminus of the receptor could recognize the 22-kDa protein, this (125)I-beta-endorphin cross-linked species could be coimmunoprecipitated with the receptor antibodies or could be isolated with a nickel resin affinity chromatography. The direct physical association of the 22-kDa protein with the receptor was demonstrated also by the observation that the 22-kDa protein could not bind to the nickel resin alone, but that its binding to the nickel resin was restored in the presence of the His-mu. Taken together, these results suggest that the 22-kDa protein cross-linked by (125)I-beta-endorphin is not a degradative product, but a protein located within the proximity of the mu-opioid receptor, and that it is tightly associated with the receptor.

Comparisons among the Holden Psychological Screening Inventory (HPSI), the Brief Symptom Inventory (BSI), and the Balanced Inventory of Desirable Responding (BIDR).

Issues of reliability, item latent structure, and faking on the Holden Psychological Screening Inventory (HPSI), the Brief Symptom Inventory (BSI), and the Balanced Inventory of Desirable Responding (BIDR) were examined with a sample of 300 university undergraduates. Reliability analyses indicated that scales from all inventories had acceptable internal consistency. Confirmatory item principal component analyses supported the structures and scoring keys of the HPSI and the BIDR, but not the BSI. Although all inventories were susceptible to faking, validity indices of the HPSI and the BIDR could correctly classify over two-thirds of test respondents as either responding honestly or as faking.

Detection of a ferrylhemoglobin intermediate in an endothelial cell model after hypoxia-reoxygenation.

A cell culture model of bovine aortic endothelial cells attached to microcarrier beads was used to study the interaction of diaspirin cross-linked hemoglobin (an oxygen-carrying blood substitute) with hypoxia-reoxygenation. Hemoglobin (200 microM) and hypoxia-volume restriction (3-5 h), together and separately, caused toxicity in this model, as measured by decreased cellular replating efficiency. Hemoglobin (60 microM) caused a reduction in hydrogen peroxide concentration and an increase in lipid peroxidation above that induced by hypoxia alone. Incubation of hemoglobin with endothelial cells caused transient oxidation of hemoglobin to its highly reactive and toxic ferryl species after >/=3 h of hypoxia, followed by 1 h of reoxygenation. Lipid peroxidation, which may occur in the presence of ferrylhemoglobin, also occurred after 1 h of reoxygenation. Hemoglobin caused a dose-dependent decrease in intracellular glutathione concentration, suggesting that it caused an oxidative stress to the cells. However, addition of ascorbate, alpha-tocopherol, or trolox did not decrease hemoglobin oxidation in the presence of normal or hypoxic cells. It is concluded that diaspirin cross-linked hemoglobin forms a ferryl intermediate in the absence of any exogenously added oxidant and contributes to the oxidative burden experienced by endothelial cells after hypoxia-reoxygenation, a condition that is likely to be encountered during trauma and surgery when hemoglobin solutions are used as perfusion agents.