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Pain is common in people with dementia, and pain can exacerbate the behavioural and psychological symptoms of dementia. Effective pain management is challenging, not least in people with dementia. Impairments of cognition, communication and abstract thought can make communicating pain unreliable or impossible. It is unclear which biopsychosocial interventions for pain management are effective in people with dementia, and which interventions for behavioural and psychological symptoms of dementia are effective in people with pain. The result is that drugs, physical therapies and psychological therapies might be either underused or overused. People with dementia and pain could be helped by assessment processes that characterise an individual’s pain experience and dementia behaviours in a mechanistic manner, phenotyping. Chronic pain management has moved from a ‘one size fits all’ approach, towards personalised medicine, where interventions recommended for an individual depend upon the key mechanisms underlying their pain, and the relative values they place on benefits and adverse effects. Mechanistic phenotyping through careful personalised evaluation would define the mechanisms driving pain and dementia behaviours in an individual, enabling the formulation of a personalised intervention strategy. Central pain processing mechanisms are particularly likely to be important in people with pain and dementia, and interventions to accommodate and address these may be particularly helpful, not only to relieve pain but also the symptoms of dementia.

BackgroundThe PRomoting Activity, Independence and Stability in Early Dementia (PrAISED) study delivered an exercise and functional activity programme to participants living with dementia. A Randomised Controlled Trial (RCT) showed no measurable benefits in activities of daily living, physical activity or quality of life.ObjectiveTo explore participants’ responses to PrAISED and explain the mechanisms behind a complex intervention that did not lead to expected health gains.MethodsA process evaluation using qualitative methods, comprising interviews and researcher notesSettingData were collected in participants’ homes or remotely by telephone or videoconferencing.SampleEighty-eight interviews were conducted with 44 participants living with dementia (n = 32 intervention group; n = 12 control group) and 39 caregivers. Sixty-nine interviews were conducted with 26 therapists.ResultsParticipants valued the intervention as proactively addressing health issues that were of concern to them, and as sources of social contact, interaction, information, and advice. Facilitators to achieving positive outcomes included perceiving progress toward desired goals, positive expectations, therapists’ skills and rapport with participants, and caregiver support. Barriers included: cognitive impairment, which prevented independent engagement and carryover between sessions; chronic physical health problems and intercurrent acute illness and injury; ‘tapering’ (progressively infrequent supervision intended to help develop habits and independent activity); and the COVID-19 pandemic.ConclusionsInterventions aiming to maintain activity, independence and stability may not be appropriate in the context of dementia even in the mild stages of the condition. Various factors affected outcomes including caregiver support, rapport with therapists, availability of supervision, motivational factors, and the limitations of remote delivery. The effects of cognitive impairment, multimorbidity and frailty overwhelmed any positive impact of the intervention. Maintenance of functional ability is valued, but in the face of inevitable progression of disease, other less tangible outcomes become important, challenging how we frame ‘health gain’ and trial outcomes.

BackgroundDementia is associated with frailty leading to increased risks of falls and hospitalisations. Interventions are required to maintain functional ability, strength and balance.DesignMulti-centre parallel group randomised controlled trial, with embedded process evaluation. Procedures were adapted during the COVID-19 pandemic.ParticipantsPeople with mild dementia or mild cognitive impairment (MCI), living at home, and a family member or carer.ObjectivesTo determine the effectiveness of an exercise and functional activity therapy intervention compared to usual care.InterventionA specially-designed dementia-specific rehabilitation programme focussing on strength, balance, physical activity and performance of ADL, which was tailored, progressive, addressed risk and the psychological and learning needs of people with dementia, providing up to 50 therapy sessions over 12 months. The control group received usual care plus a falls risk assessment.Main outcome measureThe primary outcome was the informant-reported Disability Assessment for Dementia (DAD) 12 months after randomisation. Secondary outcomes were: self-reported ADL, cognition, physical activity, quality of life, frailty, balance, functional mobility, fear of falling, mood, carer strain and service use (at 12 months) and falls (between months 4 and 15).Results365 people were randomised, 183 to intervention and 182 to control. Median age of participants was 80 years (range 65-95), median Montreal Cognitive Assessment score 20/30 (range 13-26), 58% were men. Participants received a median of 31 (IQR = 22-40) therapy sessions out of a possible maximum of 50. Participants reported completing a mean 121 minutes/week of PrAISED activity outside of supervised sessions. Primary outcome data were available for 149 (intervention) and 141 (control) participants. There was no difference in DAD scores between groups: adjusted mean difference -1.3/100, 95% Confidence Interval (−5.2 to +2.6); Cohen’s d effect size -0.06 (−0.26 to +0.15); p=0.5. Upper 95% confidence intervals excluded small to moderate effects on any of the range of secondary outcome measures. Between months 4 and 15 there were 79 falls in the intervention group and 200 falls in the control group, adjusted incidence rate ratio 0.78 (0.5 to 1.3); p= 0.3.ConclusionThe intensive PrAISED programme of exercise and functional activity training did not improve ADLs, physical activity, quality of life, reduce falls or improve any other secondary health status outcomes even though uptake was good. Future research should consider alternative approaches to risk reduction and ability maintenance.Trial registrationISRCTN15320670.FundingNational Institute for Health and Care ResearchWhat is already knownDementia is associated with progressive loss of functional ability, including activities of daily living and mobility, and a high risk of fallsExercise programmes and rehabilitation therapies may improve ability, or slow the rate of decline, but evidence from trials and systematic reviews is equivocalWhat this study tells usWe developed an intensive dementia-specific exercise and functional activity rehabilitation programme, lasting 12 months, taking account of motivation, learning needs and context, in particular the need to engage carers, and evaluated it in a randomised controlled trialThe programme was very well received by participants and therapists, but had no effect on activities of daily living, physical activity, quality of life, falls, cognition or any other health status outcomeWe are unlikely to be able to change rate of loss of ability in dementia through exercise or functionally orientated rehabilitation therapy.We need different ways of defining wellbeing after a dementia diagnosis.

People living with dementia (PLWD) are almost always admitted to the acute hospital for reasons unrelated to their dementia, finding themselves in the unfamiliar environment of a Health Care of Older Persons acute ward. The effect of this environment creates a challenge not just for a PLWD themselves, but also for the staff who care for them. Concerns have been raised by both policy makers and staff about the quality of communication between hospital staff and PLWD. Using conversation analysis, we examined 41 video recordings of healthcare professional (HCP)/PLWD interactions collected across three acute inpatient wards in a large teaching hospital in the UK. In this paper, we focus our analysis on hard-to-interpret talk (talk where there are problems in hearing, speaking and/or understanding), and the ways in which healthcare professionals respond to this. Repair of hard- to- interpret talk is common in ordinary interaction, but we find that HCPs in this setting use a range of approaches to avoid direct repair. These approaches are: the use of non-committal responses and continuers such as ‘yeah’ or nods; the use of repetitions or partial repetitions; responding to the emotional tone displayed in the PLWD's utterance; closing the current topic and shifting to the next; and treating the PLWD's talk as related to the task at hand. We suggest that the use of these approaches may be one way in which HCPs manage respecting the personhood of the PLWD, by preserving face and enabling a continuation of an interaction in which the PLWD can take an active part. Our paper provides an empirical demonstration of the high level of interactional skill involved in dementia care work. It also illustrates how these skills can be described and specified, and hence incorporated into the recommendations and tips that are produced for communication with PLWD.

Simple Summary Increasing evidence supports a role for complement in the development of cancer and the response to cancer treatments. Dysregulated complement expression within the tumour microenvironment has been linked to the suppression of anti-tumour immunity and poor clinical outcomes. Complement signals have been demonstrated to alter the immune milieu, promote proliferation and facilitate metastasis. Targeting complement signalling in combination with current treatments may have the potential to achieve improved control of tumour growth. Abstract In recent years, our knowledge of the complement system beyond innate immunity has progressed significantly. A modern understanding is that the complement system has a multifaceted role in malignancy, impacting carcinogenesis, the acquisition of a metastatic phenotype and response to therapies. The ability of local immune cells to produce and respond to complement components has provided valuable insights into their regulation, and the subsequent remodeling of the tumour microenvironment. These novel discoveries have advanced our understanding of the immunosuppressive mechanisms supporting tumour growth and uncovered potential therapeutic targets. This review discusses the current understanding of complement in cancer, outlining both direct and immune cell-mediated roles. The role of complement in response to therapies such as chemotherapy, radiation and immunotherapy is also presented. While complement activities are largely context and cancer type-dependent, it is evident that promising therapeutic avenues have been identified, in particular in combination therapies.

Introduction: The Promoting Activity, Independence and Stability in Early Dementia (PrAISED) is delivering an exercise programme for people with dementia. The Lincolnshire partnership National Health Service (NHS) foundation Trust successfully delivered PrAISED through a video-calling platform during the Coronavirus Disease 2019 (COVID-19) pandemic. Methods: This qualitative case-study aimed to identify participants that video delivery worked for, to highlight its benefits and its challenges. Interviews were conducted between May and August 2020 with five participants with dementia and their caregivers (n = 10), as well as five therapists from the Lincolnshire partnership NHS foundation Trust. The interviews were analysed through thematic analysis. Results: Video delivery worked best when participants had a supporting caregiver and when therapists showed enthusiasm and had an established rapport with the client. Benefits included time efficiency of sessions, enhancing participants’ motivation, caregivers’ dementia awareness, and therapists’ creativity. Limitations included users’ poor IT skills and resources. Discussion: The COVID-19 pandemic required innovative ways of delivering rehabilitation. This study supports that people with dementia can use tele-rehabilitation, but success is reliant on having a caregiver and an enthusiastic and known therapist.

Background Bariatric surgery improves glycemic control in patients with type 2 diabetes mellitus (T2DM), but less is known about microvascular outcomes. Objective To investigate the relationship between bariatric surgery and incident microvascular complications of T2DM. Design Retrospective matched cohort study from 2005 to 2011 with follow-up through September 2015. Setting 4 integrated health systems in the United States. Participants Patients aged 19 to 79 years with T2DM who had bariatric surgery (n = 4024) were matched on age, sex, body mass index, hemoglobin A1c level, insulin use, diabetes duration, and intensity of health care use up to 3 nonsurgical participants (n = 11 059). Intervention Bariatric procedures (76% gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) compared with usual care. Measurements Adjusted Cox regression analysis investigated time to incident microvascular disease, defined as first occurrence of diabetic retinopathy, neuropathy, or nephropathy. Results Median follow-up was 4.3 years for both surgical and nonsurgical patients. Bariatric surgery was associated with significantly lower risk for incident microvascular disease at 5 years (16.9% for surgical vs. 34.7% for nonsurgical patients; adjusted hazard ratio [HR], 0.41 [95% CI, 0.34 to 0.48]). Bariatric surgery was associated with lower cumulative incidence at 5 years of diabetic neuropathy (7.2% for surgical vs. 21.4% for nonsurgical patients; HR, 0.37 [CI, 0.30 to 0.47]), nephropathy (4.9% for surgical vs. 10.0% for nonsurgical patients; HR, 0.41 [CI, 0.29 to 0.58]), and retinopathy (7.2% for surgical vs. 11.2% for nonsurgical patients; HR, 0.55 [CI, 0.42 to 0.73]). Limitation Electronic health record databases could misclassify microvascular disease status for some patients. Conclusion In this large, multicenter study of adults with T2DM, bariatric surgery was associated with lower overall incidence of microvascular disease (including lower risk for neuropathy, nephropathy, and retinopathy) than usual care. Primary funding source National Institute of Diabetes and Digestive and Kidney Diseases.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer, being responsible for ~90% of all pancreatic cancers and having a 5-year survival rate of ~8.5%. The current clinical gold-standard for diagnosis of PDAC is the blood-based biomarker CA19-9. However, many studies have highlighted the limitations of CA19-9, specifically its relatively low sensitivity and specificity, and its inaccuracy in patients with certain underlying conditions. As such, there is an unmet need for robust diagnostic biomarkers for PDAC. Here, the diagnostic accuracy of all blood-based biomarkers examined in PDAC, reporting specifically on CA19-9, multi-marker panels containing CA19-9, novel single markers, and novel multi-marker panels for the diagnosis of PDAC. Methods: A systematic review of blood-based biomarkers for the diagnosis of PDAC was conducted in accordance with PRISMA standards. Individual search strategies using medical subject headings (MeSH) and ‘text words’ were developed for three academic databases: Medline, EMBASE and Web of Science. The 5,885 studies identified were subjected to two rounds of screening by two independent reviewers, with 250 studies being included in the meta-analysis. Data were extracted and assessed for bias using the QUADAS-2 Risk of Bias tool. Data were separated into two subgroups: those including CA19-9, and those without CA19-9 (novel). Patient cohorts examined were classified as “PDAC vs healthy”, “PDAC vs benign” and “PDAC vs mixed”. A multivariate three-level meta-analysis with subgroup moderators was run in R (v1.3.959) on all CA19-9 containing biomarker studies and subsequently on all novel biomarker studies, using reported AUC values as effect size. Results: Based on the three-level meta-analytic model, the pooled AUC value for CA19-9 alone (AUC=0.8473, 95% CI: 0.82-0.87) was significantly lower compared to the multi-marker panels containing CA19-9 (AUC=0.91, 95% CI:0.90-0.93) (p Citation Format: Laura E. Kane, Gregory S. Mellotte, Eimear Mylod, Rebecca O'Brien, Fiona O'Connell, Khanh Nguyen, Croí E. Buckley, Jennifer Arlow, David Mockler, Aidan D. Meade, Barbara M. Ryan, Stephen G. Maher. Diagnostic accuracy of blood-based multi-omic biomarkers for pancreatic adenocarcinoma: A systematic review and meta-analysis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-008.

Students who come from low-income backgrounds tend to be underidentified and underserved in gifted education. Early interventions with learners of high potential from underserved groups, including exposure to challenging curriculum and summer opportunities, are important for nurturing these students’ talents and preparing them for advanced learning opportunities in later school years. Project SPARK, based on the Young Scholars model, focuses on recognizing and responding to high-potential learners from underserved populations in the early grades. In this study, we examined the effects on mathematics achievement of participation in a summer program as part of Project SPARK in schools with substantial populations of students in poverty, as demonstrated by percentage of students eligible for free or reduced lunch. We examined summer program effects on achievement for the sample overall and specifically for students from low-income backgrounds. Students who participated in the summer program made moderately larger mathematics achievement gains than students who did not participate, with Cohen’s d-type effect sizes of 0.92. Students who qualified for free or reduced lunch saw similar gains over the summer if they participated in the summer program, indicating that the summer program experience was supportive for students across a range of income backgrounds.

IntroductionThe Promoting Activity, Independence and Stability in Early Dementia (PrAISED) is delivering an exercise programme for people with dementia. The Lincolnshire partnership NHS foundation Trust successfully delivered PrAISED through a video-calling platform during the COVID-19 pandemic.ObjectivesThis qualitative case-study identified participants that video delivery worked for, and highlighted its benefits and challenges.MethodsInterviews were conducted with participants with dementia, caregivers and therapists, and analysed through thematic analysis.ResultsVideo delivery worked best when participants had a supporting carer, when therapists showed enthusiasm and had an established rapport with the client. Benefits included time-efficiency of sessions, enhancing participants’ motivation, caregivers’ dementia awareness and therapists’ creativity. Limitations included users’ poor IT skills and resources.ConclusionsThe COVID-19 pandemic required innovative ways of delivering rehabilitation. This study supports that people with dementia can use tele rehab, but success is reliant on having a caregiver and an enthusiastic and known therapist.

The kinds of errors that children and adolescents make on phonological processing tasks were studied with a large sample between ages 4 and 19 ( N = 3,842) who were tested on the Kaufman Test of Educational Achievement–Third Edition (KTEA-3). Principal component analysis identified two phonological processing factors: Basic Phonological Awareness and Advanced Phonological Processing. Canonical analysis and correlation analysis were conducted to determine how each factor related to reading, writing, and oral language across the wide age range. Results of canonical correlation analysis indicated that the advanced error factor was more responsible for reading, writing, and oral language skills than the basic error factor. However, in the correlation analysis, both the basic and advanced factors related about equally to different aspects of achievement—including reading fluency and rapid naming—and there were few age differences.

Norm-referenced error analysis is useful for understanding individual differences in students’ academic skill development and for identifying areas of skill strength and weakness. The purpose of the present study was to identify underlying connections between error categories across five language and math subtests of the Kaufman Test of Educational Achievement–Third Edition (KTEA-3) through exploratory factor analyses (EFAs). The EFA results were supportive of models with two or three factors for each of the five subtests. Significant inter-factor correlations within subtests were identified in all subtests, except between two factors within the Math Concepts and Application (MCA) subtest. There was also consistency in the covariance patterns of some error categories across subtests, particularly within the Nonsense Word Decoding (NWD) and Spelling (SP) subtests. This consistency was supportive of the proposed factor structures. The factor structures yielded by these analyses were used as the bases for the other articles in this special issue.

This study investigated cognitive patterns of strengths and weaknesses (PSW) and their relationship to patterns of math errors on the Kaufman Test of Educational Achievement (KTEA-3). Participants, ages 5 to 18, were selected from the KTEA-3 standardization sample if they met one of two PSW profiles: high crystallized ability (Gc) paired with low processing speed/long-term retrieval (Gs/Glr; n = 375) or high Gs/Glr paired with low Gc ( n = 309). Estimates of Gc and Gs/Glr were based on five KTEA-3 subtests that measure either Gc (e.g., Listening Comprehension) or Gs/Glr (e.g., Object Naming Facility). The two groups were then compared on math error factors. Significant differences favored the High-Gc group for factors that measure math calculation, basic math concepts, and complex computation. However, the two groups did not differ in their errors on factors that measure geometry/measurement or simple addition. Results indicated that students with different PSW profiles also differed in the kinds of errors they made on math tests.

Many federal definitions and popular theories of giftedness specify creativity as a core component. Nevertheless, states rely primarily on measures of intelligence for giftedness identification. As minority and culturally diverse students continue to be underrepresented in gifted programs, it is reasonable to ask if increasing the prominence of creativity in gifted identification may help increase balance and equity. In this paper, we explore both layperson and psychometric conceptions of bias and suggest that adding creativity measures to the identification process alleviates both perceptions and the presence of bias. We recognize, however, the logistic and measurement-related challenges to including creativity assessments.

OBJECTIVE To identify and quantify any legacy effect of bariatric surgery on risk of incident microvascular disease in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted a retrospective observational cohort study (n = 4,683; 40% racial/ethnic minority) of patients with type 2 diabetes who underwent bariatric surgery from 2001 through 2011. The primary outcome measure was incident microvascular disease defined as a composite indicator of the first occurrence of retinopathy, neuropathy, and/or nephropathy. The Cox proportional hazards framework was used to investigate the associations between type 2 diabetes remission/relapse status and time to microvascular disease. RESULTS Covariate-adjusted analyses showed that patients who experienced type 2 diabetes remission had 29% lower risk of incident microvascular disease compared with patients who never remitted (hazard ratio [HR] 0.71 [95% CI 0.60, 0.85]). Among patients who experienced a relapse after remission, the length of time spent in remission was inversely related to the risk of incident microvascular disease; for every additional year of time spent in remission prior to relapse, the risk of microvascular disease was reduced by 19% (HR 0.81 [95% CI 0.67, 0.99]) compared with patients who never remitted. CONCLUSIONS Our results indicate that remission of type 2 diabetes after bariatric surgery confers benefits for risk of incident microvascular disease even if patients eventually experience a relapse of their type 2 diabetes. This provides support for a legacy effect of bariatric surgery, where even a transient period of surgically induced type 2 diabetes remission is associated with lower long-term microvascular disease risk.

A quarter of UK acute hospital beds are occupied by people living with dementia (PLWD). Concerns have been raised by both policy makers and carers about the quality of communication between hospital staff and PLWD. PLWD may experience communication impairments such as word finding difficulties, limited ability to construct coherent narratives and difficulties understanding others. Since much healthcare delivery occurs through talk, healthcare professionals (HCPs) and PLWD are likely to experience increased communication barriers. Consistent with this, HCPs report stress and reduced job satisfaction associated with difficulty communicating with PLWD. HCPs face these challenges whilst striving to deliver person-centred care, respecting the autonomy and wishes of the patient before them. However, best practice recommendations in the field tend not to be based on actual interactional evidence. This paper investigates recurring interactional difficulties around HCP requests to carry out health and social care tasks and subsequent reluctance or refusal on the part of PLWD. Using conversation analysis, we examined 41 video recordings of HCP/PLWD interactions collected across three acute inpatient wards. We identify both the nature of the refusals, and any mitigation offered, and explore the requests preceding them in terms of entitlement and contingency. We also explore the nature of HCP requests which precede PLWD agreement with a course of action. We conclude that several features of requests can be seen to precede acceptance, principally the use of higher entitlement requests, and the lowering of contingencies. Our findings underline the importance of examining the contextual interactional detail involved in the negotiation of healthcare, which here leads to an understanding of how design of HCP requests can impact on an important healthcare activity being carried out. They also emphasise the power of conversation analytic methods to identify areas of frequent interactional trouble in dementia care which have not previously been articulated.

Background\ud \ud A quarter of acute hospital beds are occupied by persons living with dementia, many of whom have communication problems. Healthcare professionals lack confidence in dementia communication skills, but there are no evidence-based communication skills training approaches appropriate for professionals working in this context. We aimed to develop and pilot a dementia communication skills training course that was acceptable and useful to healthcare professionals, hospital patients and their relatives.\ud Methods\ud \ud The course was developed using conversation analytic findings from video recordings of healthcare professionals talking to patients living with dementia in the acute hospital, together with systematic review evidence of dementia communication skills training and taking account of expert and service-user opinion. The two-day course was based on experiential learning theory, and included simulation and video workshops, reflective diaries and didactic teaching. Actors were trained to portray patients living with dementia for the simulation exercises. Six courses were run between January and May 2017. 44/45 healthcare professionals attended both days of the course. Evaluation entailed: questionnaires on confidence in dementia communication; a dementia communication knowledge test; and participants’ satisfaction. Video-recorded, simulated assessments were used to measure changes in communication behaviour.\ud Results\ud \ud Healthcare professionals increased their knowledge of dementia communication (mean improvement 1.5/10; 95% confidence interval 1.0–2.0; p

Background Limited data have been reported on bariatric surgery within a large, high-volume regional multicenter integrated healthcare delivery system. Objectives Review clinical characteristics and short- and intermediate-term outcomes and adverse events from a bariatric surgery program within an integrated healthcare delivery system. Setting Single high-volume, multicenter regional integrated healthcare delivery system. Methods Adult patients who underwent primary bariatric surgery during 2010–2011 were reviewed. Clinical characteristics, outcomes, and weight loss results were extracted from the electronic medical record. Results A total of 2399 patients were identified within the study period. The 30-day rates of clinical outcomes for Roux-en-Y gastric bypass (RYGB; n=1313) and sleeve gastrectomy (SG; n=1018) were 2.9% for readmission, 3.0% for major complications, .8% for reoperation, and 0% for mortality. One-year and 2-year weight loss results were as follows: percent weight loss (%WL) was 31.4 (±SD 8.5) and 34.2±12.0% for SG and 34.1±9.3 and 39.1±11.9 for RYGB; percent excess weight loss (%EBWL) was 64.2±18.0 and 69.8±23.7 for SG and 68.0±19.3 and 77.8±23.7 for RYGB; percent excess body mass index loss (%EBMIL) was 72.9±21.0 and 77.7±22.4 for SG and 76.6±22.1% and 85.6±21.6 for RYGB. Follow-up for each procedure at 1 year was 76% for SG (n = 778) and 80% for RYGB (n = 1052) and at 2 years was 65% for SG (n = 659) and 67% for RYGB (n = 875). Conclusions A large regional high-volume multicenter bariatric program within an integrated healthcare delivery system can produce excellent short-term results with low rates of short- and intermediate-term adverse outcomes.

Interruptions during film growth have been discussed by researchers to assist in understanding the evolution of stress in physical vapour deposition films. A change in intrinsic stress is directly related to microstructure, hence careful analysis of stress in films can provide valuable structure–stress correlated information. In this study we discuss the use of combining two X-ray diffraction (XRD) stress analysis methods to elucidate the effect of interruptions during growth on the residual stress of TiN films. The sin2ψ and crystallite group method (CGM), scanning the (220) peaks from all grains in the film and only (111) oriented crystallites respectively, were used to analyse residual stress in standard and interrupted cathodic arc TiN films 1.5, 3.5 and 6.5 μm thick, grown on high-speed steel substrates. The sin2ψ method does not reveal any changes in stress with interruptions, however, measurements using the CGM show increased compressive stress and increased a0 in the resultant TiN films. A comparison of results from both XRD methods indicates that an increased compressive stress from interruptions could be due to an increased number of defects in (111) oriented grains during the interruptions which would also affect a0 as evident. In both methods, compressive stresses are found to decrease with increased thickness of films.

The Notch signalling pathway plays a fundamental role in tissue development due to its involvement in cell fate determination and postnatal tissue differentiation. Its capacity to regulate cell growth and development has been linked to the occurrence of several cancers including that of the prostate. The transmembrane receptor Notch-1 of this pathway has been linked to the oncogenic role of Notch signalling in prostate adenocarcinoma. Other studies have suggested a tumour suppressive function for Notch-1. This review focuses on the role of Notch-1 in prostate cancer development and maintenance and relates this to the fundamental role of Notch in normal prostate development. The current understanding of the aberrant Notch signalling characteristic of prostate cancer is discussed, and recent therapeutic advances in this field are presented.

What is the central question of this study? Does crosstalk exist between leptin and interleukin-6 in colonic enteric neurons, and is this a contributory factor in gastrointestinal dysfunction associated with irritable bowel syndrome? What is the main finding and its importance? Leptin ameliorates the prosecretory and prokinetic effects of the pro-inflammatory cytokine interleukin-6 on rat colon. Leptin also suppresses the neurostimulatory effects of irritable bowel syndrome plasma, which has elevated concentrations of interleukin-6, on enteric neurons. This may indicate a regulatory role for leptin in immune-mediated bowel dysfunction. In addition to its role in regulating energy homeostasis, the adipokine leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder irritable bowel syndrome (IBS), circulating leptin concentrations are reported to differ from those of healthy control subjects. Additionally, IBS patients display altered cytokine profiles, including elevated circulating concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6), which bears structural homology and similarities in intracellular signalling to leptin. This study aimed to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorptosecretory function were assessed in organ baths and Ussing chambers in Sprague-Dawley rat colon. Calcium imaging and immunohistochemical techniques were used to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6-evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients.

Importance Macrovascular disease is a leading cause of morbidity and mortality for patients with type 2 diabetes, and medical management, including lifestyle changes, may not be successful at lowering risk. Objective To investigate the relationship between bariatric surgery and incident macrovascular (coronary artery disease and cerebrovascular diseases) events in patients with severe obesity and type 2 diabetes. Design, Setting, and Participants In this retrospective, matched cohort study, patients with severe obesity (body mass index ≥35) aged 19 to 79 years with diabetes who underwent bariatric surgery from 2005 to 2011 in 4 integrated health systems in the United States (n = 5301) were matched to 14 934 control patients on site, age, sex, body mass index, hemoglobin A1c, insulin use, observed diabetes duration, and prior health care utilization, with follow-up through September 2015. Exposures Bariatric procedures (76% Roux-en-Y gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) were compared with usual care for diabetes. Main Outcomes and Measures Multivariable-adjusted Cox regression analysis investigated time to incident macrovascular disease (defined as first occurrence of coronary artery disease [acute myocardial infarction, unstable angina, percutaneous coronary intervention, or coronary artery bypass grafting] or cerebrovascular events [ischemic stroke, hemorrhagic stroke, carotid stenting, or carotid endarterectomy]). Secondary outcomes included coronary artery disease and cerebrovascular outcomes separately. Results Among a combined 20 235 surgical and nonsurgical patients, the mean (SD) age was 50 (10) years; 76% of the surgical and 75% of the nonsurgical patients were female; and the baseline mean (SD) body mass index was 44.7 (6.9) and 43.8 (6.7) in the surgical and nonsurgical groups, respectively. At the end of the study period, there were 106 macrovascular events in surgical patients (including 37 cerebrovascular and 78 coronary artery events over a median of 4.7 years; interquartile range, 3.2-6.2 years) and 596 events in the matched control patients (including 227 cerebrovascular and 398 coronary artery events over a median of 4.6 years; interquartile range, 3.1-6.1 years). Bariatric surgery was associated with a lower composite incidence of macrovascular events at 5 years (2.1% in the surgical group vs 4.3% in the nonsurgical group; hazard ratio, 0.60 [95% CI, 0.42-0.86]), as well as a lower incidence of coronary artery disease (1.6% in the surgical group vs 2.8% in the nonsurgical group; hazard ratio, 0.64 [95% CI, 0.42-0.99]). The incidence of cerebrovascular disease was not significantly different between groups at 5 years (0.7% in the surgical group vs 1.7% in the nonsurgical group; hazard ratio, 0.69 [95% CI, 0.38-1.25]). Conclusions and Relevance In this observational study of patients with type 2 diabetes and severe obesity who underwent surgery, compared with those who did not undergo surgery, bariatric surgery was associated with a lower risk of macrovascular outcomes. The findings require confirmation in randomized clinical trials. Health care professionals should engage patients with severe obesity and type 2 diabetes in a shared decision making conversation about the potential role of bariatric surgery in the prevention of macrovascular events.

Do you find that your nurses aren't well educated on managing fatigue when working the night shift and all too frequently come to work without adequate rest? In some instances, this is due to poor sleep habits. In other cases, it's due to poor scheduling that leaves nurses with not enough ho

Objective: The Boston HAPPENS (HIV Adolescent Provider and Peer Education Network for Services) Program is a linked services network of care for HIV-positive, homeless, and at risk youth in Metropolitan Boston funded by the Special Projects of National Significance Program. This report studies the needs and use of services by HIV-positive youth compared with negative and untested at-risk youth, including gender differences. Design: Providers collected information prospectively at outreach and services encounters, including demographic information, risk behaviors, and service utilization data. Results: Youth (N=1044) were 19.6±3.0 years old; 38% male; 43% youth of color; and 4% self-identified as gay/lesbian/bisexual and 11.0% as homeless and/or runaway youth. HIV-positive clients (N=26) were more likely to use a range of network related health services. HIV-positive young women were more likely to report previous pregnancy (21% vs 5%, p=0.04) or sexual contact with high risk partners such as an injection drug user (57% vs 6%, p=0.0009), an HIV-positive person (p

Although recent findings indicate that γδ T cells influence both early innate and Ag-specific adaptive host responses, it has remained unclear what triggers γδ T cell reactivity. Investigating very early T cell activation in mouse and human models of bacterial infection, we measured CD69 expression as an indicator of early cellular activation. Both murine αβ and γδ T cells responded polyclonally to systemic bacterial infections, and to LPS. However, γδ T cells responded more strongly to the bacteria and to LPS. In vitro LPS-stimulated human T cells showed a similar differential response pattern. We identified TNF-α as mediator of the early differential T cell activation, and of differential proliferative responses. The stronger response of γδ T cells to TNF-α was correlated with higher inducible expression levels of TNF-Rp75. Among unstimulated splenocytes, more γδ T cells than αβ T cells expressed CD44 at high levels. The data suggest that TNF-Rp75 determines the differential T cell reactivity, and that most γδ T cells in the normal spleen are present in a presensitized state. As TNF-α stimulates activated T cells, it may early preferentially connect γδ T cell functions with those of cells that produce this cytokine, including activated innate effector cells and Ag-stimulated T lymphocytes.

In response to the sovereign requirement for national standards the National Measurement Institute, Australia (NMIA) has developed a measuring system using isotope dilution mass spectrometry (IDMS) to certify forensic aqueous ethanol solutions. NMIA participated in an international study, CCQM-K27, organized under the auspices of the International Committee for Weights and Measures to compare our measuring system with the techniques being used for certifying aqueous ethanol solutions in other metrology institutes. This comparison provided objective evidence that the measuring system developed was fit for the purpose of certifying aqueous ethanol solutions that ranged in concentration from 0.8 mg/g to 120 mg/g. A complete measurement uncertainty budget is presented and shows that the largest contribution to measurement uncertainty was from method precision followed by the contribution from the calibration solution. The fundamental technology of the measuring system was gas chromatography of the aqueous ethanol solutions using porous layer open tubular columns, and this effectively produced peak area measurements with both GC/MS and GC-FID. It was found that deactivation of the chromatographic system was critical for obtaining reproducible peak shapes and peak area measurements. A range of measuring systems, all using this gas chromatographic technology, was investigated. When conditions were carefully controlled there was no difference in measurement results from GC-IDMS, GC/ MS or GC-FID. There was also no difference in results from on-column or split injection systems. A significant issue with the IDMS system was the fragmentation of 13 C 2 -ethanol to produce an ion with the same mass as the molecular ion of ethanol which lead to isobaric interference; careful measurement of this fragmentation ratio was necessary to calculate accurate mass fraction values. NMIA has adopted the GC-IDMS split measuring system to certify aqueous ethanol solutions for Australian legal requirements since this measuring system provided higher analytical specificity than GC-FID, accuracy that was fit for purpose and was operationally less stringent than on-column techniques.

Coxsackieviruses are a cause of clinical myocarditis. Both virus replication and host defense mechanisms, including virus-induced autoimmunity, mediate heart injury and cardiac dysfunction. Vgamma4+ cells kill infected cardiocytes and virus-specific CD4+ Th2 cells through Fas-dependent apoptosis and CD1d. The CD4+ Th1 response is necessary for activation of the autoimmune CD8+ T cells, which kill uninfected cardiocytes through perforin-dependent mechanisms.

The insulin peptide ins2 B:9-23 is recognized by diabetogenic αβ T cells in NOD mice, and by γδ T cells. Unlike the αβ T cell response to the peptide, the γδ T cell response is independent of APCs. Furthermore, the cysteine residue in position 19 of the peptide is required for the γδ but not the αβ response. Since cysteine residues can dimerize upon oxidation, we hypothesized that γδ T cells recognize oxidized dimeric peptide molecules. We therefore compared the stimulatory activities of monomeric, copper chloride-oxidized (mostly dimeric) and DMSO-oxidized, HPLC-purified dimeric insulin peptide B:9-23 preparations. We found that oxidized and purified dimeric peptide preparations stimulated γδ T cells far better than untreated or purified monomeric preparations, which still contained some oxidized peptides. In contrast, αβ T cells responded only to monomeric peptides except when live APCs were present. The γδ T cell response to the dimeric insulin peptide was TCR dependent because responsiveness could be transferred with transduced TCR-γ/δ genes derived from the originally described B:9-23-reactive γδ T cell hybridoma SP9D11. These findings provide an explanation for the differential response requirements of insulin peptide-reactive αβ and γδ T cells, and they raise the possibility that B:9-23-reactive γδ T cells function as sensors of oxidative stress.

Vγ4+ cells, a subpopulation of peripheral γδ T cells are involved in West Nile virus (WNV) pathogenesis but the underlying mechanism is unclear. Here, we further investigated the role of Vγ4+ cells in WNV encephalitis and found that Vγ4+ cell-depleted mice had a lower viremia and reduced inflammation in the brain following WNV infection. Although Vγ4+ cells contributed to interleukin (IL-17) production during infection, blocking IL-17 signaling did not affect host susceptibility to WNV encephalitis. Furthermore, there was an enhanced magnitude of protective Vγ1+ cell expansion in the spleen and more Vγ1+ cell infiltration into the brains of Vγ4+ cell-depleted mice than controls during WNV infection. Vγ4+ cells of WNV-infected mice had a higher potential for producing transforming growth factor (TGF)-β. We noted that the difference in anti-CD3-stimulated γδ T cell proliferation between those of controls and Vγ4+ cell-depleted mice was diminished in the presence of TGF-β inhibitor. Moreover, Vγ4+ cells contributed to the production of IL-10, which is known to play a negative role in immunity against WNV infection, either directly or by increasing IL-10-producing αβ T cells. These results suggest that Vγ4+ cells may suppress Vγ1+ cell expansion via TGF-β and promote IL-10 production, which leads to higher viremia and enhanced brain inflammation during WNV infection.

Interleukin 27 (IL-27) is secreted by activated antigen presenting cells in response to inflammatory signals and plays both pro- and anti-inflammatory roles. Particularly interesting is that IL-27 has been shown to antagonize Th17 differentiation by suppressing the expression of Th17-promoting transcription factor, RORγt. However, immunoregulatory roles of IL-27 on non-CD4 T cells have not been extensively examined. γδ T cells account for a small subset of peripheral T cells and have been recently considered ‘innate’ IL-17 producers because of their spontaneous IL-17 expression. We found that in the absence of IL-27ra (WSX-1) on γδ T cells, IL-17 production was dramatically enhanced compared to WT γδ T cells. These cells possessed a highly activated phenotype where a majority was CD44high, increased expression of CCR6 consistent with increased IL-17 production, and an altered Vγ repertoire. In vitro stimulation of γδ T cells in the presence of exogenous IL-27 failed to suppress IL-17 production, consistent with the notion that fully committed Th17 effector T cells are resistant to IL-27-mediated inhibition. We also found that enhanced IL-17 production by IL-27ra-/- γδ T cells was already pronounced in CD44high post-DN4 thymic γδ T cell stage. Our results propose a previously uncharacterized pathway in which IL-17 expression by γδ Y cells in the thymus is modified via IL-27.