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The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterized by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neuronal material. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. Activation of non-canonical NF-κB signalling is also observed in cerebellar microglia of individuals with Ataxia-telangiectasia. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in ATM deficiency, potentially contributing to neurodegeneration in Ataxia-telangiectasia., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This work reports on the influence of phosphorous atoms on the phase separation process and optical properties of silicon nanocrystals (Si-NCs) embedded in phosphorus doped SiO/SiO 2 multilayers. Doped SiO/SiO 2 multilayers with different P contents have been prepared by co-evaporation and subsequently annealed at different temperatures up to 1100 °C. The sample structure and the localization of P atoms were both studied at the nanoscale by scanning transmission electron microscopy and atom probe tomography. It is found that P incorporation modifies the mechanism of Si-NC growth by promoting the phase separation during the post-growth-annealing step, leading to nanocrystal formation at lower annealing temperatures as compared to undoped Si-NCs. Hence, the maximum of Si-NC related photoluminescence (PL) intensity is achieved for annealing temperatures lower than 900 °C. It is also demonstrated that the Si-NCs mean size increases in the presence of P, which is accompanied by a redshift of the Si-NC related emission. The influence of the phosphorus content on the PL properties is studied using both room temperature and low temperature measurements. It is shown that for a P content lower than about 0.1 at%, P atoms contribute to significantly improve the PL intensity. This effect is attributed to the P-induced-reduction of the number of non-radiative defects at the interface between Si-NCs and SiO 2 matrix, which is discussed in comparison with hydrogen passivation of Si-NCs. In contrast, for increasing P contents, the PL intensity strongly decreases, which is explained by the growth of Si-NCs reaching sizes that are too large to ensure quantum confinement and to the localization of P atoms inside Si-NCs.

Marine spatial planning that addresses ocean climate-driven change ('climate-smart MSP') is a global aspiration to support economic growth, food security and ecosystem sustainability. Ocean climate change ('CC') modelling may become a key decision-support tool for MSP, but traditional modelling analysis and communication challenges prevent their broad uptake. We employed MSP-specific ocean climate modelling analyses to inform a real-life MSP process; addressing how nature conservation and fisheries could be adapted to CC. We found that the currently planned distribution of these activities may become unsustainable during the policy's implementation due to CC, leading to a shortfall in its sustainability and blue growth targets. Significant, climate-driven ecosystem-level shifts in ocean components underpinning designated sites and fishing activity were estimated, reflecting different magnitudes of shifts in benthic versus pelagic, and inshore versus offshore habitats. Supporting adaptation, we then identified: CC refugia (areas where the ecosystem remains within the boundaries of its present state); CC hotspots (where climate drives the ecosystem towards a new state, inconsistent with each sectors' present use distribution); and for the first time, identified bright spots (areas where oceanographic processes drive range expansion opportunities that may support sustainable growth in the medium term). We thus create the means to: identify where sector-relevant ecosystem change is attributable to CC; incorporate resilient delivery of conservation and sustainable ecosystem management aims into MSP; and to harness opportunities for blue growth where they exist. Capturing CC bright spots alongside refugia within protected areas may present important opportunities to meet sustainability targets while helping support the fishing sector in a changing climate. By capitalizing on the natural distribution of climate resilience within ocean ecosystems, such climate-adaptive spatial management strategies could be seen as nature-based solutions to limit the impact of CC on ocean ecosystems and dependent blue economy sectors, paving the way for climate-smart MSP., (© 2021 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

The concentration of dissolved oxygen in aquatic systems helps to regulate biodiversity 1,2 , nutrient biogeochemistry 3 , greenhouse gas emissions 4 , and the quality of drinking water 5 . The long-term declines in dissolved oxygen concentrations in coastal and ocean waters have been linked to climate warming and human activity 6,7 , but little is known about the changes in dissolved oxygen concentrations in lakes. Although the solubility of dissolved oxygen decreases with increasing water temperatures, long-term lake trajectories are difficult to predict. Oxygen losses in warming lakes may be amplified by enhanced decomposition and stronger thermal stratification 8,9 or oxygen may increase as a result of enhanced primary production 10 . Here we analyse a combined total of 45,148 dissolved oxygen and temperature profiles and calculate trends for 393 temperate lakes that span 1941 to 2017. We find that a decline in dissolved oxygen is widespread in surface and deep-water habitats. The decline in surface waters is primarily associated with reduced solubility under warmer water temperatures, although dissolved oxygen in surface waters increased in a subset of highly productive warming lakes, probably owing to increasing production of phytoplankton. By contrast, the decline in deep waters is associated with stronger thermal stratification and loss of water clarity, but not with changes in gas solubility. Our results suggest that climate change and declining water clarity have altered the physical and chemical environment of lakes. Declines in dissolved oxygen in freshwater are 2.75 to 9.3 times greater than observed in the world's oceans 6,7 and could threaten essential lake ecosystem services 2,3,5,11 .

Objectives: The use of assistive technology and telecare (ATT) has been promoted to manage risks associated with independent living in people with dementia but with little evidence for effectiveness., Methods: Participants were randomly assigned to receive an ATT assessment followed by installation of all appropriate ATT devices or limited control of appropriate ATT. The primary outcomes were time to institutionalisation and cost-effectiveness. Key secondary outcomes were number of incidents involving risks to safety, burden and stress in family caregivers and quality of life., Results: Participants were assigned to receive full ATT (248 participants) or the limited control (247 participants). After adjusting for baseline imbalance of activities of daily living score, HR for median pre-institutionalisation survival was 0.84; 95% CI, 0.63 to 1.12; P = 0.20. There were no significant differences between arms in health and social care (mean -£909; 95% CI, -£5,336 to £3,345, P = 0.678) and societal costs (mean -£3,545; 95% CI, -£13,914 to £6,581, P = 0.499). ATT group members had reduced participant-rated quality-adjusted life years (QALYs) at 104 weeks (mean - 0.105; 95% CI, -0.204 to -0.007, P = 0.037) but did not differ in QALYs derived from proxy-reported EQ-5D., Discussion: Fidelity of the intervention was low in terms of matching ATT assessment, recommendations and installation. This, however, reflects current practice within adult social care in England., Conclusions: Time living independently outside a care home was not significantly longer in participants who received full ATT and ATT was not cost-effective. Participants with full ATT attained fewer QALYs based on participant-reported EQ-5D than controls at 104 weeks., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Assistive technology and telecare have been promoted to manage the risks associated with independent living for people with dementia, but there is limited evidence of their effectiveness., Objectives: This trial aimed to establish whether or not assistive technology and telecare assessments and interventions extend the time that people with dementia can continue to live independently at home and whether or not they are cost-effective. Caregiver burden, the quality of life of caregivers and of people with dementia and whether or not assistive technology and telecare reduce safety risks were also investigated., Design: This was a pragmatic, randomised controlled trial. Blinding was not undertaken as it was not feasible to do so. All consenting participants were included in an intention-to-treat analysis., Setting: This trial was set in 12 councils in England with adult social services responsibilities., Participants: Participants were people with dementia living in the community who had an identified need that might benefit from assistive technology and telecare., Interventions: Participants were randomly assigned to receive either assistive technology and telecare recommended by a health or social care professional to meet their assessed needs (a full assistive technology and telecare package) or a pendant alarm, non-monitored smoke and carbon monoxide detectors and a key safe (a basic assistive technology and telecare package)., Main Outcome Measures: The primary outcomes were time to admission to care and cost-effectiveness. Secondary outcomes assessed caregivers using the 10-item Center for Epidemiological Studies Depression Scale, the State-Trait Anxiety Inventory 6-item scale and the Zarit Burden Interview., Results: Of 495 participants, 248 were randomised to receive full assistive technology and telecare and 247 received the limited control. Comparing the assistive technology and telecare group with the control group, the hazard ratio for institutionalisation was 0.76 (95% confidence interval 0.58 to 1.01; p  = 0.054). After adjusting for an imbalance in the baseline activities of daily living score between trial arms, the hazard ratio was 0.84 (95% confidence interval 0.63 to 1.12; p  = 0.20). At 104 weeks, there were no significant differences between groups in health and social care resource use costs (intervention group - control group difference: mean -£909, 95% confidence interval -£5336 to £3345) or in societal costs (intervention group - control group difference: mean -£3545; 95% confidence interval -£13,914 to £6581). At 104 weeks, based on quality-adjusted life-years derived from the participant-rated EuroQol-5 Dimensions questionnaire, the intervention group had 0.105 (95% confidence interval -0.204 to -0.007) fewer quality-adjusted life-years than the control group. The number of quality-adjusted life-years derived from the proxy-rated EuroQol-5 Dimensions questionnaire did not differ between groups. Caregiver outcomes did not differ between groups over 24 weeks., Limitations: Compliance with the assigned trial arm was variable, as was the quality of assistive technology and telecare needs assessments. Attrition from assessments led to data loss additional to that attributable to care home admission and censoring events., Conclusions: A full package of assistive technology and telecare did not increase the length of time that participants with dementia remained in the community, and nor did it decrease caregiver burden, depression or anxiety, relative to a basic package of assistive technology and telecare. Use of the full assistive technology and telecare package did not increase participants' health and social care or societal costs. Quality-adjusted life-years based on participants' EuroQol-5 Dimensions questionnaire responses were reduced in the intervention group compared with the control group; groups did not differ in the number of quality-adjusted life-years based on the proxy-rated EuroQol-5 Dimensions questionnaire., Future Work: Future work could examine whether or not improved assessment that is more personalised to an individual is beneficial., Trial Registration: Current Controlled Trials ISRCTN86537017., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 19. See the NIHR Journals Library website for further project information.

Background: Although abdominal trauma remains a major cause of morbidity and mortality, there has not been a large-scale multicenter study regarding outcomes in patients who incur mesenteric vascular injuries. The goal of this retrospective analysis was to investigate the factors associated with outcomes in patients with trauma diagnosed with mesenteric vascular injuries., Methods: A retrospective database analysis was performed on patients who sustained a mesenteric vascular injury (MVI, ICD-9 902.20-902.29) identified by the 2012 National Trauma Data Bank. Data were analyzed to identify differences in hospital length of stay, emergency room (ER) and final hospital disposition, and mortality based on patient age, gender, race, Injury Severity Score (ISS), and injury type (blunt or penetrating)., Results: Of the 1,133 total patients included, blunt trauma accounted for 740 (65%) of the injuries, whereas penetrating trauma accounted for 364 of the injuries (32%). Patients with penetrating injuries were 1.43 times more likely to die from their injuries than those suffering from blunt trauma (95% CI 1.04-1.98, P < 0.05). Patients with a higher ISS (>16) were 5.39 times more likely to die from their injuries than those with a lower ISS (95% CI 1.89-15.4, P = 0.002); if ISS was >25, the patient was 15.1 times more likely to die (95% CI 5.5-41.7, P < 0.001). Men were more likely to suffer from penetrating injuries than women (37% vs. 13%, P < 0.001), and African Americans were nearly 4 times more likely to present with penetrating injuries (69% vs 17%, P < 0.001). Age was also associated with mortality as patients >65 years and between 21 and 44 years were more likely to die from their injuries than patients in other age categories. Of the 740 patients with blunt MVIs, 326 (44%) were taken directly from the ER to the operating room (OR) and 306 (41%) to the intensive care unit (ICU), whereas with penetrating MVIs, 311 (85%) were taken to the OR from the emergency department and 18 (5%) to the intensive care unit. Of the 740 blunt MVIs, 115 died (16%), compared with 76 (21%) of the penetrating MVIs (P < 0.001). Injuries to the hepatic and superior mesenteric arteries were associated with higher mortality, with OR 2.03 and 3.03, respectively (P < 0.001)., Conclusions: The presence of mesenteric arterial injury warrants rapid identification and management as these injuries are associated with significant morbidity and mortality, with penetrating mechanism, injury to large mesenteric vessels, and increased ISS associated with increased mortality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Assistive technology and telecare (ATT) may alleviate psychological burden in informal caregivers of people with dementia. This study assessed the impact of ATT on informal caregivers' burden and psychological well-being., Methods: Individuals with dementia and their informal caregivers were recruited to a randomized-controlled trial assessing effectiveness of ATT. Caregivers were allocated to two groups according to their cared-for person's randomization to a full or basic package of ATT and were assessed on caregiver burden, state anxiety, and depression. Caregivers' data from three assessments over 6 months of the trial were analyzed., Results: No significant between- or within-group differences at any time point on caregivers' burden, anxiety, and depression levels were found., Discussion: Full ATT for people with dementia did not impact caregivers' psychological outcomes compared to basic ATT. The length of follow up was restricted to 6 months., Competing Interests: P.B. has received financial support from TauRx Therapeutics. J.O.B. has received financial support from TauRx, GE Healthcare, Avid/Lilly, and Eisai. No other author has any conflict of interest., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To examine the feasibility of conducting a fully powered randomized controlled trial (RCT) of Individual Placement and Support (IPS). IPS is a form of supported employment which aims to put people into open employment quickly and in accordance with their preferences. It is delivered by employment specialists collocated within clinical teams, and provides time unlimited support for the individual and their employer, along with welfare benefits counselling. Method: A feasibility cluster RCT of treatment as usual (TAU) plus IPS versus TAU alone was conducted over 12 months among patients with offending histories in a community forensic setting in the UK. The feasibility criteria were to achieve 50% recruitment rate; 50% completion rate for IPS; 50% completion rate of all outcome measures; and 80% acceptability rating for IPS. The primary efficacy outcome was the proportion of people in open employment at 12 months. The secondary outcomes were other vocational and educational activities; Brief Psychiatric Rating Scale; Rosenberg's Self-esteem Scale; Client Service Receipt Inventory; quality of life using the SF12-v2 and EQ5-D3; Social Functioning Questionnaire; Work Limitation Questionnaire; and reoffending. Results: Participants' mean age was 39.2 years. The majority were male (88.9), White British (72.2), and single (72.2%). Over 72% had no higher qualification beyond secondary education; mean years in education was 10.4. Over one third had schizophrenia, one fifth had depression, and the rest had personality disorder as their primary diagnosis. Participants had a lifetime average of 7.5 convictions for 15.5 offences. The recruitment rate of all referrals was 38.3% (IPS n = 11; TAU n = 7). Completion rate for IPS was 54.5, with 45.5% acceptability rating. Completion rates for outcome measures for the groups at baseline and 12 months ranged from 22.2 to 100%. The proportion of people in open employment at 12 months were 9.1 and 0% for IPS and TAU respectively. Conclusion: It is not feasible to conduct a full RCT of IPS in community forensic settings in the UK owing to recruitment and retention difficulties. Conducting a trial of this kind requires a large pool of patients from multiple sites and longer IPS implementation and recruitment periods than those of this study. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02442193., (Copyright © 2020 Khalifa, Talbot, Barber, Schneider, Bird, Attfield, Bates, Walker and Völlm.)

Setting: Five human immunodeficiency virus (HIV) care facilities in Eswatini., Objective: To identify critical factors that enabled persons living with HIV to successfully complete a 6-month course of isoniazid preventive therapy (IPT) provided through a choice of facility-based or community-based delivery, coordinated with antiretroviral therapy (ART) refills., Design: This was a mixed methods, retrospective cross-sectional study., Results: Between June and October 2017, we interviewed 150 participants who had completed IPT in the previous year. Fourteen participants did not recall being offered a choice, and were excluded from the analysis. Of the remaining 136, 56.6% were female and 64.7% chose facility-based care; the median age was 42.5 years. Most participants reported that having a choice was important to their treatment completion (87.7%) and that linking IPT and ART refills facilitated undergoing IPT (98.5%). Participants were knowledgeable about the benefits of IPT and valued the education received from their providers. Participants also reported a high rate of IPT disclosure (95%) to friends and family members., Conclusion: Offering patients a choice of IPT delivery, linking IPT with ART refills, emphasizing patient education and engagement with healthcare workers, and supporting disclosure of IPT are critical factors to enabling IPT completion. These interventions should be incorporated throughout Eswatini and in similar high tuberculosis and HIV burden settings., Competing Interests: Conflicts of interest: none declared., (© 2019 The Union.)

Introduction: The objective of this study was to define current assistive technology and telecare (ATT) practice for people with dementia living at home., Methods: This is a randomized controlled trial (N = 495) of ATT assessment and ATT installation intervention, compared with control (restricted ATT package). ATT assessment and installation data were collected. Qualitative work identified value networks delivering ATT, established an ATT assessment standard., Results: ATT was delivered by public and not-for-profit telecare networks. ATT assessments showed 52% fidelity to the ATT assessment standard. Areas of assessment most frequently leading to identifying ATT need were daily activities (93%), memory (89%), and problem-solving (83%). ATT needs and recommendations were weakly correlated (τ = 0.242; P  < .000), with ATT recommendations and installations moderately correlated (τ = -0.470; P  < .000). Half (53%) of recommended technology was not installed. Safety concerns motivated 38% of installations., Discussion: Assessment recommendations were routinely disregarded at the point of installation. ATT was commonly recommended for safety and seldom for supporting leisure.

The End TB Strategy diagnostic pillar calls for access to high-sensitivity diagnostic testing and universal rapid drug susceptibility testing (DST). The recommended diagnostic technologies available in low and middle-income, high-burden countries for multidrug-resistant tuberculosis (MDR-TB) are essentially limited to Xpert ® MTB/RIF and MTB/RIF Ultra assays, culture DST and the line-probe assays. The primary reasons for slow scale-up are insufficient political will, and therefore, insufficient funding for qualified human resources, and safe laboratory and health system infrastructure. Innovative approaches to enable the private health sector to provide high-quality diagnosis are also needed. The Essential Diagnostics List provides impetus and a standard benchmark for the rational implementation of MDR-TB diagnostics, but the epidemic will ultimately only be favorably impacted by complete end-to-end solutions to patients that address the complete cascade of care, including patient-centered diagnosis and treatment of TB and MDR-TB, management of comorbidities and social protection. By scaling up access to the currently available diagnostics, we lay the groundwork for future innovations for rapid accurate diagnosis of MDR-TB, which in turn will bring us closer to meeting the targets in the End TB Strategy.

The aim of this study was to characterize the outcomes of traumatic abdominal and pelvic vascular injuries. Using the 2012 National Trauma Data Bank, we identified 5858 patients with major abdominal and/or pelvic vascular injury. Patients were stratified by age group, gender, race, Injury Severity Score (ISS), and mechanism of injury. We evaluated the percentage of patients with blunt and penetrating trauma by demographic and correlated the mechanism of injury to the ISS score, emergency room disposition, and hospital disposition. We performed a logistic regression analysis to calculate predictors of death. In the final cohort, 1458 patients (25%) with abdominal/pelvic vascular injury died of trauma. In total, 3368 patients (57%) had a blunt mechanism of injury, whereas 2353 (40%) were victims of a penetrating trauma. Patients with penetrating injuries were 1.72 times more likely to die from their injuries than those with blunt traumas. Patients with higher ISS scores (>16) were more likely to die from their injuries than patients with lower ISS scores. Men were more likely to experience a penetrating vascular injury than women (48% vs 17%). Similarly, 77 per cent of black patients had a penetrating mechanism of injury compared with 20 per cent of white patients. There were 1910 patients with penetrating injuries (81%) that went immediately from the emergency room to the OR, compared with 1287 patients with blunt injuries (38%). Of the patients with blunt injuries, 695 (21%) died, whereas 727 (31%) patients with penetrating injuries died. Abdominal and pelvic traumatic vascular injuries carry a high mortality rate. Penetrating mechanism of injury, ISS score, and race are independent predictors of mortality.

Competent, efficient, and cost-effective delivery of professional development is a challenge in health care. Collaboration of teaching methodologies with academia and acute care offers fresh perspectives and delivery methods that can facilitate optimal outcomes. One multihospital system introduced the academic "flipped classroom" model to its acute care setting and integrated it into professional development requirements. The concept of the flipped classroom requires independent student engagement prior to classroom activities versus the traditional classroom lecture model. Results realized a cost savings in 2 years of $28,737 in addition to positive employee engagement.

Background: Many patients experience extended stays within forensic care, but the characteristics of long-stay patients are poorly understood. Aims: To describe the characteristics of long-stay patients in high and medium secure settings in England. Method: Detailed file reviews provided clinical, offending and risk data for a large representative sample of 401 forensic patients from 2 of the 3 high secure settings and from 23 of the 57 medium secure settings in England on 1 April 2013. The threshold for long-stay status was defined as 5 years in medium secure care or 10 years in high secure care, or 15 years in a combination of high and medium secure settings. Results: 22% of patients in high security and 18% in medium security met the definition for "long-stay," with 20% staying longer than 20 years. Of the long-stay sample, 58% were violent offenders (22% both sexual and violent), 27% had been convicted for violent or sexual offences whilst in an institutional setting, and 26% had committed a serious assault on staff in the last 5 years. The most prevalent diagnosis was schizophrenia (60%) followed by personality disorder (47%, predominantly antisocial and borderline types); 16% were categorised as having an intellectual disability. Overall, 7% of the long-stay sample had never been convicted of any offence, and 16.5% had no index offence prompting admission. Although some significant differences were found between the high and medium secure samples, there were more similarities than contrasts between these two levels of security. The treatment pathways of these long-stay patients involved multiple moves between settings. An unsuccessful referral to a setting of lower security was recorded over the last 5 years for 33% of the sample. Conclusions: Long-stay patients accounted for one fifth of the forensic inpatient population in England in this representative sample. A significant proportion of this group remain unsettled. High levels of personality pathology and the risk of assaults on staff and others within the care setting are likely to impact on treatment and management. Further research into the treatment pathways of longer stay patients is warranted to understand the complex trajectories of this group.

A recent flow cytometry-based in vivo mutagenicity assay involves the hemizygous phosphatidylinositol class A (Pig-a) gene. Pig-a forms the catalytic subunit of N-acetylglucosaminyltransferase required for glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in Pig-a prevent GPI-anchor synthesis resulting in loss of cell-surface GPI-linked proteins. The aim of the current study was to develop and validate an in vitro Pig-a assay in L5178Y mouse lymphoma cells. Ethyl methanesulfonate (EMS)-treated cells (186.24-558.72 µg/ml; 24 h) were used for method development and antibodies against GPI-linked CD90.2 and stably expressed CD45 were used to determine GPI-status by flow cytometry. Antibody concentration and incubation times were optimised (0.18 µg/ml, 30 min, 4 °C) and Zombie Violet™ (viability marker; 0.5%, 30 min, RT) was included. The optimum phenotypic expression period was 8 days. The low background mutation frequency of GPI-deficiency [GPI(-)] in L5178Y cells (0.1%) constitutes a rare event, thus flow cytometry acquisition parameters were optimised; 10 4 cells were measured at medium flow rate to ensure a CV ≤ 30%. Spiking known numbers of GPI(-) cells into a wild-type population gave high correlation between measured and spiked numbers (R 2 0.999). We applied the in vitro Pig-a assay to a selection of well-validated genotoxic and non-genotoxic compounds. EMS, N-ethyl-N-nitrosourea and 4-nitroquinoline-N-oxide dose dependently increased numbers of GPI(-) cells, while etoposide, mitomycin C, and a bacterial-specific mutagen did not. Cycloheximide and sodium chloride were negative. Sanger sequencing revealed Pig-a mutations in the GPI(-) clones. In conclusion, this in vitro Pig-a assay could complement the in vivo version, and follow up weak Ames positives and late-stage human metabolites or impurities.

A transition metal-free strategy for the dehydrogenative β-sulfonylation of tertiary cyclic amines is described. N -Iodosuccinimide facilitates regioselective oxidative sulfonylation at C-H bonds positioned β to the nitrogen atom of tertiary amines, installing enaminyl sulfone functionality in cyclic systems. Mild reaction conditions, broad functional group tolerance and a wide substrate scope are demonstrated. The nucleophilic character of the enaminyl sulfone is harnessed, demonstrating potential application for scaffold diversification.

Setting: Five human immunodeficiency virus (HIV) care facilities in Swaziland., Objective: To assess adherence and treatment completion of a 6-month course of isoniazid preventive therapy (IPT) provided to HIV-infected patients through a self-selected model of facility-based, community-based or peer-supported IPT delivery coordinated with antiretroviral refills., Design: Prospective cohort study., Results: Between February and August 2015, we enrolled 908 patients, with follow-up until February 2016. Most were female (66.2%), with a median age of 38 years (interquartile range 31-45). Most (n = 797, 87.8%) chose facility-based delivery, 111 (12.2%) selected community-based delivery, and none selected peer-supported delivery. Adherence was high in both cohorts; among those with available data, 794 (94.8%) reported taking at least 80% of their IPT (P > 0.05). Twenty-two patients screened positive for tuberculosis (TB) at any visit; all had TB excluded and most continued IPT. In total, 812 (89.4%) patients completed treatment: 711 (89.2%) were on facility-based and 111 (91.0%) on community-based IPT (P > 0.05). No confirmed treatment failures occurred. Few patients discontinued IPT (6.3%) or were lost to follow-up (4.1%)., Conclusion: Self-selected IPT delivery aligned with HIV care achieved high rates of adherence and treatment completion. This model may improve outcomes by simplifying clinic visits and conferring agency to the patient, and may be readily implemented in similar high TB-HIV burden settings.

Introduction: People with involvement in forensic psychiatric services face many obstacles to employment, arising from their offending, as well as their mental health problems. This study aims to assess the feasibility of conducting a randomised controlled trial (RCT) to evaluate the effectiveness of individual placement and support (IPS), in improving employment rates and associated psychosocial outcomes in forensic psychiatric populations. IPS has been found consistently to achieve employment rates above 50% in psychiatric patients without a history of involvement in criminal justice services., Methods/design: This is a single-centre feasibility cluster RCT. Clusters will be defined according to clinical services in the community forensic services of Nottinghamshire Healthcare NHS Foundation Trust (NHCT). IPS will be implemented into 2 of the randomly assigned intervention clusters in the community forensic services of NHCT. A feasibility cluster RCT will estimate the parameters required to design a full RCT. The primary outcome is the proportion of people in open employment at 12-month follow-up. Secondary outcome measures will include employment, educational activities, psychosocial and economic outcomes, as well as reoffending rates. Outcome measures will be recorded at baseline, 6 months and 12 months. In accordance with the UK Medical Research Council guidelines on the evaluation of complex interventions, a process evaluation will be carried out; qualitative interviews with patients and staff will explore general views of IPS as well as barriers and facilitators to implementation. Fidelity reviews will assess the extent to which the services follow the principles of IPS prior, during and at the end of the trial., Ethics and Dissemination: Ethical approval was obtained from the East Midlands Research Ethics Committee-Nottingham 1 (REC reference number 15/EM/0253). Final and interim reports will be prepared for project funders, the study sponsor and clinical research network. Findings will be disseminated through peer-reviewed journals, conferences and event presentations., Trial Registration Number: NCT02442193; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Adolescent mental health is characterized by relatively high rates of psychiatric disorders and low levels of help-seeking behaviors. Existing mental health programs aimed at addressing these issues in adolescents have repeated inconsistent results. Such programs have generally been based on techniques derived from cognitive behavioral therapy, which may not be ideally suited to early intervention among adolescent samples. Positive psychology, which seeks to improve well-being rather than alleviate psychological symptoms, offers an alternative approach. A previous community study of adolescents found that informal engagement in an online positive psychology program for up to 6 weeks yielded significant improvements in both well-being and depression symptoms. However, this approach had not been trialed among adolescents in a structured format and within a school setting., Objective: This study examines the feasibility of an online school-based positive psychology program delivered in a structured format over a 6-week period utilizing a workbook to guide students through website content and interactive exercises., Methods: Students from four high schools were randomly allocated by classroom to either the positive psychology condition, "Bite Back", or the control condition. The Bite Back condition consisted of positive psychology exercises and information, while the control condition used a series of non-psychology entertainment websites. Both interventions were delivered online for 6 hours over a period of 4-6 weeks during class time. Symptom measures and measures of well-being/flourishing and life satisfaction were administered at baseline and post intervention., Results: Data were analyzed using multilevel linear modeling. Both conditions demonstrated reductions in depression, stress, and total symptom scores without any significant differences between the two conditions. Both the Bite Back and control conditions also demonstrated significant improvements in life satisfaction scores post intervention. However, only the control condition demonstrated significant increases in flourishing scores post intervention., Conclusions: Results suggest that a structured online positive psychology program administered within the school curriculum was not effective when compared to the control condition. The limitations of online program delivery in school settings including logistic considerations are also relevant to the contradictory findings of this study., Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN1261200057831; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362489 (Archived by Webcite at http://www.webcitation.org/6NXmjwfAy).

Objectives: To evaluate the extent to which lung cancer mortality risk estimates in relation to acrylonitrile (AN) exposure may have been confounded by smoking in the presence of misclassified smoking data., Methods: Subjects were 992 white men employed for three or more months between 1960 and 1996 at a chemical plant in Lima, Ohio. We used Monte Carlo-based sensitivity analysis to address possible confounding by smoking., Results: In Monte Carlo simulations that accounted for the relationship between smoking and AN exposure, mean relative risks for lung cancer mortality in relation to AN exposure decreased and we observed somewhat less evidence of an exposure-response relationship., Conclusions: Our simulations suggest that the relationship between AN exposure and lung cancer mortality was positively confounded by smoking in the original Lima cohort study.

Setting: Health care facilities in Dar es Salaam, Pwani, and Arusha, Tanzania., Objective: To assess health care worker (HCW) knowledge and practices 1 year after specialized training in childhood tuberculosis (TB)., Design: Using a standardized survey, we interviewed a convenience sample of HCWs providing both general and specialized care to children., Results: We interviewed 117 HCWs in TB clinics, maternal and child health clinics, human immunodeficiency virus (HIV) clinics, out-patient departments, and pediatric in-patient wards at 12 facilities. A total of 81 HCWs (62% of nurses, 74% of clinicians) reported having attended the national childhood TB training course. Most HCWs responded correctly to questions on childhood TB diagnosis, treatment, and TB-HIV co-management, regardless of training history. Most HCWs reported that they routinely obtain chest radiographs, HIV testing, and a TB contact history when evaluating children for TB. Less than half of HCWs reported routinely obtaining sputum for mycobacterial culture or performing a tuberculin skin test. Three times as many trained as untrained HCWs reported having ever prescribed isoniazid preventive therapy (IPT) to a child (P < 0.05)., Conclusion: In general, levels of childhood TB knowledge were high and practices were in accordance with national guidance. Specific gaps in diagnosis, treatment and use of IPT were identified for future focused training.

To unambiguously evaluate the indium and nitrogen concentrations in In(x)Ga(1-x)N(y)As(1-y), two independent sources of information must be obtained experimentally. Based on high-resolution scanning transmission electron microscopy (STEM) images taken with a high-angle annular dark-field (HAADF) detector the strain state of the InGaNAs quantum well is determined as well as its characteristic HAADF-scattering intensity. The strain state is evaluated by applying elasticity theory and the HAADF intensity is used for a comparison with multislice simulations. The combination of both allows for determination of the chemical composition where the results are in accordance with X-ray diffraction measurements, three-dimensional atom probe tomography, and further transmission electron microscopy analysis. The HAADF-STEM evaluation was used to investigate the influence of As-stabilized annealing on the InGaNAs/GaAs sample. Photoluminescence measurements show an annealing-induced blue shift of the emission wavelength. The chemical analysis precludes an elemental diffusion as origin of the energy shift--instead the results are in agreement with a model based on an annealing-induced redistribution of the atomic next-neighbor configuration.

The present study examined the social foraging of rats in an open arena. The relative quantity of food varied across two food sources, or "patches." Five food quantity ratios (1:1, 1:2, 1:8, 8:1, 2:1) were presented in a series of 30-min sessions. Ratios varied randomly across 6-min components within sessions (Phase 1), or in a consistent order across sessions (Phase 2). Group and individual preferences were well described by the ideal free distribution and the generalized matching law, respectively, with evidence of undermatching at both group and individual levels. Sensitivity of individual and collective behavior to the relative quantities of food was higher in Phase 2 than in Phase 1. Competitiveness rankings, assessed before and after experimental sessions by delivering food in rapid succession from a single feeder, was positively related to sensitivity values in Phase 1, but less consistently so in Phase 2. This study illustrates a promising experimental method for investigating foraging in a social context., (© Society for the Experimental Analysis of Behavior.)

Cerebellar Mutism Syndrome (CMS), also known as posterior fossa syndrome (CMS/PFS), refers to a transient loss of speech followed by dysarthria and is a common complication in the pediatric population following resection of a cerebellar tumor. Recognition and rehabilitation of CMS is critical in the post-operative phases of recovery. Two case studies, including neuropsychological assessments, along with the family and patient's perspectives are reviewed.

Due to the quantum confinement, silicon nanoclusters (Si-ncs) embedded in a dielectric matrix are of prime interest for new optoelectronics and microelectronics applications. In this context, SiO(x)/SiO₂ multilayers have been prepared by magnetron sputtering and subsequently annealed to induce phase separation and Si clusters growth. The aim of this paper is to study phase separation processes and formation of nanoclusters in SiO(x)/SiO₂ multilayers by atom probe tomography. Influences of the silicon supersaturation, annealing temperature and SiO(x) and SiO₂ layer thicknesses on the final microstructure have been investigated. It is shown that supersaturation directly determines phase separation regime between nucleation/classical growth and spinodal decomposition. Annealing temperature controls size of the particles and interface with the surrounding matrix. Layer thicknesses directly control Si-nc shapes from spherical to spinodal-like structures., (Copyright © 2012 Elsevier B.V. All rights reserved.)

: Photoluminescence spectroscopy and atom probe tomography were used to explore the optical activity and microstructure of Er3+-doped Si-rich SiO2 thin films fabricated by radio-frequency magnetron sputtering. The effect of post-fabrication annealing treatment on the properties of the films was investigated. The evolution of the nanoscale structure upon an annealing treatment was found to control the interrelation between the radiative recombination of the carriers via Si clusters and via 4f shell transitions in Er3+ ions. The most efficient 1.53-μm Er3+ photoluminescence was observed from the films submitted to low-temperature treatment ranging from 600°C to 900°C. An annealing treatment at 1,100°C, used often to form Si nanocrystallites, favors an intense emission in visible spectral range with the maximum peak at about 740 nm. Along with this, a drastic decrease of 1.53-μm Er3+ photoluminescence emission was detected. The atom probe results demonstrated that the clustering of Er3+ ions upon such high-temperature annealing treatment was the main reason. The diffusion parameters of Si and Er3+ ions as well as a chemical composition of different clusters were also obtained. The films annealed at 1,100°C contain pure spherical Si nanocrystallites, ErSi3O6 clusters, and free Er3+ ions embedded in SiO2 host. The mean size and the density of Si nanocrystallites were found to be 1.3± 0.3 nm and (3.1± 0.2)×1018 Si nanocrystallites·cm-3, respectively. The density of ErSi3O6 clusters was estimated to be (2.0± 0.2)×1018 clusters·cm-3, keeping about 30% of the total Er3+ amount. These Er-rich clusters had a mean radius of about 1.5 nm and demonstrated preferable formation in the vicinity of Si nanocrystallites.

Two-dimensional hexagonally ordered honeycomb surfaces have been created by solvent casting polybutadiene films under controlled humidity. Subsequent CF(4) plasmachemical fluorination introduces cross-linking and surface texturing, leading to hierarchical surfaces with roughness on both the 10 μm (honeycomb) and micrometer (texturing) length scales. For microliter droplets, these display high water contact angle values (>170°) in combination with low contact angle hysteresis (i.e., superhydrophobicity) while displaying bouncing of picoliter water droplets. In the case of picoliter droplets, it is found that surfaces which exhibit similar static contact angles can give rise to different droplet impact dynamics, governed by the underlying surface topography. These studies are of relevance to technological processes such as rapid cooling, delayed freezing, crop spraying, and inkjet printing.

The evaporation of picoliter water and ethanol droplets generated by drop-on-demand inkjet printing was investigated on substrates with apparent contact angles between 10^{∘} and 135^{∘} and thermal conductivities between 0.25 and 149 Wm^{-1}K^{-1}. Drying times were calculated from a diffusion-limited model for droplets with both pinned and moving contact lines as a function of droplet diameter and apparent contact angle. Droplets with a moving contact line take longer to dry on hydrophilic substrates than pinned droplets. The difference in drying times between evaporative modes vanishes at large apparent contact angles. Hence similar drying times are obtained for both modes on hydrophobic substrates. The predicted drying times for glass and silicon substrates were in good quantitative agreement with experimental data, suggesting that thermal effects are negligible for substrates of these base materials. However, on a PTFE substrate which has a lower thermal conductivity more relevant to inkjet printing, evaporative cooling reduces the evaporation rate causing drying times to be underpredicted by isothermal models.

Background: Tuberculosis is the most common cause of death among patients with HIV infection living in tuberculosis endemic countries, but many cases are not diagnosed pre-mortem. We assessed the test characteristics of urinary lipoarabinomannan (LAM) and predictors of mortality among HIV-associated tuberculosis suspects in Tanzania., Methods: We prospectively enrolled hospitalized HIV-infected patients in Dar es Salaam, with ≥2 weeks of cough or fever, or weight loss. Subjects gave 2 mLs of urine to test for LAM using a commercially available ELISA, ≥2 sputum specimens for concentrated AFB smear and solid media culture, and 40 mLs of blood for culture., Results: Among 212 evaluable subjects, 143 (68%) were female; mean age was 36 years; and the median CD4 count 86 cells/mm(3). 69 subjects (33%) had culture confirmation of tuberculosis and 65 (31%) were LAM positive. For 69 cases of sputum or blood culture-confirmed tuberculosis, LAM sensitivity was 65% and specificity 86% compared to 36% and 98% for sputum smear. LAM test characteristics were not different in patients with bacteremia but showed higher sensitivity and lower specificity with decreasing CD4 cell count. Two month mortality was 64 (53%) of 121 with outcomes available. In multivariate analysis there was significant association of mortality with absence of anti-retroviral therapy (p = 0.004) and a trend toward association with a positive urine LAM (p = 0.16). Among culture-negative patients mortality was 9 (75%) of 12 in LAM positive patients and 27 (38%) of 71 in LAM negative patients (p = 0.02)., Conclusions: Urine LAM is more sensitive than sputum smear and has utility for the rapid diagnosis of culture-confirmed tuberculosis in this high-risk population. Mortality data raise the possibility that urine LAM may also be a marker for culture-negative tuberculosis.

Lipoarabinomannan (LAM) is a potential marker of active tuberculosis (TB). We performed a systematic review and meta-analysis regarding use of urinary LAM assays for diagnosing active TB. We systematically searched for published and unpublished studies that evaluated urinary LAM for active TB diagnosis. Extracted data were pooled using bivariate random effects models and hierarchical summary receiver operating characteristic curves. Heterogeneity was explored through subgroup analysis and meta-regression. Quality was assessed according to standardised QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. In seven studies that assessed test accuracy in microbiologically confirmed cases only, estimates of sensitivity ranged from 13% to 93%, while specificity ranged from 87% to 99%. In five studies that assessed accuracy in clinical and confirmed TB cases, sensitivity ranged from 8% to 80%, while specificity ranged from 88% to 99%. In five studies with results stratified by HIV status, sensitivity was 3-53% higher in HIV-positive than HIV-negative subgroups; sensitivity was highest with advanced immunosuppression. The LAM urinary assay has several characteristics that make it attractive for diagnosing active TB, but has suboptimal sensitivity for routine clinical use. Further studies are needed to evaluate the potential value of the LAM assay in individuals with advanced HIV or for diagnosis of paediatric TB.

The impact of picoliter-sized water droplets on superhydrophobic CF(4) plasma fluorinated polybutadiene surfaces is investigated with high-speed imaging. Variation of the surface topography by plasmachemical modification enables the dynamics of wetting to be precisely controlled. Final spreading ratios as low as 0.63 can be achieved. A comparison of the maximum spreading ratio and droplet oscillation frequencies to models described in the literature shows that both are found to be much lower than theoretically predicted.

In this study, we have performed nanoscale characterization of Si-clusters and Si-nanowires with a laser-assisted tomographic atom probe. Intrinsic and p-type silicon nanowires (SiNWs) are elaborated by chemical vapor deposition method using gold as catalyst, silane as silicon precursor, and diborane as dopant reactant. The concentration and distribution of impurity (gold) and dopant (boron) in SiNW are investigated and discussed. Silicon nanoclusters are produced by thermal annealing of silicon-rich silicon oxide and silica multilayers. In this process, atom probe tomography (APT) provides accurate information on the silicon nanoparticles and the chemistry of the nanolayers.

Silicon nanoclusters are of prime interest for new generation of optoelectronic and microelectronics components. Physical properties (light emission, carrier storage...) of systems using such nanoclusters are strongly dependent on nanostructural characteristics. These characteristics (size, composition, distribution, and interface nature) are until now obtained using conventional high-resolution analytic methods, such as high-resolution transmission electron microscopy, EFTEM, or EELS. In this article, a complementary technique, the atom probe tomography, was used for studying a multilayer (ML) system containing silicon clusters. Such a technique and its analysis give information on the structure at the atomic level and allow obtaining complementary information with respect to other techniques. A description of the different steps for such analysis: sample preparation, atom probe analysis, and data treatment are detailed. An atomic scale description of the Si nanoclusters/SiO2 ML will be fully described. This system is composed of 3.8-nm-thick SiO layers and 4-nm-thick SiO2 layers annealed 1 h at 900°C.

Nanosized Co clusters (of about 3 nm size) were unambiguously identified in Co-doped ZnO thin films by atom probe tomography. These clusters are directly correlated to the superparamagnetic relaxation observed by ZFC/FC magnetization measurements. These analyses provide strong evidence that the room-temperature ferromagnetism observed in the magnetization curves cannot be attributed to the observed Co clusters. Because there is no experimental evidence of the presence of other secondary phases, our results reinforce the assumption of a defect-induced ferromagnetism in Co-doped ZnO diluted magnetic semiconductors.

Objectives: This study investigated the immunologic responses and employment history of highly-active antiretroviral therapy (HAART) patients., Design: We interviewed patients and reviewed medical records to collect demographic, clinical, and employment history while on HAART. Demographic characteristics were tested as predictors of immunological response while on HAART using hierarchical linear models., Setting: Fevers Unit, Korle-Bu Teaching Hospital, Accra, Ghana, Participants: Subjects comprised a convenience sample of adult HAART patients receiving therapy for at least 9 months. 270 patients were interviewed. 38 were excluded due to inadequate time on HAART or inability to locate all necessary patient information., Intervention: This was an observational study., Main Outcome Measures: We investigated the change in CD4 cell count and weight since the initiation of therapy, and their ability to maintain or regain employment as well as the reasons for this., Results: The estimated mean ± standard error increase in CD4 cell count from baseline at 6, 12, and 18 months were 102 ± 5, 204 ± 11, and 236 ± 10 cells/µL, respectively. Overall, 147 patients (63.4%) reported remaining employed or obtaining new employment while on HAART. Patients who were asymptomatic at initial presentation were more likely to remain employed or returned to work while on HAART than those who were symptomatic (66.4% vs. 48.8%, P = 0.009). Most patients were employed in the informal sector, which made their economic situation particularly vulnerable to HIV-associated illness., Conclusion: The findings suggest that patients receiving HAART experience good clinical and immunological responses as well as improvement in employment status.

Background: Although arctic lakes have responded sensitively to 20(th)-century climate change, it remains uncertain how these ecological transformations compare with alpine and montane-boreal counterparts over the same interval. Furthermore, it is unclear to what degree other forcings, including atmospheric deposition of anthropogenic reactive nitrogen (Nr), have participated in recent regime shifts. Diatom-based paleolimnological syntheses offer an effective tool for retrospective assessments of past and ongoing changes in remote lake ecosystems., Methodology/principal Findings: We synthesized 52 dated sediment diatom records from lakes in western North America and west Greenland, spanning broad latitudinal and altitudinal gradients, and representing alpine (n = 15), arctic (n = 20), and forested boreal-montane (n = 17) ecosystems. Diatom compositional turnover (beta-diversity) during the 20(th) century was estimated using Detrended Canonical Correspondence Analysis (DCCA) for each site and compared, for cores with sufficiently robust chronologies, to both the 19(th) century and the prior approximately 250 years (Little Ice Age). For both arctic and alpine lakes, beta-diversity during the 20(th) century is significantly greater than the previous 350 years, and increases with both latitude and altitude. Because no correlation is apparent between 20(th)-century diatom beta-diversity and any single physical or limnological parameter (including lake and catchment area, maximum depth, pH, conductivity, [NO(3)(-)], modeled Nr deposition, ambient summer and winter air temperatures, and modeled temperature trends 1948-2008), we used Principal Components Analysis (PCA) to summarize the amplitude of recent changes in relationship to lake pH, lake:catchment area ratio, modeled Nr deposition, and recent temperature trends., Conclusions/significance: The ecological responses of remote lakes to post-industrial environmental changes are complex. However, two regions reveal concentrations of sites with elevated 20(th)-century diatom beta-diversity: the Arctic where temperatures are increasing most rapidly, and mid-latitude alpine lakes impacted by high Nr deposition rates. We predict that remote lakes will continue to shift towards new ecological states in the Anthropocene, particularly in regions where these two forcings begin to intersect geographically.

Tuberculosis kills over 1.7 million people worldwide every year and nearly 40% of patients with active tuberculosis remain undiagnosed because of the poor sensitivity of the current, century old diagnostic method: sputum microscopy. Sputum microscopy is not able to easily detect paediatric, extrapulmonary, or HIV-associated tuberculosis, which are now important causes of morbidity and mortality in developing countries. Newer diagnostic methods for tuberculosis remain less sensitive than sputum microscopy. Alternative strategies to diagnose tuberculosis by use of nucleic acid amplification methods to detect fragments of mycobacterial DNA in urine have been developed over the past decade with varying sensitivities and specificities. Methods using quantitative PCR on urine samples to detect transrenal mycobacterial DNA are under development. The detection of transrenal DNA makes it possible to assay the total body burden of mycobacterial infection in any age group and in extrapulmonary tuberculosis with urine samples, which can be collected non-invasively. This Review discusses the developments and application of nucleic acid amplification of mycobacterial transrenal DNA for improved tuberculosis diagnostics.

The present article reports on the platination of the human telomeric G-quadruplex by three Pt-terpyridine complexes. It is shown that extension of the aromatic surface of the terpyridine moiety surrounding the platinum atom influences both the binding affinity and the platination activity. Remarkably, the most strongly bound complex Pt-ttpy coordinates exclusively the adenine nucleobases present in the loop of the G-quadruplex. This exclusive single-site platination reflects the interaction of the compound with both the G-tetrad and the loop residues. In addition Pt-ttpy showed promising antiproliferative activity on a panel of cancer cell lines in a parallel study using cisplatin derivatives currently in clinical use.

Setting: Isoniazid preventive therapy (IPT) has not been widely implemented due to questions about acceptance, adherence and side effects., Objective: To examine factors related to completion of IPT among human immunodeficiency virus (HIV) infected subjects in Tanzania., Design: HIV-infected subjects in the DarDar TB vaccine trial with CD4 cell counts >or=200 cells/mm(3) and a positive tuberculin skin test (TST) were counseled, offered IPT for 6 months and seen monthly., Results: Among 1932 subjects, TST results were positive in 631 (33%): 568 (90%) were offered IPT, 565 (99%) accepted and three (<1%) refused. Of the 565 subjects who accepted IPT, 493 (87%) completed treatment and 72 (13%) did not. Non-completion was physician-initiated in 24 (33%, due to active TB or side effects), patient-initiated in 42 (58%, due to self-cessation or loss to follow-up) and due to death in 6 (8%, unrelated to IPT). Interviews were conducted among 109 completers and 20 non-completers (12 physician- and 8 patient-initiated). Completers were motivated by fear of TB (44%), understanding the importance of IPT (32%) and counseling (22%). Patient-initiated non-completers were dissuaded by stigma (58%), side effects (14%) and travel distance (1%)., Conclusions: HIV-infected subjects provided with counseling, monthly follow-up and travel reimbursement have high rates of IPT completion with minimal side effects.

Salmonella Newport causes more than an estimated 100,000 infections annually in the United States. In 2002, tomatoes grown and packed on the eastern shore of Virginia contaminated with a pan-susceptible S. Newport strain caused illness in 510 patients in 26 states. In July-November 2005, the same strain caused illness in at least 72 patients in 16 states. We conducted a case-control study during the 2005 outbreak, enrolling 29 cases and 140 matched neighbourhood controls. Infection was associated with eating tomatoes (matched odds ratio 9.7, 95% confidence interval 3.3-34.9). Tomatoes were traced back to the eastern shore of Virginia, where the outbreak strain was isolated from pond water used to irrigate tomato fields. Two multistate outbreaks caused by one rare strain, and identification of that strain in irrigation ponds 2 years apart, suggest persistent contamination of tomato fields. Further efforts are needed to prevent produce contamination on farms and throughout the food supply chain.

Encephalitis is an inflammation of brain tissue that can result from a number of viruses and can be contracted at any age, with prevalence in children exceeding adult incidence. In order to illustrate specific cognitive, behavioural and service provision issues related to post-encephalitis rehabilitation of children, this paper examines the pattern of referrals to a specialist regional paediatric neuropsychology service in the United Kingdom. Three case vignettes are presented to demonstrate the wide range of presentations encountered in our service ranging from mild (10%) to moderate (65%) and severe (25%) impairment with 80% of referrals relating to behaviour and educational concerns. On average 13 new referrals are received annually resulting in a cumulative case-load due to the need for serial assessment. The implications for patient care are discussed.

The presence of linkage disequilibrium violates the underlying assumption of linkage equilibrium in most traditional multipoint linkage approaches. Studies have shown that such violation leads to bias in qualitative trait linkage analysis when parental genotypes are unavailable. Appropriate handling of marker linkage disequilibrium can avoid such false positive evidence. Using the rheumatoid arthritis simulated data from Genetic Analysis Workshop 15, we examined and compared the following three approaches to handle linkage disequilibrium among dense markers in both qualitative and quantitative trait linkage analyses: a simple algorithm; SNPLINK, methods for marker selection; and MERLIN-LD, a method for modeling linkage disequilibrium by creating marker clusters. In analysis ignoring linkage disequilibrium between markers, we observed LOD score inflation only in the affected sib-pair linkage analysis without parental genotypes; no such inflation was present in the quantitative trait locus linkage analysis with severity as our phenotype with or without parental genotypes. Using methods to model or adjust for linkage disequilibrium, we found a substantial reduction of inflation of LOD score in affected sib-pair linkage analysis. Greater LOD score reduction was observed by decreasing the amount of tolerable linkage disequilibrium among markers selected or marker clusters using MERLIN-LD; the latter approach showed most reduction. SNPLINK performed better with selected markers based on the D' measure of linkage disequilibrium as opposed to the r2 measure and outperformed the simple algorithm. Our findings reiterate the necessity of properly handling dense markers in linkage analysis, especially when parental genotypes are unavailable.

Fifty-five paleolimnological records from lakes in the circumpolar Arctic reveal widespread species changes and ecological reorganizations in algae and invertebrate communities since approximately anno Domini 1850. The remoteness of these sites, coupled with the ecological characteristics of taxa involved, indicate that changes are primarily driven by climate warming through lengthening of the summer growing season and related limnological changes. The widespread distribution and similar character of these changes indicate that the opportunity to study arctic ecosystems unaffected by human influences may have disappeared.

Objective and Design: Interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and matrix metalloproteinases (MMPs) play important roles in the pathogenesis of osteoarthritis (OA). In the present study, using Affymetrix oligonucleotide array technology and real-time quantitative RT-PCR we have investigated the molecular mechanisms underlying the differential effect of IL-1 and TNF-alpha on gene expression in the human chondrosarcoma cell line, SW1353., Materials and Methods: SW1353 cells were stimulated singularly with IL-1alpha, TNF-alpha, Phorbol 12-myristate 13-acetate (PMA), or treated with the combination of cytokine and PMA. Total RNA was collected at multiple time points over a 24-h period followed by biotinylated cRNA target preparation and hybridization onto the Affymetrix HG-U95Av2 array. The differential expression patterns of several cytokine and MMP genes were further confirmed by real time quantitative RT-PCR, Western blot, and ELISA., Results: Our microarray experiments have broadly confirmed previously published data on chondrocyte gene expression regulated by IL-1 and TNF-alpha. The expression pattern of proIL-1beta, MMP-1, and MMP-13 in chondrocytes is differentially regulated when stimulated with proinflammatory cytokines. IL-1, but not TNF-alpha, can induce IL-6, bone morphogenic protein 2 (BMP-2), and cyclooxygenase (COX-2) expression in SW1353 cells. Additionally, our Western blot results provide the first evidence that IL-1beta is produced in the proform in IL-1alpha-activated chondrosarcoma cells and that additional signals are required for its posttranslational processing/activation., Conclusions: IL-1 and TNF-alpha each activate a distinct set of genes in chondrosarcoma cells, and gene expression in these cells is regulated by groups of genes related in part by their function. Chondrocyte IL-1alpha appears to serve an important role in the pathogenesis OA contributing to joint inflammation and cartilage destruction., (Copyright 2004 Birkhäuser Verlag, Basel)

To exclude tuberculosis, WHO/UNAIDS recommends considering medical history, symptom screen, and chest radiograph before starting tuberculosis prevention in people infected with HIV. The value of a chest radiograph for this purpose is unknown. We prospectively assessed 935 HIV-infected outpatients seeking isoniazid preventive therapy. Of 935 patients, 692 (74%) had no signs or symptoms of tuberculosis. Of these 692, 123 (18%) were lost during the chest radiograph process, and one (0.2%) of the remaining 563 was diagnosed with tuberculosis on the basis of the chest radiograph. A screening chest radiograph should not be required routinely for asymptomatic people taking isoniazid as preventive treatment in settings able to screen for signs and symptoms of tuberculosis.

Setting: The World Health Organization recommends that sentinel HIV surveillance be conducted on tuberculosis patients. However, serum HIV testing is complicated in the TB clinic context, and may not be acceptable to patients., Design: To determine the utility of the OraQuick HIV-1/2 Assay for the detection of HIV antibodies in sputum, we consecutively enrolled adult in-patients in Botswana who had sputum sent for acid-fast bacilli testing and serum sent for HIV ELISA testing. OraQuick HIV-1/2 Assay was applied to gingival secretions according to manufacturer's guidelines, and was also dipped into sputum specimens. A subset of 60 sputum specimens was also serially tested up to 72 hours after collection., Results: Of 377 patients, 84% were HIV-positive by serum ELISA. Compared with serum ELISA, the OraQuick HIV-1/2 Assay detected HIV in gingival secretions with 98.4% sensitivity and 98.3% specificity (95%CI 97-99 and 92-100, respectively), and 97.1% sensitivity and 98.3% specificity on initial sputum specimens (95%CI 95-99 and 92-100, respectively). OraQuick HIV-1/2 Assay performance on sputum declined slightly when tested up to 72 hours after collection., Conclusions: When applied to sputum specimens, the OraQuick HIV-1/2 Assay demonstrates sensitivity and specificity comparable to its intended application on gingival secretions. This novel testing method will be valuable in anonymous sentinel HIV surveillance surveys among tuberculosis patients.