Understanding experiences of potential harm among MSM (cis and trans) using HIV self-testing in the SELPHI randomised controlled trial in England and Wales: a mixed-methods study.

BACKGROUND: The potential of HIV self-testing (HIVST) to cause harm is a concern hindering widespread implementation. The aim of this paper is to understand the relationship between HIVST and harm in SELPHI (An HIV Self-testing Public Health Intervention), the largest randomised trial of HIVST in a high-income country to date. METHODS: 10 111 cis and trans men who have sex with men (MSM) recruited online (geolocation social/sexual networking apps, social media), aged 16+, reporting previous anal intercourse and resident in England or Wales were first randomised 60/40 to baseline HIVST (baseline testing, BT) or not (no baseline testing, nBT) (randomisation A). BT participants reporting negative baseline test, sexual risk at 3 months and interest in further HIVST were randomised to three-monthly HIVST (repeat testing, RT) or not (no repeat testing, nRT) (randomisation B). All received an exit survey collecting data on harms (to relationships, well-being, false results or being pressured/persuaded to test). Nine participants reporting harm were interviewed in-depth about their experiences in an exploratory substudy; qualitative data were analysed narratively. RESULTS: Baseline: predominantly cis MSM, 90% white, 88% gay, 47% university educated and 7% current/former pre-exposure prophylaxis (PrEP) users. Final survey response rate was: nBT=26% (1056/4062), BT=45% (1674/3741), nRT=41% (471/1147), RT=50% (581/1161).Harms were rare and reported by 4% (n=138/3691) in exit surveys, with an additional two false positive results captured in other study surveys. 1% reported harm to relationships and to well-being in BT, nRT and RT combined. In all arms combined, being pressured or persuaded to test was reported by 1% (n=54/3678) and false positive results in 0.7% (n=34/4665).Qualitative analysis revealed harms arose from the kit itself (technological harms), the intervention (intervention harms) or from the social context of the participant (socially emergent harms). Intervention and socially emergent harms did not reduce HIVST acceptability, whereas technological harms did. DISCUSSION: HIVST harms were rare but strategies to link individuals experiencing harms with psychosocial support should be considered for HIVST scale-up. TRIAL REGISTRATION NUMBER: ISRCTN20312003.

Inactivation of Group I and Group II Clostridium botulinum spores by ultraviolet irradiation in water.

Spores of Clostridium botulinum are widely distributed in the environment, including in foods. Prevention of foodborne botulism relies on the inhibition of spore germination and subsequent growth and toxin production, or the destruction of viable spores in food and beverages. This study examined the lethality of 254 nm UV radiation (UV-C) to spores of Group I and Group II C. botulinum. Spores of C. botulinum were inactivated by UV-C, with doses required for incremental log reduction (D10) values calculated using linear regression ranging from 2.87 to 3.70 mJ/cm2 for Group I strains and 4.46 to 6.15 mJ/cm2 for Group II strains. The measured D10 value for spores of C. sporogenes ATCC 19404 was 8.27 mJ/cm2 indicating it was more resistant than the strains of C. botulinum used in this study. Calculation of dose per log using a Weibull model resulted in higher D10 values of 6.67 to 8.81 mJ/cm2 for Group I strains and 9.24 to 10.7 mJ/cm2 for Group II strains. Spores of C. sporogenes possessed a D10 value of 14.4 mJ/cm2. The higher values for the Weibull model indicate the Weibull model to be more conservative as a result as it factors in the lag prior to inactivation and the tailing observed with very low numbers of survivors. Spores of both Group I and Group II C. botulinum strains tended to form large aggregates, visible with phase contrast microscopy, that resulted in severe tailing. Disruption of aggregates by ultrasonication was necessary to obtain linear destruction curves extending beyond 5 log reduction. All strains from Group I and Group II required <55 mJ/cm2 to achieve 5 log inactivation. The strain of C. sporogenes used in this work can therefore be a conservative non-pathogenic surrogate, having higher UV-C resistance than the C. botulinum strains used in this study. Overall, this study is the first detailed study to demonstrate UV-C as an effective treatment method to inactivate C. botulinum spores in a suspending medium. In addition, the study paves the way for further studies towards the applications of this technology to inactivate C. botulinum spores in beverages or other liquids.

Free HIV self-test for identification and linkage to care of previously undetected HIV infection in men who have sex with men in England and Wales (SELPHI): an open-label, internet-based, randomised controlled trial.

BACKGROUND: High levels of HIV testing in men who have sex with men remain key to reducing the incidence of HIV. We aimed to assess whether the offer of a single, free HIV self-testing kit led to increased HIV diagnoses with linkage to care. METHODS: SELPHI was an internet-based, open-label, randomised controlled trial that recruited participants via sexual and social networking sites. Eligibility criteria included being a man or trans woman (although trans women are reported separately); being resident in England or Wales, UK; being aged 16 years or older; having had anal intercourse with a man; not having a positive HIV diagnosis; and being willing to provide name, email address, date of birth, and consent to link to national HIV databases. Participants were randomly allocated (3:2) by computer-generated number sequence to receive a free HIV self-test kit (BT group) or to not receive this free kit (nBT group). Online surveys collected data at baseline, 2 weeks after enrolment (BT group only), 3 months after enrolment, and at the end of the study. The primary outcome was confirmed (linked to care) new HIV diagnosis within 3 months of enrolment, analysed by intention to treat. Those assessing the primary outcome were masked to allocation. This study is registered with the ISRCTN Clinical Trials Register, number ISRCTN20312003. FINDINGS: 10 111 participants (6049 in BT group and 4062 in nBT group) enrolled between Feb 16, 2017, and March 1, 2018. The median age of participants was 33 years (IQR 26-44 years); 9000 (89%) participants were White; 8118 (80%) participants were born in the UK; 81 (1%) participants were transgender men; 4706 (47%) participants were university educated; 1537 (15%) participants had never been tested for HIV; and 389 (4%) participants were taking pre-exposure prophylaxis. At enrolment, 7282 (72%) participants reported condomless anal sex with at least one male partner in the previous 3 months. In the BT group, of the 4511 participants for whom HIV testing information was available, 4263 (95%) reported having used the free HIV self-test kit within 3 months.Within 3 months of enrolment there were 19 confirmed new HIV diagnoses (0·31%) in 6049 participants in the BT group and 15 (0·37%) of 4062 in the nBT group (p=0·64). INTERPRETATION: The offer of a single, free HIV self-test did not lead to increased rates of new HIV diagnoses, which could reflect decreasing HIV incidence rates in the UK. Nonetheless, the offer of a free HIV self-testing kit resulted in high HIV testing rates, indicating that self-testing is an attractive testing option for a large group of men who have sex with men. FUNDING: UK National Institute for Health and Care Research.

Modeling the UV-C Inactivation Kinetics and Determination of Fluence Required for Incremental Inactivation of Cronobacter spp.

ABSTRACT: A study was undertaken to model the UV-C inactivation kinetics and determine the fluences required for the incremental inactivation of several strains of Cronobacter spp. suspended in clear phosphate-buffered saline (PBS). In total, 13 strains of Cronobacter spp. were individually suspended in PBS and treated with UV-C doses of 0, 2, 4, 6, 8, and 10 mJ cm-2 with a collimated beam device emitting UV-C at 253.7 nm. The log reduction from each treatment was identified using the plate count method and plotted against the UV-C dose and then curve fitted using several mathematical models. The UV-C dose required for incremental inactivation of each isolate was determined using both linear and nonlinear regression. For the 13 strains tested, a UV-C dose of 10 mJ cm-2 inactivated between 3.66 ± 0.101 and 5.04 ± 0.465 log CFU mL-1. The survival behavior of all strains was best fitted to the Weibull+tail model, with correlation coefficients between 97.17 and 99.71%, and was used to determine the fluences required for incremental inactivation. The UV-C fluences needed to inactivate 1 log (D10-value) of Cronobacter spp. in buffer were between 3.53 and 5.50 mJ cm-2, whereas a fluence greater than 6.57 mJ cm-2 was required to achieve a 4-log inactivation. A clear understanding of the UV-C dose-response of several strains of Cronobacter spp. lays the foundation to design effective UV-based disinfection systems.

Impact and acceptability of HIV self-testing for trans men and trans women: A mixed-methods subgroup analysis of the SELPHI randomised controlled trial and process evaluation in England and Wales.

BACKGROUND: Globally, trans people are disproportionately affected by HIV, but research on strategies to increase testing are limited. SELPHI is a randomised-controlled-trial (RCT) of 10,135 cis men, trans men, and trans women reporting lifetime anal intercourse with male partners (cis or trans), evaluating whether the offer of free HIV self-testing (HIVST) increases diagnosis. This subgroup analysis from the SELPHI RCT aims to describe key HIVST outcomes and HIVST acceptability for trans people. METHODS: SELPHI recruited using social networking and trans focused social media. Participants were randomised 60/40 to baseline HIVST (Biosure™) (BT) vs no baseline HIVST (nBT); and at 3-months (if completed the survey and reported recent CAI) 50/50 to 3-monthly HIVST (RT) vs no repeat HIVST (nRT). Outcomes were self-reported through online surveys. We conducted a qualitative study of semi-structured peer-led participant interviews (n = 20) exploring HIVST motivations and experiences. These were analysed using a framework approach. FINDINGS: SELPHI recruited and randomised 118 trans men and trans women (94 trans men, 24 trans women), of whom 20 (16 trans men, 4 trans women) underwent the second randomisation. Median age at baseline was 29 (IQR: 22, 37), 79% were white, 79% were UK born, 37% had degree level education, and 31% had never tested for HIV. 62% (n = 59) of trans men completed the 3-month survey, but survey completion by trans women in nBT was too low (1/11) for randomised comparison. In trans men HIV testing uptake by 3 months was significantly higher in BT (95% 36/38) vs nBT (29%, 6/21) (RR=3.32 (1.68, 6.55) p<0.001). Trans people randomised to RT reported 3 times higher rate of HIV testing compared to nRT during the two-year follow-up (IRR 3.66 (1.86, 8.01) p<0.0001). STI testing frequency (mean number of tests during each 13 week period/ 2-year follow-up) was not significantly different across interventions: RT (0.03) and nRT (0.01) (IRR=1.86 95%CI; 0.77, 5.15; p = 0.15). Social harms were rare. Acceptability was very high in BT: 97% (38/39) found instructions easy to understand, 97% (37/38) found the HIVST simple to use and 100% (39/39) reported good overall experience. In interviews, reported HIVST benefits included increased autonomy, privacy, convenience and avoidance of health care providers perceived to be discriminatory and services that increased dysphoria. Minor lancet and test processing issues were reported. INTERPRETATION: HIVST significantly increased testing uptake and frequency in trans men and trans people overall, although recruitment and retention of trans women was low. HIVST acceptability was high and indicates easy access to this novel technology may increase HIV testing access for this key population.

Exploring Mechanisms of Action: Using a Testing Typology to Understand Intervention Performance in an HIV Self-Testing RCT in England and Wales.

SELPHI involves two interventions: (A) It provides one HIV self-testing (HIVST) kit; (B) It offers 3-monthly repeat HIVST kits if participants report ongoing risk. A logic model underpinned by the Behaviour Change Wheel informed the design of the intervention. SELPHI recruited 10,135 cis-men and trans people in England and Wales, all reporting anal sex with a man. This paper explores how the interventions were experienced and the pathways to impact for different groups of trial participants. In-depth interviews with 37 cis-men who have sex with men (MSM) were used to inductively categorise participants based on sexual and HIV testing histories. Themes relating to intervention experiences and impacts were mapped onto SELPHI-hypothesised intermediate outcomes to consider intervention impacts. Three groups were identified: 'Inexperienced testers' engaged with SELPHI to overcome motivational and social and physical opportunity testing barriers. For 'pro self-testers', testing frequency was constrained by psychological and social barriers and lack of opportunity. 'Opportunistic adopters' engaged in HIVST for novelty and convenience. Perceived impacts for inexperienced testers were most closely aligned with the logic model, but for opportunistic adopters there was little evidence of impact. Distinctive groups were discernible with divergent intervention experiences. Using COM-B as a model for understanding behaviour change in relation to HIVST, our results indicate how HIVST interventions could be adapted to respond to different needs based on the target population's demographic and behavioural features.

Ultraviolet irradiation of trypsin, lysozyme and ß-galactosidase: how does UVC affect these enzymes when used as a secondary barrier against adventitious agents?

Trypsin is one of the essential raw materials used in the manufacturing of biopharmaceutical products. As an animal derived product, it can potentially carry a serious risk of contamination with adventitious agents that can result in production shut down and lost product. To mitigate these risks, several methods are currently being used in the industry to remove contamination including physical and chemical methods. Ultraviolet-C (UVC) light is known to inactivate adventitious agents that are resistant to physical and chemical methods and could be a secondary barrier strategy. In this study, we investigated the effect of UVC irradiation on the activity and structure of trypsin. Extreme doses of UVC light were applied to trypsin using a collimated beam apparatus. The effect of UVC light on trypsin enzymatic activity was measured using a colorimetric activity assay and the effect on structure was analyzed by spectrophotometry, gel electrophoresis, and mass spectrometry. To broaden the scope, the effect of UVC light on the activity of two additional enzymes, lysozyme and ß-galactosidase, was also examined. At high doses of UVC light, changes to protein structure and protein fragmentation resulted in decreased trypsin activity. However, minimal damage was observed at doses applicable to inactivating adventitious agents, making UVC a feasible treatment for viral inactivation of trypsin products.

Pilot phase of an internet-based RCT of HIVST targeting MSM and transgender people in England and Wales: advertising strategies and acceptability of the intervention.

BACKGROUND: The SELPHI study (An HIV Self-Testing Public Health Intervention) is an online randomised controlled trial (RCT) of HIV self-testing (HIVST). The aim of this study was to assess the feasibility of recruiting UK men who have sex with men (cis and trans) and trans women who have sex with men to the SELPHI pilot, and the acceptability of the HIVST intervention used among those randomised to receive a kit. METHODS: A mixed-methods approach to assessing trial feasibility and intervention acceptability was taken, using quantitative data from advertising sources and RCT surveys alongside qualitative data from a nested sub-study. RESULTS: Online recruitment and intervention delivery was feasible. The recruitment strategy led to the registration of 1370 participants of whom 76% (1035) successfully enrolled and were randomised 60/40 to baseline testing vs no baseline testing. Advertising platforms performed variably. Reported HIVST kit use increased from 83% at two weeks to 96% at three months. Acceptability was very high across all quantitative measures. Participants described the instructions as easy to use, and the testing process as simple. The support structures in SELPHI were felt to be adequate. Described emotional responses to HIVST varied. CONCLUSIONS: Recruiting to a modest sized HIVST pilot RCT is feasible, and the recruitment, intervention and HIVST kit were acceptable. Research on support needs of individuals with reactive results is warranted.

Switching at the contacts in Ge9Sb1Te5 phase-change nanowire devices.

Phase-change random access memory is a promising approach to non-volatile memory. However, the inability to secure consistent, reliable switching on a nanometre scale may limit its practical use for high density applications. Here, we report on the switching behaviour of PCRAM cells comprised of single crystalline Ge9Sb1Te5 (GST) nanowires. We show that device switching is dominated by the contacts and does not result in a resistance change within the bulk of the wire. For the devices studied, the typical contact resistance was ∼30 kΩ, whereas the resistance of the GST channel was 1.8 kΩ. The applied voltage was predominately dropped across the passivating oxide on the surface of the GST nanowires, resulting in local resistive switching at the contacts and local power dissipation, which limited the endurance of the devices produced. The optimal device must balance low resistance contacts with a more resistive channel, to facilitate phase change switching within the nanowires. These results highlight the importance of contact formation on the switching properties in phase change devices and help guide the future design of more reliable neuromorphic devices.

Protocol, rationale and design of SELPHI: a randomised controlled trial assessing whether offering free HIV self-testing kits via the internet increases the rate of HIV diagnosis.

BACKGROUND: Among men who have sex with men (MSM) in the UK, an estimated 28% have never tested for HIV and only 27% of those at higher risk test at least every 6 months. HIV self-testing (HIVST), where the person takes their own blood/saliva sample and processes it themselves, offers the opportunity to remove many structural and social barriers to testing. Although several randomised controlled trials are assessing the impact of providing HIVST on rates of HIV testing, none are addressing whether this results in increased rates of HIV diagnoses that link to clinical care. Linking to care is the critical outcome because it is the only way to access antiretroviral treatment (ART). We describe here the design of a large, internet-based randomised controlled trial of HIVST, called SELPHI, which aims to inform this key question. METHODS/DESIGN: The SELPHI study, which is ongoing is promoted via social networking website and app advertising, and aims to enroll HIV negative men, trans men and trans women, aged over 16 years, who are living in England and Wales. Apart from the physical delivery of the test kits, all trial processes, including recruitment, take place online. In a two-stage randomisation, participants are first randomised (3:2) to receive a free baseline HIVST or no free baseline HIVST. At 3 months, participants allocated to receive a baseline HIVST (and meeting further eligibility criteria) are subsequently randomised (1:1) to receive the offer of regular (every 3 months) free HIVST, with testing reminders, versus no such offer. The primary outcome from both randomisations is a laboratory-confirmed HIV diagnosis, ascertained via linkage to a national HIV surveillance database. DISCUSSION: SELPHI will provide the first reliable evidence on whether offering free HIVST via the internet increases rates of confirmed HIV diagnoses and linkage to clinical care. The two randomisations reflect the dual objectives of detecting prevalent infections (possibly long-standing) and the more rapid diagnosis of incident HIV infections. It is anticipated that the results of SELPHI will inform future access to HIV self-testing provision in the UK. TRIAL REGISTRATION: DOI 10.1186/ISRCTN20312003 registered 24/10/2016.

N6-Furfuryladenine is protective in Huntington's disease models by signaling huntingtin phosphorylation.

The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington's disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA adducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.

Carbon and Phosphorus Removal from Primary Municipal Wastewater Using Recovered Aluminum.

In this work, recovery of aluminum from coagulated primary sludge and its reuse potential as secondary coagulant were investigated. The recovery process consisted of releasing the particle-bound aluminum from primary sludge by acidification (HCl or H2SO4), followed by separation using centrifugation for dissolved coagulant recovery. The recovered coagulant was then reused for treating primary wastewater and overall coagulation efficiency was determined. While with fresh alum, the removal efficiencies of total suspended solids, chemical oxygen demand, total phosphorus, and total nitrogen were 85%, 65%, 80% and 33%, respectively, a drop in removal efficiency of total suspended solids and chemical oxygen demand was observed for recovered aluminum (85-60% and 65-50%, respectively). Nitrogen concentration remained almost constant with each cycle, while phosphorus in the effluent increased by 1 mg/L and 3 mg/L in the first and second cycle, respectively. Precipitation of various aluminum species was modeled for determining the recovery potential of aluminum at low pH. Preliminary cost analysis indicates that optimum recovery of aluminum occurred at a pH of 1.5 for both acids. Struvite precipitation effectively removed increased phosphorus solubilized by acidification at the end of second cycle, however, it also decreased the amount of aluminum available for recycle.

Improving Family Meetings in Intensive Care Units: A Quality Improvement Curriculum.

BACKGROUND: Family meetings in the intensive care unit are associated with beneficial outcomes for patients, their families, and health care systems, yet these meetings often do not occur in a timely, effective, reliable way. OBJECTIVE: The Department of Veterans Affairs Comprehensive End-of-Life Care Implementation Center sponsored a national initiative to improve family meetings in Veterans Affairs intensive care units across the United States. Process measures of success for the initiative were identified, including development of a curriculum to support facility-based quality improvement projects to implement high-quality family meetings. METHODS: Identified curriculum requirements included suitability for distance learning and applicability to many clinical intensive care units. Curriculum modules were cross-mapped to the "Plan-Do-Study-Act" model to aid in planning quality improvement projects. A questionnaire was e-mailed to users to evaluate the curriculum's effectiveness. RESULTS: Users rated the curriculum's effectiveness in supporting and achieving aims of the initiative as 3.6 on a scale of 0 (not effective) to 4 (very effective). Users adapted the curriculum to meet local needs. The number of users increased from 6 to 17 quality improvement teams in 2 years. All but 3 teams progressed to implementation of an action plan. CONCLUSION: Users were satisfied with the effectiveness and adaptability of a family-meeting quality improvement curriculum to support implementation of a quality improvement project in Veterans Affairs intensive care units. This tool may be useful in facilitating projects to improve the quality of family meetings in other intensive care units.

Imaging Spatial Variations in the Dissipation and Transport of Thermal Energy within Individual Silicon Nanowires Using Ultrafast Microscopy.

Thermal management is an important consideration for most nanoelectronic devices, and an understanding of the thermal conductivity of individual device components is critical for the design of thermally efficient systems. However, it can be difficult to directly probe local changes in thermal conductivity within a nanoscale system. Here, we utilize the time-resolved and diffraction-limited imaging capabilities of ultrafast pump-probe microscopy to determine, in a contact-free configuration, the local thermal conductivity in individual Si nanowires (NWs). By suspending single NWs across microfabricated trenches in a quartz substrate, the properties of the same NW both on and off the substrate are directly compared. We find the substrate has no effect on the recombination lifetime or diffusion length of photogenerated charge carriers; however, it significantly impacts the thermal relaxation properties of the NW. In substrate-supported regions, thermal energy deposited into the lattice by the ultrafast laser pulse dissipates within ∼10 ns through thermal diffusion and coupling to the substrate. In suspended regions, the thermal energy persists for over 100 ns, and we directly image the time-resolved spatial motion of the thermal signal. Quantitative analysis of the transient images permits direct determination of the NW's local thermal conductivity, which we find to be a factor of ∼4 smaller than in bulk Si. Our results point to the strong potential of pump-probe microscopy to be used as an all-optical method to quantify the effects of localized environment and morphology on the thermal transport characteristics of individual nanostructured components.

Integrating Palliative Care Into the Care of Neurocritically Ill Patients: A Report From the Improving Palliative Care in the ICU Project Advisory Board and the Center to Advance Palliative Care.

OBJECTIVES: To describe unique features of neurocritical illness that are relevant to provision of high-quality palliative care; to discuss key prognostic aids and their limitations for neurocritical illnesses; to review challenges and strategies for establishing realistic goals of care for patients in the neuro-ICU; and to describe elements of best practice concerning symptom management, limitation of life support, and organ donation for the neurocritically ill. DATA SOURCES: A search of PubMed and MEDLINE was conducted from inception through January 2015 for all English-language articles using the term "palliative care," "supportive care," "end-of-life care," "withdrawal of life-sustaining therapy," "limitation of life support," "prognosis," or "goals of care" together with "neurocritical care," "neurointensive care," "neurological," "stroke," "subarachnoid hemorrhage," "intracerebral hemorrhage," or "brain injury." DATA EXTRACTION AND SYNTHESIS: We reviewed the existing literature on delivery of palliative care in the neurointensive care unit setting, focusing on challenges and strategies for establishing realistic and appropriate goals of care, symptom management, organ donation, and other considerations related to use and limitation of life-sustaining therapies for neurocritically ill patients. Based on review of these articles and the experiences of our interdisciplinary/interprofessional expert advisory board, this report was prepared to guide critical care staff, palliative care specialists, and others who practice in this setting. CONCLUSIONS: Most neurocritically ill patients and their families face the sudden onset of devastating cognitive and functional changes that challenge clinicians to provide patient-centered palliative care within a complex and often uncertain prognostic environment. Application of palliative care principles concerning symptom relief, goal setting, and family emotional support will provide clinicians a framework to address decision making at a time of crisis that enhances patient/family autonomy and clinician professionalism.

Integration of palliative care in the context of rapid response: a report from the Improving Palliative Care in the ICU advisory board.

Rapid response teams (RRTs) can effectively foster discussions about appropriate goals of care and address other emergent palliative care needs of patients and families facing life-threatening illness on hospital wards. In this article, The Improving Palliative Care in the ICU (IPAL-ICU) Project brings together interdisciplinary expertise and existing data to address the following: special challenges for providing palliative care in the rapid response setting, knowledge and skills needed by RRTs for delivery of high-quality palliative care, and strategies for improving the integration of palliative care with rapid response critical care. We discuss key components of communication with patients, families, and primary clinicians to develop a goal-directed treatment approach during a rapid response event. We also highlight the need for RRT expertise to initiate symptom relief. Strategies including specific clinician training and system initiatives are then recommended for RRT care improvement. We conclude by suggesting that as evaluation of their impact on other outcomes continues, performance by RRTs in meeting palliative care needs of patients and families should also be measured and improved.

Systematic investigation of hierarchical phosphorylation by protein kinase CK2.

Although multiple phosphorylation sites are often clustered in substrates, the mechanism of phosphorylation within clusters has not been systematically investigated. Intriguingly, in addition to acidic residues, protein kinase CK2 can use phosphoserine residues as consensus determinants suggesting that CK2 may act in concert with other kinases. We used a peptide array approach to outline optimal consensus sequences for hierarchical phosphorylation by CK2, both in the context of processive, multisite phosphorylation, and in concert with a priming proline-directed kinase. Results suggest that hierarchical phosphorylation involving CK2 requires precise positioning of either multiple phosphodeterminant residues or specific combinations of canonical determinants and phosphodeterminants, and can be as enzymatically favorable as canonical CK2 phosphorylation. Over 1600 human proteins contain at least one CK2 hierarchical consensus motif, and ~20% of these motifs contain at least one reported in vivo phosphorylation site. These motifs occur non-randomly in the human proteome, with significant enrichment in proteins controlling specific cellular processes. Taken together, our results provide strong in vitro evidence that hierarchical phosphorylation may contribute to the regulation of crucial biological processes. In addition, the results suggest a mechanism by which CK2, a constitutively active kinase, can be a regulatory participant in cellular processes. BIOLOGICAL SIGNIFICANCE: Phosphorylation is a crucial regulatory mechanism governing cellular signal transduction pathways, and despite the large number of identified sites to date, most mechanistic studies remain focused on individual phosphorylation sites. This study is the first to systematically determine specific consensus sequences for hierarchical phosphorylation events. The results indicate that individual phosphorylation sites should not be studied in isolation, and that larger, multisite phosphorylation motifs may have profound impact on cellular signaling. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras.

Reversible strain-induced electron-hole recombination in silicon nanowires observed with femtosecond pump-probe microscopy.

Strain-induced changes to the electronic structure of nanoscale materials provide a promising avenue for expanding the optoelectronic functionality of semiconductor nanostructures in device applications. Here we use pump-probe microscopy with femtosecond temporal resolution and submicron spatial resolution to characterize charge-carrier recombination and transport dynamics in silicon nanowires (NWs) locally strained by bending deformation. The electron-hole recombination rate increases with strain for values above a threshold of ∼1% and, in highly strained (∼5%) regions of the NW, increases 6-fold. The changes in recombination rate are independent of NW diameter and reversible upon reduction of the applied strain, indicating the effect originates from alterations to the NW bulk electronic structure rather than introduction of defects. The results highlight the strong relationship between strain, electronic structure, and charge-carrier dynamics in low-dimensional semiconductor systems, and we anticipate the results will assist the development of strain-enabled optoelectronic devices with indirect-bandgap materials such as silicon.

Integrating palliative care into the PICU: a report from the Improving Palliative Care in the ICU Advisory Board.

OBJECTIVE: This review highlights benefits that patients, families and clinicians can expect to realize when palliative care is intentionally incorporated into the PICU. DATA SOURCES: We searched the MEDLINE database from inception to January 2014 for English-language articles using the terms "palliative care" or "end of life care" or "supportive care" and "pediatric intensive care." We also hand-searched reference lists and author files and relevant tools on the Center to Advance Palliative Care website. STUDY SELECTION: Two authors (physicians with experience in pediatric intensive care and palliative care) made final selections. DATA EXTRACTION: We critically reviewed the existing data and tools to identify strategies for incorporating palliative care into the PICU. DATA SYNTHESIS: The Improving Palliative Care in the ICU Advisory Board used data and experience to address key questions relating to: pain and symptom management, enhancing quality of life, communication and decision-making, length of stay, sites of care, and grief and bereavement. CONCLUSIONS: Palliative care should begin at the time of a potentially life-limiting diagnosis and continue throughout the disease trajectory, regardless of the expected outcome. Although the PICU is often used for short term postoperative stabilization, PICU clinicians also care for many chronically ill children with complex underlying conditions and others receiving intensive care for prolonged periods. Integrating palliative care delivery into the PICU is rapidly becoming the standard for high quality care of critically ill children. Interdisciplinary ICU staff can take advantage of the growing resources for continuing education in pediatric palliative care principles and interventions.