Corticosteroids for the prevention and treatment of bronchopulmonary dysplasia: an overview of systematic reviews.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD, explaining the rationale for investigating postnatal corticosteroids. Multiple systematic reviews (SRs) have summarised the evidence from numerous randomised controlled trials (RCTs) investigating different aspects of administrating postnatal corticosteroids. Besides beneficial effects on the outcome of death or BPD, potential short- and long-term harms have been reported. OBJECTIVES: The primary objective of this overview was to summarise and appraise the evidence from SRs regarding the efficacy and safety of postnatal corticosteroids in preterm infants at risk of developing BPD. METHODS: We searched the Cochrane Database of Systematic Reviews, MEDLINE, Embase, CINAHL, and Epistemonikos for SRs in April 2023. We included all SRs assessing any form of postnatal corticosteroid administration in preterm populations with the objective of ameliorating pulmonary disease. All regimens and comparisons were included. Two review authors independently checked the eligibility of the SRs comparing corticosteroids with placebo, and corticosteroids with different routes of administration and regimens. The included outcomes, considered key drivers in the decision to administer postnatal corticosteroids, were the composite outcome of death or BPD at 36 weeks' postmenstrual age (PMA), its individual components, long-term neurodevelopmental sequelae, sepsis, and gastrointestinal tract perforation. We independently assessed the methodological quality of the included SRs by using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) and ROBIS (Risk Of Bias In Systematic reviews) tools. We assessed the certainty of the evidence using GRADE. We provided a narrative description of the characteristics, methodological quality, and results of the included SRs. MAIN RESULTS: We included nine SRs (seven Cochrane, two non-Cochrane) containing 87 RCTs, 1 follow-up study, and 9419 preterm infants, investigating the effects of postnatal corticosteroids to prevent or treat BPD. The quality of the included SRs according to AMSTAR 2 varied from high to critically low. Risk of bias according to ROBIS was low. The certainty of the evidence according to GRADE ranged from very low to moderate. Early initiated systemic dexamethasone (< seven days after birth) likely has a beneficial effect on death or BPD at 36 weeks' PMA (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.81 to 0.95; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 10 to 41; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA (RR 0.72, 95% CI 0.63 to 0.82; NNTB 13, 95% CI 9 to 21; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence). Early initiated systemic hydrocortisone may also have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.90, 95% CI 0.82 to 0.99; NNTB 18, 95% CI 9 to 594; I2 = 43%; 9 studies; 1376 infants; low-certainty evidence). However, these benefits are likely accompanied by harmful effects like cerebral palsy or neurosensory disability (dexamethasone) or gastrointestinal perforation (both dexamethasone and hydrocortisone). Late initiated systemic dexamethasone (≥ seven days after birth) may have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.75, 95% CI 0.67 to 0.84; NNTB 5, 95% CI 4 to 9; I2 = 61%; 12 studies; 553 infants; low-certainty evidence), mostly contributed to by a beneficial effect on BPD at 36 weeks' PMA (RR 0.76, 95% CI 0.66 to 0.87; NNTB 6, 95% CI 4 to 13; I2 = 14%; 12 studies; 553 infants; low-certainty evidence). No harmful side effects were shown in the outcomes chosen as key drivers to the decision to start or withhold late systemic dexamethasone. No effects, either beneficial or harmful, were found in the subgroup meta-analyses of late hydrocortisone studies. Early initiated inhaled corticosteroids probably have a beneficial effect on death and BPD at 36 weeks' PMA (RR 0.86, 95% CI 0.75 to 0.99; NNTB 19, 95% CI not applicable; I2 = 0%; 6 studies; 1285 infants; moderate-certainty evidence), with no apparent adverse effects shown in the SRs. In contrast, late initiated inhaled corticosteroids do not appear to have any benefits or harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier likely has a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.60, 95% CI 0.49 to 0.74; NNTB 4, 95% CI 3 to 6; I2 = 0%; 2 studies; 381 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA. No evidence of harmful effects was found. There was little evidence for effects of different starting doses or timing of systemic corticosteroids on death or BPD at 36 weeks' PMA, but potential adverse effects were observed for some comparisons. Lowering the dose might result in a more unfavourable balance of benefits and harms. Moderately early initiated systemic corticosteroids, compared with early systemic corticosteroids, may result in a higher incidence of BPD at 36 weeks' PMA. Pulse dosing instead of continuous dosing may have a negative effect on death and BPD at 36 weeks' PMA. We found no differences for the comparisons of inhaled versus systemic corticosteroids. AUTHORS' CONCLUSIONS: This overview summarises the evidence of nine SRs investigating the effect of postnatal corticosteroids in preterm infants at risk for BPD. Late initiated (≥ seven days after birth) systemic administration of dexamethasone is considered an effective intervention to reduce the risk of BPD in infants with a high risk profile for BPD, based on a favourable balance between benefits and harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is a promising intervention, based on the beneficial effect on desirable outcomes without (so far) negative side effects. Pending results of ongoing large, multicentre RCTs investigating both short- and long-term effects, endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is not appropriate for clinical practice at present. Early initiated (< seven days after birth) systemic dexamethasone and hydrocortisone and late initiated (≥ seven days after birth) hydrocortisone are considered ineffective interventions, because of an unfavourable balance between benefits and harms. No conclusions are possible regarding early and late inhaled corticosteroids, as more research is needed.

Common challenges and suggestions for risk of bias tool development: a systematic review of methodological studies.

OBJECTIVES: To review the findings of studies that have evaluated the design and/or usability of key risk of bias (RoB) tools for the assessment of RoB in primary studies, as categorized by the Library of Assessment Tools and InsTruments Used to assess Data validity in Evidence Synthesis Network (a searchable library of RoB tools for evidence synthesis): Prediction model Risk Of Bias ASessment Tool (PROBAST) , Risk of Bias-2 (RoB2), Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I), Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2), Quality Assessment of Diagnostic Accuracy Studies-Comparative (QUADAS-C), Quality Assessment of Prognostic Accuracy Studies (QUAPAS), Risk Of Bias in Non-randomised Studies of Exposures (ROBINS-E), and the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) RoB checklist. STUDY DESIGN AND SETTING: Systematic review of methodological studies. We conducted a forward citation search from the primary report of each tool, to identify primary studies that aimed to evaluate the design and/or usability of the tool. Two reviewers assessed studies for inclusion. We extracted tool features into Microsoft Word and used NVivo for document analysis, comprising a mix of deductive and inductive approaches. We summarized findings within each tool and explored common findings across tools. RESULTS: We identified 13 tool evaluations meeting our inclusion criteria: PROBAST (3), RoB2 (3), ROBINS-I (4), and QUADAS-2 (3). We identified no evaluations for the other tools. Evaluations varied in clinical topic area, methodology, approach to bias assessment, and tool user background. Some had limitations affecting generalizability. We identified common findings across tools for 6/14 themes: (1) challenging items (eg, RoB2/ROBINS-I "deviations from intended interventions" domain), (2) overall RoB judgment (concerns with overall risk calculation in PROBAST/ROBINS-I), (3) tool usability (concerns about complexity), (4) time to complete tool (varying demands on time, eg, depending on number of outcomes assessed), (5) user agreement (varied across tools), and (6) recommendations for future use (eg, piloting) and development (add intermediate domain answer to QUADAS-2/PROBAST; provide clearer guidance for all tools). Of the other eight themes, seven only had findings for the QUADAS-2 tool, limiting comparison across tools, and one ("reorganization of questions") had no findings. CONCLUSION: Evaluations of key RoB tools have posited common challenges and recommendations for tool use and development. These findings may be helpful to people who use or develop RoB tools. Guidance is necessary to support the design and implementation of future RoB tool evaluations.

The influence of carbon dioxide on cerebral metabolism and oxygen consumption: combining multimodal monitoring with dynamic systems modelling.

Hypercapnia increases cerebral blood flow. The effects on cerebral metabolism remain incompletely understood although studies show an oxidation of cytochrome c oxidase, Complex IV of the mitochondrial respiratory chain. Systems modelling was combined with previously published non-invasive measurements of cerebral tissue oxygenation, cerebral blood flow, and cytochrome c oxidase redox state to evaluate any metabolic effects of hypercapnia. Cerebral tissue oxygen saturation and cytochrome oxidase redox state were measured with broadband near infrared spectroscopy and cerebral blood flow velocity with transcranial Doppler ultrasound. Data collected during 5-min hypercapnia in awake human volunteers were analysed using a Fick model to determine changes in brain oxygen consumption and a mathematical model of cerebral hemodynamics and metabolism (BrainSignals) to inform on mechanisms. Either a decrease in metabolic substrate supply or an increase in metabolic demand modelled the cytochrome oxidation in hypercapnia. However, only the decrease in substrate supply explained both the enzyme redox state changes and the Fick-calculated drop in brain oxygen consumption. These modelled outputs are consistent with previous reports of CO2 inhibition of mitochondrial succinate dehydrogenase and isocitrate dehydrogenase. Hypercapnia may have physiologically significant effects suppressing oxidative metabolism in humans and perturbing mitochondrial signalling pathways in health and disease.

Clinical effectiveness of point of care tests for diagnosing urinary tract infection: a systematic review.

BACKGROUND: Point of care tests (POCTs) have the potential to improve the urinary tract infection (UTI) diagnostic pathway, as they can provide a diagnosis quickly in near-patient settings, and some also identify causative pathogens/antimicrobial sensitivity. OBJECTIVES: To assess the clinical impact, accuracy, and technical characteristics of POCT for diagnosing UTI. METHODS OF DATA SYNTHESIS: Narrative summary and bivariate random effects meta-analyses to estimate summary sensitivity and specificity. DATA SOURCES: Five electronic databases, two clinical trial registries, study reports and review reference lists, and websites. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials/non-randomized studies and diagnostic test accuracy studies published since 2000. PARTICIPANTS: People with suspected UTI. TESTS: Rapid tests (results <40 minutes): Astrego PA-100 system, Lodestar DX, Uriscreen, UTRiPLEX. Culture tests (results <24 hours): Flexicult Human, ID Flexicult, Diaslide, Dipstreak, Chromostreak, Uricult, Uricult Trio, Uricult Plus. REFERENCE STANDARD: Any. ASSESSMENT OF RISK OF BIAS: Risk of Bias-2, Quality Assessment of Diagnostic Accuracy Studies-2, Quality Assessment of Diagnostic Accuracy Studies-C. RESULTS: Two randomized controlled trials evaluated Flexicult Human (one against standard care; one against ID Flexicult). No difference was reported in antibiotic use concordant with culture results (OR 0.84 95% CI 0.58-1.20) or appropriate antibiotic prescribing (OR 1.44 95% CI 1.03-1.99). Initial antibiotic prescribing was lower with Flexicult than standard care (OR 0.56 95% CI 0.35-0.88). No difference for other measures of antibiotic use, symptom duration, patient enablement, or resource use. Fifteen studies reported accuracy data. Limited data were available, with most POCT evaluated in single studies or not evaluated at all. Uriscreen (four studies), Uricult Trio (three studies), Flexicult Human (four studies), and ID Flexicult (two studies) had modest sensitivity and specificity. POCTs were easier to use and interpret than standard culture. CONCLUSIONS: There is currently insufficient evidence to support the use of POCTs in UTI diagnosis. Due to the rapid development of POCT, this review should be updated regularly.

Cold-Water Immersion and Lower Limb Muscle Oxygen Consumption as Measured by Near-Infrared Spectroscopy in Trained Endurance Athletes.

CONTEXT: Cold-water immersion (CWI) has been reported to reduce tissue metabolism postimmersion, but physiological data are lacking regarding the muscle metabolic response to its application. Near-infrared spectroscopy (NIRS) is a noninvasive optical technique that can inform muscle hemodynamics and tissue metabolism. OBJECTIVE: To investigate the effects of CWI at 2 water temperatures (10°C and 15°C) on NIRS-calculated measurements of muscle oxygen consumption (mVO2). DESIGN: Crossover study. SETTING: University sports rehabilitation center. PATIENTS OR OTHER PARTICIPANTS: A total of 11 male National Collegiate Athletic Association Division II long-distance runners (age = 23.4 ± 3.4 years, height = 1.8 ± 0.1 m, mass = 68.8 ± 10.7 kg, mean adipose tissue thickness = 6.7 ± 2.7 mm). INTERVENTION(S): Cold-water immersion at 10°C and 15°C for 20 minutes. MAIN OUTCOME MEASURE(S): We calculated mVO2 preimmersion and postimmersion at water temperatures of 10°C and 15°C. Changes in tissue oxyhemoglobin (O2Hb), deoxyhemoglobin (HHb), total hemoglobin (tHb), hemoglobin difference (Hbdiff), and tissue saturation index (TSI %) were measured during the 20-minute immersion at both temperatures. RESULTS: We observed a decrease in mVO2 after immersion at both 10°C and 15°C (F1,9 = 27.7801, P = .001). During the 20-minute immersion at both temperatures, we noted a main effect of time for O2Hb (F3,27 = 14.227, P = .001), HHb (F3,27 = 5.749, P = .009), tHb (F3,27 = 24.786, P = .001), and Hbdiff (F3,27 = 3.894, P = .020), in which values decreased over the course of immersion. Post hoc pairwise comparisons showed that these changes occurred within the final 5 minutes of immersion for tHb and O2Hb. CONCLUSIONS: A 20-minute CWI at 10°C and 15°C led to a reduction in mVO2. This was greater after immersion at 10°C. The reduction in mVO2 suggests a decrease in muscle metabolic activity (ie, O2 use after CWI). Calculating mVO2 via the NIRS-occlusion technique may offer further insight into muscle metabolic responses beyond what is attainable from observing the NIRS primary signals.

The effect of machine learning tools for evidence synthesis on resource use and time-to-completion: protocol for a retrospective pilot study.

BACKGROUND: Machine learning (ML) tools exist that can reduce or replace human activities in repetitive or complex tasks. Yet, ML is underutilized within evidence synthesis, despite the steadily growing rate of primary study publication and the need to periodically update reviews to reflect new evidence. Underutilization may be partially explained by a paucity of evidence on how ML tools can reduce resource use and time-to-completion of reviews. METHODS: This protocol describes how we will answer two research questions using a retrospective study design: Is there a difference in resources used to produce reviews using recommended ML versus not using ML, and is there a difference in time-to-completion? We will also compare recommended ML use to non-recommended ML use that merely adds ML use to existing procedures. We will retrospectively include all reviews conducted at our institute from 1 August 2020, corresponding to the commission of the first review in our institute that used ML. CONCLUSION: The results of this study will allow us to quantitatively estimate the effect of ML adoption on resource use and time-to-completion, providing our organization and others with better information to make high-level organizational decisions about ML.

Evaluation of effects-based methods as monitoring tools for assessing ecological impacts of metals in aquatic ecosystems.

Effects-based methods (EBMs) are considered part of a more integrative strategy for regulating substances of concern under the European Union Water Framework Directive. In general, EBMs have been demonstrated as useful indicators of effects on biota, although links to population and community-level effects are sometimes uncertain. When EBMs are sufficiently specific and sensitive, and links between measured endpoints and apical or higher level effects are established, they can be a useful tool in assessing effects from a specific toxicant or class of toxicants. This is particularly valuable for toxicants that are difficult to measure and for assessing the effects of toxicant mixtures. This paper evaluates 12 EBMs that have been proposed for potential use in the assessment of metals. Each EBM was evaluated with respect to metal specificity and sensitivity, sensitivity to other classes of toxicants, and the strength of the relationship between EBM endpoints and effects observed at the whole organism or population levels of biological organization. The evaluation concluded that none of the EBMs evaluated meet all three criteria of being sensitive to metals, insensitive to other classes of toxicants, and a strong indicator of effects at the whole organism or population level. Given the lack of suitable EBMs for metals, we recommended that the continued development of mixture biotic ligand models (mBLMs) may be the most effective way to achieve the goal of a more holistic approach to regulating metals in aquatic ecosystems. Given the need to further develop and validate mBLMs, we suggest an interim weight-of-evidence approach that includes mBLMs, macroinvertebrate community bioassessment, and measurement of metals in key macroinvertebrate species. This approach provides a near-term solution and simultaneously generates data needed for the refinement and validation of mBLMs. Once validated, it should be possible to rely primarily on mBLMs as an alternative to EBMs for metals. Integr Environ Assess Manag 2023;19:24-31.  © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Clinician perspectives on what constitutes good practice in community services for people with complex emotional needs: A qualitative thematic meta-synthesis.

INTRODUCTION: The need to improve the quality of community mental health services for people with Complex Emotional Needs (CEN) (who may have a diagnosis of 'personality disorder') is recognised internationally and has become a renewed policy priority in England. Such improvement requires positive engagement from clinicians across the service system, and their perspectives on achieving good practice need to be understood. AIM: To synthesise qualitative evidence on clinician perspectives on what constitutes good practice, and what helps or prevents it being achieved, in community mental health services for people with CEN. METHODS: Six bibliographic databases were searched for studies published since 2003 and supplementary citation tracking was conducted. Studies that used any recognised qualitative method and reported clinician experiences and perspectives on community-based mental health services for adults with CEN were eligible for this review, including generic and specialist settings. Meta-synthesis was used to generate and synthesise over-arching themes across included studies. RESULTS: Twenty-nine papers were eligible for inclusion, most with samples given a 'personality disorder' diagnosis. Six over-arching themes were identified: 1. The use and misuse of diagnosis; 2. The patient journey into services: nowhere to go; 3. Therapeutic relationships: connection and distance; 4. The nature of treatment: not doing too much or too little; 5. Managing safety issues and crises: being measured and proactive; 6. Clinician and wider service needs: whose needs are they anyway? The overall quality of the evidence was moderate. DISCUSSION: Through summarising the literature on clinician perspectives on good practice for people with CEN, over-arching priorities were identified on which there appears to be substantial consensus. In their focus on needs such as for a long-term perspective on treatment journeys, high quality and consistent therapeutic relationships, and a balanced approach to safety, clinician priorities are mainly congruent with those found in studies on service user views. They also identify clinician needs that should be met for good care to be provided, including for supervision, joint working and organisational support.

A Technical Review of the ISPOR Presentations Database Identified Issues in the Search Interface and Areas for Future Development.

OBJECTIVE: To undertake a technical review of the search interface of the ISPOR Presentations Database. By technical review, we mean an evaluation of the technical aspects of the search interface and functionality, which a user must navigate to complete a search. METHODS: A validated checklist (Bethel and Rogers, 2014, Health Info Libr J, 31, 43-53) was used to identify where the interface performed well, where the interface was adequate, where the interface performed poorly, where functionality available in core biomedical bibliographic databases does not exist in the ISPOR database, and to establish a list of any issues arising during the review. Two researchers independently undertook the technical review in October 2021. RESULTS: The ISPOR database scored 35 of a possible 165 (27/111 essential criteria and 8/54 desirable criteria). Two issues arising were identified, both of which will cause searchers to miss potentially eligible abstracts: (i) that search terms, which include * or ? as truncation or wildcard symbols should not be capitalized (e.g., cost* not Cost*; organi?ation not Organi?ation) and (ii) that quotation marks should be straight sided in phrase searching (e.g., "cost analyses" not "cost analyses"). CONCLUSIONS: The ISPOR database is a promising and free database to identify abstracts/posters presented at ISPOR. We summarize two key issues arising, and we set out proposed changes to the search interface, including: adding the ability to export abstracts to a bibliographic tool, exporting search strategies, adding a researcher account, and updating the help guide. All suggestions will further improve this helpful database.

Searching for medical devices - Practical guidance.

Systematic reviews of medical devices have generally adopted the same methodology for the conduct of their reviews as reviews of other clinical interventions, in particular, medicines. It has been suggested that these methods may need to be developed to account for the challenges of reviewing the evidence for medical devices when compared to reviews of medicines. The purpose of this research note is to focus on the methods of searching for medical devices. Our aim is to set out guidance on 'how to search' for medical devices. This includes: Defining what you are searching for; How to design a search strategy; Searching bibliographic databases; Searching beyond bibliographic databases; and Search reporting. The research note is written by three experienced searchers/researchers with experience of critically appraising Medical Technologies Evaluation Programme (MTEP) submissions, undertaking systematic searches and/or reviews of medical devices, or developing guidance for searching for studies for systematic reviews of the effectiveness of interventions, including medical devices. The research note includes a worked example of a search for a fictitious medical device.

Universal Subsidized Continuous Glucose Monitoring Funding for Young People With Type 1 Diabetes: Uptake and Outcomes Over 2 Years, a Population-Based Study.

OBJECTIVE: Continuous glucose monitoring (CGM) is increasingly used in type 1 diabetes management; however, funding models vary. This study determined the uptake rate and glycemic outcomes following a change in national health policy to introduce universal subsidized CGM funding for people with type 1 diabetes aged <21 years. RESEARCH DESIGN AND METHODS: Longitudinal data from 12 months before the subsidy until 24 months after were analyzed. Measures and outcomes included age, diabetes duration, HbA1c, episodes of diabetic ketoacidosis and severe hypoglycemia, insulin regimen, CGM uptake, and percentage CGM use. Two data sources were used: the Australasian Diabetes Database Network (ADDN) registry (a prospective diabetes database) and the National Diabetes Service Scheme (NDSS) registry that includes almost all individuals with type 1 diabetes nationally. RESULTS: CGM uptake increased from 5% presubsidy to 79% after 2 years. After CGM introduction, the odds ratio (OR) of achieving the HbA1c target of <7.0% improved at 12 months (OR 2.5, P < 0.001) and was maintained at 24 months (OR 2.3, P < 0.001). The OR for suboptimal glycemic control (HbA1c ≥9.0%) decreased to 0.34 (P < 0.001) at 24 months. Of CGM users, 65% used CGM >75% of time, and had a lower HbA1c at 24 months compared with those with usage <25% (7.8 ± 1.3% vs. 8.6 ± 1.8%, respectively, P < 0.001). Diabetic ketoacidosis was also reduced in this group (incidence rate ratio 0.49, 95% CI 0.33-0.74, P < 0.001). CONCLUSIONS: Following the national subsidy, CGM use was high and associated with sustained improvement in glycemic control. This information will inform economic analyses and future policy and serve as a model of evaluation diabetes technologies.

Pharmacological Medical Treatment of Epilepsy in Patients with Dementia: A Systematic Review.

BACKGROUND: Patients with dementia have an increased risk of developing epilepsy, especially in patients with vascular dementia and Alzheimer's disease. In selecting the optimal anti- epileptic drug (AED), the possible side effects such as drowsiness and worsening of cognitive function should be taken into consideration, together with co-morbidities and type of epilepsy. OBJECTIVE: The current systematic review investigates the efficacy, tolerability, and changes in cognitive function after administration of AED in patients with dementia and epilepsy. METHODS: We searched six databases, including MEDLINE and CENTRAL, checked reference lists, contacted experts, and searched Google Scholar to identify studies reporting randomized trials. Studies identified were independently screened, data extracted, and quality appraised by two researchers. A narrative synthesis was used to report findings. RESULTS: We included one study with 95 patients with Alzheimer's disease randomized to either levetiracetam, lamotrigine, or phenobarbital. No significant differences were found for efficacy, but patients receiving levetiracetam showed an improvement in mini-mental state examination scores and had fewer adverse events. CONCLUSION: High-quality evidence in the form of randomized controlled trials to guide clinicians in choosing an AED in patients with dementia and concomitant epilepsy remains scarce. However, levetiracetam has previously been shown to possibly improve cognition in patients with both mild cognitive impairment and Alzheimer's disease, is better tolerated in the elderly population, and has no clinically relevant interaction with either cholinesterase inhibitors or NMDA receptor antagonists.

Stability of Maleimide-PEG and Mono-Sulfone-PEG Conjugation to a Novel Engineered Cysteine in the Human Hemoglobin Alpha Subunit.

In order to use a Hemoglobin Based Oxygen Carrier as an oxygen therapeutic or blood substitute, it is necessary to increase the size of the hemoglobin molecule to prevent rapid renal clearance. A common method uses maleimide PEGylation of sulfhydryls created by the reaction of 2-iminothiolane at surface lysines. However, this creates highly heterogenous mixtures of molecules. We recently engineered a hemoglobin with a single novel, reactive cysteine residue on the surface of the alpha subunit creating a single PEGylation site (ßCys93Ala/αAla19Cys). This enabled homogenous PEGylation by maleimide-PEG with >80% efficiency and no discernible effect on protein function. However, maleimide-PEG adducts are subject to deconjugation via retro-Michael reactions and cross-conjugation to endogenous thiol species in vivo. We therefore compared our maleimide-PEG adduct with one created using a mono-sulfone-PEG less susceptible to deconjugation. Mono-sulfone-PEG underwent reaction at αAla19Cys hemoglobin with > 80% efficiency, although some side reactions were observed at higher PEG:hemoglobin ratios; the adduct bound oxygen with similar affinity and cooperativity as wild type hemoglobin. When directly compared to maleimide-PEG, the mono-sulfone-PEG adduct was significantly more stable when incubated at 37°C for seven days in the presence of 1 mM reduced glutathione. Hemoglobin treated with mono-sulfone-PEG retained > 90% of its conjugation, whereas for maleimide-PEG < 70% of the maleimide-PEG conjugate remained intact. Although maleimide-PEGylation is certainly stable enough for acute therapeutic use as an oxygen therapeutic, for pharmaceuticals intended for longer vascular retention (weeks-months), reagents such as mono-sulfone-PEG may be more appropriate.

Assessing the feasibility and value of employing an ecosystem services approach in chemical environmental risk assessment under the Water Framework Directive.

The feasibility and added value of an ecosystem services approach in retrospective environmental risk assessment were evaluated using a site-specific case study in a lowland UK river. The studied water body failed to achieve good ecological status temporarily in 2018, due in part to the exceedance of the environmental quality standard (annual average EQS) for zinc. Potential ecosystem service delivery was quantified for locally prioritised ecosystem services: regulation of chemical condition; maintaining nursery populations and habitats; recreational fishing; nature watching. Quantification was based on observed and expected taxa or functional groups within WFD biological quality elements, including macrophytes, benthic macroinvertebrates and fish, and on published functional trait data for constituent taxa. Benthic macroinvertebrate taxa were identified and enumerated before, during and after zinc EQS exceedance, enabling a generic retrospective risk assessment for this biological quality element, which was found to have good ecosystem service potential. An additional targeted risk assessment for zinc was based on laboratory-based species sensitivity distributions normalised using biotic-ligand modelling to account for site-specific, bioavailability-corrected zinc exposure. Risk to ecosystem services for diatoms (microalgae) was found to be high, while risks for benthic macroinvertebrates and fish were found to be low. The status of potential ecosystem service delivery (ESD) by fish was equivalent to high ecological status defined under the WFD, while ESD was higher for benthic macroinvertebrates than defined by WFD methods. The illustrated ecosystem services approach uses readily available data and adds significantly to the taxonomic approach currently used under the WFD by using functional traits to evaluate services that are prioritised as being important in water bodies. The main shortcomings of the illustrated approach were lack of: representation of bacteria and fungi; WFD predicted species lists for diatoms and macrophytes; site-specific functional trait data required for defining actual (rather than potential) ecosystem service delivery.

A systematic review and meta-analysis of group peer support interventions for people experiencing mental health conditions.

BACKGROUND: Peer support is being integrated within mental health services to further the development of a recovery approach. However, the most effective models and formats of intervention delivery are unknown. We conducted this systematic review and meta-analysis to determine the effectiveness of peer support for improving outcomes for people with lived experience of mental health conditions, when delivered as group interventions. METHODS: Studies reporting randomised controlled trials of group peer support interventions for people experiencing mental health conditions were identified by searching MEDLINE, PsycINFO, Embase and Cochrane CENTRAL, from inception until July 12th 2019 and undertaking supplementary searches. Included studies were assessed for risk of bias and meta-analyses were conducted if three or more trials provided usable data. RESULTS: Eight trials met eligibility criteria, providing data from 2131 participants. Six trials had either high or unclear risk of bias. Interventions were categorised as mutual support groups, or peer support groups, sub-categorised as anti-stigma or self-management interventions. Meta-analyses were only possible for peer support groups and five outcomes. We found evidence that group peer support may make small improvements to overall recovery but not hope or empowerment individually, or to clinical symptoms. Evidence for effectiveness for outcomes which could not be meta-analysed was mixed. CONCLUSIONS: Findings from the few eligible trials suggest group peer support interventions may be specifically effective for supporting personal recovery and have a limited impact on other outcomes, though there were some risks of bias to study findings. Interventions were heterogeneous and most social outcomes were absent in the literature, highlighting further limitations to the current evidence-base. There is insufficient evidence available from trials of group peer support torecommend the routine implementation of these interventions across mainstream mental health services at present. More high-quality trials of peer-developed, group peer support interventions are needed in order tomake firm conclusions about intervention effectiveness.

Service user experiences of community services for complex emotional needs: A qualitative thematic synthesis.

BACKGROUND: There is a recognised need to develop clear service models and pathways to provide high quality care in the community for people with complex emotional needs, who may have been given a "personality disorder" diagnosis. Services should be informed by the views of people with these experiences. AIMS: To identify and synthesise qualitative studies on service user experiences of community mental health care for Complex Emotional Needs. METHODS: We searched six bibliographic databases for papers published since 2003. We included peer reviewed studies reporting data on service user experiences and views about good care from community-based mental health services for adults with CEN, including generic mental health services and specialist "personality disorder" services. Studies using any qualitative method were included and thematic synthesis used to identify over-arching themes. RESULTS: Forty-seven papers were included. Main themes were: 1) The need for a long-term perspective on treatment journeys; 2) The need for individualised and holistic care; 3) Large variations in accessibility and quality of mental health services; 4) The centrality of therapeutic relationships; 5) Impacts of 'personality disorder' diagnosis. Themes tended to recur across studies from different countries and years. DISCUSSION: Recurrent major themes included wanting support that is individualised and holistic, provides continuity over long journeys towards recovery, and that is delivered by empathetic and well-informed clinicians who are hopeful but realistic about the prospects of treatment. Care that met these simple and clearly stated priorities tended to be restricted to often limited periods of treatment by specialist "personality disorder" services: generic and primary care services were often reported as far from adequate. There is an urgent need to co-design and test strategies for improving long-term support and treatment care for people with "personality disorders" throughout the mental health care system.