Predictive coding across the left fronto-temporal hierarchy during language comprehension.

We used magnetoencephalography (MEG) and event-related potentials (ERPs) to track the time-course and localization of evoked activity produced by expected, unexpected plausible, and implausible words during incremental language comprehension. We suggest that the full pattern of results can be explained within a hierarchical predictive coding framework in which increased evoked activity reflects the activation of residual information that was not already represented at a given level of the fronto-temporal hierarchy ("error" activity). Between 300 and 500 ms, the three conditions produced progressively larger responses within left temporal cortex (lexico-semantic prediction error), whereas implausible inputs produced a selectively enhanced response within inferior frontal cortex (prediction error at the level of the event model). Between 600 and 1,000 ms, unexpected plausible words activated left inferior frontal and middle temporal cortices (feedback activity that produced top-down error), whereas highly implausible inputs activated left inferior frontal cortex, posterior fusiform (unsuppressed orthographic prediction error/reprocessing), and medial temporal cortex (possibly supporting new learning). Therefore, predictive coding may provide a unifying theory that links language comprehension to other domains of cognition.

Closed Incisional Negative Pressure Therapy Reduces Perineal Wound Complications After Abdominoperineal Resection.

BACKGROUND: Perineal wound complications after abdominoperineal resection continue to be a significant challenge. Complications, ranging from 14% up to 60%, prolong hospitalization, increase risk of readmission and reoperation, delay the start of adjuvant therapy, and place psychological stress on the patient and family. OBJECTIVE: This study aimed to evaluate the impact of closed incision negative pressure therapy on perineal wound healing. DESIGN: This was a retrospective study. SETTINGS: The study was conducted in an academic community hospital. PATIENTS: Patients who underwent abdominoperineal resection from 2012 to 2020 were included. MAIN OUTCOME MEASURES: Perineal wound complications within 30 and 180 days were the primary outcome measures. RESULTS: A total of 45 patients were included in the study. Of these, 31 patients were managed with closed incision negative pressure therapy. The overall perineal wound complications were less frequent in the closed incision negative pressure therapy group (10/31; 32.2%) compared to the control group (10/14; 71.4%; = 5.99 [ p = 0.01]). In the closed incision negative pressure therapy group, 2 patients (20%) did not heal within 180 days and no patient required reoperation or readmission. In the control group, 4 patients (44%) had not healed at 180 days and 1 patient required flap reconstruction. When the effect of other variables was controlled, closed incision negative pressure therapy resulted in an 85% decrease in the odds of wound complications (adjusted OR 0.15 [95% CI, 0.03-0.60]; p = 0.01). LIMITATIONS: The nonrandomized nature and use of historical controls in this study are its limitations. CONCLUSIONS: The ease of application and the overall reduction in the incidence and severity of complications may offer an option for perineal wound management and possibly obviate the need for more expensive therapies. Further prospective controlled trials are required to effectively study its efficacy. See Video Abstract at http://links.lww.com/DCR/B895 . LA TERAPIA POR PRESIN NEGATIVA INCISIONAL CERRADA, REDUCE LAS COMPLICACIONES DE LA HERIDA PERINEAL DESPUS DE LA RESECCIN ABDOMINOPERINEAL: ANTECEDENTES:Las complicaciones de la herida perineal, después de la resección abdominoperineal, continúan siendo un desafío importante. Las complicaciones, que van desde el 14% hasta el 60%, prolongan la hospitalización, aumentan el riesgo de reingreso y reintervención, retrasan el inicio de la terapia adyuvante y generan estrés psicológico en el paciente y su familia.OBJETIVO:Evaluar el impacto de la terapia de presión negativa con incisión cerrada en la cicatrización de heridas perineales.DISEÑO:Estudio retrospectivo.ENTORNO CLINICO:Hospital comunitario académico.PACIENTES:Se incluyeron pacientes sometidos a resección abdominoperineal entre 2012 y 2020.PRINCIPALES MEDIDAS DE VALORACION:Las complicaciones de la herida perineal dentro de los 30 y 180 días fueron las principales medidas de valoración.RESULTADOS:Se incluyeron en el estudio a un total de 45 pacientes. De estos, 31 pacientes fueron tratados con terapia de presión negativa con incisión cerrada. Las complicaciones generales de la herida perineal fueron menos frecuentes en el grupo de terapia de presión negativa con incisión cerrada (10/31, 32,2%) en comparación con el grupo de control (10/14, 71,4%) (X_1 ^ 2 = 5,99 [ p = 0,01]). En el grupo de terapia de presión negativa con incisión cerrada, dos pacientes (20%) no cicatrizaron en 180 días y ningún paciente requirió reintervención o readmisión. En el grupo de control, cuatro pacientes (44%) no habían cicatrizado a los 180 días y un paciente requirió reconstrucción con colgajo. Cuando se controló el efecto de otras variables, la terapia de presión negativa con incisión cerrada resultó con una disminución del 85% en las probabilidades de complicaciones de la herida (OR ajustado, 0.15 [IC 95%, 0,03-0,60]; p = 0,01).LIMITACIONES:La naturaleza no aleatoria y el uso de controles históricos en este estudio, son limitaciones.CONCLUSIÓNES:La facilidad de aplicación, reducción general de la incidencia y gravedad de las complicaciones, pueden ofrecer una opción para el manejo de las heridas perineales y posiblemente obviar la necesidad de tratamientos más costosos. Se necesitan más ensayos controlados prospectivos para efectivamente estudiar la eficacia. Consulte Video Resumen en http://links.lww.com/DCR/B895 . (Traducción-Dr. Fidel Ruiz Healy ).

Strengthening open disclosure after incidents in maternity care: a realist synthesis of international research evidence.

BACKGROUND: Open Disclosure (OD) is open and timely communication about harmful events arising from health care with those affected. It is an entitlement of service-users and an aspect of their recovery, as well as an important dimension of service safety improvement. Recently, OD in maternity care in the English National Health Service has become a pressing public issue, with policymakers promoting multiple interventions to manage the financial and reputational costs of communication failures. There is limited research to understand how OD works and its effects in different contexts. METHODS: Realist literature screening, data extraction, and retroductive theorisation involving two advisory stakeholder groups. Data relevant to families, clinicians, and services were mapped to theorise the relationships between contexts, mechanisms, and outcomes. From these maps, key aspects for successful OD were identified. RESULTS: After realist quality appraisal, 38 documents were included in the synthesis (22 academic, 2 training guidance, and 14 policy report). 135 explanatory accounts were identified from the included documents (with n = 41 relevant to families; n = 37 relevant to staff; and n = 37 relevant to services). These were theorised as five key mechanism sets: (a) meaningful acknowledgement of harm, (b) opportunity for family involvement in reviews and investigations, (c) possibilities for families and staff to make sense of what happened, (d) specialist skills and psychological safety of clinicians, and (e) families and staff knowing that improvements are happening. Three key contextual factors were identified: (a) the configuration of the incident (how and when identified and classified as more or less severe); (b) national or state drivers, such as polices, regulations, and schemes, designed to promote OD; and (c) the organisational context within which these these drivers are recieived and negotiated. CONCLUSIONS: This is the first review to theorise how OD works, for whom, in what circumstances, and why. We identify and examine from the secondary data the five key mechanisms for successful OD and the three contextual factors that influence this. The next study stage will use interview and ethnographic data to test, deepen, or overturn our five hypothesised programme theories to explain what is required to strengthen OD in maternity services.

Neural Evidence for the Prediction of Animacy Features during Language Comprehension: Evidence from MEG and EEG Representational Similarity Analysis.

It has been proposed that people can generate probabilistic predictions at multiple levels of representation during language comprehension. We used magnetoencephalography (MEG) and electroencephalography (EEG), in combination with representational similarity analysis, to seek neural evidence for the prediction of animacy features. In two studies, MEG and EEG activity was measured as human participants (both sexes) read three-sentence scenarios. Verbs in the final sentences constrained for either animate or inanimate semantic features of upcoming nouns, and the broader discourse context constrained for either a specific noun or for multiple nouns belonging to the same animacy category. We quantified the similarity between spatial patterns of brain activity following the verbs until just before the presentation of the nouns. The MEG and EEG datasets revealed converging evidence that the similarity between spatial patterns of neural activity following animate-constraining verbs was greater than following inanimate-constraining verbs. This effect could not be explained by lexical-semantic processing of the verbs themselves. We therefore suggest that it reflected the inherent difference in the semantic similarity structure of the predicted animate and inanimate nouns. Moreover, the effect was present regardless of whether a specific word could be predicted, providing strong evidence for the prediction of coarse-grained semantic features that goes beyond the prediction of individual words.SIGNIFICANCE STATEMENT Language inputs unfold very quickly during real-time communication. By predicting ahead, we can give our brains a "head start," so that language comprehension is faster and more efficient. Although most contexts do not constrain strongly for a specific word, they do allow us to predict some upcoming information. For example, following the context of "they cautioned the…," we can predict that the next word will be animate rather than inanimate (we can caution a person, but not an object). Here, we used EEG and MEG techniques to show that the brain is able to use these contextual constraints to predict the animacy of upcoming words during sentence comprehension, and that these predictions are associated with specific spatial patterns of neural activity.

Elaborative feedback: Engaging reward and task-relevant brain regions promotes learning in pseudoword reading aloud.

Although much is known about the cognitive and neural basis of establishing letter-sound mappings in learning word forms, relatively little is known about what makes for the most effective feedback during this process. We sought to determine the neural basis by which elaborative feedback (EF), which contains both reward-related and content-specific information, may be more helpful than feedback containing only one kind of information (simple positive feedback, PF) or the other (content feedback, CF) in learning orthography-phonology (spelling-sound) mappings for novel letter strings. Compared to CF, EF activated the ventromedial prefrontal cortex, implicated in reward processing. Compared to PF, EF activated the posterior middle temporal, superior temporal, and supramarginal gyri-regions implicated in orthography-phonology conversion. In the same comparison, EF also activated the left fusiform gyrus/visual word form area-implicated in orthographic processing. Also EF, but not CF or PF, modulated activity in the caudate nucleus. In a postscan questionnaire, EF and PF were rated as more pleasant than CF, suggesting that modulation of the caudate for EF may be due to the coupling of reward and skill content. These findings suggest the enhanced effectiveness of EF may be due to concurrent activation of reward-related and task-relevant brain regions.

Reversing the Standard Neural Signature of the Word-Nonword Distinction.

The distinction between letter strings that form words and those that look and sound plausible but are not meaningful is a basic one. Decades of functional neuroimaging experiments have used this distinction to isolate the neural basis of lexical (word level) semantics, associated with areas such as the middle temporal, angular, and posterior cingulate gyri that overlap the default mode network. In two fMRI experiments, a different set of findings emerged when word stimuli were used that were less familiar (measured by word frequency) than those typically used. Instead of activating default mode network areas often associated with semantic processing, words activated task-positive areas such as the inferior pFC and SMA, along with multifunctional ventral occipitotemporal cortices related to reading, whereas nonwords activated default mode areas previously associated with semantics. Effective connectivity analyses of fMRI data on less familiar words showed activation driven by task-positive and multifunctional reading-related areas, whereas highly familiar words showed bottom-up activation flow from occipitotemporal cortex. These findings suggest that functional neuroimaging correlates of semantic processing are less stable than previously assumed, with factors such as word frequency influencing the balance between task-positive, reading-related, and default mode networks. More generally, this suggests that results of contrasts typically interpreted in terms of semantic content may be more influenced by factors related to task difficulty than is widely appreciated.

Mothers working to prevent early stillbirth study (MiNESS 20-28): a case-control study protocol.

INTRODUCTION: In the UK, 1600 babies die every year before, during or immediately after birth at 20-28 weeks' gestation. This bereavement has a similar impact on parental physical and psychological well-being to late stillbirth (>28 weeks' gestation). Improved understanding of potentially modifiable risk factors for late stillbirth (including supine going-to-sleep position) has influenced international clinical practice. Information is now urgently required to similarly inform clinical practice and aid decision-making by expectant mothers/parents, addressing inequalities in pregnancy loss between 20 and 28 weeks. METHODS AND ANALYSIS: This study focuses on what portion of risk of pregnancy loss 20-28 weeks' gestation is associated with exposures amenable to public health campaigns/antenatal care adaptation. A case-control study of non-anomalous singleton baby loss (via miscarriage, stillbirth or early neonatal death) 20+0 to 27+6 (n=316) and randomly selected control pregnancies (2:1 ratio; n=632) at group-matched gestations will be conducted. Data is collected via participant recall (researcher-administered questionnaire) and extraction from contemporaneous medical records. Unadjusted/confounder-adjusted ORs will be calculated. Exposures associated with early stillbirth at OR≥1.5 will be detectable (p<0.05, ß>0.80) assuming exposure prevalence of 30%-60%. ETHICS AND DISSEMINATION: NHS research ethical approval has been obtained from the London-Seasonal research ethics committee (23/LO/0622). The results will be presented at international conferences and published in peer-reviewed open-access journals. Information from this study will enable development of antenatal care and education for healthcare professionals and pregnant people to reduce risk of early stillbirth. TRIAL REGISTRATION NUMBER: NCT06005272.

Treating tumors with a vaccinia virus expressing IFNß illustrates the complex relationships between oncolytic ability and immunogenicity.

Since previous work using a nonreplicating adenovirus-expressing mouse interferon-ß (Ad.mIFNß) showed promising preclinical activity, we postulated that a vector-expressing IFNß at high levels that could also replicate would be even more beneficial. Accordingly a replication competent, recombinant vaccinia viral vector-expressing mIFNß (VV.mIFNß) was tested. VV.mIFNß-induced antitumor responses in two syngeneic mouse flank models of lung cancer. Although VV.mIFNß had equivalent in vivo efficacy in both murine tumor models, the mechanisms of tumor killing were completely different. In LKRM2 tumors, viral replication was minimal and the tumor killing mechanism was due to activation of immune responses through induction of a local inflammatory response and production of antitumor CD8 T-cells. In contrast, in TC-1 tumors, the vector replicated well, induced an innate immune response, but antitumor activity was primarily due to a direct oncolytic effect. However, the VV.mIFNß vector was able to augment the efficacy of an antitumor vaccine in the TC-1 tumor model in association with increased numbers of infiltrating CD8 T-cells. These data show the complex relationships between oncolytic viruses and the immune system which, if understood and harnessed correctly, could potentially be used to enhance the efficacy of immunotherapy.

Systematic in vitro analysis of therapy resistance in glioblastoma cell lines by integration of clonogenic survival data with multi-level molecular data.

Despite intensive basic scientific, translational, and clinical efforts in the last decades, glioblastoma remains a devastating disease with a highly dismal prognosis. Apart from the implementation of temozolomide into the clinical routine, novel treatment approaches have largely failed, emphasizing the need for systematic examination of glioblastoma therapy resistance in order to identify major drivers and thus, potential vulnerabilities for therapeutic intervention. Recently, we provided proof-of-concept for the systematic identification of combined modality radiochemotherapy treatment vulnerabilities via integration of clonogenic survival data upon radio(chemo)therapy with low-density transcriptomic profiling data in a panel of established human glioblastoma cell lines. Here, we expand this approach to multiple molecular levels, including genomic copy number, spectral karyotyping, DNA methylation, and transcriptome data. Correlation of transcriptome data with inherent therapy resistance on the single gene level yielded several candidates that were so far underappreciated in this context and for which clinically approved drugs are readily available, such as the androgen receptor (AR). Gene set enrichment analyses confirmed these results, and identified additional gene sets, including reactive oxygen species detoxification, mammalian target of rapamycin complex 1 (MTORC1) signaling, and ferroptosis/autophagy-related regulatory circuits to be associated with inherent therapy resistance in glioblastoma cells. To identify pharmacologically accessible genes within those gene sets, leading edge analyses were performed yielding candidates with functions in thioredoxin/peroxiredoxin metabolism, glutathione synthesis, chaperoning of proteins, prolyl hydroxylation, proteasome function, and DNA synthesis/repair. Our study thus confirms previously nominated targets for mechanism-based multi-modal glioblastoma therapy, provides proof-of-concept for this workflow of multi-level data integration, and identifies novel candidates for which pharmacological inhibitors are readily available and whose targeting in combination with radio(chemo)therapy deserves further examination. In addition, our study also reveals that the presented workflow requires mRNA expression data, rather than genomic copy number or DNA methylation data, since no stringent correlation between these data levels could be observed. Finally, the data sets generated in the present study, including functional and multi-level molecular data of commonly used glioblastoma cell lines, represent a valuable toolbox for other researchers in the field of glioblastoma therapy resistance.

The Vaccinia virus complement control protein modulates adaptive immune responses during infection.

Complement activation is an important component of the innate immune response against viral infection and also shapes adaptive immune responses. Despite compelling evidence that complement activation enhances T cell and antibody (Ab) responses during viral infection, it is unknown whether inhibition of complement by pathogens alters these responses. Vaccinia virus (VACV) modulates complement activation by encoding a complement regulatory protein called the vaccinia virus complement control protein (VCP). Although VCP has been described as a virulence factor, the mechanisms by which VCP enhances VACV pathogenesis have not been fully defined. Since complement is necessary for optimal adaptive immune responses to several viruses, we hypothesized that VCP contributes to pathogenesis by modulating anti-VACV T cell and Ab responses. In this study, we used an intradermal model of VACV infection to compare pathogenesis of wild-type virus (vv-VCPwt) and a virus lacking VCP (vv-VCPko). vv-VCPko formed smaller lesions in wild-type mice but not in complement-deficient mice. Attenuation of vv-VCPko correlated with increased accumulation of T cells at the site of infection, enhanced neutralizing antibody responses, and reduced viral titers. Importantly, depleting CD8(+) T cells together with CD4(+) T cells, which also eliminated T helper cell-dependent Ab responses, restored vv-VCPko to wild-type levels of virulence. These results suggest that VCP contributes to virulence by dampening both antibody and T cell responses. This work provides insight into how modulation of complement by poxviruses contributes to virulence and demonstrates that a pathogen-encoded complement regulatory protein can modulate adaptive immunity.

Development of a salivary IgA detection method for accurate diagnosis of amebiasis.

An amebiasis detection method was developed based on identifying anti-Entamoeba histolytica IgA in the saliva of infected individuals. The enzyme-linked immunosorbent assay (ELISA)-based detection method was tested along with microscopy and polymerase chain reaction (PCR) on saliva and stool samples from 110 asymptomatic individuals visiting the Manila Health Department - Public Health Laboratory of the City of Manila, Philippines. A receiver operating curve (ROC) was constructed to compare the ELISA results with PCR results. E. histolytica infection was detected in 18 of the 110 individuals. The developed method had an accuracy of 90%, sensitivity of 88.89%, specificity of 90.22%, positive predictive value of 64%, and negative predictive value of 97.65% if a 1:2 dilution of crude saliva sample in phosphate-buffered saline (PBS) was used for diagnosis when compared to PCR. The area under the curve (AUC) of the ROC was 0.9436 if a 1:2 dilution of a crude saliva sample was used. The developed assay presents an easy and accurate method of detecting amebiasis in infected individuals using saliva samples instead of stool or blood samples and has potential applications in both diagnosis and epidemiological studies.

Investigation of the critical factors required to improve the disclosure and discussion of harm with affected women and families: a study protocol for a qualitative, realist study in NHS maternity services (the DISCERN study).

Patients and families are entitled to an open disclosure and discussion of healthcare incidents affecting them. This reduces distress and contributes to learning for safety improvement. Complex barriers prevent effective disclosure and continue in the English NHS, despite a legal duty of candour. NHS maternity services are the focus of significant efforts to improve this. There is limited understanding of how, and to what effect, they are achieving this. METHODS AND ANALYSIS: A 27-month, three-phased realist evaluation identifying the critical factors contributing to improvements in the disclosure and discussion of incidents with affected families. The evaluation asks 'what works, for whom, in what circumstances, in why respects and why?'.Phase 1: establish working hypotheses of key factors and outcomes of interventions improving disclosure and discussion, by realist literature review and in-depth realist interviews with key stakeholders (n=approximately 20]Phase 2: refine or overturn hypotheses, by ethnographic case-study analysis using triangulated qualitative methods (non-participant observation, interviews (n=12) and documentary analysis) in up to 4 purposively sampled NHS trusts.Phase 3: consider hypotheses and design outputs during seven interpretive forums. ETHICS AND DISSEMINATION: Phase 1 study approval by King's College London's Ethics Panel (BDMRESC 22033) and National Research Ethical Approval for Phases 2-3 (IRASID:262197) (CAG:20/CAG/0121) (REC:20/LO/1152). Study sponsorship by King's College London (HS&DR 17/99/85).Findings to be disseminated through tailored management briefings; clinician and family guidance (written and video); lay summaries, academic papers, and report with outputs tailored to maximise academic and societal impact. Views of women/family groups are represented throughout.

Vestibular Imaging and Function in Patients With Inner Ear Malformation Presenting With Profound Hearing Loss.

Objective: Vestibular impairment has been observed in patients with congenital hearing loss, but little is known about the vestibular anatomy and function of those in this group with inner ear malformations. This study aims to investigate the association between vestibulocochlear anatomy and vestibular function test results in children with inner ear malformations. Study Design: Case series with chart review. Setting: Pediatric patients with inner ear malformations presenting with bilateral profound hearing loss at a tertiary hospital from 1999 to 2017. Methods: Ears were classified into subgroups based on anatomic abnormalities seen on computed tomography imaging. Cervical vestibular evoked myogenic potential (cVEMP), rotatory chair, and caloric test results were obtained and collated. Descriptive and inferential statistics were calculated. Results: Of 82 ears, 29.3% had incomplete partition type II malformation, the most common type. The second-most common type was isolated vestibular organ anomaly (20.7%), which is not included in currently accepted categories. Most ears exhibited abnormal vestibular function. Abnormal vestibule volume was associated with a nonreactive cVEMP (P < .001). Radiologically abnormal lateral semicircular canals were associated with abnormal caloric and rotatory chair results (P < .001). Conclusion: With a relatively large number of cases of isolated vestibular organ anomaly not only in our study but also in previous publications, we suggest that this category be added to the subsets of inner ear malformations. Abnormal vestibule volume was significantly associated with a nonreactive cVEMP finding. The majority of patients with hearing loss secondary to inner ear malformations have abnormal vestibular function test results.

Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy.

BACKGROUND: Inherent resistance to radio/chemotherapy is one of the major reasons for early recurrence, treatment failure, and dismal prognosis of glioblastoma. Thus, the identification of resistance driving regulators as prognostic and/or predictive markers as well as potential vulnerabilities for combined modality treatment approaches is of pivotal importance. METHODS: We performed an integrative analysis of treatment resistance and DNA damage response regulator expression in a panel of human glioblastoma cell lines. mRNA expression levels of 38 DNA damage response regulators were analyzed by qRT-PCR. Inherent resistance to radiotherapy (single-shot and fractionated mode) and/or temozolomide treatment was assessed by clonogenic survival assays. Resistance scores were extracted by dimensionality reduction and subjected to correlation analyses with the mRNA expression data. Top-hit candidates with positive correlation coefficients were validated by pharmacological inhibition in clonogenic survival assays and DNA repair analyses via residual γH2AX/53BP1-foci staining. RESULTS: Inherent resistance to single-shot and similarly also to fractionated radiotherapy showed strong positive correlations with mRNA expression levels of known vulnerabilities of GBM, including PARP1, NBN, and BLM, as well as ATR and LIG4-two so far underestimated targets. Inhibition of ATR by AZD-6738 resulted in robust and dose-dependent radiosensitization of glioblastoma cells, whereas LIG4 inhibition by L189 had no noticeable impact. Resistance against temozolomide showed strong positive correlation with mRNA expression levels of MGMT as to be expected. Interestingly, it also correlated with mRNA expression levels of ATM, suggesting a potential role of ATM in the context of temozolomide resistance in glioblastoma cells. ATM inhibition exhibited slight sensitization effects towards temozolomide treatment in MGMT low expressing glioblastoma cells, thus encouraging further characterization. CONCLUSIONS: Here, we describe a systematic approach integrating clonogenic survival data with mRNA expression data of DNA damage response regulators in human glioblastoma cell lines to identify markers of inherent therapy resistance and potential vulnerabilities for targeted sensitization. Our results provide proof-of-concept for the feasibility of this approach, including its limitations. We consider this strategy to be adaptable to other cancer entities as well as other molecular data qualities, and its upscaling potential in terms of model systems and observational data levels deserves further investigation.

Protocol for the development of a core outcome set for stillbirth care research (iCHOOSE Study).

INTRODUCTION: Stillbirth is associated with significant physical, psychosocial and economic consequences for parents, families, wider society and the healthcare system. There is emerging momentum to design and evaluate interventions for care after stillbirth and in subsequent pregnancies. However, there is insufficient evidence to inform clinical practice compounded by inconsistent outcome reporting in research studies. To address this paucity of evidence, we plan to develop a core outcome set for stillbirth care research, through an international consensus process with key stakeholders including parents, healthcare professionals and researchers. METHODS AND ANALYSIS: The development of this core outcome set will be divided into five distinct phases: (1) Identifying potential outcomes from a mixed-methods systematic review and analysis of interviews with parents who have experienced stillbirth; (2) Creating a comprehensive outcome long-list and piloting of a Delphi questionnaire using think-aloud interviews; (3) Choosing the most important outcomes by conducting an international two-round Delphi survey including high-income, middle-income and low-income countries; (4) Deciding the core outcome set by consensus meetings with key stakeholders and (5) Dissemination and promotion of the core outcome set. A parent and public involvement panel and international steering committee has been convened to coproduce every stage of the development of this core outcome set. ETHICS AND DISSEMINATION: Ethical approval for the qualitative interviews has been approved by Berkshire Ethics Committee REC Reference 12/SC/0495. Ethical approval for the think-aloud interviews, Delphi survey and consensus meetings has been awarded from the University of Bristol Faculty of Health Sciences Research Ethics Committee (Reference number: 116535). The dissemination strategy is being developed with the parent and public involvement panel and steering committee. Results will be published in peer-reviewed specialty journals, shared at national and international conferences and promoted through parent organisations and charities. PROSPERO REGISTRATION NUMBER: CRD42018087748.

Experimental evaluation of genomic selection prediction for rust resistance in sugarcane.

The total sugarcane (Saccharum L.) production has increased worldwide; however, the rate of growth is lower compared with other major crops, mainly due to a plateauing of genetic gain. Genomic selection (GS) has proven to substantially increase the rate of genetic gain in many crops. To investigate the utility of GS in future sugarcane breeding, a field trial was conducted using 432 sugarcane clones using an augmented design with two replications. Two major diseases in sugarcane, brown and orange rust (BR and OR), were screened artificially using whorl inoculation method in the field over two crop cycles. The genotypic data were generated through target enrichment sequencing technologies. After filtering, a set of 8,825 single nucleotide polymorphic markers were used to assess the prediction accuracy of multiple GS models. Using fivefold cross-validation, we observed GS prediction accuracies for BR and OR that ranged from 0.28 to 0.43 and 0.13 to 0.29, respectively, across two crop cycles and combined cycles. The prediction ability further improved by including a known major gene for resistance to BR as a fixed effect in the GS model. It also substantially reduced the minimum number of markers and training population size required for GS. The nonparametric GS models outperformed the parametric GS suggesting that nonadditive genetic effects could contribute genomic sources underlying BR and OR. This study demonstrated that GS could potentially predict the genomic estimated breeding value for selecting the desired germplasm for sugarcane breeding for disease resistance.

Parents' Active Role and ENgagement in The review of their Stillbirth/perinatal death 2 (PARENTS 2) study: a mixed-methods study of implementation.

OBJECTIVE: When a formal review of care takes places after the death of a baby, parents are largely unaware it takes place and are often not meaningfully involved in the review process. Parent engagement in the process is likely to be essential for a successful review and to improve patient safety. This study aimed to evaluate an intervention process of parental engagement in perinatal mortality review (PNMR) and to identify barriers and facilitators to its implementation. DESIGN: Mixed-methods study of parents' engagement in PNMR. SETTING: Single tertiary maternity unit in the UK. PARTICIPANTS: Bereaved parents and healthcare professionals (HCPs). INTERVENTIONS: Parent engagement in the PNMR (intervention) was based on principles derived through national consensus and qualitative research with parents, HCPs and stakeholders in the UK. OUTCOMES: Recruitment rates, bereaved parents and HCPs' perceptions. RESULTS: Eighty-one per cent of bereaved parents approached (13/16) agreed to participate in the study. Two focus groups with bereaved parents (n=11) and HCP (n=7) were carried out postimplementation to investigate their perceptions of the process.Overarching findings were improved dialogue and continuity of care with parents, and improvements in the PNMR process and patient safety. Bereaved parents agreed that engagement in the PNMR process was invaluable and helped them in their grieving. HCP perceived that parent involvement improved the review process and lessons learnt from the deaths; information to understand the impact of aspects of care on the baby's death were often only found in the parents' recollections. CONCLUSIONS: Parental engagement in the PNMR process is achievable and useful for parents and HCP alike, and critically can improve patient safety and future care for mothers and babies. To learn and prevent perinatal deaths effectively, all hospitals should give parents the option to engage with the review of their baby's death.

Adaptation of intercalated cells along the collecting duct to systemic acid/base changes.

Collecting duct intercalated cells respond to short-term acid/base perturbations by rapidly shuttling H(+)-ATPase to and from the plasma membrane. Purkerson et al. provide information on the regulation of the anion transporters during chronic acidosis and acute recovery (alkalosis). They found that the major mechanism for both acute and chronic states is regulation of both the H(+)-ATPase and the anion exchangers plus changes in the overall expression level of these anion transporters in chronic adaptation.

Delaware's inclusive trauma system: impact on mortality.

BACKGROUND: The impact of implementing an inclusive state trauma system on injury-related mortality for patients with life-threatening injuries was assessed. METHODS: Using the state trauma registry, trauma patients evaluated in all of Delaware's acute care hospitals from 1998 to 2007 were identified. Patients were categorized by injury severity score (ISS) groups (1-9, 10-15, 16-24, and >24). Each category was analyzed by mortality and interfacility transfer rate to the Level I trauma center for each year. An analysis of the National Trauma Data Bank (NTDB) for these ISS groups and mortality was performed to provide a comparative benchmark. Chi(2) and analysis of variance were used where appropriate (p 24 group. For this group, there was an incremental mortality decrease from 45.7% (1998) to 20.5% (2007) (p 24 group managed at the Level I hospital significantly increased over the same period. CONCLUSION: Since its inception, Delaware's trauma system, in which all acute care hospitals participate, has been associated with an incremental, significant decrease in mortality of the most critically injured patients. This decrease is more substantial than that experienced nationally as depicted within the NTDB. These findings and our evolving experience support the concept and benefits of an "inclusive" trauma system.

The decontaminative effects of acidic electrolyzed water for Escherichia coli O157:H7, Salmonella typhimurium, and Listeria monocytogenes on green onions and tomatoes with differing organic demands.

Acidic electrolyzed water (AC-EW) has strong bactericidal activity against foodborne pathogens on fresh vegetables. However, the efficacy of AC-EW is influenced by soil or other organic materials present. This study examined the bactericidal activity of AC-EW in the presence of organic matter, in the form of bovine serum against foodborne pathogens on the surfaces of green onions and tomatoes. Green onions and tomatoes were inoculated with a culture cocktail of Escherichia coli O157:H7, Salmonella typhimurium, and Listeria monocytogenes. Treatment of these organisms with AC-EW containing bovine serum concentrations of 5, 10, 15, and 20 ml/l was performed for 15s, 30s, 1 min, 3 min and 5 min. The total residual chlorine concentrations of AC-EW decreased proportional to the addition of serum. The bactericidal activity of AC-EW also decreased with increasing bovine serum concentration, whereas unamended AC-EW treatment reduced levels of cells to below the detection limit (0.7 logCFU/g) within 3 min.