Sepsis-associated encephalopathy is a severe neurologic syndrome characterized by a diffuse dysfunction of the brain caused by sepsis. This review provides a concise overview of diagnostic tools and management strategies for SAE at the acute phase and in the long term. Early recognition and diagnosis of SAE are crucial for effective management. Because neurologic evaluation can be confounded by several factors in the intensive care unit setting, a multimodal approach is warranted for diagnosis and management. Diagnostic tools commonly employed include clinical evaluation, metabolic tests, electroencephalography, and neuroimaging in selected cases. The usefulness of blood biomarkers of brain injury for diagnosis remains limited. Clinical evaluation involves assessing the patient's mental status, motor responses, brainstem reflexes, and presence of abnormal movements. Electroencephalography can rule out non-convulsive seizures and help detect several patterns of various severity such as generalized slowing, epileptiform discharges, and triphasic waves. In patients with acute encephalopathy, the diagnostic value of non-contrast computed tomography is limited. In septic patients with persistent encephalopathy, seizures, and/or focal signs, magnetic resonance imaging detects brain injury in more than 50% of cases, mainly cerebrovascular complications, and white matter changes. Timely identification and treatment of the underlying infection are paramount, along with effective control of systemic factors that may contribute to secondary brain injury. Upon admission to the ICU, maintaining appropriate levels of oxygenation, blood pressure, and metabolic balance is crucial. Throughout the ICU stay, it is important to be mindful of the potential neurotoxic effects associated with specific medications like midazolam and cefepime, and to closely monitor patients for non-convulsive seizures. The potential efficacy of targeted neurocritical care during the acute phase in optimizing patient outcomes deserves to be further investigated. Sepsis-associated encephalopathy may lead to permanent neurologic sequelae. Seizures occurring in the acute phase increase the susceptibility to long-term epilepsy. Extended ICU stays and the presence of sepsis-associated encephalopathy are linked to functional disability and neuropsychological sequelae, underscoring the necessity for long-term surveillance in the comprehensive care of septic patients. Sepsis-associated encephalopathy (SAE) is a severe neurologic syndrome characterized by a diffuse dysfunction of the brain caused by sepsis, a life-threatening condition resulting from the dysregulated response of the body to an infection. At the acute phase, patients with SAE typically present with an acute onset of encephalopathy, ranging from delirium to coma . The patIn the present article, we review recent findings in the field of SAE focusing on its epidemiology, diagnosis, and management at the acute phase. We also provide an update on long-term effects of SAE observed in sepsis survivors.SAE is most frequently defined as an acute encephalopathy occurring during sepsis or septic shock, and not attributable to any other cause than sepsis itself . SAE is Most of the available data on acute encephalopathy in the ICU has been generated from studies conducted in the general population. Few specific epidemiological studies have been conducted in patients with sepsis, and risk factors for SAE identified in these studies are described in Table ~10% of cases) and dysautonomia are less frequent [~2% of cases) and focal signs (~1% of cases) are uncommon and should trigger investigations to rule out brain injury. Thus, underdiagnosis of SAE is probable in the absence of systematic screening with validated tools [Clinical evaluation of SAE is challenging in the ICU because neurologic assessment can be confounded by several factors, including fever, metabolic derangements, and the use of hypnotic agents in mechanically ventilated patients. SAE manifests as a rapid change from baseline cognitive status or level of consciousness, and presents with a wide range of symptoms, from mild delirium 19%) to coma (40%) 9% to com. Coma orfrequent . Convulsed tools . ConversData on the usefulness of brain CT studies in patients with SAE is limited. In a meta-analysis conducted in adults with acute non-traumatic encephalopathy, CT abnormal findings were observed in 11% of cases . In mediBrain magnetic resonance imaging (MRI) is indicated in presence of focal signs, brainstem symptoms, new-onset seizures, and in case of persistent encephalopathy in the absence of common confounders (i.e. metabolic/toxic factors and sedation). It is recommended to include a diffusion-weighted imaging (DWI) sequence in the MRI protocol, which is the most sensitive sequence for detection of cerebral ischemia and inflammatory changes. MRI alterations diagnosed at the acute phase of SAE include parenchymal lesions and atrophy, that are reported in about 55% and 16% of cases, respectively , 18. IscWhite matter lesions (WML) are observed in a significant percentage (14–81%) of SAE patients presenting with persistent encephalopathy , 21. TheBrain atrophy is more pronounced in patient with SAE than in healthy controls . This atAcute neuroimaging changes have prognostic significance as predictors of disability and survival in the first year following SAE. In a single-center study, ischemic stroke was found to be independently associated with increased ICU mortality and poor functional status at 6 months . In anotEEG can be a valuable tool in the positive diagnosis of SAE, for excluding non-convulsive status epilepticus, and for prognostication Fig. . In non-One of the main challenges is the impact of sedation on EEG background, which is dependent on the dosage and the specific sedative used. Sedatives can lead to a dose-dependent slowing of the EEG background. Benzodiazepines often produce diffuse rapid rhythms > 13Hz), whereas propofol and barbiturates may result in low voltage, discontinuous patterns at moderate doses, and burst suppression or suppression patterns at higher doses , 26  introduced specific terms for critical care EEG to address this issue .Early EEG abnormalities may precede clinical neurologic impairment and correlate with the severity of encephalopathy , 29. In The pathophysiology of electrographic seizures (ESz) in SAE remains debated, but could be related to the increased neuronal excitotoxicity and epileptogenic factors, including neurotoxic antimicrobials, metabolic disturbances, and severe acute kidney injury. Most ESz are non-convulsive, highlighting the interest of continuous EEG recording . ESz areSome EEG patterns are associated with delirium, including slow delta rhythm, absence of EEG reactivity, discontinuity, and presence/burden periodic discharges (PDs) , 34, 37.Some EEG patterns are also associated with ICU mortality. The absence of reactivity has been shown to be independently associated with ICU and 1 year mortality , 32, 36.Evoked potentials (EPs) are neural responses time-locked to some stimulus and differ from EEG signals as they are stimulus-induced. EPs reflect the combined activity of many neurons firing together and necessitate averaging multiple sensory or auditory stimulations. These components are labeled based on their polarity (negative as "N" and positive as "P") and their latency (measured in milliseconds) from the stimulus. . Somato-Blood biomarkers associated with neuronal injury, specifically neuron-specific enolase (NSE) and neurofilament light (NfL), as well as biomarkers linked to glial injury, such as protein S100 beta (PS100), were evaluated in sepsis patients to anticipate the onset of SAE and predict outcomes. NSE is the most accessible biomarker, and the prevalence of elevated NSE levels (i.e. > 12.5µg/L) in sepsis varies between 28 and 53% , 46. PreIn a single-center study, a NSE threshold > 24.15µg/L (AUC 0.66) had a specificity of 83% and a sensitivity of 54.2% for the diagnosis of SAE . One proThe prognostic value of glial injury biomarkers was examined in several studies, highlighting conflicting results. Previous prospective cohort studies indicated that high PS100 levels were associated with hospital mortality  , but alsOne study investigated the link between serum NfL levels and SAE outcomes . Among sOne prospective study found that serum concentrations of Glial Fibrillary Acidic Protein (GFAP), a protein expressed by astrocytes, were higher in SAE patients compared to non-SAE patients . Serum GUsing blood biomarkers for SAE diagnosis faces challenges due to undefined optimal assessment timing, uncertainty about the precise SAE onset, inconclusive findings about prognostic benefits and definitive thresholds, and limited access to certain biomarkers, impeding their routine clinical use. The profile of biomarkers differs between SAE, sepsis, and delirium patients, suggesting that pathways related to SAE are different from those related to delirium and sepsis itself.Multidisciplinary care is frequently necessary for the comprehensive management of SAE. Prompt identification and treatment of the infection are vital, typically involving the administration of antibiotics and supportive measures such as fluid resuscitation and vasopressors. Moreover, it is essential to control factors contributing to secondary brain injury, which includes maintaining adequate levels of oxygenation and blood pressure, addressing metabolic imbalances, and detecting/treating seizures. Delirium prevention is of paramount importance and implementation of the ABCDEF bundle is associated with improved survival and a reduction in the number of days of delirium and coma . A simplTo prevent secondary insults resulting from agitation, or dysautonomia in severe cases, the use of sedatives  or antipsychotics may be necessary. In two randomized controlled trials conducted in patients with sepsis, the use of dexmedetomidine compared to standard sedation did not result in lower rates of delirium or coma , 56. TheSystemic causes of secondary brain injury are frequent at sepsis onset and are linked to poorer outcomes . These cThree distinct phenotypes of antibiotic-associated encephalopathy have been identified: First, an acute-onset encephalopathy commonly accompanied by clinical seizure (mostly stereotyped clonus or myoclonus) or non-epileptic myoclonus, typically manifesting within days of antibiotic administration ; second, an encephalopathy characterized by psychosis that arises within days of antibiotic administration ; and third, a subacute encephalopathy linked to cerebellar signs and MRI abnormalities that develop weeks after initiating antibiotic therapy (commonly associated with metronidazole) . The mosCefepime remains the most frequently reported molecule associated with neurologic events, with renal dysfunction being the primary risk factor for cefepime-induced neurotoxicity –73. The Although most studies on long term outcomes have focused on the general ICU population, current data suggest that sepsis survivors experience a wide range of cognitive, psychiatric, physical, and social impairment after ICU discharge . A generInflammatory processes are thought to participate in early brain alterations but also in long-term cognitive impairment . In a prSepsis survivors face a higher long-term risk of seizures than other hospitalized patients. In a large cohort, the annual incidence of seizure after sepsis was 1.29%, with incidence rate ratios of 4.98 and 4.33, compared to the general population and hospitalized patients without sepsis, respectively . Among sSepsis survivors experience long-term emotional and behavioral changes, including depressive symptoms, anxiety and post-traumatic stress disorder (PTSD) . A studyCompared to mechanically ventilated patients of similar acuity and length of stay without sepsis, patients with sepsis have an increased risk of mortality and a similar risk of new disability at 6 months . CriticaICU-acquired weakness is another frequent complication associated with sepsis resulting from alterations of small nerve fibers . TypicalSAE is a complex condition that requires a multidisciplinary approach for its diagnosis and management. Timely identification and treatment of the underlying infection are paramount, along with effective control of systemic factors that may contribute to secondary brain injury. Upon admission to the ICU, maintaining appropriate levels of oxygenation, blood pressure, and metabolic balance is crucial. Throughout the ICU stay, it is important to be mindful of the potential neurotoxic effects associated with specific medications like midazolam and cefepime, and to closely monitor patients for non-convulsive seizures. A multimodal approach based on clinical evaluation, neuroimaging and bedside available non-invasive tools may have important prognostic implications both at the acute phase and in the long term. The potential efficacy of targeted neurocritical care during the acute phase in optimizing patient outcomes deserves to be further investigated.SAE may lead to permanent neurologic sequelae. Seizures occurring in the acute phase increase the susceptibility to long-term epilepsy. Extended ICU stays and the presence of sepsis-associated encephalopathy are linked to functional disability and neuropsychological sequelae, underscoring the necessity for long-term surveillance in the comprehensive care of septic patients.


Peronophythora litchii accounts for severe losses in the field and during storage. While ample quantitative studies have shown that 6-pentyl-2H-pyran-2-one (6PP) possesses antifungal activities against multiple plant pathogenic fungi, the regulatory mechanisms of 6PP-mediated inhibition of fungal pathogenesis and growth are still unknown. Here, we investigated the potential molecular targets of 6PP in the phytopathogenic oomycetes P. litchii through integrated deployment of RNA-sequencing, functional genetics, and biochemical techniques to investigate the regulatory effects of 6PP against P. litchii. Previously we demonstrated that 6PP exerted significant oomyticidal activities. Also, comparative transcriptomic evaluation of P. litchii strains treated with 6PP Revealed significant up-regulations in the expression profile of TOR pathway-related genes, including PlCytochrome C and the transcription factors PlYY1. We also noticed that 6PP treatment down-regulated putative negative regulatory genes of the TOR pathway, including PlSpm1 and PlrhoH12 in P. litchii. Protein-ligand binding analyses revealed stable affinities between PlYY1, PlCytochrome C, PlSpm1, PlrhoH12 proteins, and the 6PP ligand. Phenotypic characterization of PlYY1 targeted gene deletion strains generated in this study using CRISPR/Cas9 and homologous recombination strategies significantly reduced the vegetative growth, sporangium, encystment, zoospore release, and pathogenicity of P. litchii. These findings suggest that 6PP-mediated activation of PlYY1 expression positively regulates TOR-related responses and significantly influences vegetative growth and the virulence of P. litchii. The current investigations revealed novel targets for 6PP and underscored the potential of deploying 6PP in developing management strategies for controlling the litchi downy blight pathogen.The litchi downy blight disease of litchi caused by  Litchi chinensis Sonn.) is an economically important evergreen fruit tree crop cultivated across selected subtropical and tropical regions, including southern provinces of China, South Africa, Australia, Hawaii, and Israel [P. litchii is one of the most destructive diseases of Litchi and accounts for 20–30% onfield and post-harvest losses per year [P. litchii heavily relies on the application of synthetic agrochemicals [P. litchii [Litchi . However, the action mechanism of 6PP against P. litchii is unclear, and TOR pathway-related genes of response to 6PP stress in P. litchii are not understood.Previous studies have shown that 6-Pentyl-2H-Pyran-2-One , a bioactive secondary metabolite isolated from  glaucus ,13,14,15Botrytis cinerea, V. dahliae, F. oxysporum, and Fusarium graminearum [Magnaporthe oryzae [Arabidopsis, the TOR pathway is associated with the response to sugar and the maintenance of root tip homeostasis [P. litchii and its influence on essential pathways associated with microbial pathogenesis, including the TOR pathway, remain unclear.Core cellular pathways, including the conserved Ser/Thr protein kinase target of the rapamycin (TOR) pathway, have been identified as a key regulator of cellular growth, survival, metabolism, ribosome biogenesis, translation, and transcription, processes ,17,18. Sminearum ,27,28,29e oryzae . In Arabeostasis . Also, Teostasis . HoweverP. litchii treated with 6PP and identified 6PP-responsive genes, including the YinYang1 (YY1) transcription factor. Additional results from molecular docking analyses and phenotypic characterization of YY1 gene deletion strains indicated that 6PP possibly suppresses vegetative growth, sporulation, cyst formation, and pathogenesis of P. litchii by regulating the activation of the TOR pathway. These findings highlight the critical role of 6PP-mediated regulation of YY1 expressions on the TOR pathway and the impact on cellular/vegetative development and the pathogenesis of phytopathogenic oomycetes.Here, we monitored the transcriptomic dynamics in Tender litchi leaves (cv. Baitangying) were collected from a Hainan University orchard . Leaf shapes and sizes were uniform and disease-free. Fresh and healthy Litchi fruits were harvested from orchards in Haikou, China, for infection assays. All fruits were healthy, uniform in shape, and at 80% ripe.Carrot juice agar (CJA) medium was prepared by incorporating the juice from 0.2 kg of crushed carrots into the water to attain a final volume of 1 L, adding 15 g agar/L for solid media.The 6PP was an analytical-grade standard purchased from Shanghai Aladdin Bio-Chem Technology Co., Ltd., Shanghai, China.P. litchii by air fumigation. The fumigation device is composed of two petri dish bottoms. One bottom of the petri dish contains P. litchii, and the other bottom of the petri dish contains 6PP, then wrapped with parafilm. The fumigation device allows air exchange, but 6PP has no direct contact with P. litchii. P. litchii was cultured on CJA medium for 3 days, and fumigated with 6PP (86 μg/mL) for another day, then the biomass was collected and frozen in liquid nitrogen. The 6PP concentration (86 μg/mL) was selected based on our preliminary results, which are the 2.0 × EC50 values of 6PP against P. litchii mycelial growth  in the P. litchii database we have established. After searching and matching to transcriptome data, TOR pathway genes regulated by 6PP were identified based on their differential expression pattern and predicted domains, molecular weight, and isoelectric points using Simple Modular Architecture Research Tool (SMART) database, NCBI Batch CD-Search  and online program ExPASy ProtParam . Additionally, we deployed MEME suit for further DNA-biding motif analyses  online website.Genome (ID: PRJNA290406) and proteome (GWHAOTU00000000.1) data for https://services.healthtech.dtu.dk./service.hph?SignalP-4.1, accessed on 22 December 2021), and then homology modeling was processed and analyzed for applicability by SWISS-MODEL  and SAVES v.6.0 . Furthermore, autodock software (version 1.5.6) and python software (version 2.5) was used for docking analyses using the default parameters to calculate the binding affinities between ligand and receptors, and 50 interaction models were accepted to establish with default docking parameter [Ligand 6PP structure, obtained from PubChem database, was converted from a two-dimensional model to mol 2 format by Openbable (version 3.1.1) process. Target protein structures were required for signal peptide prediction by SignalP-4.1 , using primer pairs listed in PlYY1 were inoculated in liquid SD-Trp media and diluted into different concentration solutions to compare growth volumes . Consecutively, pGBKT7-PlYY1 was cultured at SD-Trp-Leu, SD-Trp-Leu-His-Ade, and SD-Trp-Leu-His-Ade+X-α-gal medium separately to ascertain whether the target vector had been transferred into yeast AH109 correctly and has a Transcriptional activation ability. In order to determine the accuracy of the experiment, positive co-transformed control pGBKT7-p53+pGADT7-ADT and negative control pGBKT7 were conducted. This experiment was performed by three times.Transcriptional activation is a ubiquitously essential process that regulates gene modification. Additional tests were performed to examine the activation abilities of the HPH) and two homologous flanking sequences (about 1kb) were connected by overlap extension PCR and cloned to linearized plasmid pBluescript II KS+. According to the previous gene knock-out technique [P. litchii, and transformants were separated by CJA medium supplemented with G418 at concentration 20 μg/mL. The conventional cetyltrimethylammonium bromide (CTAB) method was used to extract genomic DNA. Moreover, transformants were verified and identified by polymerase chain reaction (PCR) in three rounds. Also, PCR products were sequenced if transformants identification was verified, and all primers are provided in To knock out the gene efficiently, two fragments of sgRNA were synthesized and cloned into an “all-in-one” pYF515 vector, respectively. Donor DNA hygromycin B resistance gene , the wild-type, and the complementation (▲PlYY1-2) strains were inoculated in CJA medium at 25 °C for 5-days in darkness, and mycelial growth rate, sporangia production, and zoospore release rate were investigated. The total harvest volume of sporangia was 30 mL for each plate, and the release of zoospore was induced by low temperature (12 °C). To determine the oospores production, P. litchii was inoculated on CJA medium, and the 10th and 15th day, plugs (1 cm × 1 cm) were cut from 1 cm around the inoculation site, and oospores were counted under a microscope. All experiments were repeated five times, with three replicates in each experiment.For phenotypic examinations, the two independent 4 sporangia/mL. Lesion size and pattern were analyzed at 48 hpi and 60 hpi at room temperature. Results were generated from three independent biological experiments, with each experiment comprising three technical replicates. Each biological replicate consists of 27 leaves and 30 fruits. To investigate whether the pathogenic capacity of mutants was affected, both the leaves and lychee fruits were used for testing. Three strains, WT, ∆PlYY1-1, and ∆PlYY1-2, were incubated as described in Air fumigation was utilized, and both WT and mutant strains’ discs (Φ = 6 mm) were inoculated in CJA medium, which was fumigated with 6PP for 5 days at 25 ± 1 °C. The concentration of 6PP is 1.0 × EC50. Mycelial growth was measured and used in deriving the inhibition rate. Negative control (NK) was set up without 6PP. This experiment was replicated three times with five copies each time.p < 0.05, while double asterisks (**) represented p < 0.01, and ns represented no significant difference.Statistical computations were performed using the one-way ANOVA  with Tukey’s multiple comparisons test, and all results exhibited mean ± SEM. Significance differences recorded between treatments and control groups are denoted with an asterisk (*). A single asterisk (*) represented p-value < 0.05 and |log2Fold change| ≥ 1. A comprehensive analysis of 17,959 genes was conducted in the Transcriptome data, comparing the treatment and control groups. Of these, 1428 genes exhibited differential expression, with 406 genes up-regulated and 1022 genes down-regulated.  were identified from P. litchii through homologous gene comparison. Furthermore, by conducting transcriptome differential expression gene analysis, it was observed that two TOR pathway-related genes, g1902.t1  and g12953.t1 , were significantly up-regulated, while two other TOR pathway-related genes, g125.t1  and g2677.t1 , were significantly down-regulated. whereas no autophagy gene was not affected  were identified using a threshold gulated. A. This saffected B,C. Protectively D. Furtheectively E, suggesTo elucidate the potential action mechanism of the TOR pathway and 6PP at the molecular level, we conducted molecular docking analyses of the ligand (6PP) to the binding sites of PlYY1.t1, g12953.t1, g125.t1, and g2677.t. Our findings revealed that the main forces involved in the interactions were hydrogen bonding, van der Waals forces, and conjugate bonding A–D. The A binding energy below −5.0 kcal/mol signifies a strong binding capability, with lower binding energy implying a more stable interaction between the ligand and molecule. The outcomes of the docking analysis indicate that four proteins possess potential binding sites for 6PP.PlYY1 versus control pGBKT7 indicated that the pGBKT7-PlYY1 construct did not impact yeast growth, as the undifferentiated growth was performed in the same diluted concentration solutions on the SD-Trp medium. Meanwhile, the pGBKT7-PlYY1 cassette had been successfully transferred to the yeast strain . The findings revealed a marked reduction in the mutants’ pathogenicity compared to the WT strain.The contribution of 2 at 48 hpi, while the lesion areas infected by mutant strains ∆PlYY1-1 and ∆PlYY1-2 were approximately 0.40 and 0.42 cm2, respectively. Similarly, at 60 hpi, the lesion area infected by the WT strain increased to 1.71 cm2, whereas the lesion areas infected by mutant strains ∆PlYY1-1 and ∆PlYY1-2 were approximately 0.57 and 0.70 cm2 respectively , and Arabidopsis thaliana, YY1 functions have been linked to vegetative growth [P. litchii and other phytopathogenic oomycetes, including P. litchii. In this study, we demonstrated using transcriptional activation assays to confirm that the transcription factor YY1 in P. litchii binds to regulatory proteins associated with the TOR pathway, but further experiments are needed to confirm this speculation. Genetic deactivation of the PlYY1 gene triggered significant inhibition in vegetative growth, sporangia production, encystment, zoospore release, and virulence of P. litchii without altering oospore production. These findings indicated that PlYY1 is essential in vegetable growth and asexual reproduction in P. litchii. The current observations partly and independently validate previous reports linking the YY1 transcription factor to embryonic (peri-implantation) survival in mice [Previous studies showed that YY1 promotes cancer and tumor development in humans. Also, in e growth ,45,46,47 in mice  and as a in mice .PlYY1 defective strains to 6PP. These observations revealed PlYY1 as a probable novel target for 6PP. Additionally, we reasoned that 6PP influences vegetative development, cellular differentiation, and pathogenesis in P. litchii via PlYY1-mediated regulation of the TOR pathway.Similarly, we demonstrated that 6PP treatments triggered a significant enhancement in the expression pattern of the PlYY1 gene and compromised the sensitivity of P. litchii by identifying and analyzing TOR pathway-related genes expression, molecular docking, knocking out the PlYY1 gene, and the sensitivity of the PlYY1 gene to 6PP. These results will help improve our understanding of the mechanism response to 6PP stress and promote more effective disease management strategies in P. litchii. However, the function of TOR is complex in eukaryotes and provides clues into the pathological significance of the TOR in P. litchii.In the study, we preliminarily explored the response of the TOR pathway to 6PP stress in


Background: Despite the development of patient-centred or patient-reported outcome measures (PCOMs or PROMs) in palliative and end-of-life care over recent years, their routine use in practice faces continuing challenges.Objective: To update a highly cited literature review, identify and synthesise new evidence on facilitators, barriers, lessons learned, PCOMs used, models of implementation, implementation outcomes, costs, and consequences of implementing PCOMs in palliative care clinical practice.Methods: We will search MEDLINE, PsycINFO, CINAHL, Embase, Emcare, SCI-Expanded, SSCI, ESCI, and BNI. The database search will be supplemented by a list of studies from the expert advisory committee, hand-searching of reference lists for included articles, and citations of the original review. We will include primary studies using a PCOM during clinical care of adult patients with advanced disease in palliative care settings and extract data on reported models of implementation, PCOMs, facilitators, barriers, lessons learned, costs, and implementation outcomes. Gough’s Weight of Evidence Framework will be used to assess the robustness and relevance of the studies. We will narratively synthesise and tabulate the findings. This review will follow PRISMA, PRISMA-Abstract, PRISMA-P, and PRISMA-Search as the reporting guidelines.Source of funding: Marie Curie. The funder is not involved in designing or conducting this study.Protocol registration: CRD42023398653 (13/02/2023) The importance of using outcome measures to understand the effect and effectiveness of health interventions has been growing as they are increasingly credited as an essential component of evidence-based clinical practice, specifically, outcome measures that the patient completes - so-called patient-reported outcome measures or PROMs - because of their specificity to patients’ individual needs. Data collected at the individual patient level can be used immediately for patient-centred care, as it allows healthcare professionals to act on any distressing symptoms or palliative needs they might have. It can also inform shared decision-making and advance care planning . AdditioIn palliative and end-of-life care, it is equally important to learn about physical effects and psychological, existential, emotional and practical outcomes. However, implementing PROMs as a routine part of palliative care clinical practice has been slow and challenging in a number of countries. Compared to other settings and conditions, measuring outcomes in palliative care faces unique challenges. One reason is that patients’ health is expected to deteriorate, and symptoms may worsen; deterioration will make the outcome measurement challenging, as well as changes in cognitive abilities towards the end of life. PROMs are impossible to use closer to the time of death once the patient becomes unable to communicate .Our previous review summarised barriers, facilitators, and lessons learned from the published palliative care literature and provided recommendations for implementing outcome measures at the patient, healthcare professional, and management and policy-makers levels for three timepoints: preparation, implementation, and assessment/improvement  to include both patient-reported and proxy-reported measures that focus on the concerns important to patients.Palliative Medicine and included the literature published between 1985 and 2013. In the last decade, there has been a plethora of publications demonstrating the exponential growth in palliative care outcome measurement. An update on these developments is warranted.The original systematic review (cited 307 times on 16 January 2023) was published in1.To identify the patient-centred outcome measures implemented in palliative care clinical practice;2.To identify the facilitators of implementing patient-centred outcome measures in palliative care clinical practice;3.To identify the barriers to implementing patient-centred outcome measures in palliative care clinical practice;4.To identify lessons learned on implementing patient-centred outcome measures in palliative care clinical practice;5.To identify the implementation models used when implementing patient-centred outcome measures in palliative care clinical practice;6.To identify what implementation outcomes were measured and how, when implementing patient-centred outcome measures in palliative care clinical practice;7.To assess the financial costs of implementing patient-centred outcome measures in palliative care clinical practice;8.To update the recommendations from our previous literature to inform the implementation process in palliative care clinical practice for stakeholders at different levels.th February 2023.This systematic literature review and narrative synthesis was reported based on PRISMA-P (Types of studiesPrimary research studies reporting information related to one of the eight objectives of this review outlined above. All types of evidence synthesis will be considered research studies and included.Types of participantsAdult patients (18 years old and over) with advanced diseases and receiving palliative and end-of-life care, their informal carers, and healthcare professionals.Types of settingAll settings in which palliative care is provided. As in the original review, we will include studies conducted both in specialist and non-specialist palliative care settings, provided that in the non-specialist settings, a palliative care measure was implemented.Implementation of outcome measures as the interventionThe included articles will report on the implementation of PROMs. PROMs are a form of outcome measure and comprise standardised, validated questionnaires that patients complete to measure their perceptions of their own health status and well-being .Types of studiesNarrative reviews, editorials, commentaries, and case reports will be excluded. If we identify relevant narrative reviews, we will check their references for eligible studies.Types of participantsStudies with a paediatric or mixed population where fewer than 50% of participants are 18 years old or over.Types of settingStudies with non-palliative care settings or mixed settings when fewer than 50% of participants are from palliative care settings.Implementation of outcome measures as the interventionStudies reporting data from routine outcome measurement without information on the implementation process as they relate to settings in which implementation has already taken place.Studies reporting exclusively on the development, testing and feasibility phases of new measures or validation of the linguistic translation of measures, as they do not relate to implementing measures in clinical practice.Electronic searchesMEDLINE,Embase, andEmcare via Ovid SP,CINAHL andPsycINFO via EBSCOhost,British Nursing Index via ProQuest,Science Citation Index-Expanded,Social Science Citation Index, andEmerging Sources Citation Index via Web of Science without any limitations to language, date, document type, or publication status.An information specialist will systematically searchThe searches were designed by an expert information scientist and peer-reviewed by another information scientist in collaboration with two clinical experts. The search strategies were tailored based on the included studies in the original review and tested against a new set of relevant studies supplied by the experts in MEDLINE before the agreement on the final search strategy.Extended data -Outcome reporter -Factors  related to the implementation-Implementation models used-Outcomes of implementation -Country-Date of research and publication-Age groups-Healthcare conditions -Setting -Scale of the study -Study design-Objectives of the study-Limitations and strengths of the study-Sample size-Notes (including relevant information not matching other data points)-Potentially relevant references-Lead author's name and email addressThe data extraction form will be designed, piloted and revised based on the following data points:We will initially use the form in Google Docs document format for piloting, and when finalised, we will use Google Sheets to extract data.Qualitative data will be extracted and analysed following the Guidance on the Conduct of Narrative Synthesis in Systematic Reviews  describing/guiding the process of translating effective interventions and research evidence into practice (process frameworks); (b) analysing what influences implementation outcomes (determinant frameworks); and (c) evaluating implementation efforts (outcome frameworks) . We willWe will consider and, where feasible, extract the PROGRESS plus : A generic and non-review-specific judgement about the coherence and integrity of the evidence in its own terms, i.e. the generally accepted criteria for evaluating the quality of this type of evidence.Weight of Evidence B (WoE B): A review-specific judgement about the appropriateness of that form of evidence for answering the review questions, i.e. the fitness for the purpose of that form of evidence.Weight of Evidence C (WoE C): A review-specific judgement about the relevance of the focus of the evidence for the review question, e.g. the relevance of the type of sample, evidence gathering or analysis in relation to the review question.These three sets of judgements can then be combined to form an overall assessment Weight of Evidence D (WoE D) of the extent that a study contributes evidence to answer a review question.Two reviewers will independently make the assessments, with any disagreement resolved by discussion and, if needed, by a third assessor.We have replaced the terminology patient-reported outcome measures (PROMs) with patient-centred outcome measures (PCOMs).Four new objectives in this update were not part of the previous review: implementation outcomes, costs, implementation models, and updating the recommendations. As a result of adding an objective to extract implementation models, we may have enough information to report on implementation processes using the multilevel framework for health program evaluation   outcome measures in palliative and end-of-life care. The study objective is the identification of new evidence on facilitators, barriers, lessons learned, used instruments, models of implementation, implementation outcomes, costs, and conseqences of implementing PCOMs. Therfore, the authors describe the search tools, types of studies, participants and settings. Proxy outcome measures will be considered in the presented review to include patients in bad conditions. The study protocol describes the exclusion criteria and search methods in detail. The description of the underlying disease (e.g. cancer vs non-cancer) would be helpful in the "Data extraction" section. The changes from the original systematic review are clearly described and relevant. In sum, the authors deal with an important update of the systamatic review for PROMs in palliative care. Therefore, I would accept this manuscript for indexing with only the described little minor revision.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?YesReviewer Expertise:Palliative Care, patient reported outcome measurementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This is a protocol describing a planned update of a systematic review. The justification for updating the review is sound, and the objectives are clear. In the Design section of the methods, four PRISMA reporting guidelines are referenced, including PRISMA-P (for systematic review protocols). I would imagine that this protocol should be reported according to PRISMA-P, with the review itself reported according to PRISMA and PRISMA-S. Other changes from the previous review were reported, however not consistently. I would like to understand which things changed, and also which remained the same. For example, in 'Data synthesis', you are using an implementation framework published after the original review. What did you previously use to guide data synthesis? The contrast would be helpful here. Overall, this will be an interesting update, which has been well-justified and well described.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Epidemiology, biostatisticsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.