The roles and responsibilities of advanced practice nurses in intensive care units: A scoping review.

INTRODUCTION: Since the intensive care units are one of the most sensitive hospital settings and critically ill patients undergo various stressful factors that put their lives in danger, a more advanced level of nursing practice is imperative to accommodate these issues and provide optimal care of patients. OBJECTIVES: To review the literature describing the roles and activities performed by advanced practice nurses in intensive care units. REVIEW METHODS: We conducted a scoping review to search published articles using Scopus, PubMed, CINAHL (EBSCOhost), Science Direct, MEDLINE (EBSCOhost) and Cochrane Library during a 10-year period from 2013 to 2023. RESULTS: We identified 729 records, from which eleven articles were included in the review. We included six reviews and five original articles or research papers. With regard to the target area of our review, we used the information provided by these studies and categorized the contents related to the roles of advanced practice nurses in intensive care units into five sections, including direct practice, education and counseling, research, collaboration, and leadership. CONCLUSION: Advanced practice nurses are essential members of critical care team by playing various roles in practice, education, research, collaboration, and leadership, and therefore, they can increase patients' access to critical care and improve healthcare outcomes. The advancement of technology and complexity of care in intensive care units have led to the role expansion of these nurses which results in task-shifting between doctors and nurses. Therefore, it is considered essential for nursing and medical professionals to reach an agreement to establish standardized roles for advanced practice nurses.

Pediatric Acute Respiratory Distress Syndrome Severity and Health-Related Quality of Life Outcomes: Single-Center Retrospective Cohort, 2011-2017.

OBJECTIVES: To determine factors associated with health-related quality of life (HRQL) decline among pediatric acute respiratory distress syndrome (PARDS) survivors. DESIGN: Retrospective cohort study. SETTING: Academic children's hospital. PATIENTS: Three hundred fifteen children 1 month to 18 years old with an unplanned PICU admission from December 2011 to February 2017 enrolled in the hospital's Outcomes Assessment Program. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pre-admission baseline and median 6-week post-discharge HRQL were assessed using the Pediatric Quality of Life Inventory or the Functional Status II-R. Patients meeting retrospectively applied Second Pediatric Acute Lung Injury Consensus Conference criteria for PARDS were identified, and PARDS severity was classified using binary (mild/moderate, severe) and trichotomous (mild, moderate, severe) categorization for noninvasive ventilation and invasive mechanical ventilation (IMV). PARDS occurred in 41 of 315 children (13.0%). Clinically important HRQL decline (≥ 4.5 points) occurred in 17 of 41 patients (41.5%) with PARDS and 64 of 274 without PARDS (23.4%). On multivariable generalized linear regression adjusted for age, baseline Pediatric Overall Performance Category, maximum nonrespiratory Pediatric Logistic Organ Dysfunction score, diagnosis, length of stay, and time to follow-up, PARDS was associated with HRQL decline (adjusted relative risk [aRR], 1.70; 95% CI, 1.03-2.77). Four-hour and maximum PARDS severity were the only factors associated with HRQL decline. HRQL decline occurred in five of 18 patients with mild PARDS at 4 hours, five of 13 with moderate PARDS (aRR 2.35 vs. no PARDS [95% CI, 1.01-5.50]), and seven of ten with severe PARDS (aRR 2.56 vs. no PARDS [95% CI, 1.45-4.53]). The area under the receiver operating characteristic curve for discrimination of HRQL decline for IMV patients was 0.79 (95% CI, 0.66-0.91) for binary and 0.80 (95% CI, 0.69-0.93) for trichotomous severity categorization. CONCLUSIONS: HRQL decline is common among children surviving PARDS, and risk of decline is associated with PARDS severity. HRQL decline from baseline may be an efficient and clinically meaningful endpoint to incorporate into PARDS clinical trials.

Parents' Experiences Caring for a Child after a Critical Illness: A Qualitative Study.

Objectives This article described parents' experience and identifies outcomes important to parents following their child's critical illness. Methods Semistructured interviews with 22 female and 4 male parents representing 26 critically ill children with predominately neurologic and respiratory diagnoses. Most children were younger than 5 years at discharge with a median (interquartile range) of 2 (2.0-3.0) years from discharge to interview. Results Many children returned home with life-altering physical and cognitive disabilities requiring months to years of rehabilitation. Parents remembered feeling unprepared and facing an intense, chaotic time when the child first returned home. They described how they suddenly had to center their daily activities around the child's needs amidst competing needs of siblings and partners, and in some cases, the medicalization of the home. They recounted negotiating adjustments almost daily with insurance agencies, medical doctors and therapists, employers, the child, and other family members to keep the family functioning. In the long term, families developed a new norm, choosing to focus on what the child could still do rather than what they could not. Even if the child returned to baseline, parents remembered the adjustments made to keep the child alive and the family functioning. Conclusion Heightened awareness of family experiences after pediatric critical illness will allow health care providers to improve family preparedness for the transition from hospital to home.

Association of minor electrocardiographic (ECG) abnormalities with epilepsy duration in children: A manifestation of the epileptic heart?

PURPOSE: Cardiac abnormalities resulting from chronic epilepsy ("the epileptic heart") constitute a well-recognized comorbidity. However, the association of cardiac alterations with epilepsy duration remains understudied. We sought to evaluate this association using electrocardiogram (ECG). METHODS: We prospectively enrolled children between 1 months and 18 years of age without known cardiac conditions or ion channelopathies during routine clinic visits. ECGs were categorized as abnormal if there were alterations in rhythm; PR, QRS, or corrected QT interval; QRS axis or morphology; ST segment or T wave. An independent association between ECG abnormalities and epilepsy duration was evaluated using multivariable logistic regression modeling. RESULTS: 213 children were enrolled. 100 ECGs (47%) exhibited at least one alteration; most commonly in the ST segment (37, 17%) and T wave (29, 11%). Children with normal ECGs had shorter epilepsy duration as compared to those with ECG abnormalities (46 [18-91] months vs. 73 [32-128 months], p = 0.004). A multivariable logistic regression model demonstrated that increasing epilepsy duration was independently associated with the presence of ECG abnormalities (OR=1.09, 95% CI=1.02-1.16, p = 0.008), adjusted for seizure frequency, generalized tonic-clonic/focal to bilateral tonic-clonic seizures as the predominant seizure type, and number of channel-modifying anti-seizure medications. Increasing epilepsy duration was also independently associated with the presence of ST/T wave abnormalities (OR=1.09, 95% CI=1.01-1.16, p = 0.017), adjusted for the same covariates. SIGNIFICANCE: Increasing epilepsy duration is independently associated with the presence of minor ECG abnormalities. Additional studies are needed to evaluate whether this finding may represent a manifestation of the "epileptic heart".

Retinoids in the treatment of photoageing: A histological study of topical retinoid efficacy in black skin.

BACKGROUND: Photoageing describes complex cutaneous changes that occur due to chronic exposure to solar ultraviolet radiation (UVR). The 'gold standard' for the treatment of photoaged white skin is all-trans retinoic acid (ATRA); however, cosmetic retinol (ROL) has also proven efficacious. Recent work has identified that black skin is susceptible to photoageing, characterized by disintegration of fibrillin-rich microfibrils (FRMs) at the dermal-epidermal junction (DEJ). However, the impact of topical retinoids for repair of black skin has not been well investigated. OBJECTIVES: To determine the potential of retinoids to repair photoaged black skin. METHODS: An exploratory intervention study was performed using an in vivo, short-term patch test protocol. Healthy but photoaged black volunteers (>45 years) were recruited to the study, and participant extensor forearms were occluded with either 0.025% ATRA (n = 6; 4-day application due to irritancy) or ROL (12-day treatment protocol for a cosmetic) at concentrations of 0.3% (n = 6) or 1% (n = 6). Punch biopsies from occluded but untreated control sites and retinoid-treated sites were processed for histological analyses of epidermal characteristics, melanin distribution and dermal remodelling. RESULTS: Treatment with ATRA and ROL induced significant acanthosis (all p < 0.001) accompanied by a significant increase in keratinocyte proliferation (Ki67; all p < 0.01), dispersal of epidermal melanin and restoration of the FRMs at the DEJ (all p < 0.01), compared to untreated control. CONCLUSIONS: This study confirms that topical ATRA has utility for the repair of photoaged black skin and that ROL induces comparable effects on epidermal and dermal remodelling, albeit over a longer timeframe. The effects of topical retinoids on black photoaged skin are similar to those reported for white photoaged skin and suggest conserved biology in relation to repair of UVR-induced damage. Further investigation of topical retinoid efficacy in daily use is warranted for black skin.

Stress Among Parents of Children With Severe Neurological Impairment in the Pediatric Intensive Care Unit.

Background: Children with severe neurological impairment (SNI) often receive care in the pediatric intensive care unit (PICU), yet little is known about their parents' experiences. Objective: To examine sources of and changes in stress among parents of children with SNI in the PICU. To compare stressors with "good parent" attributes that describe duties parents aim to uphold for their child. Design/Setting/Subjects: Prospective mixed-methods cohort study at a single U.S. children's hospital. Participants included English-speaking parents/legal guardians of a child with SNI with an expected length of stay >1 week and life expectancy >4 weeks. Measurements: Ten-point stress scale administered at PICU admission and discharge with open-ended response items. A subset of parents completed 1:1 semistructured interviews. Data were integrated to examine differences among participants whose stress increased, stayed the same, or decreased, and themes were compared with "good parent" attributes. Results: Twenty-five parents/legal guardians completed the surveys; 15 completed the interviews. Children were a median of 7 years old (interquartile range [IQR] 4, 9; range 1-21) and had a median PICU length of stay of 10 days (IQR 7, 15; range 3-62). Twenty percent (n = 5) of parents were fathers, and 36% (n = 9) had a minority racial/ethnic background. Stress was moderate at admission (mean 6.8, standard deviation [SD] ±1.7) and discharge (mean 6, SD ±2); 32% (n = 8) reported stress trajectories that stayed the same or increased. Major themes included uncertainty, advocacy, and vulnerability and related closely to "good parent" attributes. Conclusion: Stress among parents of children with SNI related to uncertainty, advocacy, and vulnerability and suggested tensions with "good parent" attributes.

Meaning-Making Among Parents of Children With Severe Neurologic Impairment in the PICU.

BACKGROUND AND OBJECTIVES: Parents and family caregivers of children with severe neurologic impairment (SNI) experience many stressors, especially during their child's critical illness. This study aimed to examine parent experiences around the time of their child's PICU care to explore ways parents make meaning in relation to these stressors. METHODS: This qualitative study of data from a single center in the United States followed Consolidated Criteria for Reporting Qualitative Research guidelines. One to one semistructured interviews queried parents' psychosocial well-being around the time of their child's PICU care. Eligible participants had a child with an SNI condition for >3 months admitted to the PICU for >24 hours with an expected length of stay >1 week. RESULTS: Data were analyzed by a research team with expertise in palliative care, psychology, critical care, and qualitative methods. Fifteen family caregivers of 15 children participated. Children were a median of 8 years old (interquartile range 4-11.5) and 80% (n = 12) had congenital/genetic conditions. Parent/family caregivers were a median age of 39 years old (interquartile range 36-42.5); 20% (n = 3) self-identified as fathers and 47% (n = 7) as having to a minority racial background. Parents discussed ongoing meaning-making that occurred through domains of comprehension and purpose, and themes of understanding of other people and the world around them. Subthemes focused on appreciation/acceptance, adaptability/accountability, valuing all lives, and learning/teaching about their child. CONCLUSIONS: Meaning-making may be an opportunity for support in the PICU among parents/family caregivers of children with SNI.

Acoustic field visualisation using local absorption of ultrasound and thermochromic liquid crystals.

Acoustic field and vibration visualisation is important in a wide range of applications. Laser vibrometry is often used for such visualisation, however, the equipment has a high cost and requires significant user expertise, and the method can be slow, as it requires scanning point by point. Here we suggest a different approach to visualisation of acoustic fields in the kHz - MHz range, using paint-on or removable film sensors, which produce a direct visual map of ultrasound displacement. The sensors are based on a film containing thermochromic liquid crystals (TLC), along with a backing/underlay layer which improves absorption of ultrasound. The absorption generates heat, which can be seen by a change in colour of the TLC film. A removable sensor is used to visualise the resonant modes of an air-coupled flexural transducer operated from 410 kHz to 7.23 MHz, and to visualise 40 kHz standing waves in a Perspex plate. The thermal basis of the visualisation is confirmed using thermal imaging. The speed and cost of visualisation makes the new sensor attractive for use in condition monitoring, for fast assessment of transducer quality, or for analysis of acoustic field distribution in power ultrasonic systems.

Design and rationale of the Post-Intensive Care Syndrome - paediatrics (PICS-p) Longitudinal Cohort Study.

INTRODUCTION: As paediatric intensive care unit (PICU) mortality declines, there is growing recognition of the morbidity experienced by children surviving critical illness and their families. A comprehensive understanding of the adverse physical, cognitive, emotional and social sequelae common to PICU survivors is limited, however, and the trajectory of recovery and risk factors for morbidity remain unknown. METHODS AND ANALYSIS: The Post-Intensive Care Syndrome - paediatrics Longitudinal Cohort Study will evaluate child and family outcomes over 2 years following PICU discharge and identify child and clinical factors associated with impaired outcomes. We will enrol 750 children from 30 US PICUs during their first PICU hospitalisation, including 500 case participants experiencing ≥3 days of intensive care that include critical care therapies (eg, mechanical ventilation, vasoactive infusions) and 250 age-matched, sex-matched and medical complexity-matched control participants experiencing a single night in the PICU with no intensive care therapies. Children, parents and siblings will complete surveys about health-related quality of life, physical function, cognitive status, emotional health and peer and family relationships at multiple time points from baseline recall through 2 years post-PICU discharge. We will compare outcomes and recovery trajectories of case participants to control participants, identify risk factors associated with poor outcomes and determine the emotional and social health consequences of paediatric critical illness on parents and siblings. ETHICS AND DISSEMINATION: This study has received ethical approval from the University of Pennsylvania Institutional Review Board (protocol #843844). Our overall objective is to characterise the ongoing impact of paediatric critical illness to guide development of interventions that optimise outcomes among children surviving critical illness and their families. Findings will be presented at key disciplinary meetings and in peer-reviewed publications at fixed data points. Published manuscripts will be added to our public study website to ensure findings are available to families, clinicians and researchers. TRIALS REGISTRATION NUMBER: NCT04967365.

Recovery Trajectories in Children Requiring 3 or More Days of Invasive Ventilation.

OBJECTIVES: To characterize health-related quality of life (HRQL) and functional recovery trajectories and risk factors for prolonged impairments among critically ill children receiving greater than or equal to 3 days of invasive ventilation. DESIGN: Prospective cohort study. SETTING: Quaternary children's hospital PICU. PATIENTS: Children without a preexisting tracheostomy who received greater than or equal to 3 days of invasive ventilation, survived hospitalization, and completed greater than or equal to 1 postdischarge data collection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated 144 children measuring HRQL using proxy-report Pediatric Quality of Life Inventory and functional status using the Functional Status Scale (FSS) reflecting preillness baseline, PICU and hospital discharge, and 1, 3, 6, and 12 months after hospital discharge. They had a median age of 5.3 years (interquartile range, 1.1-13.0 yr), 58 (40%) were female, 45 (31%) had a complex chronic condition, and 110 (76%) had normal preillness FSS scores. Respiratory failure etiologies included lung disease ( n = 49; 34%), neurologic failure ( n = 23; 16%), and septic shock ( n = 22; 15%). At 1-month postdischarge, 68 of 122 (56%) reported worsened HRQL and 35 (29%) had a new functional impairment compared with preillness baseline. This improved at 3 months to 54 (46%) and 24 (20%), respectively, and remained stable through the remaining 9 months of follow-up. We used interaction forests to evaluate relative variable importance including pairwise interactions and found that therapy consultation within 3 days of intubation was associated with better HRQL recovery in older patients and those with better preillness physical HRQL. During the postdischarge year, 76 patients (53%) had an emergency department visit or hospitalization, and 62 (43%) newly received physical, occupational, or speech therapy. CONCLUSIONS: Impairments in HRQL and functional status as well as health resource use were common among children with acute respiratory failure. Early therapy consultation was a modifiable characteristic associated with shorter duration of worsened HRQL in older patients.

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. Objective: To update and evaluate criteria for sepsis and septic shock in children. Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively. Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Cognitive, Functional, and Quality of Life Outcomes 6 Months After Mechanical Ventilation for Bronchiolitis: A Secondary Analysis of Data From the Randomized Evaluation of Sedation Titration for Respiratory Failure Trial ( RESTORE ).

OBJECTIVES: To describe rates and associated risk factors for functional decline 6 months after critical bronchiolitis in a large, multicenter dataset. DESIGN: Nonprespecified secondary analysis of existing 6-month follow-up data of patients in the Randomized Evaluation of Sedation Titration for Respiratory Failure trial ( RESTORE , NCT00814099). SETTING: Patients recruited to RESTORE in any of 31 PICUs in the United States, 2009-2013. PATIENTS: Mechanically ventilated PICU patients under 2 years at admission with a primary diagnosis of bronchiolitis. INTERVENTIONS: There were no interventions in this secondary analysis; in the RESTORE trial, PICUs were randomized to protocolized sedation versus usual care. MEASUREMENTS AND MAIN RESULTS: "Functional decline," defined as worsened Pediatric Overall Performance Category and/or Pediatric Cerebral Performance Category (PCPC) scores at 6 months post-PICU discharge as compared with preillness baseline. Quality of life was assessed using Infant Toddler Quality of Life Questionnaire (ITQOL; children < 2 yr old at follow-up) or Pediatric Quality of Life Inventory (PedsQL) at 6 months post-PICU discharge. In a cohort of 232 bronchiolitis patients, 28 (12%) had functional decline 6 months postdischarge, which was associated with unfavorable quality of life in several ITQOL and PedsQL domains. Among 209 patients with normal baseline functional status, 19 (9%) had functional decline. In a multivariable model including all subjects, decline was associated with greater odds of worse baseline PCPC score and longer PICU length of stay (LOS). In patients with normal baseline status, decline was also associated with greater odds of longer PICU LOS. CONCLUSIONS: In a random sampling of RESTORE subjects, 12% of bronchiolitis patients had functional decline at 6 months. Given the high volume of mechanically ventilated patients with bronchiolitis, this observation suggests many young children may be at risk of new morbidities after PICU admission, including functional and/or cognitive morbidity and reduced quality of life.

Family Presence at the PICU Bedside: A Single-Center Retrospective Cohort Study.

OBJECTIVES: To determine factors associated with bedside family presence in the PICU and to understand how individual factors interact as barriers to family presence. DESIGN: Mixed methods study. SETTING: Tertiary children's hospital PICU. SUBJECTS: Five hundred twenty-three children of less than 18 years enrolled in the Seattle Children's Hospital Outcomes Assessment Program from 2011 to 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Quantitative: Family was documented every 2 hours. Exposures included patient and illness characteristics and family demographic and socioeconomic characteristics. We used multivariable logistic regression to identify factors associated with presence of less than 80% and stratified results by self-reported race. Longer PICU length of stay (LOS), public insurance, and complex chronic conditions (C-CD) were associated with family presence of less than 80%. Self-reported race modified these associations; no factors were associated with lower bedside presence for White families, in contrast with multiple associations for non-White families including public insurance, C-CD, and longer LOS. Qualitative: Thematic analysis of social work notes for the 48 patients with family presence of less than 80% matched on age, LOS, and diagnosis to 48 patients with greater than or equal to 95% family presence. Three themes emerged: the primary caregiver's prior experiences with the hospital, relationships outside of the hospital, and additional stressors during the hospitalization affected bedside presence. CONCLUSIONS: We identified sociodemographic and illness factors associated with family bedside presence in the PICU. Self-reported race modified these associations, representing racism within healthcare. Family presence at the bedside may help identify families facing greater disparities in healthcare access.

Protocol of a Phase II Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial of S-Adenosyl Methionine in Participants with Mild Cognitive Impairment or Dementia Due to Alzheimer's Disease.

BACKGROUND: S-adenosyl methionine (SAMe) is a pivotal metabolite in multiple pathways required for neuronal homeostasis, several of which are compromised in Alzheimer's disease (AD). Correction of the SAMe deficiency that is characteristic of the AD brain may attenuate or prevent pathological processes driving AD-associated neurodegeneration including aberrant tau hyperphosphorylation and DNA hypomethylation. OBJECTIVES: The primary aim is to test the hypothesis that daily treatment with 400 mg oral SAMe for 180 days will lead to a greater reduction from baseline in plasma levels of p-tau181 compared to placebo in patients with mild cognitive impairment or dementia due to AD. DESIGN, SETTING, PARTICIPANTS: This is a phase II, randomized, multi-center, double-blind, placebo-controlled trial among 60 participants with mild cognitive impairment or dementia due to AD. Participants will be randomized in a 1:1 ratio to receive either SAMe or matching placebo, to be taken as an adjunct to their AD standard of care. MEASUREMENTS AND RESULTS: The primary outcome is change in plasma p-tau181 concentration between baseline and following 180 days of treatment, which will be compared between the active and placebo group. Secondary outcomes are the safety of SAMe administration (incidence of serious adverse events), change from baseline in cognitive performance (as measured by the Repeatable Battery for the Assessment of Neuropsychological Status), and epigenetic changes in DNA methylation. CONCLUSION: Demonstration of effective and safe lowering of plasma p-tau181 with SAMe in this phase II trial would pave the way for an exciting field of translational research and a larger phase III trial.

Clinical decision support tools for paediatric sepsis in resource-poor settings: an international qualitative study.

OBJECTIVE: New paediatric sepsis criteria are being developed by an international task force. However, it remains unknown what type of clinical decision support (CDS) tools will be most useful for dissemination of those criteria in resource-poor settings. We sought to design effective CDS tools by identifying the paediatric sepsis-related decisional needs of multidisciplinary clinicians and health system administrators in resource-poor settings. DESIGN: Semistructured qualitative focus groups and interviews with 35 clinicians (8 nurses, 27 physicians) and 5 administrators at health systems that regularly provide care for children with sepsis, April-May 2022. SETTING: Health systems in Africa, Asia and Latin America, where sepsis has a large impact on child health and healthcare resources may be limited. PARTICIPANTS: Participants had a mean age of 45 years, a mean of 15 years of experience, and were 45% female. RESULTS: Emergent themes were related to the decisional needs of clinicians caring for children with sepsis and to the needs of health system administrators as they make decisions about which CDS tools to implement. Themes included variation across regions and institutions in infectious aetiologies of sepsis and available clinical resources, the need for CDS tools to be flexible and customisable in order for implementation to be successful, and proposed features and format of an ideal paediatric sepsis CDS tool. CONCLUSION: Findings from this study will directly contribute to the design and implementation of CDS tools to increase the uptake and impact of the new paediatric sepsis criteria in resource-poor settings.

Predicting functional and quality-of-life outcomes following pediatric sepsis: performance of PRISM-III and PELOD-2.

BACKGROUND: Illness severity scores predict mortality following pediatric critical illness. Given declining PICU mortality, we assessed the ability of the Pediatric Risk of Mortality-III (PRISM) and Pediatric Logistic Organ Dysfunction-2 (PELOD) scores to predict morbidity outcomes. METHODS: Among 359 survivors <18 years in the Life After Pediatric Sepsis Evaluation multicenter prospective cohort study, we assessed functional morbidity at hospital discharge (Functional Status Scale increase ≥3 points from baseline) and health-related quality of life (HRQL; Pediatric Quality of Life Inventory or Functional Status II-R) deterioration >25% from baseline at 1, 3, 6, and 12 months post-admission. We determined discrimination of admission PRISM and admission, maximum, and cumulative 28-day PELOD with functional and HRQL morbidity at each timepoint. RESULTS: Cumulative PELOD provided the best discrimination of discharge functional morbidity (area under the receive operating characteristics curve [AUROC] 0.81, 95% CI 0.76-0.87) and 3-month HRQL deterioration (AUROC 0.71, 95% CI 0.61-0.81). Prediction was inferior for admission PRISM and PELOD and for 6- and 12-month HRQL assessments. CONCLUSIONS: Illness severity scores have a good prediction of early functional morbidity but a more limited ability to predict longer-term HRQL. Identification of factors beyond illness severity that contribute to HRQL outcomes may offer opportunities for intervention to improve outcomes. IMPACT: Illness severity scores are commonly used for mortality prediction and risk stratification in pediatric critical care research, quality improvement, and resource allocation algorithms. Prediction of morbidity rather than mortality may be beneficial given declining pediatric intensive care unit mortality. The PRISM and PELOD scores have moderate to good ability to predict new functional morbidity at hospital discharge following pediatric septic shock but limited ability to predict health-related quality of life outcomes in the year following PICU admission. Further research is needed to identify additional factors beyond illness severity that may impact post-discharge health-related quality of life.

Development, Validation, and Clinical Utility of a Six-gene Signature to Predict Aggressive Prostate Cancer.

BACKGROUND: Molecular signatures in prostate cancer (PCa) tissue can provide useful prognostic information to improve the understanding of a patient's risk of harbouring aggressive disease. OBJECTIVE: To develop and validate a gene signature that adds independent prognostic information to clinical parameters for better treatment decisions and patient management. DESIGN, SETTING, AND PARTICIPANTS: Expression of 14 genes was evaluated in radical prostatectomy (RP) tissue from an Irish cohort of PCa patients (n = 426). A six-gene molecular risk score (MRS) was identified with strong prognostic performance to predict adverse pathology (AP) at RP or biochemical recurrence (BCR). The MRS was combined with the Cancer of the Prostate Risk Assessment (CAPRA) score, to create a molecular and clinical risk score (MCRS), and validated in a Swedish cohort (n = 203). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary AP outcome was assessed by the likelihood ratio statistics and area under the receiver operating characteristics curves (AUC) from logistic regression models. The secondary time to BCR outcome was assessed by likelihood ratio statistics and C-indexes from Cox proportional hazard regression models. RESULTS AND LIMITATIONS: The six-gene signature was significantly (p < 0.0001) prognostic and added significant prognostic value to clinicopathological features for AP and BCR outcomes. For both outcomes, both the MRS and the MCRS increased the AUC/C-index when added to European Association of Urology (EAU) and CAPRA scores. Limitations include the retrospective nature of this study. CONCLUSIONS: The six-gene signature has strong performance for the prediction of AP and BCR in an independent clinical validation study. MCRS improves prognostic evaluation and can optimise patient management after RP. PATIENT SUMMARY: We found that the expression panel of six genes can help predict whether a patient is likely to have a disease recurrence after radical prostatectomy surgery.