Plasma metabolomics changes comparing daytime to overnight infusions of home parenteral nutrition in adult patients with short bowel syndrome: Secondary analysis of a clinical trial.

BACKGROUND: Home parenteral nutrition (HPN) is often cycled nocturnally and is expected to result in glucose intolerance and sleep disruption partly due to circadian misalignment. This study aimed to define the metabolic response when HPN is cycled during the daytime compared to overnight. METHODS: This secondary analysis leveraged samples from a clinical trial in adults with short bowel syndrome consuming HPN (ClinicalTrials.gov: NCT04743960). Enrolled patients received 1 week of HPN overnight followed by 1 week of HPN during the daytime. Fasting blood samples were collected following each study period and global metabolic profiles were examined from plasma samples. Differential metabolite abundance was determined from normalized and scaled data using adjusted Linear Models for MicroArray Data models followed by pathway enrichment analysis. RESULTS: Nine patients (mean age, 52.6 years; 78% female; mean BMI 20.7 kg/m2) provided samples. Among 622 identified metabolites, changes were observed in 36 metabolites at Punadj < 0.05 with higher abundance of fatty acids, long-chain and polyunsaturated fatty acids (Dihomo-gamma-linolenic acid, arachidonate (20:4n6), docosahexaenoate (DHA; 22:6n3)) and glycerolipids with daytime infusions. Enrichment analysis identified changes in pathways related to the biosynthesis of unsaturated fatty acids, d-arginine, and d-ornithine metabolism, and linoleic acid metabolism (Punadj<0.05). CONCLUSION: Daytime infusions of HPN may result in changes in circulating lipids and amino acid composing metabolic pathways previously implicated in circadian rhythms. As this is the first untargeted metabolomics study of HPN, larger studies are needed.

Long-term outcome of combined radiologic and surgical strategy for the management of biliary complications after pediatric liver transplantation.

OBJECTIVES: We aimed to analyze the risk factors for management failure of BC after pediatric liver transplantation (pLT) by retrospectively analyzing primary pLT performed between 1997 and 2018 (n = 620 patients). RESULTS: In all, 117/620 patients (19%) developed BC. The median (range) follow-up was 9 (1.4-21) years. Patient survival at 1, 5 and 10 years was 88.9%, 85.7%, 84.4% and liver graft survival was 82.4%, 77.4%, and 74.3% respectively. Graft not patient survival was impaired by BC (p = 0.01). Multivariate analysis identified the number of dilatation courses > 2 (p = 0.008), prolonged cold ischemia time (p = 0.004), anastomosed multiple biliary ducts (p = 0.019) and hepatic artery thrombosis (p = 0.01) as factors associated with impaired graft survival. The number of dilatation courses > 2 (p < 0.001) and intrahepatic vs anastomotic stricture (p = 0.014) were associated with management failure. Thus, repeated (> 2) radiologic dilatation courses are associated with impaired graft survival and management failure. Overall, graft but not patient survival was impaired by BC.

Criteria and Indicators for Centers of Clinical Excellence in Stroke Recovery and Rehabilitation: A Global Consensus Facilitated by ISRRA.

BACKGROUND: The aim of the International Stroke Recovery and Rehabilitation Alliance is to create a world where worldwide collaboration brings major breakthroughs for the millions of people living with stroke. A key pillar of this work is to define globally relevant criteria for centers that aspire to deliver excellent clinical rehabilitation and generate exceptional outcomes for patients. OBJECTIVES: This paper presents consensus work conducted with an international group of expert stroke recovery and rehabilitation researchers, clinicians, and people living with stroke to identify and define criteria and measurable indicators for Centers of Clinical Excellence (CoCE) in stroke recovery and rehabilitation. These were intentionally developed to be ambitious and internationally relevant, regardless of a country's development or income status, to drive global improvement in stroke services. METHODS: Criteria and specific measurable indicators for CoCE were collaboratively developed by an international panel of stroke recovery and rehabilitation experts from 10 countries and consumer groups from 5 countries. RESULTS: The criteria and associated indicators, ranked in order of importance, focused upon (i) optimal outcome, (ii) research culture, (iii) working collaboratively with people living with stroke, (iv) knowledge exchange, (v) leadership, (vi) education, and (vii) advocacy. Work is currently underway to user-test the criteria and indicators in 14 rehabilitation centers in 10 different countries. CONCLUSIONS: We anticipate that use of the criteria and indicators could support individual organizations to further develop their services and, more widely, provide a mechanism by which clinical excellence can be articulated and shared to generate global improvements in stroke care.

Guidance for assessment of the inflammation etiologic criterion for the GLIM diagnosis of malnutrition: A modified Delphi approach.

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) approach to malnutrition diagnosis is based on assessment of three phenotypic (weight loss, low body mass index, and reduced skeletal muscle mass) and two etiologic (reduced food intake/assimilation and disease burden/inflammation) criteria, with diagnosis confirmed by fulfillment of any combination of at least one phenotypic and at least one etiologic criterion. The original GLIM description provided limited guidance regarding assessment of inflammation, and this has been a factor impeding further implementation of the GLIM criteria. We now seek to provide practical guidance for assessment of inflammation. METHODS: A GLIM-constituted working group with 36 participants developed consensus-based guidance through a modified Delphi review. A multiround review and revision process served to develop seven guidance statements. RESULTS: The final round of review was highly favorable, with 99% overall "agree" or "strongly agree" responses. The presence of acute or chronic disease, infection, or injury that is usually associated with inflammatory activity may be used to fulfill the GLIM disease burden/inflammation criterion, without the need for laboratory confirmation. However, we recommend that recognition of underlying medical conditions commonly associated with inflammation be supported by C-reactive protein (CRP) measurements when the contribution of inflammatory components is uncertain. Interpretation of CRP requires that consideration be given to the method, reference values, and units (milligrams per deciliter or milligram per liter) for the clinical laboratory that is being used. CONCLUSION: Confirmation of inflammation should be guided by clinical judgment based on underlying diagnosis or condition, clinical signs, or CRP.

Guidance for assessment of the inflammation etiologic criterion for the GLIM diagnosis of malnutrition: A modified Delphi approach.

BACKGROUND & AIMS: The Global Leadership Initiative on Malnutrition (GLIM) approach to malnutrition diagnosis is based on assessment of three phenotypic (weight loss, low body mass index, and reduced skeletal muscle mass) and two etiologic (reduced food intake/assimilation and disease burden/inflammation) criteria, with diagnosis confirmed by fulfillment of any combination of at least one phenotypic and at least one etiologic criterion. The original GLIM description provided limited guidance regarding assessment of inflammation and this has been a factor impeding further implementation of the GLIM criteria. We now seek to provide practical guidance for assessment of inflammation in support of the etiologic criterion for inflammation. METHODS: A GLIM-constituted working group with 36 participants developed consensus-based guidance through a modified-Delphi review. A multi-round review and revision process served to develop seven guidance statements. RESULTS: The final round of review was highly favorable with 99 % overall "agree" or "strongly agree" responses. The presence of acute or chronic disease, infection or injury that is usually associated with inflammatory activity may be used to fulfill the GLIM disease burden/inflammation criterion, without the need for laboratory confirmation. However, we recommend that recognition of underlying medical conditions commonly associated with inflammation be supported by C-reactive protein (CRP) measurements when the contribution of inflammatory components is uncertain. Interpretation of CRP requires that consideration be given to the method, reference values, and units (mg/dL or mg/L) for the clinical laboratory that is being used. CONCLUSION: Confirmation of inflammation should be guided by clinical judgement based upon underlying diagnosis or condition, clinical signs, or CRP.

Comparison between self-reported and actigraphy-derived sleep measures in patients receiving home parenteral nutrition: Secondary analysis of observational data.

BACKGROUND: Patients receiving home parenteral nutrition (HPN) frequently report disrupted sleep. However, there are often inconsistencies between objectively measured and questionnaire-derived sleep measures. We compared sleep measures estimated from wrist actigraphy and self-report in adults receiving HPN. METHODS: In this secondary analysis, we pooled data from two sleep-related studies enrolling adults receiving habitual HPN. We compared measures from 7-day averages of wrist actigraphy against comparable responses to a sleep questionnaire. Sleep measures included bedtime, wake time, time in bed, total sleep time, and sleep onset latency (SOL). Spearman correlation coefficients, Bland-Altman plots, and linear regression models for each set of sleep measures provided estimates of agreement. RESULTS: Participants (N = 35) had a mean age of 52 years, body mass index of 21.6 kg/m2 , and 77% identified as female. Correlation coefficients ranged from 0.35 to 0.90, were highest for wake time (r = 0.90) and bedtime (r = 0.74), and lowest for total sleep time (r = 0.35). Actigraphy overestimated self-reported bedtime, wake time, and total sleep time and underestimated self-reported time in bed and SOL. Regression coefficients indicated the highest calibration for bedtime and wake time and lower calibration for time in bed, total sleep time, and SOL. CONCLUSION: We observed strong-to-moderate agreement between sleep measures derived from wrist actigraphy and self-report in adults receiving HPN. Weaker correlations for total sleep time and SOL may indicate low wrist actigraphy sensitivity. Low-quality sleep resulting from sleep disruptions may have also contributed to an underreporting of perceived sleep quantity and lower concordance.

Glycemic and sleep effects of daytime compared with those of overnight infusions of home parenteral nutrition in adults with short bowel syndrome: A quasi-experimental pilot trial.

BACKGROUND: Patients with short bowel syndrome (SBS) dependent on home parenteral nutrition (HPN) commonly cycle infusions overnight, likely contributing to circadian misalignment and sleep disruption. METHODS: The objective of this quasi-experimental, single-arm, controlled, pilot trial was to examine the feasibility, safety, and efficacy of daytime infusions of HPN in adults with SBS without diabetes. Enrolled patients were fitted with a continuous glucose monitor and wrist actigraph and were instructed to cycle their infusions overnight for 1 wk, followed by daytime for another week. The 24-h average blood glucose, the time spent >140 mg/dL or <70 mg/dL, and sleep fragmentation were derived for each week and compared using Wilcoxon signed-rank test. Patient-reported quality-of-life outcomes were also compared between the weeks. RESULTS: Twenty patients (mean age, 51.7 y; 75% female; mean body mass index, 21.5 kg/m2) completed the trial. Overnight infusions started at 21:00 and daytime infusions at 09:00. No serious adverse events were noted. There were no differences in 24-h glycemia (daytime-median: 93.00 mg/dL; 95% CI: 87.7-99.9 mg/dL, compared with overnight-median: 91.1 mg/dL; 95% CI: 89.6-99.0 mg/dL; P = 0.922). During the day hours (09:00-21:00), the mean glucose concentrations were 13.5 (5.7-22.0) mg/dL higher, and the time spent <70 mg/dL was 15.0 (-170.0, 22.5) min lower with daytime than with overnight HPN. Conversely, during the night hours (21:00-09:00), the glucose concentrations were 16.6 (-23.1, -2.2) mg/dL lower with daytime than with overnight HPN. There were no differences in actigraphy-derived measures of sleep and activity rhythms; however, sleep timing was later, and light at night exposure was lower with daytime than with overnight HPN. Patients reported less sleep disruptions due to urination and fewer episodes of uncontrollable diarrhea or ostomy output with daytime HPN. CONCLUSIONS: Daytime HPN was feasible and safe in adults with SBS and, compared with overnight HPN, improved subjective sleep without increasing 24-h glucose concentrations. This trial was registered at clinicaltrials.gov as NCT04743960 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT04743960).

Enabling the evaluation of COVID-19 vaccines with correlates of protection.

In February 2023, a meeting about correlates of protection (CoPs) against COVID-19 was organized by the International Alliance for Biological Standardization, the European Plotkin Institute for Vaccinology, and Vaccinopolis. The meeting aimed at reviewing the evidence, drawing conclusions, and identifying knowledge gaps. Collection of evidence is not straightforward. Neutralizing antibodies correlate with protection and are used for immunobridging studies within and between vaccine platforms for approval of new COVID-19 vaccines. In preparation for the next pandemic, it is vital that rapidly authorized initial vaccines are available to perform immunobridging studies very early. Additional components of the immune response likely contribute to protection against symptomatic infection. Current evidence is strongest for T lymphocytes and binding antibodies. Further studies are needed to consolidate this evidence and define their potential role in the evaluation of vaccines. For evaluation of mucosal vaccines, identifying CoPs against infection and transmission is key; further research is needed to identify and standardize methods suitable for clinical studies. CoPs for broadly protective beta-coronavirus vaccines remain a critical area of research. The knowledge, expertise, and capacity exist to conduct clinical studies using different designs in different populations to discover and validate CoPs, facilitating and accelerating evaluation of novel vaccines/vaccination platforms.

Amplifying the lived experiences of parenteral nutrition consumers through the thematic analysis of social media posts.

BACKGROUND: Consumers of parenteral nutrition (PN) and their caregivers use social media to seek advice and support from their peers and to share experiences. We aimed to leverage posts from a social media patient community to identify common lived experiences of consumers of PN to prioritize opportunities for support through advocacy, education, and research. METHODS: Anonymous posts with high engagement were collected over 4 months from a PN-focused social media support group platform. No personal information was collected or analyzed. Post content was reviewed for demographic characteristics. Thematic analysis involved inductive coding to identify content-based keywords. Keywords were then used to form major themes and subthemes that were then quantified by post counts. RESULTS: A total of 306 social media posts were analyzed. Most were from adult PN consumers (80.4%) and pertained to home-based PN (82%). Equivalent number of posts (5%) were from new consumers and those who had not yet started or restarting PN. The analysis revealed 12 major themes with 2-11 subthemes each, spanning medical, nutrition, emotional, and social aspects. The most prevalent theme was "Best practices, care, and safety of PN use" (36.9%), covering posts seeking guidance on line care, personal hygiene, equipment use, and vascular access devices. Others included "Symptoms" (23.9%) and "Patient safety concerns of PN handling by healthcare providers" (16.0%). CONCLUSIONS: The identified themes provide a broader understanding of contemporary shared lived experiences and concerns relevant to PN consumers and their caregivers. Given the evolving nature of daily stressors, periodic reanalysis may be necessary.

The Unmet Needs of Caregiving Skills, Support, Emotions, and Finances of Stroke Caregivers: A Multicenter Study.

​​​​​​Background Informal stroke caregivers in Malaysia play an important role in supporting stroke survivors following acute care. Nevertheless, there is a lack of available data to inform the sufficiency of help and resources available to address the needs of local stroke caregivers. This study aimed to determine the unmet needs in caregiving skills, support, emotions, and finances as well as the associated factors of stroke caregivers in Malaysia. Methodology This multicenter, cross-sectional study used a self-administered survey developed and validated for the Malaysian population. It was prepared in paper-based and web-based formats, and it was distributed via direct contact with the respondents, post, and email. Respondents were recruited from different sites in Malaysia. In this study, unmet needs were defined as "help that was needed more or was not provided to assist caregivers and address their specific needs." This article only presents the quantitative data of this study. Data were analyzed using descriptive analysis and logistic regression to determine factors associated with unmet needs. Results Almost all study respondents (91%) reported having unmet needs. Unmet needs ranged from 1 to 10, while the mean unmet needs was 5. The highest unmet need was related to financial support (72.5%), followed by support from professionals to address their own needs (59.2%), skills to care for stroke survivors, i.e., skills in caring for stroke survivors with their daily activities (57.9%), and skills in supporting stroke survivors to perform rehabilitation at home (53.1%). The lowest unmet need was related to support in transporting stroke survivors from place to place (45.3%). Additionally, this study did not identify an association between the reported unmet needs and gender, age, ethnicity, duration of caregiving, and site of participation. Conclusions This study reported a range of unmet needs perceived by stroke caregivers in Malaysia. Further research is warranted to understand the gaps in supporting local stroke caregivers to inform future post-stroke support and services in the country.

Development of the stroke patient concerns inventory: A modified Delphi study.

OBJECTIVES: Stroke survivors often have unmet physical, psychological and/or social concerns. Patient Concerns Inventories (PCIs) have been developed for other health conditions to address concerns. Our objective was to develop a PCI for stroke care. METHODS: This was a development study, including Modified Delphi study design, with academic and healthcare professionals with stroke care expertise. In Stage 1, a draft Stroke PCI (Version 1a) was created through identifying patient-reported concerns post-stroke from three previous studies and through expert panel discussions using Nominal Group Technique. In Stage 2, Version 1a was sent to 92 academic and healthcare professionals with stroke care expertise. Participants ranked their top 20 Stroke PCI items in order of importance and provided feedback. Rankings were converted into scores, and, with the feedback, used to amend the Stroke PCI. Two further rounds of feedback followed until consensus was reached between participants. A final draft of the Stroke PCI was created. RESULTS: In stage 1, 64 potential Stroke PCI items were generated. In Stage 2, 38 participants (41.3%) responded to the request to rank Stroke PCI items. The three highest ranked items were 'Risk of another stroke', 'Walking', 'Recovery'. After three rounds of feedback and amendments, the final draft of the Stroke PCI consisted of 53 items. CONCLUSIONS: A Stroke PCI has been developed using patient-reported concerns in previous studies and input from academic and healthcare professionals. Future work will involve gathering further feedback on the tool and exploring its acceptability and usability in a pilot study.

Approaches to demonstrating the effectiveness of filovirus vaccines: Lessons from Ebola and COVID-19.

Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV) and Marburg virus (MARV), are members of the Filoviridae family that can cause severe disease and death in humans and animals. The reemergence of Ebola, Sudan and Marburg virus disease highlight the need for continued availability of safe and effectives vaccines as well as development of new vaccines. While randomized controlled trials using disease endpoints provide the most robust assessment of vaccine effectiveness, challenges to this approach include the unpredictable size, location, occurrence and duration of filovirus disease outbreaks. Thus, other approaches to demonstrating vaccine effectiveness have been considered. These approaches are discussed using examples of preventive vaccines against other infectious diseases. In addition, this article proposes a clinical immunobridging strategy using licensed EBOV vaccines as comparators for demonstrating the effectiveness of filovirus vaccine candidates that are based on the same licensed vaccine platform technology.

Infusion timing and sleep habits of adults receiving home parenteral and enteral nutrition: A patient-oriented survey study.

BACKGROUND: The emerging field of chrononutrition investigates the effects of the timing of nutritional intake on human physiology and disease pathology. It remains largely unknown when patients receiving home nutrition support routinely administer home parenteral nutrition (HPN) and/or home enteral nutrition (HEN). METHODS: The present descriptive study included data collected from a patient-oriented survey designed to assess the timing of infusions and sleep habits of patients receiving HPN and HEN in the United States. RESULTS: A total of 100 patients were included. Patients had a mean age of 44.1 years and 81% were female. Among 73 patients supported with HPN and 27 patients supported with HEN, 86% and 44% reported overnight infusions, respectively. The median start and end times of overnight infusions were 2100 (interquartile range [IQR] = 1900-2200) and 0800 (IQR = 0700-1000), respectively, for HPN and 2000 (IQR = 1845-2137) and 0845 (IQR = 0723-1000), respectively, for HEN. Overnight infusions started 2.0 h (IQR = 1.1-3.0) and 2.0 h (IQR = 0.6-3.3) before bedtime for HPN and HEN, respectively, and stopped 12.9 min (IQR = -21.3 to 29.1) and 30.0 min (IQR = -17.1 to 79.3) after wake time for HPN and HEN, respectively. Sleep disruption because of nutrition support or urination was most common among patients receiving infusions overnight compared with those receiving infusions continuously or during the daytime. CONCLUSIONS: Our survey study focusing on a novel and medically relevant dimension of nutrition found that most HPN-dependent and HEN-dependent patients receive infusions overnight while asleep. Our findings suggest that overnight infusions coinciding with sleep may result in sleep and circadian disruption.

Computational epitope mapping of class I fusion proteins using low complexity supervised learning methods.

Antibody epitope mapping of viral proteins plays a vital role in understanding immune system mechanisms of protection. In the case of class I viral fusion proteins, recent advances in cryo-electron microscopy and protein stabilization techniques have highlighted the importance of cryptic or 'alternative' conformations that expose epitopes targeted by potent neutralizing antibodies. Thorough epitope mapping of such metastable conformations is difficult but is critical for understanding sites of vulnerability in class I fusion proteins that occur as transient conformational states during viral attachment and fusion. We introduce a novel method Accelerated class I fusion protein Epitope Mapping (AxIEM) that accounts for fusion protein flexibility to improve out-of-sample prediction of discontinuous antibody epitopes. Harnessing data from previous experimental epitope mapping efforts of several class I fusion proteins, we demonstrate that accuracy of epitope prediction depends on residue environment and allows for the prediction of conformation-dependent antibody target residues. We also show that AxIEM can identify common epitopes and provide structural insights for the development and rational design of vaccines.

Three-Dimensional Collagen Topology Shapes Cell Morphology, beyond Stiffness.

Cellular heterogeneity is associated with many physiological processes, including pathological ones, such as morphogenesis and tumorigenesis. The extracellular matrix (ECM) is a key player in the generation of cellular heterogeneity. Advances in our understanding rely on our ability to provide relevant in vitro models. This requires obtainment of the characteristics of the tissues that are essential for controlling cell fate. To do this, we must consider the diversity of tissues, the diversity of physiological contexts, and the constant remodeling of the ECM along these processes. To this aim, we have fabricated a library of ECM models for reproducing the scaffold of connective tissues and the basement membrane by using different biofabrication routes based on the electrospinning and drop casting of biopolymers from the ECM. Using a combination of electron microscopy, multiphoton imaging, and AFM nanoindentation, we show that we can vary independently protein composition, topology, and stiffness of ECM models. This in turns allows one to generate the in vivo complexity of the phenotypic landscape of ovarian cancer cells. We show that, while this phenotypic shift cannot be directly correlated with a unique ECM feature, the three-dimensional collagen fibril topology patterns cell shape, beyond protein composition and stiffness of the ECM. On this line, this work is a further step toward the development of ECM models recapitulating the constantly remodeled environment that cells face and thus provides new insights for cancer model engineering and drug testing.

China's Elder Care Policies 1994-2020: A Narrative Document Analysis.

Until the 1980s, institutional elder care was virtually unknown in China. In a few decades, China had to construct a universal social safety net and assure basic elderly care. China's government has been facing several challenges: the eroding traditional family care, the funding to assure care services for the older population, as well as the shortage of care delivery services and nursing staff. This paper examines China's Five-Year Policy Plans from 1994 to 2020. Our narrative review analysis focuses on six main topics revealed in these policies: care infrastructure, community involvement, home-based care, filial piety, active aging and elder industry. Based on this analysis, we identified several successive and often simultaneously strategic steps that China introduced to contend with the aging challenge. In Western countries, elder care policies have been shifting to the home care approach. China introduced home care as the elder care cornerstone and encouraged the revival of the filial piety tradition. Although China has a unique approach, the care policies for the aged population in China and Western countries are converging by emphasizing home-based care, informal care and healthy aging.

A Qualitative Study Exploring the Lives and Caring Practices of Young Carers of Stroke Survivors.

This study investigated the life transformation of children when a parent returned home from hospital after a stroke. The study explored children's experiences of taking on caring roles in partnership with their well parent and stroke survivors' perceptions of the young carer roles. The study aimed to identify unmet support needs in order to inform future service provision. Semi-structured interviews were conducted separately with stroke survivors (n = 7) (age range 41-60 years, mean 50.6) and their young carers (n = 11) (age range 11-20 years, mean 16). Interviews were audio recorded, transcribed and analysed using reflexive thematic analysis. Three overarching themes were identified: the lives of young carers, impact of stroke, and insulating the family. All the children were providing some level of care. None were in receipt of any formal support. Children moved in and out of the caring role in the absence of an adult, to act as primary carer. Young carers valued the life skills they were gaining but reported gaps in their knowledge and understanding of stroke. The well parent and young carers worked together in a bi-directional partnership to ameliorate the impact of stroke on the family. The study concluded that age appropriate and stroke specific information for children of stroke survivors could enhance agency and optimise positive outcomes of caring.