bluuebunny/crossref_metadata_2025 huggingface dataset:
2000 Cause of death amongst frail and non-frail older people post-hospital admission in northern Tanzania
Authors: Moore D T , Davidson S L , Murray A , Randall T , Hardy J , Lyimo G , Kilasara J , Urasa S , Walker R W , Dotchin C L
Published: January 2024

Introduction

Verbal autopsy (VA) is a tool used to determine cause of death (COD) in regions lacking routine medical certification. Automated algorithms are widely used to interpret VA data. This study aimed to investigate potential differences in COD between frail and non-frail older people in northern Tanzania.

Method

This work forms part of a longitudinal study investigating the clinical outcomes of 308 consecutive adults aged ≥60 years following admission to four hospitals in northern Tanzania. Frailty status was established on admission using the Clinical Frailty Scale (CFS) and dichotomised with CFS ≥5 indicating frailty. For participants who passed away in the 10-12 months following admission, VA data were collected through telephone interview using the 2022 World Health Organization (WHO) VA instrument. COD estimates were established using the SmartVA-Analyze program, implementing the Tariff 2.0 Method.

Results

After a mean follow-up period of 10.8 (±0.9) months, VA data were available for 69 participants. At admission screening, 51 (73.9%) were frail, while 18 (26.1%) were non-frail. SmartVA produced COD estimates for 42 (60.9%) participants, while 27 (39.1%) remained undetermined. Cause Specific Mortality Fractions (CSMFs) for non-communicable disease were higher for those with frailty than the non-frail group (70.6% vs. 54.0%, respectively). An undetermined COD was more likely in those with frailty. Of the 27 undetermined COD, 22 (81.5%) were attributed to frail individuals and 5 (18.5%) to non-frail. These undetermined COD represent 43.1% of frailty-related deaths and 27.8% of non-frailty-related deaths.

Conclusions

Older people with frailty living in Tanzania are more likely to die from non-communicable diseases compared to non-frail older people. Although employing SmartVA to analyse VA data from this population was feasible, it faced challenges ascribing COD to all participants. This limitation may be due to the multi-morbidity often present in older populations where multiple factors combine to cause mortality.
2004 How confident are we in decision making? The quantitative analysis of ambulance response to older adult fallers: A pilot survey
Authors: Gunson I , Bullock L , Kingstone T , Bucknall M
Published: January 2024

Introduction

The number one reason for older people to be taken to hospital emergency departments is a fall1. An “Ambulance Improvement Programme Pillar”2 is trying to reduce conveyance to hospital for falls, however it is not understood how the attending clinician’s confidence impacts decision-making. The objectives were to assess recruitment rate and feasibility of online survey delivery, and determine the experiences and confidence of frontline emergency clinicians in attending older adults who have fallen.

Method

Online cross-sectional survey, undertaken in one English ambulance service in May 2023. Items included participant demographics and 5-point Likert scales of confidence. Data were summarised using descriptive statistics and Chi-square analyses to compare confidence between localities and years’ experience.

Results

81 responses were received from across the regional ambulance service’s 16 localities, supporting online survey delivery to be feasible in this population. 76% of respondents were paramedics, and 53% were aged 25-34. 60% of respondents rated being ‘Somewhat confident’ in assessing older adults who have fallen, with responses ranging between ‘Neither confident nor unconfident’ to ‘Completely confident’. No significant difference was found between the locality and confidence levels for assessing this patient population. However, there appeared to be significant variation between confidence levels relating to utilisation of hospital pathways and localities (p-value=.0045). Length of experience in both frontline ambulance and overall healthcare provision was not significantly associated with different levels of confidence.

Conclusion

Online survey delivery is an effective method in this population. Locality of work had a relationship with confidence in utilising hospital avoidance pathways, however, it did not relate to assessing this population. Confidence levels were not found to be related to the number of years providing care.

References

1. Dewhirst. (2023). National Falls Prevention Coordination Group. https://committees.parliament.uk/writtenevidence/117837/pdf/

2. NHS England and NHS Improvement. (2019). Ambulance Improvement Programme. https://www.england.nhs.uk/wp-content/uploads/2019/09/planning-to-safetly-reduce-avoidable-conveyance-v4.0.pdf
2005 How do emergency ambulance clinicians decide what to do for older adults who have fallen? An analysis of qualitative survey data
Authors: Gunson I , Bullock L , Kingstone T , Bucknall M
Published: January 2024

Introduction

Around 10% of calls received by English ambulance services are for older adults who have fallen1; with an ageing population there are significant care provision needs. Decision-making on the treatment for people who fall, can impact their future physical and mental health. Previous research in decision-making of ambulance staff found perception of role, confidence, service demands and training to be key drivers2. The previous work highlighting drivers, but not the experiences that explain why they occur, leads this study aim to determine the experiences and confidence of frontline emergency clinicians in attending older adults who have fallen.

Method

Online cross-sectional survey of frontline emergency clinicians from one English ambulance service in May 2023. Open questions generated qualitative data for thematic analysis3. Ethical and regulatory approvals, and informed consent, were obtained. Results: 81 participants completed the survey. Analysis identified three themes. Care Provision: Provision of hospital avoidance pathways varies throughout the region. Concerns arose from not knowing what different areas had and reduced accessibility out of hours. Communication: Decision-making confidence was impacted by the participants’ experiences; positive experiences encouraged use of hospital avoidance pathways, whilst negative experiences impeded willingness to avoid hospital for fear of repercussion. Shared Decision-Making: Patients, family and clinicians were all valued as part of shared decision-making, with past feedback on decision-making informing future practice.

Conclusion

Confidence of frontline ambulance staff was impacted by the challenge of a regional and 24/7 ambulance service not having consistent pathways available. This variation led to concerns when responding to patients outside of the clinician’s usual area, and further challenges ambulance clinicians must balance in their practice.

References

1. Snooks, Anthony, Chatters. et al. Health Technology Assessment 2017; 21: 1–218.

2. Simpson, Thomas, Bendall. et al. BMC Health Services Research. 2017; 17: 299.

3. Braun and Clarke. (2022) Thematic Analysis: A practical guide.
2075 Systematic review of ‘Ageing well’ interventions to improve and maintain independent living for community housebound populations
Authors: Thomas D , Voss S , Hoskins R
Published: January 2024

Introduction

The housebound population are growing in number, with a large proportion living rurally or in coastal areas, which increases the risks of isolation and health inequalities. This population are an under researched and underserved group (Public Health England, 2019). Being unable to leave the home is a factor for living in the poorest of health, which contributes to advancing levels of frailty, Curtis et al (2018). Considering the current focus of empowerment to ‘age well’ (NHS England Long Term Plan, 2019), a granular understanding of community focused ageing well interventions is the focus of this systematic review to empower clinicians to ‘make every contact count’ (NHS England 2020).

Method

A narrative evidence review of findings has been completed entitled ‘ageing well interventions to improve and maintain independent living for community housebound populations.’ The review was registered with PROSPERO international prospective register of systematic reviews (CRD 42022371047) and reported according to the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA). Data screening was undertaken by two reviewers at each stage to ensure accuracy, quality, and reliability.

Results

The results have identified key health interventions designed and delivered by community clinicians, including benefits of exercise, medication review, oral health, and health empowerment to improve outcomes for the housebound population. The results have outlined a total of twenty-nine outcome measures, which have been examined intrinsically and extrinsically to explore greatest impact for housebound health.

Conclusion

At the time of the Autumn conference, the research study will have completed the systematic review and be able to present findings to illustrate areas of intervention synthesized for the target population. Key to this will be understanding application, effectiveness, and generalizability for community delivery. The poster presentation will share progress of the wider study with opportunities to take part in the next Delphi panel stage.
1892 Non-governmental organisations’ digital engagement in providing services for older people's needs: a scoping review
Authors: Bhattacharjee S , Kebede A , Raja M , Sandic-Spaho R , Uhrenfeldt L , Kymre I G , Galvin K
Published: January 2024

Introduction

Digital technologies can play a significant role in addressing care needs of older people. The process of establishing an effective and efficient digital engagement with older people demands multi-sectoral collaboration from various stakeholders including non-governmental organisations. The role non-governmental organisations play in such digital programs, their process of engagement with older people and factors which influence such multi-sectoral collaboration is an under researched area.

Methods

A scoping review was performed to map existing literature on older people’s engagement with digital health technologies delivered through NGOs. The focus was on exploring the factors influencing the process of digital engagement, delineating modes of digital engagement and exploring the caring needs of older people. Multiple databases and grey literature sources were searched to retrieve articles from 2000 till 2023. JBI methodology for scoping reviews was adopted for this review.

Results

Out of 8970 citations, 50 articles (27 original articles, 9 reports, 12 website sources, 1 handbook and 1 research summary) were included in the final review. NGOs engage with older people either directly by delivering the program or indirectly through other program stakeholders through various inter-organisational processes (collaboration, co-ordination, partnership, delegation, sector-wide participation and association). Different types of NGOs (national, regional, provincial and local) were involved in this process of delivering care. Majority of the studies implemented programs through smartphone or tablet based digital applications. Individual factors, organisational factors, technological factors and system-wide factors influence the process of digital engagement between older people and NGOs.

Conclusion

The number of studies included in this scoping review, concerning older people’s engagement with digital health technologies, through NGOs were informative, but limited information was present on the process of engagement. Acknowledgement of NGOs work, and the societal role they play do also indicate that our developing digital societies more or less depend on these organisations.
1947 Process evaluation of a home-based intervention to promote independence among older people living with mild frailty
Authors: Barrado-Martín Y , Frost R , Catchpole J , Rookes T , Gibson S , Hopkins J , Gardner B , Gould R , Chadwick P , Jowett C , Kumar R , Drennan V M , Elaswarapu R , Kharicha K , Avgerinou C , Marston L , Walters K
Published: January 2024

Introduction

Frailty is a condition that makes it increasingly difficult for individuals to recover from adverse health events and gradually erodes independence. NHS interventions in England have focused on those with more severe frailty. We tested HomeHealth, a home-based, tailored, multi-domain (six-session) behaviour change intervention to promote independence in the over-65s living with mild frailty, in a RCT recruiting 388 people (intervention 195; control 193). HomeHealth was delivered by the voluntary sector in three diverse areas and addressed mobility, nutrition, socialising, and psychological goals, among other domains. We aimed to explore acceptability, participant engagement, and experiences of delivering and receiving the service.

Methods

Following a mixed-methods approach, we extracted quantitative data on types of goals and progress towards goals from Health and Wellbeing plans and appointment checklists. Between July 2022 and May 2023, we interviewed 49 older participants, 7 HomeHealth workers and 8 stakeholders. Older people were purposively sampled for diversity in socio-demographic characteristics, cognitive and physical functioning, intervention adherence and allocated HomeHealth worker. Interviews explored their motivations to engage; experience of participation, delivery and study support followed by their suggestions for improvement. We analysed qualitative data thematically and quantitative data descriptively.

Results

Most participants set mobility goals (49%), followed by a combination of goals (31%), and made moderate progress towards these. The intervention (completed by 93.3% participants) was positively received, boosted participants’ confidence, and provided emotional support. Participants reported that sometimes behaviour was maintained post-intervention, but further appointments would have been welcomed to fill the gap in other services. However, some people found it difficult to identify goals to work on, particularly when they already felt independent and well supported.

Conclusions

Services to support older people with mild frailty are acceptable, have good engagement, and can lead to behaviour change, particularly among those who self-identify a need for change.
2036 “I didn’t personally think it would change my life, but it has”: The experience following emergency laparotomy for older people
Authors: Price A , Pearce L , Smith J , Martin P , Griffiths J
Published: January 2024

Introduction

Older people living with frailty are at high risk of adverse clinical outcomes following emergency laparotomy, including early death, hospital readmission and functional decline. Despite this, there is a paucity of literature exploring patient experience of surgery in this group, particularly following hospital discharge. As a result, there is limited information to guide the development of service delivery models that support optimal post-operative recovery and improve overall experience.

Methods

Twenty older people, aged ≥65 years, with a Clinical Frailty Scale score of ≥ 4 and who had undergone emergency laparotomy were recruited from eight participating hospital sites. Participants were interviewed at 3 weeks following their surgery, or the earliest convenient date. Semi-structured interviews were undertaken either face to face or via telephone and explored the peri-operative and early recovery experience. Data were analysed using reflexive thematic analysis.

Results

Participants described physical, psychological, and social implications following emergency laparotomy which extended further than hospital discharge. Recovery was perceived to be an ongoing and slow process of returning to ‘normal self’ however participants displayed resilience towards achieving this by ‘knuckling down’ and ‘pushing forward’. The experience of hospital care was generally positive, but lack of access to discharge advice and community follow up left some participants feeling ‘abandoned’ and uncertain once they returned home. Many were reliant on family support during this period.

Conclusions

Older people living with frailty experience multifaceted consequences of emergency laparotomy that result in a prolonged recovery period. Multi-disciplinary post-operative care pathways are essential in addressing the holistic care needs of this group following surgery. The provision of robust discharge information and enhanced access to support in the community could improve patient experience and facilitate ongoing recovery at home.
1743 Frailty is associated with poor cardiopulmonary resuscitation outcomes in the COVID-19 pandemic
Authors: Gurney J
Published: January 2024

Background

This study aims to investigate the relationship between frailty and in-hospital cardiopulmonary resuscitation (CPR) outcomes in the COVID-19 pandemic.

Methods

The study was carried out in a tertiary hospital in Scotland and included all patients over the age of 18 who had an in-hospital CPR attempt between April 2020 and March 2022. Patients were identified via the pre-existing National Cardiac Arrest Audit Database which was collected prospectively. Data collected from this included age, sex, initial arrest rhythm, return of spontaneous circulation (ROSC) and in-hospital mortality. The electronic and paper patient notes were retrospectively reviewed to calculate a Rockwood clinical frailty scale (CFS) and Charlson comorbidity index (CCI). The data was stratified in to frail (CFS ≥5) and non-frail (CFS <5) groups.

Results

65 patients were included in the study. In univariate analysis, there was a significant difference between the frail and non-frail groups in age (p=0.006), ROSC (p=0.02) and survival to discharge (p=0.004). Only 10 out of 34 (29.4%) frail patients had ROSC and of those only 3 (8.8%) survived to discharge compared to 12 out of 31 (35.3%) of non-frail patients. In a binary logistic regression, there was a significant association between frailty and both ROSC (adjusted OR 3.31 [95% CI: 1.12-9.78}) and survival to discharge (adjusted OR 6.33 [95% CI: 1.48-27.13]) and no significant association with age, CCI or sex.

Conclusion

The findings support the relationship between frailty and poor CPR outcomes independent of age and co-morbidity during the COVID-19 pandemic.
2007 Willingness of older adults and their informal caregivers to deprescribe medication: UK survey study
Authors: Garnett R , Barnes R , Buckell J , McManus R , Sheppard J
Published: January 2024

Introduction

Reducing inappropriate polypharmacy is a major public health goal and deprescribing is considered one potential solution. Although patient attitudes towards deprescribing have been well studied, little consideration has been given to the informal caregiver perspective, how this differs from the views of patients and how that might influence care.

Method

A survey including demographic questions and the revised Patients’ Attitude Towards Deprescribing (rPATD) questionnaire was undertaken. The primary outcome was to identify the willingness of respondents to deprescribe. This survey was distributed as online, telephone or paper versions, via social media, community centres, day care centres, local organisations, and personal networks. It had two sections composed of equivalent questions: one for the ‘patient’ (age 65+, based in England, taking 1 prescription medication) and one for their ‘informal caregiver’ (age 18+). Data were analysed using descriptive statistics and binomial logistic regression.

Results

After exclusion of ineligible respondents, a total of 1,307 survey responses were received (861 patients and 446 caregivers). The average patient was 76±9 years, female (526; 61.6%), white (831; 97%), and educated to degree level (482; 56.9%). The average informal caregiver was 73±14 years, female (278; 62.9%), white (426; 96.4%) and educated to degree level (258; 58.2%). A total of 77.1% patients agreed that they were willing to deprescribe medications if their doctor said it was possible. In contrast, significantly fewer informal caregivers were happy for their patient to have medications deprescribed (59.7%; p-value for difference <0.001). Trust in physician, concerns about stopping medication and belief in the appropriateness of withdrawal were all associated with respondent willingness to deprescribe.

Conclusion

This large study suggests patients are more willing to deprescribe than their informal caregivers. Better understanding of these attitudes and how they differ between patients and informal caregivers, will help inform interventions to improve involvement in medication-related decisions.
1992 Long-term condition reviews in General Practice: The experiences of people with Dementia and their informal carers
Authors: Cole J , Parretti H M , Hanson S , Hornberger M
Published: January 2024

“I would imagine it needed a review…” A Qualitative Study Exploring the Experiences of People with Dementia and their Informal Carers of Long-term Condition Reviews in Primary Care

Introduction

Multimorbidity is common for people with dementia (PWD) and is associated with increased healthcare utilisation and poorer outcomes. Part of the management of long-term conditions (LTCs) occurs through annual LTC reviews conducted in primary care. Little is known about the experiences or needs of people with dementia and informal carers in regard to LTC reviews.

Aim

To explore the experiences of PWD and their informal carers of the review and management of LTCs in primary care.

Method

Qualitative research study, protocol informed by discussion with people with lived experience as an informal carer. Institutional ethical approval (ref ETH2122-1035, University of East Anglia) was granted 25/3/2022. Semi-structured interviews were conducted with PWD and informal carers recruited through Join Dementia Research and local (to Norfolk, UK) charities. Thematic analysis was undertaken with reference to Braun and Clarke (2006).

Results

16 participants were interviewed: two PWD, 10 informal carers and two informal care/PWD dyads. Our findings fall into four main themes: 1) What matters to people; medication optimisation and holistic care 2) What is a review; the diversity of experiences 3) The importance of communication and 4) Preference for shared decision making.

Conclusion

Consideration should be given to ensuring patients and carers are aware when a LTC review will take place and providing an opportunity to be involved, thus allowing shared decision making and patient centred care. Further research into the clinician experience and their views on patients’ needs and how to meet them is required to inform how LTC reviews for people with dementia can be optimised.
Deep brain stimulation does not modulate resting-state functional connectivity in essential tremor
Authors: Awad Amar , Grill Filip , Blomstedt Patric , Nyberg Lars , Eriksson Johan
Published: January 2024

While the effectiveness of deep brain stimulation in alleviating essential tremor is well-established, the underlying mechanisms of the treatment are unclear. Essential tremor, as characterized by tremor during action, is proposed to be driven by a dysfunction in the cerebello-thalamo-cerebral circuit that is evident not only during motor actions but also during rest. Stimulation effects on resting-state functional connectivity were investigated by functional MRI in 16 essential tremor patients with fully implanted deep brain stimulation in the caudal zona incerta during On-and-Off therapeutic stimulation, in a counterbalanced design. Functional connectivity was calculated between different constellations of sensorimotor as well as non-sensorimotor regions (as derived from seed-based and data-driven approaches), and compared between On and Off stimulation. We found that deep brain stimulation did not modulate resting-state functional connectivity. The lack of modulation by deep brain stimulation during resting-state, in combination with previously demonstrated effects on the cerebello-thalamo-cerebral circuit during motor tasks, suggests an action-dependent modulation of the stimulation in essential tremor.
Local structure of concentrated NaFSA solutions in propylene carbonate studied by X-ray and neutron diffraction methods
Authors: Kameda Yasuo , Kowaguchi Misaki , Amo Yuko , Usuki Takeshi , Nawa Kazuhiro , Sato Taku J
Published: January 2024

The microscopic structure of 10 mol% NaFSA [FSA: bis(fluorosulfonyl)amide]-propylene carbonate (PC) solution has been investigated by means of X-ray and neutron diffraction techniques. The solvation structure of Na+ has been determined from least-squares fitting analysis of X-ray intermolecular difference interference terms observed for 10 mol% NaFSA-PC solution and pure liquid PC. In the present solution, onaverage, 6(1) PC molecules are involved in the first solvation shell of Na+ with intermolecular distance rNaO = 2.26(7) Å, and bond angle ∠Na+…O = C = 169(9)°. Intermolecular correlation between neighboring PC molecules in the solution has been derived from simultaneous least-squares fitting analysis of observed H–H, H–X, and X–X (X: atoms except for H) intermolecular partial structure factors determined from neutron diffraction data for H/D isotopically-substituted sample solutions. An indication of anti-parallel configuration of the nearest neighbor PC molecules has been suggested.
Human papillomavirus (HPV) DNA methylation changes in HPV-associated head and neck cancer
Authors: Ekanayake Weeramange Chameera , Tang Kai Dun , Irwin Darryl , Hartel Gunter , Langton-Lockton Julian , Ladwa Rahul , Kenny Lizbeth , Taheri Touraj , Whitfield Bernard , Vasani Sarju , Punyadeera Chamindie
Published: January 2024

Despite the rising incidence, currently, there are no early detection methods for HPV-driven HNC (HPV-HNC). Cervical cancer studies suggest that HPV DNA methylation changes can be used as a biomarker to discriminate cancer patients from HPV-infected individuals. As such, this study was designed to establish a protocol to evaluate DNA methylation changes in HPV late genes and long control region (LCR) in saliva samples of HPV-HNC patients and HPV-positive controls. Higher methylation levels were detected in HPV late genes (L1 and L2) in both tumour and saliva samples of HPV-HNC patients compared with HPV-positive controls. Moreover, methylation patterns between tumours and corresponding saliva samples were observed to have a strong correlation (Passing-Bablok regression analysis; τ = 0.7483, P < 0.0001). Considering the differences between HNC and controls in methylation levels in late genes, and considering primer amplification efficiencies, 13 CpG sites located at L1 and L2 genes were selected for further evaluation. A total of 18 HNC saliva samples and 10 control saliva samples were assessed for the methylation levels in the selected sites. From the CpG sites evaluated statistically significant differences were identified for CpG sites at L2—CpG 6 (P = 0.0004), L1—CpG 3 (P = 0.0144), L1—CpG 2 (P = 0.0395) and L2—CpG 19 (P = 0.0455). Our pilot data indicate that higher levels of DNA methylation in HPV late genes are indicative of HPV-HNC risk, and it is a potential supplementary biomarker for salivary HPV detection-based HPV-HNC screening.
Functional genetic variants of the disulfidptosis-relatedINF2gene predict survival of hepatitis B virus-related hepatocellular carcinoma
Authors: Wei Junjie , Wen Qiuping , Zhan Shicheng , Cao Ji , Jiang Yanji , Lian Jiawei , Mai Yuejiao , Qiu Moqin , Liu Yingchun , Chen Peiqin , Lin Qiuling , Wei Xiaoxia , Wei Yuying , Huang Qiongguang , Zhang Ruoxin , He Songqing , Yuan Guandou , Wei Qingyi , Zhou Zihan , Yu Hongping
Published: January 2024

Disulfidptosis is a novel form of programmed cell death involved in migration and invasion of cancer cells, but few studies investigated the roles of genetic variants in disulfidptosis-related genes in survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We used Cox proportional hazards regression analyses, Kaplan–Meier curves and receiver operating characteristic curves to assess effects of genetic variants in 14 disulfidptosis-related genes on overall survival of 866 HBV-HCC patients. The Bayesian false discovery probability was used for multiple testing corrections. We also investigated biological mechanisms of the significant variants through expression quantitative trait loci analyses using the data from publicly available databases, luciferase reporter assays and differential expression analyses. As a result, we identified two independently functional single nucleotide polymorphisms (SNPs) (INF2 rs4072285 G > A and INF2 rs4444271 A > T) that predicted overall survival of HBV-HCC patients, with adjusted hazard ratios of 1.60 (95% CI = 1.22–2.11, P = 0.001) and 1.50 (95% CI = 1.80–1.90, P < 0.001), respectively, after multiple testing correction. Luciferase reporter assays indicated that both INF2 rs4072285 A and INF2 rs4444271 T alleles increased INF2 mRNA expression levels (P < 0.001) that were also higher in HCC tumor tissues than in adjacent normal tissues (P < 0.001); such elevated INF2 expression levels were associated with a poorer survival of HBV-HCC patients (P < 0.001) in the TCGA database. In summary, this study supported that INF2 rs4072285 and INF2 rs4444271 may be novel biomarkers for survival of HBV-HCC patients.
The impact of early-onset hidradenitis suppurativa
Authors: Wolinska Anna , Beatty Paula , Costa Blasco Marta , McFeely Orla , Murphy Lisa , Andrawis Madonna , Doyle Claire , Tobin Anne-Marie
Published: January 2024

Early-onset hidradenitis suppurativa can lead to significant impairments in a patient’s quality of life, especially for children and adolescents, who face challenges related to self-esteem and physical and emotional development. Prioritizing a review of paediatric patients who present with symptoms suggestive of HS can facilitate a timely diagnosis and allow for the initiation of early and effective management, which may limit the potential for long-term physical and psychological comorbidities to develop in the future.
Three-dimensional structure prediction of [GADS]-proteins as tentative primitive proteins
Authors: Nakayoshi Tomoki , Kato Koichi , Kurimoto Eiji , Oda Akifumi
Published: January 2024

[GADV]-protein is a random peptide constructed from glycine (G), alanine (A), aspartic acid (D), and valine (V), whereas [GADS]-protein is constructed from G, A, D, and serine (S). Both [GADV]- and [GADS]-proteins are candidates of primitive proteins. In this study, the three-dimensional structure formation ability of [GADS]-proteins was compared with that of [GADV]-proteins. Based on the results of molecular dynamics simulations, the secondary structure formation ability and rigid structure formation ability of [GADS]-proteins were inferior to those of [GADV]-proteins.
Understanding the German criticism of Target
Authors: Perotti Roberto
Published: January 2024

Does the accumulation of large Target imbalances threaten the viability of the monetary union? Several German and central European scholars have responded in the affirmative: in the case of a disorderly break-up, debtor countries might have an incentive to default on their Target balances, and this would represent a real loss to Target creditors. Most academics have rejected this argument: in their view, a Target default would be only a paper loss to creditors. I propose a simple and unified framework to study the working of the Target system in response to different shocks. I then argue that the German criticism of the Target system is not so unfounded after all, and should be taken seriously. The underlying problem is the co-existence of separate central banks within the Eurozone; if one wants to preserve this feature, no alternative to the current Target system and its problems seems to be realistically available. In particular, comparisons with the Interdistrict Settlement Account of the US Federal Reserve system are misleading.
On the Role of Personality in Successful Aging: A Scoping Review
Authors: Serrat Rodrigo , Cannella Valentina , Chacur-Kiss Karima , Pons-Vila Joan , Tesch-Römer Clemens
Published: January 2024

Background and Objectives

This study aimed to critically examine current knowledge on the role of personality in successful aging, considering Hooker and McAdams’ 3-level, 6-foci model of personality. The aim was also to pinpoint knowledge gaps that research should address in the future.

Research Design and Methods

We carried out a scoping review of the literature on successful aging and personality, following the 5-step framework proposed by Arksey and O’Malley and further expanded by Levac et al.

Results

Research into the role of personality in successful aging has grown significantly over the last 20 years. However, the increasing number of publications on the topic was primarily accounted for by studies focused on Layer 1 and particularly Layer 2 of McAdams’ model of personality, with Layer 3 being scarcely addressed. Research that included more than 1 layer of personality was rare.

Discussion and Implications

Our study pinpointed gaps that should be considered in future research in this area. These gaps were related to advancing toward agreed-upon definitions of successful aging and personality, broadening the scope of research on this topic, and integrating personality dimensions on research on successful aging.
Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression
Authors: Wong Chao-Jen , Friedman Seth D , Snider Lauren , Bennett Sean R , Jones Takako I , Jones Peter L , Shaw Dennis W W , Blemker Silvia S , Riem Lara , DuCharme Olivia , Lemmers Richard J F L , van der Maarel Silvère M , Wang Leo H , Tawil Rabi , Statland Jeffrey M , Tapscott Stephen J
Published: January 2024

Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA, indicating that regional biopsies can accurately measure progression in the whole muscle and providing a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design. An unanticipated finding was the strong correlations of molecular signatures in the bilateral comparisons, including markers of B-cells and other immune cell populations, suggesting that a systemic immune cell infiltration of skeletal muscle might have a role in disease progression.
A NEW APPROACH FOR TREATMENT OF ULCERATIVE COLITIS: A MELANOCORTIN RECEPTOR AGONIST PL8177
Authors: Dhingra Priyanka , Obr Alison , Spana Carl , Dodd John , Kayne Paul
Published: January 2024

INTRODUCTION

The melanocortin system plays an important role in resolving inflammatory processes. The melanocortin 1 receptor (MC1R)–specific agonist PL8177 has demonstrated MC1R binding affinity and functional activity that mirrors that of α-melanocyte–stimulating hormone. The effect of PL8177 on inflammation, cell population composition, and gene and protein expression was investigated in colons from a dextran sulfate sodium (DSS)–induced rat model of colitis.

METHODS

Colitis was induced by 5% DSS in drinking water. Rats received vehicle control (placebo) capsules, oral PL8177 capsules (20, 50, and 100 μg per animal), or mesalazine (positive control). Colons were harvested on day 8. Samples were analyzed for cytokines, and by single nuclei RNA-seq and data-independent acquisition tandem mass spectrometry phosphoproteome profiling. Colitis was assessed by diarrhea and rectal bleeding, colon length shortening, colon weight gain, and histopathology. Total colitis index assessed inflammatory damage.

RESULTS

PL8177 50 μg showed a significant (P<0.05) improvement in colon weight (53% reduction), stool consistency, and fecal occult blood score vs vehicle, and there was significant improvement in the total colitis index for the PL8177 100-μg group vs vehicle. All PL8177 cohorts showed greater improvement in the total colitis index than mesalazine. Mesalazine produced a marked reduction in colon length, but only moderate improvement (35%) in colon weight. Single nuclei RNA-seq showed that in the PL8177 100-μg group, relative cell populations and key gene expression levels were closer to those of healthy controls PL8177 100-μg treatment caused a relative decrease in immune cells and an increase in enterocytes and enteric glial cells compared to vehicle control. Subclustering analysis revealed significant differences between PL8177 100-μg and vehicle populations. Although both showed the presence of macrophages, vehicle-treated colons were primarily M1 macrophages involved in inflammation. In PL8177 100 μg–treated colons, macrophages were primarily pro-resolution M2. Proteomic analysis showed that PL8177-treated colons are more similar to sham colons than to vehicle colons. Also after treatment with PL8177, Smad 2 and 3, proteins known to promote intestinal homeostasis showed expression similar to that seen in the sham group, a result not seen in vehicle-treated colons.

DISCUSSION

Oral PL8177 treatment showed significant improvement in anatomical markers of colitis vs the vehicle and mesalazine control groups, supporting the aim of treating inflammatory bowel disease (IBD). Transcriptomics and proteomics data show that oral PL8177 treatment causes diseased colons to move toward the healthy state and to resolve inflammation. Resolving inflammation—rather than blocking it—provides the possibility of efficacy coupled with safety in treating IBD.
GROUP 3 INNATE LYMPHOID CELLS RELY ON ER STRESS RESPONSE FOR CYTOKINE PRODUCTION IN IBD
Authors: Cao Siyan , Ciorba Matthew , Kaufman Randal , Deepak Parakkal , Colonna Marco
Published: January 2024

BACKGROUNDS

Group 3 innate lymphoid cells (ILC3s) recently emerged as important regulators and potential drug targets for IBD. However, the response of ILC3s to environmental stimuli during intestinal inflammation remains elusive. IRE1a-XBP1 serves as the regulatory hub of the endoplasmic reticulum stress response that plays a vital role in intestinal inflammation.

METHODS

We generated conditional knockout Ire1aflo/flox,Rorc-Cre (Ire1aΔRorc) and Rag-/-Ire1aΔRorc mice with Ire1a deleted in ILC3s. Intestinal infections were induced by Citrobacter rodentium and Clostridium difficile. ILC3s-derived cytokines including IL-22 is crucial for host defense in the acute phase of C. rodentium and C. difficile infection. Dextran sodium sulfate (DSS) was given in drinking water to induce acute colitis. We recruited patients with active Crohn’s disease (CD) and collected ileal biopsies during routine colonoscopy before starting ustekinumab, a non-selective anti-IL-23 antibody. Mucosal ILC3s were isolated for analysis of ILC3s by flow cytometry.

RESULTS

In murine intestinal ILC3s, the activity of IRE1a-XBP1 pathway follows a robust 24h circadian rhythm which parallels that of clock genes and cytokines including IL-22. XBP1s is activated in ILC3s ex vivo by vasoactive intestinal peptide, which was previous shown to orchestrate the circadian expression of IL-22 by ILC3s. IRE1a-XBP1 in intestinal ILC3s is further activated in response to IL-23 and colitis in mice, as well as in inflamed IBD tissues compared to normal tissues from healthy individuals. We further showed that IRE1a-XBP1 activation in stimulated ILC3s requires mitochondrial reactive oxygen species (mtROS) (Fig 1). Using the Ire1aΔRorc mice, we demonstrated that IRE1a-XBP1 is critical for cytokine expression by ILC3s. Ire1aΔRorc mice are highly susceptible to acute C. rodentium and C. difficile infection as well as acute DSS colitis (similar vulnerabilities were found in Rag-/-Ire1aΔRorc mice compared to Rag-/-Ire1aflox/flox littermates). Ire1aΔRorc mice exhibit reduced IL-22 and IL-17A in ILC3s and impaired epithelial barrier function with diminished expression of mucins and antimicrobial peptides. The susceptibilities of Ire1aΔRorc and Rag-/-Ire1aΔRorc mice to colitis were rescued by administration of recombinant IL-22 (Fig 2). Moreover, the frequency of XBP1s+ ILC3s in ileal mucosa from CD patients before initiation of ustekinumab positively correlates with response to therapy.

CONCLUSIONS

We demonstrate that a non-canonical mtROS-IRE1a-XBP1 pathway augments cytokine production by intestinal ILC3s. Loss of IRE1a-XBP1 in ILC3s impairs the optimal and rhythmic expression of protective cytokines and renders the mice more susceptible to intestinal infections and colitis. We also identify XBP1+ ILC3s as a potential biomarker for predicting responsiveness to anti-IL-23 therapies in IBD.
P2Y1 RECEPTOR SIGNALING INFLUENCES EPITHELIAL RESPONSE TO INTESTINAL INFLAMMATION
Authors: Engevik Kristen , Hyser Joseph
Published: January 2024

Purines are among the most influential and ancient biochemical molecules in evolutionary history. In recent years, several studies have identified that nucleotides are released from cells during infection and tissue injury and serve as paracrine signaling molecules that help coordinate host defense and repair responses. These important extracellular signaling molecules activate purinergic receptors, of which there are 19 different purinergic receptor subtypes, which are classified into P1 and P2 receptors. Several studies have revealed crucial roles for P2 purinergic receptors during inflammatory and infectious diseases; however, these studies have largely examined purinergic signaling in immune cells and the enteric nervous system. Yet, while epithelial cells serve as the first barrier against infection and inflammation, the role of purinergic signaling within the gastrointestinal tract remains largely unknown. Our group recently discovered a novel and prominent role for P2Y1 in mediating host responses during rotavirus infection. To extend these studies, we sought to elucidate the P2 purinergic receptor repertoire expressed within gut epithelium and assess their functional role during insult. Using the Human Protein Atlas, we queried single-cell RNA sequencing data for P2 purinergic receptor expression in small intestine, colon, and rectum. In silico analysis revealed high expression of P2Y1, P2Y2, P2Y11 and P2X4 among the purinergic receptors throughout the gastrointestinal tract. Interestingly, P2Y1 showed highest expression in intestinal enterocytes and goblet cells. Further, we compared P2 receptor expression between commonly used, cancer-derived intestinal cell lines (T84, HT29 and Caco2) and crypt-derived human intestinal organoids (HIOs). Both HIOs and T84 and Caco2 cell lines had similar mRNA expressions of P2Y1, P2Y2, P2Y11 and P2X4. However, live calcium imaging studies showed robust responses to P2Y receptor-specific agonists in HIOs, particularly P2Y1 and P2Y2 agonists, but the cancer-derived cell lines failed to respond to these agonists, suggesting these cell lines have defects in P2Y signaling. Functionally, blocking P2Y1, but not P2Y2, significantly delayed wound healing in epithelial scratch assays, indicating a potential role in epithelial injury repair. To delineate the role of epithelial P2Y1 in vivo, we generated VillinCre P2Y1flex/flox mice. At baseline, the knockout animals did not exhibit any overt intestinal defects; however, in the DSS-induced colitis model, the epithelial P2Y1 KO mice had significantly greater weight loss and epithelial damage than their wildtype littermates. These findings confirm that the gastrointestinal tract express P2Y1, P2Y2, P2Y11 and P2X4 purinergic receptors and P2Y1 signaling plays important functional roles in both gastrointestinal epithelial homeostasis and repair of injury.
PERFUSED IN VITRO INTESTINE TISSUE FOR STUDYING INFLAMMATORY BOWEL DISEASE RESPONSE TO DRUG THERAPIES
Authors: Rudolph Sara , Roh Terrence , Longo Brooke , Shokoufandeh Mina , Mumuney Fatimah , Chadha Anushka , Chen Ying , Kaplan David
Published: January 2024

A dynamic perfusion system was designed for cultivation an in vitro model comprising human intestinal colonoids, intestinal myofibroblasts, and monocyte-derived macrophages. The primary aim was to investigate the effect of therapeutic interventions on inflammatory bowel disease (IBD) using this bioengineered system. The approach involved creating a a colonoid epithelial monolayer on a scaffold lumen with myofibroblasts and macrophages in the subepithelial compartment, which was then integrated into a bioreactor enabling controlled perfusion mimicking the dynamic intestinal microenvironment to introduce inflammation and assess responses to traditional and innovative therapies. Inflammation induction in the model resulted in decreased epithelial integrity along with the upregulation of pro-inflammatory cytokines. The addition of myofibroblasts amplified the secretion of pro-inflammatory cytokines GCP-1, GM-CSF, and IL-1α, while concurrently reducing MCP-1 levels. The introduction of myofibroblasts contributed to an enhanced inflammatory response in the tissue. This system is poised to serve as a valuable tool for evaluating potential therapeutic strategies aimed at addressing IBD.
LIQUID-BIOPSY FOR ASSESSING SEVERITY OF INFLAMMATORY BOWEL DISEASE VIA PLASMA MICROBIAL CELL-FREE DNA
Authors: Kale Shiv , Babb Paul , Noll Nicholas , Bercovici Sivan
Published: January 2024

Plasma cell-free DNA (cfDNA) has emerged as a robust biomarker utilized in multiple applications that span cancer screening, diagnosis and monitoring, prenatal testing, and characterization of organ health post-transplantation. Cell-free DNA-based assays leverage the occurrence of processed extracellular DNA that produce unique signatures to discern a variety of biological states, disease manifestations, as well as forms of cell death. Similar to human cells, microbes produce cfDNA when they turnover, providing evident clinical utility in diagnosing and treating deep-seated infections in immunocompromised patients.

Here, we describe the use of plasma microbial cell-free DNA (mcfDNA) as a unique means to assess inflammatory bowel disease type and severity. A total of 392 plasma samples encompassing remission and active (mild, moderate, severe) Crohn’s disease (N=196) and ulcerative colitis (N=196) were provided by the Crohn’s and Colitis Foundation for this study. All samples were derived from patients who had an endoscopic assessment within a 30-day window of plasma collection. Our classifiers, based solely on plasma mcfDNA signatures, are able to discriminate between Crohn’s disease, Ulcerative colitis, or otherwise healthy patient populations with an AUC >0.95. Similarly, a second set of classifiers are able to distinguish between endoscopically validated remission, mild, moderate, and severe disease cases (as determined by Mayo Endoscopic score or Crohn’s disease activity index) with AUCs >0.75. These results correspond to greater than 37% (UC) and 18% (CD) increase in sensitivity in comparison to standard of care measurements via fecal-calprotectin and high sensitivity-C-reactive protein for this cohort. Upon investigation, critical features in our classifiers correspond with well-known signatures from microbes associated with IBD or well-curated from the human microbiome.

The use of mcfDNA for IBD diagnosis and assessment of disease severity may provide clinicians and patients a valuable non-invasive means to gain additional insight into disease progression in a routine manner. Further opportunities to leverage these signatures to predict response to therapy, and validate classifier performance on an independent cohort are currently being explored.