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The emergence of persistent symptoms following SARS-CoV-2 infection, known as long COVID, is providing a new challenge to healthcare systems. The cardinal features are fatigue and reduced exercise tolerance. Vitamin D is known to have pleotropic effects far beyond bone health and is associated with immune modulation and autoimmunity. We hypothesize that vitamin D levels are associated with persistent symptoms following COVID-19. Herein, we investigate the relationship between vitamin D and fatigue and reduced exercise tolerance, assessed by the Chalder Fatigue Score, six-minute walk test and modified Borg scale. Multivariable linear and logistic regression models were used to evaluate the relationships. A total of 149 patients were recruited at a median of 79 days after COVID-19 illness. The median vitamin D level was 62 nmol/L, with n = 36 (24%) having levels 30–49 nmol/L and n = 14 (9%) with levels <30 nmol/L. Fatigue was common, with n = 86 (58%) meeting the case definition. The median Borg score was 3, while the median distance covered for the walk test was 450 m. No relationship between vitamin D and the measures of ongoing ill-health assessed in the study was found following multivariable regression analysis. These results suggest that persistent fatigue and reduced exercise tolerance following COVID-19 are independent of vitamin D.

Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (67/128; 52.3%) at median of 10 weeks after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.

People experiencing homelessness are more likely to experience poor health with physical functioning deficits and frailty commonly reported. It is not well known how strategies to target physical functioning deficits and frailty work in practice in this group. The primary aim of this study was to explore the feasibility of an exercise intervention with protein supplementation to target physical functioning and frailty in people experiencing homelessness evaluated by recruitment and retention rates, adherence to the exercise sessions and protein supplement, adverse effects, programme feedback and characteristics of non-returners, sporadic and frequent attenders. The secondary aim was to evaluate changes in effectiveness outcomes of grip strength, muscle mass, lower extremity physical function, pain, frailty, and risk of malnutrition. This prospective single-arm study evaluated the feasibility of a 16-week rolling, low-threshold, 'drop-in' once weekly exercise programme with protein supplementation. The main recruitment site was a day-service centre for people who are homeless. Feasibility was assessed by the recruitment and retention rates, adherence to the exercise sessions and protein supplement as well as adverse effects, programme feedback and evaluation of characteristics of non-returners, sporadic (≤50% of available sessions) and frequent attenders (≥50% of available sessions). Effectiveness outcomes included pain (Visual Analogue Scale), physical functioning and performance (hand-grip dynamometry, limb circumference, the Short Physical Performance Battery), frailty (SHARE-FI and Clinical Frailty Scale) and nutritional status (Mini Nutritional Assessment). Thirty-one participants were recruited mean (SD) age 45(16) years. There was a recruitment rate of a median (IQR) of 2(1-3) new participants per week. The retention rate was 45% (n = 14) to the main recruitment site. Adherence to the exercise sessions and nutritional intervention was 90% and 100% respectively. Three adverse events were recorded during 74 interventions over the 16-week programme. The acceptability of the programme was highlighted in participant feedback. Characteristics of frequent returners (≥50%) were older age, female, more stably housed and more stable in addiction. The programme did not induce any changes in effectiveness outcomes. The feasibility of this programme was demonstrated. Overall, the programme was well received with higher retention rates in older participants, females, those more stably housed and those stable in addiction. A higher powered, more intense programme is needed to demonstrate programme effectiveness.

Frailty is a complex multi-dimensional state of increased vulnerability to adverse outcomes and is associated with older age but there is growing evidence of accelerated ageing and frailty in non-geriatric populations, including those experiencing socio-economic deprivation and extreme social exclusion, such as people experiencing homelessness. Addiction, as a coping mechanism for prior trauma, is common among people who are homeless and can have a gendered dimension. Women experiencing homelessness and addiction have unique needs which require a gendered approach. The aim of this study is to evaluate the feasibility and impact of an exercise intervention to target the known physical functioning deficits and frailty which this population experiences. This quantitatively driven, sequential single-arm mixed-methods feasibility study will evaluate the feasibility and impact of a low threshold trauma informed exercise intervention on physical functioning and frailty in women experiencing homelessness and addiction. Physical function (10m Walk Test, 2Min Walk Test, Single Leg Stance, Chair Stand Test, hand grip dynamometry), frailty (Clinical Frailty Scale and the SHARE-Frailty Instrument) and nutritional status (Mini-Nutritional Status), pain (Numerical Rating Scale) and quality of life (SF 12-V2) will be evaluated. The 10-week intervention will involve a 3-times weekly exercise programme with protein supplementation. Following this, qualitative interviews, which will be thematically analysed using Braun & Clarke methodology, will be conducted. This study will be conducted in Dublin from February to July 2024. Little is known about frailty-focussed interventions in women experiencing homelessness and addiction. This proposed study will help to increase the knowledge base regarding the physical health burden and frailty experienced by this vulnerable population and will deliver a targeted intervention with a gendered dimension to mitigate its affects. The findings of this research will help narrow the research gap and will guide clinicians and policy makers to implement unique gender-based treatment strategies for this population. (300). NCT05700305.

Objective Public and patient involvement is increasingly embedded as a core activity in research funding calls and best practice guidelines. However, there is recognition of the challenges that prevail to achieve genuine and equitable forms of engagement. Our objective was to identify the mechanisms and resources that enable the reciprocal involvement of seldom heard groups in health and social care research. Methods A rapid realist review of the literature that included: (a) a systematic search of CINAHL, PsycINFO, PubMed and Open Grey (2007‐2017); (b) documents provided by expert panel members of relevant journals and grey literature. Six reference panels were undertaken with homeless, women's, transgender, disability and Traveller and Roma organizations to capture local insights. Data were extracted into a theory‐based grid linking context to behaviour change policy categories. Main results From the review, 20 documents were identified and combined with the reference panel summaries. The expert panel reached consensus about 33 programme theories. These relate to environmental and social planning (7); service provision (6); guidelines (4); fiscal measures (6); communication and marketing (4); and regulation and legislation (6). Conclusions While there is growing evidence of the merits of undertaking PPI, this rarely extends to the meaningful involvement of seldom heard groups. The 33 programme theories agreed by the expert panel point to a variety of mechanisms and resources that need to be considered. Many of the programme theories identified point to the need for a radical shift in current practice to enable the reciprocal involvement of seldom heard groups.

Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported reduced type I interferon in severe COVID-19 patients preceded clinical worsening. Further studies identified genetic mutations in loci of the TLR3- or TLR7-dependent interferon-I pathways, or neutralizing interferon-I autoantibodies as risk factors for development of COVID-19 pneumonia. Here we show in patient cohorts with different severities of COVID-19, that baseline plasma interferon α measures differ according to the immunoassay used, timing of sampling, the interferon α subtype measured, and the presence of autoantibodies. We also show a consistently reduced induction of interferon-I proteins in hospitalized COVID-19 patients upon immune stimulation, that is not associated with detectable neutralizing autoantibodies against interferon α or interferon ω. Intracellular proteomic analysis shows increased monocyte numbers in hospitalized COVID-19 patients but impaired interferon-I response after stimulation. We confirm this by ex vivo whole blood stimulation with interferon-I which induces transcriptomic responses associated with inflammation in hospitalized COVID-19 patients, that is not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to interferon-I based treatments in late stage COVID-19, despite the importance of interferon-I in early acute infection and may guide alternative therapeutic strategies. The interferon response has been shown to be linked to severity of SARS-CoV-2 infection and is an essential component of the immune response to COVID-19. Here the authors stratify patients according to COVID-19 severity and asses the interferon response showing defective responses in severe infection and highlight the importance of assay variables and confounding factors that impact the detection of interferon.

ObjectivesThis study aims to identify practical, trauma-informed strategies to improve engagement of populations experiencing homelessness in observational health research.DesignData from three real-world observational studies involving people experiencing homelessness (PEH) and housed participants were analysed for study completion rates and participant demographics. A team of researchers, clinicians and people with lived experience of homelessness, reviewed their experience of study design, recruitment and assessment study procedures to identify strategies found to be effective in recruitment and retention of PEH.SettingThe Inclusion Health Research Group (IHRG) consists of 10 clinicians and researchers who study the effect of social exclusion, such as homelessness, on health. Many members of the group also provide clinical care to PEH. The three observational studies which informed this paper recruited participants in Dublin, Ireland between 2021 and 2025. Approximately 15 000 adults are currently experiencing homelessness in Ireland, of whom two-thirds reside in Dublin and more than 70% are accommodated in hostels.ParticipantsThe three observational studies that informed this paper, designed and carried out by members of the IHRG, included populations of PEH recruited from sites in the community across Dublin.ResultsPEH were predominantly male with an average age in their mid-40s and a high prevalence of smoking, drug use and alcohol consumption. Study completion rates were high (83.3% to 94.1%). On review of the study design and implementation, eight key strategies were identified as effective in recruitment and retention of PEH: (1) involvement of people with lived experience in study design; (2) flexible recruitment locations; (3) flexible assessment timings; (4) trust-building through consistent communication; (5) collaboration with gatekeeper organisations and peer advocates; (6) use of non-financial incentives like health screenings; (7) validated assessment tools and (8) tailored support for participants with addiction.ConclusionsUsing flexible, trauma-informed, participant-centred approaches informed by the involvement of people with lived experience and gatekeeper organisations can ensure high levels of recruitment and retention of PEH. This may enhance research inclusivity and ultimately contribute to better understanding of the complex health needs of populations experiencing homelessness within public health.

ObjectiveLow physical functioning and frailty are prevalent in non-geriatric vulnerable populations such as people experiencing homelessness, addiction and mental health challenges. The objective of this study was to explore the feasibility and impact of a targeted exercise intervention with protein supplementation for women experiencing homelessness, addiction and mental health challenges.DesignMixed-methods feasibility study.SettingA women’s-only day service for people with homelessness and addiction issues, in Dublin, Ireland.ParticipantsWomen experiencing homelessness, addiction and mental health challenges.InterventionsThe intervention was a 10-week low-threshold exercise and protein supplementation pre-post programme (LEAP-W). Qualitative interviews were conducted following the intervention with programme participants and key stakeholders.Primary and secondary outcome measuresThe primary outcome was feasibility measured by recruitment, retention, adherence, safety and acceptability, and secondary outcomes measured pre-post intervention change in physical function, pain, nutritional and frailty status, and overall health status.ResultsOverall, 33 participants were recruited. Data generated demonstrated that LEAP-W was feasible by its safety, acceptability and high retention in certain subgroups, and high adherence to the exercise and protein supplement; its impact was demonstrated by pre-post intervention improvement in multiple domains (strength (chair stand test), balance (the single leg stance test), pain and quality of life/mental health (mental component summary of the Short Form-12; 95% CI, p<0.05)). Three themes emerged from the qualitative inquiry: (1) the power of exercise; (2) challenges to engagement and (3) the LEAP approach, driven by the trauma-informed and low threshold approach.ConclusionTargeted exercise interventions with trauma-sensitive, flexible design can be successfully delivered and yield impact in women with complex needs who experience homelessness, addiction and mental health challenges. Service design should be considered when delivering interventions to this population. Further higher-powered longitudinal studies are warranted.Trial registration numberNCT06264895.

Unusually for a viral infection, the immunological phenotype of severe COVID-19 is characterised by a depleted lymphocyte and elevated neutrophil count, with the neutrophil-to-lymphocyte ratio correlating with disease severity. Neutrophils are the most abundant immune cell in the bloodstream and comprise different subpopulations with pleiotropic actions that are vital for host immunity. Unique neutrophil subpopulations vary in their capacity to mount antimicrobial responses, including NETosis (the generation of neutrophil extracellular traps), degranulation and de novo production of cytokines and chemokines. These processes play a role in antiviral immunity, but may also contribute to the local and systemic tissue damage seen in acute SARS-CoV-2 infection. Neutrophils also contribute to complications of COVID-19 such as thrombosis, acute respiratory distress syndrome and multisystem inflammatory disease in children. In this Progress review, we discuss the anti-viral and pathological roles of neutrophils in SARS-CoV-2 infection, and potential therapeutic strategies for COVID-19 that target neutrophil-mediated inflammatory responses.