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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.

Invasive pulmonary aspergillosis (IPA) is a serious condition resulting in significant mortality and morbidity among patients in intensive care units (ICUs). There is a growing number of at-risk patients for this condition with the increasing use of immunosuppressive therapies. The diagnosis of IPA can be difficult in ICUs, and relies on integration of clinical, radiological, and microbiological features. In this review, we discuss patient populations at risk for IPA, as well as the diagnostic criteria employed. We review the fungal biomarkers used, as well as the challenges in distinguishing colonization with Aspergillus from invasive disease. We also address the growing concern of multidrug-resistant Aspergillosis and review the new and novel therapeutics which are in development to combat this.

The long-term clinical and physiological consequences of COVID-19 infection remain unclear. While fatigue has emerged as a common symptom following infection, little is known about its links with autonomic dysfunction. SARS-CoV-2 is known to infect endothelial cells in acute infection, resulting in autonomic dysfunction. Here we set out to test the hypothesis that this results in persistent autonomic dysfunction and is associated with post-COVID fatigue in convalescent patients. We recruited 20 fatigued and 20 non-fatigued post-COVID patients (median age 44.5 years, 36/40 (90%) female, median time to follow up 166.5 days). Fatigue was assessed using the Chalder Fatigue Scale. These underwent the Ewing's autonomic function test battery, including deep breathing, active standing, Valsalva manoeuvre and cold-pressor testing, with continuous electrocardiogram and blood pressure monitoring, as well as near-infrared spectroscopy-based cerebral oxygenation. 24-hour ambulatory blood pressure monitoring was also conducted, and patients completed the generalised anxiety disorder-7 questionnaire. We assessed between-group differences in autonomic function test results and used unadjusted and adjusted linear regression to investigate the relationship between fatigue, anxiety, and autonomic test results. We found no pathological differences between fatigued and non-fatigued patients on autonomic testing or on 24-hour blood pressure monitoring. Symptoms of orthostatic intolerance were reported by 70% of the fatigued cohort at the time of active standing, with no associated physiological abnormality detected. Fatigue was strongly associated with increased anxiety (p <0.001), with no patients having a pre-existing diagnosis of anxiety. These results demonstrate the significant burden of fatigue, symptoms of autonomic dysfunction and anxiety in the aftermath of COVID-19 infection, but reassuringly do not demonstrate pathological findings on autonomic testing.

Background Published studies suggest physical recovery from the COVID-19 is complex, with many individuals experiencing persistent symptoms. There is a paucity of data investigating the longer-term trajectory of physical recovery from COVID-19. Methods A prospective longitudinal design was utilised to investigate the impact COVID-19 has on physical functioning at 10-weeks (T1), 6-months (T2) and 1-year (T3) post-hospital discharge. Objective measures of recovery included 6-Minute Walk Test Distance (6MWTD), frailty (Clinical Frailty Scale), quantification of falls following hospital-discharge, return to work status and exercise levels. Subjective markers included symptoms (COVID-19-Specific Patient Concerns Assessment), fatigue (Chalder Fatigue Score) and health-related quality of life (HrQOL) [Short-Form-36 Health Survey Questionnaire (SF-36-II)]. Univariate analysis was performed using t-test, Wilcoxon rank-sum, and Chi-squared test, paired analysis using one-way analysis of variance and Krustal Wallis testing and correlation analysis with Spearman correlation tests. Results Sixty-one subjects participated. Assessments were conducted at a median of 55 days(T1), 242 days(T2), and 430 days(T3) following hospital-discharge. 6MWTD improved significantly overtime ( F  = 10.3, p  < 0.001) from 365(209)m at T1 to 447(85)m at T3, however remained below population norms and with no associated improvement in perceived exertion. Approximately half (n = 27(51%)) had returned to pre-diagnosis exercise levels at T3. At least one concern/symptom was reported by 74%, 59% and 64% participants at T1, T2 and T3 respectively. Fatigue was the most frequently reported symptom at T1(40%) and T2(49%), while issues with memory/concentration was the most frequently reported at T3(49%). SF-36 scores did not change in any domain over the study period, and scores remained lower than population norms in the domains of physical functioning, energy/vitality, role limitations due to physical problems and general health. Return-to-work rates are low, with 55% of participants returning to work in some capacity, and 31% of participants don’t feel back to full-health at 1-year following infection. Conclusion Hospitalised COVID-19 survivors report persistent symptoms, particularly fatigue and breathlessness, low HrQOL scores, sub-optimal exercise levels and continued work absenteeism 1-year following infection, despite some objective recovery of physical functioning. Further research is warranted to explore rehabilitation goals and strategies to optimise patient outcomes during recovery from COVID-19. Clinical message Hospitalised COVID-19 survivors report significant ongoing rehabilitation concerns 1-year following infection, despite objective recovery of physical functioning. Our findings suggest those who returned to exercise within 1-year may have less fatigue and breathlessness. The impact of exercise, and other rehabilitative strategies on physical functioning outcomes following COVID-19 should be investigated in future research.

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.

The immunological and inflammatory changes following acute COVID-19 are hugely variable. Persistent clinical symptoms following resolution of initial infection, termed , are also hugely variable, but association with immunological changes has not been described. We investigate changing immunological parameters in convalescent COVID-19 and interrogate their potential relationships with persistent symptoms. We performed paired immunophenotyping at initial SARS-CoV-2 infection and convalescence (n=40, median 68 days) and validated findings in 71 further patients at median 101 days convalescence. Results were compared to 40 pre-pandemic controls. Fatigue and exercise tolerance were assessed as cardinal features of using the Chalder Fatigue Scale and 6-minute-walk test. The relationships between these clinical outcomes and convalescent immunological results were investigated. We identify persistent expansion of intermediate monocytes, effector CD8+, activated CD4+ and CD8+ T cells, and reduced naïve CD4+ and CD8+ T cells at 68 days, with activated CD8+ T cells remaining increased at 101 days. Patients >60 years also demonstrate reduced naïve CD4+ and CD8+ T cells and expanded activated CD4+ T cells at 101 days. Ill-health, fatigue, and reduced exercise tolerance were common in this cohort. These symptoms were not associated with immune cell populations or circulating inflammatory cytokines. We demonstrate myeloid recovery but persistent T cell abnormalities in convalescent COVID-19 patients more than three months after initial infection. These changes are more marked with age and are independent of ongoing subjective ill-health, fatigue and reduced exercise tolerance.

Midlife Type 2 Diabetes Mellitus (T2DM) is associated with an increased risk of Alzheimer Disease (AD) in later life, with altered inflammatory responses postulated as key pathological drivers. Previous studies have demonstrated increased responsiveness to NLR family pyrin domain containing 3 (NLRP3) inflammasome agonists, both in individuals with untreated T2DM in addition to those with established AD. We hypothesised that peripheral NLRP3 inflammasome responses may be altered during the early stages of T2DM-related cognitive dysfunction. Here, we assessed the relationship between NLPR3 responses in peripheral blood mononuclear cells (including to Aβ-42, the putative pathogenic protein in AD) and neuropsychological performance in uncomplicated midlife T2DM to identify early signatures of immune dysregulation which may predispose to later cognitive decline. We recruited a cross-sectional cohort of middle-aged adults with uncomplicated T2DM and matched Healthy Controls (HCs) for comprehensive neuropsychological assessment and in vitro PBMC responses to a range of NLRP3 agonists were assessed. T2DM was associated with subtle decrements on neuropsychological tests of delayed memory and executive function (both p<0.05). Overall, there were no differences between T2DM and HCs in immune responses induced by NLRP3 agonists. Further, we observed no relationship between the subtle neuropsychological decrements observed in T2DM and PBMC responsiveness to NLRP3 agonists. Our data suggests that peripheral NLRP3 inflammasome response dysregulation may not play a role in the early stages of cognitive dysfunction in midlife T2DM. Further longitudinal studies are warranted to examine the contribution of peripheral NLRP3 responses towards disease pathology and as cognitive decline accelerates in T2DM.

Introduction Long Covid and other infection‐associated chronic condition communities have been integral in advocating for patient engagement in all stages of research, from design and conduct, and implementation, through to interpretation and knowledge translation; nevertheless, the process varies across research teams. In this paper, we (1) describe our process undertaking a community‐engaged Long Covid research study; (2) evaluate our community‐engaged approach, highlighting strengths and limitations with our process; and (3) identify recommendations for engaging in community‐engaged patient‐oriented research in Long Covid. Methods Guided by the 4PI (Principles; Purpose; Presence; Process; Impact) Framework and Patient‐Led Research Scorecards, we describe our community‐engaged approach within the Long COVID and Episodic Disability Study, followed by an evaluation of our community engagement using a multistage consultation with members of the Long COVID and Episodic Disability Study team. We conducted an online group‐based discussion among persons with lived experiences and administered a web‐based Scorecard questionnaire rating the collaboration as it relates to four domains of patient burden, governance, integration into the research process, and organisation readiness to all members of the team, to assess strengths and limitations of our approach. Scores ranged from −2 (non‐collaboration) to +2 (ideal collaboration). Results Ten team members, five of whom were persons with lived experiences, completed the Scorecard questionnaire. Median Scorecard scores ranged from +1 to +2 for all domains. Five team members with lived experiences, representing four community support groups and organisations that participated in the community‐engagement discussion. We describe the practices and principles that enabled meaningful community engagement, with the strengths and limitations of our approach embedded throughout. Conclusion Our community‐engaged approach to the Long COVID and Episodic Disability Study enhanced the quality and relevance of the study to the community while highlighting areas to heighten meaningful engagement throughout. This study builds on foundational community‐based research principles of patient‐oriented research. Recommendations derived from our experiences may be used by other research teams conducting community‐engaged patient‐oriented research. Patient or Public Contribution The Long COVID and Episodic Disability Study is a community‐engaged research study involving 25 members, including 12 persons living with long Covid, 13 researchers and 5 clinicians (categories are not mutually exclusive), referred to as the Full Team. Persons with lived experiences possessed a range of professional and personal experiences spanning research, clinical, policy and private sector/business contexts; team members wore multiple hats and perspectives which collectively strengthened the diversity of expertise, perspectives and insights to the team and process. Engagement of people with lived experiences with Long Covid ensured that the study was fully co‐created with people living with Long Covid. During the development of the study proposal, community partners from organisations in Canada, Ireland, the United Kingdom and the United States, who were linked to larger networks of people living with Long Covid, were purposefully invited to join the study team. Several Long Covid community networks and organisations, represented by persons living with Long Covid, were involved in all stages of the research, including: COVID Long‐Haulers Support Group Canada (S.G.); Long COVID Advocacy Ireland (I.O., S.O. and R.S.); Long COVID Ireland (N.R. and R.S.); Long COVID Physio (D.A.B. and C.T.); Long Covid Support UK (M.O.H.); and Patient‐Led Research Collaborative (L.M., N.M. and H.W.). These representatives along with the Co‐PIs (K.K.O. and D.A.B.) and co‐ordinator (K.M.) comprised the Core Long COVID and Episodic Disability Community Collaborator Team (Core Team). Team members with lived experiences were provided yearly remuneration for their time and expertise dedicated to the study, either as an individual, or to the community organisation which they represented on the study according to their preference.

Background In 2016, the Canada-International HIV and Rehabilitation Research Collaborative established a framework of research priorities in HIV, aging and rehabilitation. Our aim was to review and identify any new emerging priorities from the perspectives of people living with HIV, clinicians, researchers, and representatives from community organizations. Methods We conducted a multi-stakeholder international consultation with people living with HIV, researchers, clinicians and representatives of community-based organizations. Stakeholders convened for a one-day Forum in Manchester, United Kingdom (UK) to discuss research priorities via a web-based questionnaire and facilitated discussions. We analyzed data using conventional content analytical techniques and mapped emerging priorities onto the foundational framework. Results Thirty-five stakeholders from the UK(n = 29), Canada(n = 5) and Ireland(n = 1) attended the Forum, representing persons living with HIV or representatives from community-based organizations(n = 12;34%), researchers or academics(n = 10;28%), service providers(n = 6;17%), clinicians(n = 4;11%); and trainees(n = 4;11%). Five priorities mapped onto the Framework of Research Priorities across three content areas: A–Episodic Health and Disability Aging with HIV (disability, frailty, social participation), B-Rehabilitation Interventions for Healthy Aging across the Lifespan (role, implementation and impact of digital and web-based rehabilitation interventions) and C–Outcome Measurement in HIV and Aging (digital and web-based rehabilitation health technology to measure physical activity). Stakeholders indicated methodological considerations for implementing digital and web-based rehabilitation interventions into research and practice and the importance of knowledge transfer and exchange among the broader community. Conclusion Results highlight the sustained importance of the Framework of Research Priorities and provide further depth and areas of inquiry related to digital and web-based rehabilitation interventions and technology aging with HIV.

The prevention of SARS-CoV-2 acquisition and transmission among healthcare workers is an ongoing challenge. Vaccination has been introduced to mitigate these risks. Vaccine uptake varies among healthcare workers in the absence of vaccine mandates. We investigated engagement with SARS-CoV-2 vaccination among healthcare workers and identified characteristics associated with lower vaccine uptake. This multi-site cross-sectional study recruited n = 1260 healthcare workers in both clinical and non-clinical roles over a three-month period from November 2022. Participants reported their engagement with the primary SARS-CoV-2 vaccination programme and subsequent booster programmes, as well as providing demographic, occupational and personal medical history information. Multivariable linear regression identified characteristics associated with vaccine uptake. Engagement with vaccination programmes was high, with 88% of participants receiving at least one booster dose after primary vaccination course. Younger age and female sex were associated with reduced vaccine uptake. Healthcare workers in non-clinical roles also had reduced vaccine uptake. These findings should inform vaccination strategies across healthcare settings and target populations with reduced vaccine uptake directly, in particular young, female, and non-clinical healthcare workers, both for SARS-CoV-2 and other healthcare-associated vaccine-preventable infections.