Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID.

Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions. Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID. We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS. Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients. Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.

An integrative genomics approach identifies KDM4 as a modulator of trained immunity.

Innate immune cells are able to build memory characteristics via a process termed "trained immunity." Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro-induced trained immunity responses were assessed in two independent population-based cohorts of healthy individuals, the 300 Bacillus Calmette-Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta-analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K-Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec-5 and Siglec-14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions.

Feasibility study for supporting medication adherence for adults with cystic fibrosis: mixed-methods process evaluation.

OBJECTIVES: To undertake a process evaluation of an adherence support intervention for people with cystic fibrosis (PWCF), to assess its feasibility and acceptability. SETTING: Two UK cystic fibrosis (CF) units. PARTICIPANTS: Fourteen adult PWCF; three professionals delivering adherence support ('interventionists'); five multi-disciplinary CF team members. INTERVENTIONS: Nebuliser with data recording and transfer capability, linked to a software platform, and strategies to support adherence to nebulised treatments facilitated by interventionists over 5 months (± 1 month). PRIMARY AND SECONDARY MEASURES: Feasibility and acceptability of the intervention, assessed through semistructured interviews, questionnaires, fidelity assessments and click analytics. RESULTS: Interventionists were complimentary about the intervention and training. Key barriers to intervention feasibility and acceptability were identified. Interventionists had difficulty finding clinic space and time in normal working hours to conduct review visits. As a result, fewer than expected intervention visits were conducted and interviews indicated this may explain low adherence in some intervention arm participants. Adherence levels appeared to be >100% for some patients, due to inaccurate prescription data, particularly in patients with complex treatment regimens. Flatlines in adherence data at the start of the study were linked to device connectivity problems. Content and delivery quality fidelity were 100% and 60%-92%, respectively, indicating that interventionists needed to focus more on intervention 'active ingredients' during sessions. CONCLUSIONS: The process evaluation led to 14 key changes to intervention procedures to overcome barriers to intervention success. With the identified changes, it is feasible and acceptable to support medication adherence with this intervention. TRIAL REGISTRATION NUMBER: ISRCTN13076797; Results.

Is a definitive trial of prehospital continuous positive airway pressure versus standard oxygen therapy for acute respiratory failure indicated? The ACUTE pilot randomised controlled trial.

OBJECTIVES: To determine the feasibility of a large-scale definitive multicentre trial of prehospital continuous positive airway pressure (CPAP) in acute respiratory failure. DESIGN: A single-centre, open-label, individual patient randomised, controlled, external pilot trial. SETTING: A single UK Ambulance Service, between August 2017 and July 2018. PARTICIPANTS: Adults with respiratory distress and peripheral oxygen saturations below British Thoracic Society target levels despite controlled oxygen treatment. INTERVENTIONS: Patients were randomised to prehospital CPAP (O-Two system) versus standard oxygen therapy in a 1:1 ratio using simple randomisation. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility outcomes comprised recruitment rate, adherence to allocated treatment, retention and data completeness. The primary clinical outcome was 30-day mortality. RESULTS: 77 patients were enrolled (target 120), including 7 cases with a diagnosis where CPAP could be ineffective or harmful. CPAP was fully delivered in 74% (target 75%). There were no major protocol violations. Full data were available for all key outcomes (targets ≥90%). Overall 30-day mortality was 27.3%. Of these deceased patients, 14/21 (68%) either did not have a respiratory condition or had ceiling of treatment decisions implemented excluding hospital non-invasive ventilation and critical care. CONCLUSIONS: Recruitment rate was below target and feasibility was not demonstrated. Limited compliance with CPAP, and difficulty in identifying patients who could benefit from CPAP, indicate that prehospital CPAP is unlikely to materially reduce mortality. A definitive effectiveness trial of CPAP is therefore not recommended. TRIAL REGISTRATION NUMBER: ISRCTN12048261; Post-results.

The role of Toll-like receptor 10 in modulation of trained immunity.

Toll-like receptor 10 (TLR10) is the only member of the human Toll-like receptor family with an inhibitory function on the induction of innate immune responses and inflammation. However, its role in the modulation of trained immunity (innate immune memory) is unknown. In the present study, we assessed whether TLR10 modulates the induction of trained immunity induced by ß-glucan or bacillus Calmette-Guérin (BCG). Interleukin 10 receptor antagonist production was increased upon activation of TLR10 ex vivo after BCG vaccination, and TLR10 protein expression on monocytes was increased after BCG vaccination, whereas anti-TLR10 antibodies did not significantly modulate ß-glucan or BCG-induced trained immunity in vitro. A known immunomodulatory TLR10 missense single-nucleotide polymorphism (rs11096957) influenced trained immunity responses by ß-glucan or BCG in vitro. However, the in vivo induction of trained immunity by BCG vaccination was not influenced by TLR10 polymorphisms. In conclusion, TLR10 has a limited, non-essential impact on the induction of trained immunity in humans.

Supporting medication adherence for adults with cystic fibrosis: a randomised feasibility study.

BACKGROUND: Preventative medication reduces hospitalisations in people with cystic fibrosis (PWCF) but adherence is poor. We assessed the feasibility of a randomised controlled trial of a complex intervention, which combines display of real time adherence data and behaviour change techniques. METHODS: Design: Pilot, open-label, parallel-group RCT with concurrent semi-structured interviews. PARTICIPANTS: PWCF at two Cystic Fibrosis (CF) units. Eligible: aged 16 or older; on the CF registry. Ineligible: post-lung transplant or on the active list; unable to consent; using dry powder inhalers. INTERVENTIONS: Central randomisation on a 1:1 allocation to: (1) intervention, linking nebuliser use with data recording and transfer capability to a software platform, and behavioural strategies to support self-management delivered by trained interventionists (n = 32); or, (2) control, typically face-to-face meetings every 3 months with CF team (n = 32). OUTCOMES: RCT feasibility defined as: recruitment of ≥ 48 participants (75% of target) in four months (pilot primary outcome); valid exacerbation data available for ≥ 85% of those randomised (future RCT primary outcome); change in % medication adherence; FEV1 percent predicted (key secondaries in future RCT); and perceptions of trial procedures, in semi-structured interviews with intervention (n = 14) and control (n = 5) participants, interventionists (n = 3) and CF team members (n = 5). RESULTS: The pilot trial recruited to target, randomising 33 to intervention and 31 to control in the four-month period, June-September 2016. At study completion (30th April 2017), 60 (94%; Intervention = 32, Control =28) participants contributed good quality exacerbation data (intervention: 35 exacerbations; control: 25 exacerbation). The mean change in adherence and baseline-adjusted FEV1 percent predicted were higher in the intervention arm by 10% (95% CI: -5.2 to 25.2) and 5% (95% CI -2 to 12%) respectively. Five serious adverse events occurred, none related to the intervention. The mean change in adherence was 10% (95% CI: -5.2 to 25.2), greater in the intervention arm. Interventionists delivered insufficient numbers of review sessions due to concentration on participant recruitment. This left interventionists insufficient time for key intervention procedures. A total of 10 key changes that were made to RCT procedures are summarised. CONCLUSIONS: With improved research processes and lower monthly participant recruitment targets, a full-scale trial is feasible. TRIAL REGISTRATION: ISRCTN13076797 . Prospectively registered on 07/06/2016.

A pilot study of positive mood induction in euthymic bipolar subjects compared with healthy controls.

BACKGROUND: Demonstrating differences between euthymic bipolar subjects and healthy controls in response to positive (happy) mood induction may help elucidate how mania evolves. This pilot study evaluates the Go task in a reward paradigm as a method for inducing a happy mood state and compares the response of euthymic bipolar subjects and healthy controls. METHOD: The Sense of Hyperpositive Self Scale, the Tellegen positive and negative adjectives, the Global-Local task and a visual analogue scale for measuring positive affect were administered to 15 euthymic bipolar subjects and 19 age-and-sex-matched healthy control subjects before and after they had performed the Go task in a reward paradigm. RESULTS: Significant differences were found between subjects and controls on several measures at each time-point but there were no differences across the groups across time except for the visual analogue scales, where subjects had a more sustained duration in self-reported happiness compared with controls. CONCLUSIONS: This pilot study has shown that a positive affect can be induced in bipolar subjects and controls which can be demonstrated by changes in scores on several tasks. However, only the visual analogue scales showed a significant difference between cases and controls over time. Such tests may prove valuable in furthering understanding about the evolution of manic mood states.