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Abstract The radioisotope thorium-229 (229Th) is renowned for its extraordinarily low-energy, long-lived nuclear first-excited state. This isomeric state can be excited by vacuum ultraviolet (VUV) lasers and 229Th has been proposed as a reference transition for ultra-precise nuclear clocks. To assess the feasibility and performance of the nuclear clock concept, time-controlled excitation and depopulation of the 229Th isomer are imperative. Here we report the population of the 229Th isomeric state through resonant X-ray pumping and detection of the radiative decay in a VUV transparent 229Th-doped CaF2 crystal. The decay half-life is measured to 447(25) s, with a transition wavelength of 148.18(42) nm and a radiative decay fraction consistent with unity. Furthermore, we report a new “X-ray quenching” effect which allows to de-populate the isomer on demand and effectively reduce the half-life. Such controlled quenching can be used to significantly speed up the interrogation cycle in future nuclear clock schemes.

Abstract Background Mild hypoxic ischemic encephalopathy is associated with sub optimal cognition and learning difficulties at school age. Although whole-body hypothermia reduces death and disability after moderate or severe encephalopathy in high-income countries, the safety and efficacy of hypothermia in mild encephalopathy is not known. The cooling in mild encephalopathy (COMET) trial will examine if whole-body hypothermia improves cognitive development of neonates with mild encephalopathy. Methods The COMET trial is a phase III multicentre open label two-arm randomised controlled trial with masked outcome assessments. A total of 426 neonates with mild encephalopathy will be recruited from 50 to 60 NHS hospitals over 2 ½ years following parental consent. The neonates will be randomised to 72 h of whole-body hypothermia (33.5 ± 0.5 C) or normothermia (37.0 ± 0.5 C) within six hours or age. Prior to the recruitment front line clinical staff will be trained and certified on expanded modified Sarnat staging for encephalopathy. The neurological assessment of all screened and recruited cases will be video recorded and centrally assessed for quality assurance. If recruitment occurs at a non-cooling centre, neonates in both arms will be transferred to a cooling centre for continued care, after randomisation. All neonates will have continuous amplitude integrated electroencephalography (aEEG) at least for the first 48 h to monitor for seizures. Predefined safety outcomes will be documented, and data collected to assess resource utilization of health care. A central team masked to trial group allocation will assess neurodevelopmental outcomes at 2 years of age. The primary outcome is mean difference in composite cognitive scores on Bayley scales of Infant and Toddler development 4th Edition. Discussion The COMET trial will establish the safety and efficacy of whole-body hypothermia for mild hypoxic ischaemic encephalopathy and inform national and international guidelines in high income countries. It will also provide an economic assessment of whole-body hypothermia therapy for mild encephalopathy in the NHS on cost-effectiveness grounds. Trial registration number NCT05889507 June 5, 2023.

Abstract Objective To assess asymptomatic rates and severity of SARS‐CoV‐2 infection in people with epilepsy and their healthcare workers in a long‐term care facility which had implemented weekly surveillance testing between April 2020 and June 2022. Methods Questionnaires focused on objective and subjective COVID‐19 symptoms for people with epilepsy residing in and their healthcare workers at the Chalfont Centre for Epilepsy in June 2022. Demographic information, comorbidities, and seizure frequency were gathered from medical records. We also collected responses on objective and subjective COVID‐19 symptoms from healthcare workers who participated in a prospective study assessing the reaction to COVID‐19 vaccinations (SAFER). Results Fifty‐five out of 89 (62%) residents tested positive at least once on weekly PCR testing for SARS‐CoV‐2 during the period of interest; 20 of those (37%) were asymptomatic. In comparison, of those 63 healthcare workers who tested positive at least once on weekly testing during the same period, only four (6%) were asymptomatic. Of the 159 healthcare workers who also participated in the SAFER study, 41 tested positive at least once, and seven (17%) were completely asymptomatic during infection with SARS‐CoV‐2. Significance People with epilepsy living in a long‐term care facility were more likely to present with asymptomatic SARS‐CoV‐2 infections than healthcare workers at the same facility. Despite possible bias in the reporting of subjective symptoms due to management‐by‐proxy, there is no evidence that vulnerable people living in an epilepsy long‐term care facility showed reduced resilience towards infections. Plain Language Summary People with epilepsy living in care home facilities had a surprisingly high degree of asymptomatic infections with SARS‐CoV‐2. Very few residents had severe or fatal outcomes. This is in stark contrast to the widely reported bad outcomes for people without epilepsy in other care homes. People with epilepsy reported significantly less symptoms than their healthcare workers. No changes in seizure frequency during or after infection were observed.

ObjectiveWe hypothesized that the insulin-sensitizing adipokine adiponectin (ADP) is upregulated in cystic fibrosis (CF) related diabetes (CFRD) and underweight adults with CF. We aimed to assess correlations between glucose metabolism, body composition and ADP in CF.MethodsWe performed a cross-sectional study among adults with CF at the Copenhagen CF Center. The study included a fasting level of ADP, an oral glucose tolerance test (OGTT), and a dual energy-x-ray absorptiometry scan.ResultsIn total, 115 patients were included of whom 104 had an OGTT performed. Glucose intolerance was not correlated with ADP in multivariable analysis, while increased hepatic insulin resistance (i.e., HOMA-IR) was correlated with reduced ADP levels. ADP declined by 4% (eβ 0.96, 95% CI: 0.94, 0.98), 5% (eβ 0.95, 95% CI: 0.93, 0.98), 9% (eβ 0.91, 95% CI: 0.87, 0.95), and 83% (eβ 0.17, 95% CI: 0.08, 0.37) for each one unit (kg/m2) increase in body mass index, fat mass index, muscle mass index, and bone mineral content index, respectively.ConclusionsIn CF, ADP was negatively correlated with hepatic insulin resistance as well as low fat, muscle, and bone mass, but not with glucose intolerance. This suggests that malnutrition leads to higher ADP levels in CF.

Abstract Vibrio cholerae, a facultative human pathogen and causative agent of the severe diarrheal disease cholera, transits between the human intestinal tract and aquatic reservoirs. Like other bacterial species, V. cholerae continuously releases bacterial extracellular vesicles (BEVs) from its surface, which have been recently characterised for their role during in vivo colonisation. However, between epidemic outbreaks, V. cholerae persists in the biofilm mode for extended periods in aquatic reservoirs, which enhances environmental fitness and host transition. In this study, we investigated the effect of V. cholerae BEVs on biofilm formation, a critical feature for ex vivo survival. In contrast to BEVs from planktonic cultures, our results show that physiological concentrations of BEVs from dynamic biofilm cultures facilitate V. cholerae biofilm formation, which could be linked to a proteinaceous factor. Comparative proteomic analyses of planktonic‐ and biofilm‐derived BEVs identified a previously uncharacterised outer membrane protein as an abundant component of dynamic biofilm‐derived BEVs, which was found to be responsible for the BEV‐dependent enhancement of biofilm production. Consequently, this protein was named outer membrane‐associated biofilm facilitating protein A (ObfA). Comprehensive molecular studies unravelled ObfA as a negative modulator of HapR activity. HapR is a key transcriptional regulator of the V. cholerae quorum sensing (QS) cascade acting as a potent repressor of biofilm formation and virulence. Consistently, obfA mutants not only exhibited reduced biofilm production but also reduced colonisation fitness. Surprisingly, our results demonstrate that ObfA does not affect HapR through the canonical QS system but via the Csr‐cascade altering the expression of the small regulatory RNAs CsrC and CsrD. In summary, this study elucidates a novel intraspecies BEV‐based communication in V. cholerae that influences biofilm formation and colonisation fitness via a new regulatory pathway involving HapR, Csr‐cascade and the BEV‐associated protein ObfA.

Abstract Objective To evaluate the pharmacokinetics (PK), safety, and tolerability of brivaracetam (BRV) in neonates with repeated electroencephalographic seizures not controlled with previous antiseizure medications (ASMs). Methods Phase 2/3, multicenter, open‐label, single‐arm study (N01349/NCT03325439) in neonates with repeated electroencephalographic seizures (lasting ≥10 s) confirmed by video‐electroencephalography, and inadequate seizure control with at least one ASM. A screening period (up to 36 h) was followed by a 48‐h evaluation period during which patients received 0.5 mg/kg BRV twice daily (b.i.d) intravenously (IV). Patients who benefitted from BRV (investigator's opinion) could continue 0.5 mg/kg b.i.d (IV or oral solution) in an extension period. Outcomes included plasma concentrations of BRV following the first dose (primary), and incidence of treatment‐emergent adverse events (TEAEs). Results Six patients (median [range] postnatal age: 1.5 [1.0, 6.0] days) received ≥1 dose of BRV. All six patients completed the evaluation period; two entered and completed the extension period. Overall (evaluation and extension periods), three patients received one dose of 0.5 mg/kg BRV and three received more than one dose. The median (range) duration of exposure to BRV (IV and oral solution) was 1.5 (1.0, 29.0) days (n = 6). At 0.5–1, 2–4, and 8–12 h following IV BRV administration, the GeoMean (GeoCV) plasma concentrations of BRV were 0.53 mg/L (15.40% [n = 5]), 0.50 mg/L (28.20% [n = 6]), and 0.34 mg/L (13.20% [n = 5]), respectively. Individual and population BRV PK profiles were estimated, and individual PK parameters were calculated using Bayesian feedback. The observed concentrations were consistent with the predicted PK. Three patients experienced four TEAEs, none of which were considered related to BRV. Significance BRV plasma concentrations in neonates were consistent with data in older children receiving BRV oral solution, and with data from adults receiving a nominal IV dose of 25 mg b.i.d. BRV was well tolerated, with no drug‐related TEAEs reported. Plain Language Summary Few drugs are available to treat seizures in newborn babies. Brivaracetam is approved to treat focal‐onset seizures in children and adults in Europe (patients 2 years of age and older) and the United States (patients 1 month of age or older). In this study, six newborns with repeated seizures were treated with intravenous brivaracetam. The study doctors took samples of blood from the newborns and measured the levels of brivaracetam. The concentrations of brivaracetam in the newborns’ blood plasma were consistent with data from studies in older children and in adults. No brivaracetam‐related medical problems were reported.

Abstract Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. Methods In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. Discussion Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. Trial registration Registration Number: NCT05710770 . Registered on 02 February 2023.

BACKGROUND: Depressive symptoms, brain-derived neurotrophic factor (BDNF) Val66Met, and apolipoprotein (APOE)-ε4 may moderate response to computerized cognitive training (CCT) interventions among patients with heart failure (HF). OBJECTIVES: The purpose of this study was to examine moderators of intervention response to CCT over 8 months among patients with HF enrolled in a 3-arm randomized controlled trial. Outcomes were memory, serum BDNF, working memory, instrumental activities of daily living (IADLs), and health-related quality of life (HRQL). METHODS: 256 patients with HF were randomized to CCT, computerized crossword puzzles active control, and usual care control groups for 8 weeks. Data were collected at enrollment, baseline, 10 weeks, and 4 and 8 months. Mixed effects models were computed to evaluate moderators. RESULTS: As previously reported, there were no statistically significant group by time effects in outcomes among the 3 groups over 8 months. Tests of moderation indicated that depressive symptoms and presence of BDNF Val66Met and APOE-ε4 were not statistically significant moderators of intervention response in outcomes of delayed recall memory, serum BDNF, working memory, IADLs, and HRQL. In post hoc analysis evaluating baseline global cognitive function, gender, age, and HF severity as moderators, no significant effects were found. HF severity was imbalanced among groups (P = .049) which may have influenced results. CONCLUSIONS: Studies are needed to elucidate biological mechanisms of cognitive dysfunction in HF and test novel interventions to improve memory, serum BDNF, working memory, IADLs and HRQL. Patients may need to be stratified or randomized by HF severity within intervention trials.

Objectives Lung disease progression in people with cystic fibrosis (pwCF) varies from one individual to another. Different immunological characteristics have been suggested to explain this variation, and we hypothesised that lung capacity may be associated with the innate immune response in pwCF. In an exploratory study, we aimed to investigate potential links between the innate immune response and lung function in pwCF using the standardised immune function assay TruCulture. Methods In a single-centre study with combined cross-sectional and longitudinal data before and after intravenous antibiotics, blood was sampled from Pseudomonas aeruginosa-infected pwCF. Whole blood was analysed by TruCulture to reveal the unstimulated and stimulated cytokine release. Tobit regressions and Spearman's correlations were used to estimate the associations between lung function and cytokine release. Results We included 52 pwCF in the cross-sectional study and 24 in the longitudinal study. In the cross-sectional study, we found that compared to a healthy population, the release of toll-like receptor (TLR)3, TLR4- and TLR7/8-stimulated interferon-γ, and interleukin (IL)-12p40 was reduced. Although TLR3-stimulated IL-1β and IL-6 release increased with lung function, overall, cytokine release did not correlate well with lung function. In the longitudinal study, the cytokine release was modified by antibiotic treatment, but the cytokine release before antibiotic treatment did not associate with changes in lung function after treatment. Conclusion The stimulated cytokine release could not predict lung function levels or changes in pwCF, but our data indicate that pwCF experience exhaustion in the innate immune response after years of chronic bacterial infection.

In Spring 2023, I worked with 24 Ball State University students enrolled in HIST 240: 'Introduction to Public History' to practice oral history methods. Ball State is a R2 public [...]

Abstract The COVID-19 pandemic, triggered by severe acute respiratory syndrome coronavirus 2, has affected millions of people worldwide. Much research has been dedicated to our understanding of COVID-19 disease heterogeneity and severity, but less is known about recovery associated changes. To address this gap in knowledge, we quantified the proteome from serum samples from 29 COVID-19 convalescents and 29 age-, race-, and sex-matched healthy controls. Samples were acquired within the first months of the pandemic. Many proteins from pathways known to change during acute COVID-19 illness, such as from the complement cascade, coagulation system, inflammation and adaptive immune system, had returned to levels seen in healthy controls. In comparison, we identified 22 and 15 proteins with significantly elevated and lowered levels, respectively, amongst COVID-19 convalescents compared to healthy controls. Some of the changes were similar to those observed for the acute phase of the disease, i.e. elevated levels of proteins from hemolysis, the adaptive immune systems, and inflammation. In contrast, some alterations opposed those in the acute phase, e.g. elevated levels of CETP and APOA1 which function in lipid/cholesterol metabolism, and decreased levels of proteins from the complement cascade (e.g. C1R, C1S, and VWF), the coagulation system (e.g. THBS1 and VWF), and the regulation of the actin cytoskeleton (e.g. PFN1 and CFL1) amongst COVID-19 convalescents. We speculate that some of these shifts might originate from a transient decrease in platelet counts upon recovery from the disease. Finally, we observed race-specific changes, e.g. with respect to immunoglobulins and proteins related to cholesterol metabolism.

BackgroundMetabolic syndrome (MetS) is defined by the presence of central obesity plus ≥two metabolic/cardiovascular risk factors (RF), with inflammation being a major disease-driving mechanism. Structured endurance exercise training (ET) may positively affect these traits, as well as cardiorespiratory fitness (V̇O2peak).AimsWe explore individual ET-mediated improvements of MetS-associated RF in relation to improvements in V̇O2peak and inflammatory profile.MethodsMetS patients from two randomized controlled trials, ExMET (n = 24) and OptimEx (n = 34), had performed 4- or 3-months supervised ET programs according to the respective trial protocol. V̇O2peak, MetS-defining RFs (both RCTs), broad blood leukocyte profile, cytokines and plasma proteins (ExMET only) were assessed at baseline and follow-up. Intra-individual changes in RFs were analysed for both trials separately using non-parametric approaches. Associations between changes in each RF over the exercise period (n-fold of baseline values) were correlated using a non-parametrical approach (Spearman). RF clustering was explored by uniform manifold approximation and projection (UMAP) and changes in RF depending on other RF or exercise parameters were explored by recursive partitioning.ResultsFour months of ET reduced circulating leukocyte counts (63.5% of baseline, P = 8.0e-6), especially effector subtypes. ET response of MetS-associated RFs differed depending on patients’ individual RF constellation, but was not associated with individual change in V̇O2peak. Blood pressure lowering depended on cumulative exercise duration (ExMET: ≥102 min per week; OptimEx-MetS: ≥38 min per session) and baseline triglyceride levels (ExMET: