Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact

Objective: To characterize the symptom profile and time course in patients with Long COVID, along with the impact on daily life, work, and return to baseline health. / Design: International web-based survey of suspected and confirmed COVID-19 cases with illness lasting over 28 days and onset prior to June 2020. / Setting: Survey distribution via online COVID-19 support groups and social media. / Participants: 3,762 respondents from 56 countries completed the survey. 1166 (33.7%) were 40-49 years old, 937 (27.1%) were 50-59 years old, and 905 (26.1%) were 30-39 years old. 2961 (78.9%) were women, 718 (19.1%) were men, and 63 (1.7%) were nonbinary. 8.4% reported being hospitalized. 27% reported receiving a laboratory-confirmed diagnosis of COVID-19. 96% reported symptoms beyond 90 days. / Results: Prevalence of 205 symptoms in 10 organ systems was estimated in this cohort, with 66 symptoms traced over seven months. Respondents experienced symptoms in an average of 9.08 (95% confidence interval 9.04 to 9.13) organ systems. The most frequent symptoms reported after month 6 were: fatigue (77.7%, 74.9% to 80.3%), post-exertional malaise (72.2%, 69.3% to 75.0%), and cognitive dysfunction (55.4%, 52.4% to 58.8%). These three symptoms were also the three most commonly reported overall. In those who recovered in less than 90 days, the average number of symptoms peaked at week 2 (11.4, 9.4 to 13.6), and in those who did not recover in 90 days, the average number of symptoms peaked at month 2 (17.2, 16.5 to 17.8). Respondents with symptoms over 6 months experienced an average of 13.8 (12.7 to 14.9) symptoms in month 7. 85.9% (84.8% to 87.0%) experienced relapses, with exercise, physical or mental activity, and stress as the main triggers. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 45.2% (42.9% to 47.2%) reported requiring a reduced work schedule compared to pre-illness and 22.3% (20.5% to 24.3%) were not working at the time of survey due to their health conditions. / Conclusions: Patients with Long COVID report prolonged multisystem involvement and significant disability. Most had not returned to previous levels of work by 6 months. Many patients are not recovered by 7 months, and continue to experience significant symptom burden

Characterizing long COVID in an international cohort: 7 months of symptoms and their impact

Background: A significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. Few systematic studies have investigated this population, particularly in outpatient settings. Hence, relatively little is known about symptom makeup and severity, expected clinical course, impact on daily functioning, and return to baseline health. // Methods: We conducted an online survey of people with suspected and confirmed COVID-19, distributed via COVID-19 support groups (e.g. Body Politic, Long COVID Support Group, Long Haul COVID Fighters) and social media (e.g. Twitter, Facebook). Data were collected from September 6, 2020 to November 25, 2020. We analyzed responses from 3762 participants with confirmed (diagnostic/antibody positive; 1020) or suspected (diagnostic/antibody negative or untested; 2742) COVID-19, from 56 countries, with illness lasting over 28 days and onset prior to June 2020. We estimated the prevalence of 203 symptoms in 10 organ systems and traced 66 symptoms over seven months. We measured the impact on life, work, and return to baseline health. // Findings: For the majority of respondents (>91%), the time to recovery exceeded 35 weeks. During their illness, participants experienced an average of 55.9+/- 25.5 (mean+/-STD) symptoms, across an average of 9.1 organ systems. The most frequent symptoms after month 6 were fatigue, post-exertional malaise, and cognitive dysfunction. Symptoms varied in their prevalence over time, and we identified three symptom clusters, each with a characteristic temporal profile. 85.9% of participants (95% CI, 84.8% to 87.0%) experienced relapses, primarily triggered by exercise, physical or mental activity, and stress. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 1700 respondents (45.2%) required a reduced work schedule compared to pre-illness, and an additional 839 (22.3%) were not working at the time of survey due to illness. Cognitive dysfunction or memory issues were common across all age groups (~88%). Except for loss of smell and taste, the prevalence and trajectory of all symptoms were similar between groups with confirmed and suspected COVID-19. // Interpretation: Patients with Long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden

A GPU-based real time trigger for rare kaon decays at NA62

Abstract This thesis reports a study for a new real-time trigger for the NA62 experiment based on Graphical Processing Units (GPUs). The NA62 experiment was devised to study with unprecedented precision the ultra-rare decay K+ → π+ ν anti-ν, a process mediated by Flavour-Changing Neutral Currents (FCNC) whose exceptional theoretical cleanliness provides a unique probe to test the Standard Model. The use of a high-rate kaon beam will result in an event rate of about 15 MHz, so high that it will be impossible to store data on disk without an efficient selection. The experiment therefore devised three trigger levels, allowing to reduce the data rate fed to the readout PC farm down to ∼10 kHz. For this thesis I developed an online trigger algorithm that uses data fed by the RICH (Ring Imaging CHerenkov counter) detector in real-time to allow a rejection of the dominant background K+ → π+ π 0 based on kinematical constraints. As a starting point for the development of this algorithm, I verified the feasibility of such a trigger through Montecarlo simulations. I measured the reconstruction resolution, achieved by the RICH detector alone, of the kinematical variables used for the event selection. After that, I analysed the background rejection power and the signal efficiency of several kinematical constraints, and I designed an actual trigger algorithm. The necessity of running the algorithm in real-time, with a maximum latency of 1 ms per event, drove the choice of exploiting the parallel computing power of GPUs. A parallelized algorithm was therefore developed, that can fit up to 4 Cherenkov rings per event. Moreover, a large number of events are processed concurrently. No parallelized and seedless multi-ring fitting algorithm existed before. The developed algorithm consists of a pattern recognition stage, to assign the hits to up to 4 ring candidates, and of a robust single-ring fit routine. The program was tested on GPUs, and its performance and execution latency proved to be compatible with the requirements. This work proves that alternative trigger designs are possible for the NA62 experiment, and represents a starting point for the introduction of flexible GPU-based real-time triggers in High Energy Physics. Sommario La mia tesi costituisce uno studio per un algoritmo di trigger in tempo reale basato su GPU (Graphical Processing Units) per l’esperimento NA62. NA62 è un esperimento progettato per misurare con precisione il decadimento ultra raro K+ → π+ ν anti-ν, un canale mediato da correnti neutre flavour-changing estremamente sensibile all’eventuale presenza di nuova fisica. L’elevato rate di eventi rivelati, dell’ordine di 15 MHz, non permetterà una archiviazione su disco dei dati non moderata da severi criteri di selezione. Sono perciò necessari dei livelli di trigger che consentano di ridurre il rate di eventi salvati fino a circa una decina di kHz. L’algoritmo sviluppato si basa sull’uso del rivelatore RICH (Ring Imaging CHerenkov counter). Le informazioni primitive inviate dal RICH vengono valutate in tempo reale, per produrre una decisione di trigger basata prevalentemente su considerazioni di cinematica. In una prima fase ho verificato, tramite simulazione Montecarlo, la fattibilità e significatività di tale progetto. Ho dapprima misurato la risoluzione sulla ricostruzione di alcune quantità cinematiche ricavate utilizzando unicamente il rivelatore RICH, poiché per un trigger di primo livello in tempo reale non sarà possibile mettere in relazione dati forniti da rivelatori diversi. Ho studiato poi fino a che livello fosse possibile separare il segnale dal fondo, misurando l’efficienza di reiezione e l’accettanza per il segnale al variare di alcuni parametri di selezione. Data la necessità di eseguire il programma in tempo reale, con una latenza massima di 1 ms per evento, si è deciso di sfruttare il potere computazionale parallelo proprio delle GPU (processori grafici ad elevato parallelismo). E’ stato quindi sviluppato un algoritmo in grado di eseguire simultaneamente non solo le istruzioni relative ad eventi diversi, ma anche i fit di fino a 4 anelli Cherenkov diversi appartenenti allo stesso evento. Nessun algoritmo parallelo e seedless di questo tipo esisteva in letteratura. L’algoritmo implementato è composto di due parti: una iniziale di riconoscimento di pattern, che estrae il numero di anelli presenti nella matrice ed identifica gli hit appartenenti a ciascuno di essi, ed una di fit dei singoli cerchi. Il programma è stato testato su GPU, ed efficienza e tempi di esecuzione risultano compatibili con le richieste. Questo lavoro apre la possibilità di implementare trigger alternativi e flessibili per NA62 e rappresenta un primo esempio prototipale dell’uso di GPU in tempo reale

Minimum sample size for external validation of a clinical prediction model with a binary outcome

In prediction model research, external validation is needed to examine an existing model's performance using data independent to that for model development. Current external validation studies often suffer from small sample sizes and consequently imprecise predictive performance estimates. To address this, we propose how to determine the minimum sample size needed for a new external validation study of a prediction model for a binary outcome. Our calculations aim to precisely estimate calibration (Observed/Expected and calibration slope), discrimination (C-statistic), and clinical utility (net benefit). For each measure, we propose closed-form and iterative solutions for calculating the minimum sample size required. These require specifying: (i) target SEs (confidence interval widths) for each estimate of interest, (ii) the anticipated outcome event proportion in the validation population, (iii) the prediction model's anticipated (mis)calibration and variance of linear predictor values in the validation population, and (iv) potential risk thresholds for clinical decision-making. The calculations can also be used to inform whether the sample size of an existing (already collected) dataset is adequate for external validation. We illustrate our proposal for external validation of a prediction model for mechanical heart valve failure with an expected outcome event proportion of 0.018. Calculations suggest at least 9835 participants (177 events) are required to precisely estimate the calibration and discrimination measures, with this number driven by the calibration slope criterion, which we anticipate will often be the case. Also, 6443 participants (116 events) are required to precisely estimate net benefit at a risk threshold of 8%. Software code is provided.</p

Terahertz underdamped vibrational motion governs protein-ligand binding in solution

Low-frequency collective vibrational modes in proteins have been proposed as being responsible for efficiently directing biochemical reactions and biological energy transport. However, evidence of the existence of delocalized vibrational modes is scarce and proof of their involvement in biological function absent. Here we apply extremely sensitive femtosecond optical Kerr-effect spectroscopy to study the depolarized Raman spectra of lysozyme and its complex with the inhibitor triacetylchitotriose in solution. Underdamped delocalized vibrational modes in the terahertz frequency domain are identified and shown to blue-shift and strengthen upon inhibitor binding. This demonstrates that the ligand-binding coordinate in proteins is underdamped and not simply solvent-controlled as previously assumed. The presence of such underdamped delocalized modes in proteins may have significant implications for the understanding of the efficiency of ligand binding and protein–molecule interactions, and has wider implications for biochemical reactivity and biological function

Dietary Supplementation with Soluble Plantain Non-Starch Polysaccharides Inhibits Intestinal Invasion of Salmonella Typhimurium in the Chicken

Soluble fibres (non-starch polysaccharides, NSP) from edible plants but particularly plantain banana (Musa spp.), have been shown in vitro and ex vivo to prevent various enteric pathogens from adhering to, or translocating across, the human intestinal epithelium, a property that we have termed contrabiotic. Here we report that dietary plantain fibre prevents invasion of the chicken intestinal mucosa by Salmonella. In vivo experiments were performed with chicks fed from hatch on a pellet diet containing soluble plantain NSP (0 to 200 mg/d) and orally infected with S.Typhimurium 4/74 at 8 d of age. Birds were sacrificed 3, 6 and 10 d post-infection. Bacteria were enumerated from liver, spleen and caecal contents. In vitro studies were performed using chicken caecal crypts and porcine intestinal epithelial cells infected with Salmonella enterica serovars following pre-treatment separately with soluble plantain NSP and acidic or neutral polysaccharide fractions of plantain NSP, each compared with saline vehicle. Bacterial adherence and invasion were assessed by gentamicin protection assay. In vivo dietary supplementation with plantain NSP 50 mg/d reduced invasion by S.Typhimurium, as reflected by viable bacterial counts from splenic tissue, by 98.9% (95% CI, 98.1–99.7; P<0.0001). In vitro studies confirmed that plantain NSP (5–10 mg/ml) inhibited adhesion of S.Typhimurium 4/74 to a porcine epithelial cell-line (73% mean inhibition (95% CI, 64–81); P<0.001) and to primary chick caecal crypts (82% mean inhibition (95% CI, 75–90); P<0.001). Adherence inhibition was shown to be mediated via an effect on the epithelial cells and Ussing chamber experiments with ex-vivo human ileal mucosa showed that this effect was associated with increased short circuit current but no change in electrical resistance. The inhibitory activity of plantain NSP lay mainly within the acidic/pectic (homogalacturonan-rich) component. Supplementation of chick feed with plantain NSP was well tolerated and shows promise as a simple approach for reducing invasive salmonellosis

Surface pretreatment for prolonged survival of cemented tibial prosthesis components: full- vs. surface-cementation technique

BACKGROUND: One of few persisting problems of cemented total knee arthroplasty (TKA) is aseptic loosening of tibial component due to degradation of the interface between bone cement and metallic tibial shaft component, particularly for surface cemented tibial components. Surface cementation technique has important clinical meaning in case of revision and for avoidance of stress shielding. Degradation of the interface between bone cement and bone may be a secondary effect due to excessive crack formation in bone cement starting at the opposite metallic surface. METHODS: This study was done to prove crack formation in the bone cement near the metallic surface when this is not coated. We propose a newly developed coating process by PVD layering with SiO(x )to avoid that crack formation in the bone cement. A biomechanical model for vibration fatigue test was done to simulate the physiological and biomechanical conditions of the human knee joint and to prove excessive crack formation. RESULTS: It was found that coated tibial components showed a highly significant reduction of cement cracking near the interface metal/bone cement (p < 0.01) and a significant reduction of gap formation in the interface metal-to-bone cement (p < 0.05). CONCLUSION: Coating dramatically reduces hydrolytic- and stress-related crack formation at the prosthesis interface metal/bone cement. This leads to a more homogenous load transfer into the cement mantle which should reduce the frequency of loosening in the interfaces metal/bone cement/bone. With surface coating of the tibial component it should become possible that surface cemented TKAs reveal similar loosening rates as TKAs both surface and stem cemented. This would be an important clinical advantage since it is believed that surface cementing reduces metaphyseal bone loss in case of revision and stress shielding for better bone health

Mapping oral health related quality of life to generic health state values

BACKGROUND: A summary utility index is useful for deriving quality-adjusted life years (QALY) for cost analyses or disability weights for burden of disease studies. However, many quality of life instruments provide descriptive profiles rather than a single utility index. Transforming quality of life instruments to a utility index could extend the use of quality of life instruments to costs analyses and burden of disease studies. The aims of the study were to map a specific oral health measure, the Oral Health Impact Profile to a generic health state measure, the EuroQol, in order to enable the estimation of health state values based on OHIP data. METHODS: Data were collected from patients treated by a random sample of South Australian dentists in 2001–02 using mailed self-complete questionnaires. Dentists recorded the diagnosis of dental conditions and provided patients with self-complete questionnaires to record the nature, severity and duration of symptoms using the EuroQol (EQ-5D) and 14-item version of the Oral Health Impact Profile (OHIP-14) instruments. Data were available from 375 patients (response rate = 72%). A random two-thirds sample of patients was used in tobit regressions of EQ-5D health state values estimated using OHIP-14 in a model with categories of OHIP responses as indicator variables and in a model with OHIP responses as continuous variables. Age and sex were included as covariates in both models. The remaining one-third sample of patients was used to test the models. RESULTS: The OHIP item 'painful aching in mouth' was significantly related to health state values in both models while 'life less satisfying' was also significant in the continuous model. Mean forecast errors relative to the mean observed health state value were higher when fitted to the categorical model (17.4%) compared to the continuous model (15.2%) (P < 0.05). CONCLUSION: The findings enable health state values to be derived from OHIP-14 scores for populations where utility has not or cannot be measured directly

Populist communication in the new media environment: a cross-regional comparative perspective

The changing terms of mediation place new demands, opportunities and risks on the performance of the political persona. Visibility has become a double-edged sword, leaving representatives vulnerable to exposure while new tools provide opportunities for emerging entrepreneurial actors. This double risk to elites’ mediated personas—exposure and challenge from entrepreneurs—renders their armour of authenticity dangerously fragile, which nourishes a public sense of being inefficaciously represented. It is this climate in which populism currently flourishes around the globe. Three primary criteria of mediated self-representation by politicians—visibility, authenticity and efficacy—form the focus of this paper: how do populists negotiate such demands in different democratic contexts, and wherein lies the symbiosis between populism and the new media environment suggested by the literature? To answer this, the paper compares two populist cases responding to different democratic contexts: UKIP, a right-wing party from an established democracy (UK), and the Economic Freedom Fighters (EFF), a left-wing party from a transitional democracy (South Africa). The objects of study are disruptive performances by these parties, which are considered emblematic manifestations of populist ideology as they establish a Manichaean relationship between the elite and populist actors who embody the people. The paper introduces disruption as a multi-faceted and significant analytical concept to explain the populist behaviour and strategies that underlie populist parties’ responses to the demands for visibility, authenticity and efficacy that the new media environment places upon political representatives. Using mixed methods with an interpretive focus, the paper paints a rich picture of the contexts, meanings and means of construction of populist performances

Impact of asthma on educational attainment in a socioeconomically deprived population: a study linking health, education and social care datasets

BACKGROUND: Asthma has the potential to adversely affect children's school examination performance, and hence longer term life chances. Asthma morbidity is especially high amongst UK ethnic minority children and those experiencing social adversity, populations which also have poor educational outcomes. We tested the hypothesis that asthma adversely affects performance in national school examinations in a large cohort from an area of ethnic diversity and social deprivation. METHODS AND FINDINGS: With a novel method (using patient and address-matching algorithms) we linked administrative and clinical data for 2002-2005 for children in east London aged 5-14 years to contemporaneous education and social care datasets. We modelled children's performance in school examinations in relation to socio-demographic and clinical variables. The dataset captured examination performance for 12,136 children who sat at least one national examination at Key Stages 1-3. For illustration, estimates are presented as percentage changes in Key Stage 2 results. Having asthma was associated with a 1.1% increase in examination scores (95%CI 0.4 to 1.7)%,p = 0.02. Worse scores were associated with Bangladeshi ethnicity -1.3%(-2.5 to -0.1)%,p = 0.03; special educational need -14.6%(-15.7 to -13.5)%,p = 0.02; mental health problems -2.5%(-4.1 to -0.9)%,p = 0.003, and social adversity: living in a smoking household -1.2(-1.7 to -0.6)%,p<0.001; living in social housing -0.8%(-1.3 to -0.2)% p = 0.01, and entitlement to free school meals -0.8%(-1.5 to -0.1)%,p<0.001. CONCLUSIONS: Social adversity and ethnicity, but not asthma, are associated with poorer performance in national school examinations. Policies to improve educational attainment in socially deprived areas should focus on these factors