Research Ltd Research Articles

Investigating Skeletal Muscle Pump Function Using Thigh EMG, Thigh NIRS, And Stroke Volume Data In The FRAILMatics Physiological Cohort

Abstract Background The pioneering female physiologist Frances Hellebrandt first highlighted the significance of the skeletal muscle pump in circulation in the 1930s. However, the mechanisms underlying the muscle pump's function remain elusive, particularly in older individuals. It is thought that during muscle contraction, increased intramuscular pressure facilitates the expulsion of blood from the muscle's veins, aiding venous return. This contraction-induced pressure gradient assists in pushing blood towards the heart, increasing preload, and subsequently stroke volume (SV). In this study we investigated muscle pump activity using continuous measurements of thigh muscle activity, thigh total haemoglobin concentration (Hb), and cardiac SV. Methods 22 individuals (aged 70.8±5.3 years, 77.3% female) recruited from a Falls and Syncope Unit (St James’s Hospital, Dublin) underwent non-invasive measurements of Hb (NIRS PortaLite, Artinis Medical Systems, The Netherlands), electromyography (EMG) (Shimmer3, Research Ltd, Ireland), and SV (Finapres Nova, Finapres Medical Systems, The Netherlands) during a 10-second thigh squeeze test. Pre-processing involved data quality checks, alignment, and resampling. 60-second regions of interest were extracted, normalised, and processed using MATLAB (R2023a, TheMathWorks, Inc., Natick, MA, USA). Cross-correlation and Granger causality analyses were conducted to explore relationships between signals. Results Thigh Hb and EMG signals lagged 8.4 and 8.5 seconds behind SV, respectively. Granger Causality analysis revealed a significant causal relationship from both Hb and EMG to SV in 68% of participants at measured lags. Conclusion The observed ~8.5-second lag between thigh measurements and SV implies a plausible temporal relationship between muscle activation and venous return, further supported by significant causal relationships found in a substantial portion of participants using Granger causality analysis. These findings underscore the importance of continued research in this area, not only for advancing our understanding of physiological mechanisms but also for informing potential clinical applications aimed at optimising cardiovascular health and function.

Effect of nicotine mouth spray on urges to vape: A randomized, placebo-controlled, pharmacodynamic clinical trial in exclusive e-cigarette users.

To determine whether nicotine mouth spray provides rapid and prolonged relief of urges to vape and measure the steady-state plasma nicotine levels during vaping and ad libitum mouth spray usage in e-cigarette users. Randomized, parallel group, double-blind trial. Single site at Hammersmith Medicines Research Ltd (HMR), London, UK. 216 (25.9% females, average age 27.6±7.63 [standard deviation, SD]) exclusive vapers who used their e-cigarette within 30 minutes of waking up and had vaped about 2years on average. Two sprays of 1mg nicotine mouth spray (Nicorette QuickMist Freshmint, n = 109), or placebo (identical in appearance and presentation, n = 107). Urge to vape was rated on a 100 mm visual analogue scale before and repeatedly for 2hours after administration. The primary outcome measured average change from baseline in urges to vape ratings during the first hour. Nicotine mouth spray achieved statistically significantly greater reductions in urges to vape than placebo from the first assessment point at 30 seconds to 1hour, when the estimated mean treatment difference was 11.90 mm (95% confidence interval [CI] = 6.86-16.95, P < 0.001). The integrated urge to vape over 11 hours ad libitum usage showed a statistically significant benefit compared with placebo (2.00 [0.88 SD] vs 2.51 [0.84 SD], P< 0.001). Mean steady-state plasma nicotine concentrations were lower after nicotine mouth spray usage compared with vaping (6.22 [4.70 SD] ng/ml vs 9.91 [7.59 SD] ng/ml, respectively). Adverse events were more commonly reported in the nicotine mouth spray group and were mostly mild. Among regular e-cigarette users, nicotine mouth spray provided statistically significant and fast relief of urges to vape one hour after dosing. Nicotine mouth spray showed statistically significant reductions in urges to vape as soon as 30 seconds and up to 2hours after dosing compared with placebo, and nicotine mouth spray was well-tolerated and safe.

Comparing silent reading performance for single sentences and paragraphs: an eye movement-based analysis

ABSTRACT Clinical relevance Reading performance in clinical practice is commonly evaluated by reading ‘aloud’ and ‘as fast as possible’ single sentences. Assessing comprehensive silent reading performance using passages, composed of multiple sentences, is the preferred reading mode in real-life reading conditions. Background The purpose of this study was to compare eye movement-based silent reading performance for standardised short sentences and paragraphs. Methods A group of 15 young volunteers (age range: 22–36 years) read silently and comprehensively in two sessions: (a) a paragraph with continuous text and (b) standardised short sentences. Text print size was 0.4 logMAR (1.0 M at 40 cm distance). Eye movements during reading were recorded using video oculography (EyeLink II, SR Research Ltd). Data analysis included computation of reading speed, fixation duration, the number of fixations, saccadic amplitude and percentage of regressions. Moreover, frequency distributions of fixation durations were analysed with ex-Gaussian fittings. Results Repeatability coefficient in silent reading speed was found better for the paragraph (66 wpm) than for short sentences (88 wpm). The superiority in repeatability coefficient for the corresponding eye movement parameters, i.e. fixation duration (35 vs 73 ms), regressions (10.1 vs. 22.3%) and fixations per word (0.21 vs. 0.37 fpw), was even more pronounced. In addition, a statistically significant improvement with the paragraph was found in average fixation duration (19 ± 26 ms, p = 0.02), regressions (4.2 ± 7.0%, p = 0.04) and ex-Gaussian fixation parameter, τ (82 vs. 111 ms). No statistically significant difference was found between average reading speed with the paragraph (220 ± 59 wpm) and the short sentences (206 ± 57 wpm) (p = 0.11). Discussion Due to their superior repeatability, paragraphs are preferable to short sentences when evaluating silent comprehensive reading. The concurrent recording of eye movement parameters in silent reading further improves variability and could offer an efficient measure of reading performance and a reliable biomarker of visuo-motor function.

Surface roughness and microhardness of enamel white spot lesions treated with different treatment methods

ObjectiveTo analyse the surface roughness and microhardness of artificial enamel white spot lesions before and after WSL formation, after treatment (Opalsutre™ microabrasion, Sylc® bioactive glass, and ICON® resin infiltration), and after pH cycling with the help of the profilometer surface roughness tester and the digital Vickers microhardness tester. Materials and methodsSeventy-five extracted molars were used to acquire one hundred specimens. 50 specimens were randomly assigned to five groups (n = 10) for the surface roughness study: 1) Sound group, 2) WSL group, 3) micro abrasion (MA; Opalustre, Ultradent, South Jordan, UT, USA), 4) bioactive glass 45S5 Sylc powder (Sylc; Denfotex Research Ltd, Inverkeithing, UK), and 5) ICON resin infiltration (ICON; DMG, Hamburg, Germany). An additional 25 specimens were used to obtain 50 enamel slabs for the surface microhardness study, which were also assigned to the same groups. All groups underwent a final stage of pH cycling. Surface roughness and surface microhardness measurements were performed at different stages for all groups. ResultsRegarding surface roughness, ICON significantly reduced the surface roughness compared to Opalustre and Sylc, with no significant difference between Opalustre and Sylc. In terms of surface microhardness, ICON showed the highest improvement, followed by Sylc and then Opalustre. Both surface roughness and microhardness were significantly affected by demineralization, partially improved after treatment, and then regressed significantly after pH cycling. ConclusionICON resin infiltrant can be considered as a superior treatment option for improving surface roughness and microhardness, while Opalustre demonstrated relatively the poorest performance compared to the other treatment options. It is noteworthy that the pH cycling procedure had an adverse impact irrespective of the treatment option used.

1218-P: All-Cause Mortality in Individuals Aged 65+ Years with Type 2 Diabetes With and Without Frailty—Clinical Utility of Electronic Frailty Index to Individualise HbA1c Targets

Frailty and type 2 diabetes (T2D) is fast becoming a clinical challenge especially in the elderly population. Despite clear guidance on the need to evaluate individualised HbA1c targets in connection with frailty status with mortality risk, there is a lack of formal evidence on these associations. To guide healthcare professionals in setting appropriate HbA1c targets, this study aimed to investigate the association between mortality in connection with electronic frailty index (eFI) and HbA1c, as well as exploring the clinical utility of eFI as a tool to individualise HbA1c targets in frail patients with T2D. Methods: We included patients with T2D aged 65+ within UK primary care electronic database (the Clinical Practice Research Datalink) and Hospital Episode Statistics from 2014-19. All-cause mortality (ACM) risk associated with 4 frailty groups (non-frail; mild; moderate and severe) (defined by electronic frailty index scores, eFI) and seven HbA1c groups at 1.0% intervals were assessed using multivariate Cox regression analysis adjusted for demographic and clinical characteristics. The reference group was defined as “non-frail” individuals with HbA1c 6.5-7.5%. Results: 179,723 individuals (mean±SD; age 74.8±7.6years, diabetes duration 7.3±6.1years, HbA1c 55.7±15.8mmol/mol) were followed for mean 1.7 years. Within all frailty groups, the risk of ACM was greatest at HbA1c&amp;lt;5.5%, with highest risk observed in moderate (HR 3.34; 95%CI 2.80, 3.99) and severe frailty (HR 3.27; 95%CI 2.73, 3.91) groups. In all groups, ACM risk increased with higher HbA1c levels compared to HbA1c 6.5-7.5% (a “U-shaped” curve). Conclusion: Both high and low HbA1c levels increase the risk of ACM for people 65+ with T2D and frailty in a “U-shaped” association between HbA1c and ACM. This study supports eFI as a useful tool to facilitate HbA1c target setting in older patients with T2D and to manage ACM risk. Disclosure T.S.J.Crabtree: Speaker's Bureau; Abbott Diabetes, Novo Nordisk, Lilly, Sanofi, Insulet Corporation. Y.Vinogradova: None. R.Aldafas: None. J.Gordon: Employee; Health Economics and Outcomes Research Ltd. I.R.Idris: None.

Presbyopia correction with multifocal contact lenses: Evaluation of silent reading performance using eye movements analysis

PurposeMany activities of daily living rely on reading, thus is not surprising that complaints from presbyopes originate in reading difficulties rather in visual acuity. Here, the effectiveness of presbyopia correction with multifocal contact lenses (CLs) is evaluated using an eye-fixation based method of silent reading performance. ΜethodsVisual performance of thirty presbyopic volunteers (age: 50 ± 5 yrs) was assessed monocularly and binocularly following 15 days of wear of monthly disposable CLs (AIR OPTIX™ plus HydraGlyde™, Alcon Laboratories) with: (a) single vision (SV) lenses – uncorrected for near (b) aspheric multifocal (MF) CLs. LogMAR acuity was measured with ETDRS charts. Reading performance was evaluated using standard IReST paragraphs displayed on a screen (0.4 logMAR print size at 40 cm distance). Eye movements were monitored with an infrared eyetracker (Eye-Link II, SR Research Ltd). Data analysis included computation of reading speed, fixation duration, fixations per word and percentage of regressions. ResultsAverage reading speed was 250 ± 68 and 235 ± 70 wpm, binocularly and monocularly, with SV CLs, improving statistically significantly to 280 ± 67 (p = 0.002) and 260 ± 59 wpm (p = 0.01), respectively, with MF CLs. Moreover, fixation duration, fixations per word and ex-Gaussian parameter of fixation duration, μ, showed a statistically significant improvement when reading with MF CLs, with fixation duration exhibiting the stronger correlation (r = 0.79, p < 0.001) with improvement in reading speed. The correlation between improvement in VA and reading speed was moderate (r = 0.46, p = 0.016), as was the correlation between VA and any eye fixation parameter. ConclusionAverage silent reading speed in a presbyopic population was found improved with MF compared to SV CL correction and was faster with binocular compared to monocular viewing: this was mainly due to the faster average fixation duration and the lower number of fixations. Evaluating reading performance using eye fixation analysis could offer a reliable outcome of functional vision in presbyopia correction.

Pharmacokinetic and Pharmacodynamic Comparison of Fluticasone Propionate/Formoterol Fumarate Administered via a Pressurized Metered-Dose Inhaler and a Novel Breath-Actuated Inhaler in Healthy Volunteers.

Introduction: Fluticasone propionate/formoterol fumarate (fluticasone/formoterol) exposures, following administration of Flutiform® K-haler®, a breath-actuated inhaler (BAI), were compared with the Flutiform pressurized metered-dose inhaler (pMDI) with/without spacer in two healthy volunteer studies. In addition, formoterol-induced systemic pharmacodynamic (PD) effects were examined in the second study. Methods: Study 1: single-dose, three-period, crossover pharmacokinetic (PK) study with oral charcoal administration. Fluticasone/formoterol 250/10 μg was administered via BAI, pMDI, or pMDI with spacer (pMDI+S). Pulmonary exposure for BAI was deemed no less than for pMDI (primary comparator) if the lower limit of 94.12% confidence intervals (CIs) for BAI:pMDI maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUCt) ratios was ≥80%. Study 2: two-stage adaptive design, both stages being single-dose, crossover without charcoal administration. The PK stage compared fluticasone/formoterol 250/10 μg via BAI, pMDI, or pMDI+S. The primary comparisons were as follows: BAI versus pMDI+S for fluticasone and BAI versus pMDI for formoterol. Systemic safety with BAI was deemed no worse than primary comparator if the upper limit of 94.12% CIs for Cmax and AUCt ratios was ≤125%. PD assessment was to be conducted if BAI safety was not confirmed in the PK stage. Based on PK results, only formoterol PD effects were evaluated. The PD stage compared fluticasone/formoterol 1500/60 μg via BAI, pMDI, or pMDI+S; fluticasone/formoterol 500/20 μg pMDI; and formoterol 60 μg pMDI. The primary endpoint was maximum reduction in serum potassium within 4 hours postdose. Equivalence was defined as 95% CIs for BAI versus pMDI+S and pMDI ratios within 0.5-2.0. Results: Study 1: lower limit of 94.12% CIs for BAI:pMDI ratios >80%. Study 2, PK stage: upper limit of 94.12% CIs for fluticasone (BAI:pMDI+S) ratios <125%; upper limit of 94.12% CIs for formoterol (BAI:pMDI) ratios >125% (for Cmax, not AUCt). Study 2, PD stage: 95% CIs for serum potassium ratios 0.7-1.3 (BAI:pMDI+S) and 0.4-1.5 (BAI:pMDI). Conclusions: Fluticasone/formoterol BAI performance was within the range observed for the pMDI with/without a spacer. Sponsor: Mundipharma Research Ltd. EudraCT 2012-003728-19 (Study 1) and 2013-000045-39 (Study 2).

Bayesian penalized likelihood PET reconstruction impact on quantitative metrics in diffuse large B-cell lymphoma.

Evaluate the quantitative, subjective (Deauville score [DS]) and reader agreement differences between standard ordered subset expectation maximization (OSEM) and Bayesian penalized likelihood (BPL) positron emission tomography (PET) reconstruction methods. A retrospective review of 104 F-18 fluorodeoxyglucose PET/computed tomography (CT) exams among 52 patients with diffuse large B-cell lymphoma. An unblinded radiologist moderator reviewed both BPL and OSEM PET/CT exams. Four blinded radiologists then reviewed the annotated cases to provide a visual DS for each annotated lesion. Significant (P < .001) differences in BPL and OSEM PET methods were identified with greater standard uptake value (SUV) maximum and SUV mean for BPL. The DS was altered in 25% of cases when BPL and OSEM were reviewed by the same radiologist. Interobserver DS agreement was higher for OSEM (>1 cm lesion = 0.89 and ≤1 cm lesion = 0.84) compared to BPL (>1 cm lesion = 0.85 and ≤1 cm lesion = 0.81). Among the 4 readers, average intraobserver visual DS agreement between OSEM and BPL was 0.67 for lesions >1cm and 0.4 for lesions ≤1 cm. F-18 Fluorodeoxyglucose PET/CT of diffuse large B-cell lymphoma reconstructed with BPL has higher SUV values, altered DSs and reader agreement when compared to OSEM. This report finds volumetric PET measurements such as metabolic tumor volume to be similar between BPL and OSEM PET reconstructions. Efforts such as adoption of European Association Research Ltd accreditation should be made to harmonize PET data with an aim at balancing the need for harmonization and sensitivity for lesion detection.

A comparative study of shear bond strength of four different light cure orthodontic adhesives: An in vitro study

To compare the shear bond strength and Adhesive Remnent Index (ARI) of metal brackets using four different bonding systems: Heliosit Orthodontic Bonding Material (Ivoclar Vivadent), Ormco Enlight Light Cure Adhesive, Transbond XT Light Cure Adhesive (3M UNITEK) and Light cured Orthofix (Anabond Stedman Pharma Research (P) Ltd. In the present study 120 extracted sound human upper bicuspids were taken and divided into four groups. Group 1: Heliosit Orthodontic Bonding Material (Ivoclar Vivadent), Group 2 : Ormco Enlight Light Cure Adhesive ,Group 3: Transbond XT Light Cure Adhesive(3M UNITEK) and Group 4: Light cured Orthofix (Anabond Stedman Pharma Research (P) Ltd. In all the groups (n = 120) orthodontic metal brackets were bonded with the four different light cure adhesives respectively and all the samples were evaluated for shear bond strength using Instron(3366) universal testing machine at a cross speed of 1 mm/min. The bracket failure mode was examined using Adhesive Remnant Index (ARI). The Inter group comparison (&amp;#62;2 groups) was done using one way ANOVA followed by pair wise comparison using post hoc test. Comparison of frequencies of categories of variables with groups was done using Chi square test. For all the statistical tests, p&amp;#60;0.05 was considered to be statistically significant, keeping α error at 5% and β error at 20%, thus giving a power to the study as 80%.: It was concluded that the mean shear bond strength of the Transbond XT was highest among the four adhesives studied. However all the adhesives tested exhibits adequate bond strength for clinical use and ARI scores was nearly same for the Transbond and Enlight adhesives studied.

Effect of light-emitting photobiomodulation therapy on the rate of orthodontic tooth movement : Arandomized controlled clinical trial.

The aim of this study was to evaluate the effect of light-emitting photobiomodulation therapy (LPT) on the rate of canine distalization. This study was performed on 60extraction spaces formed by extraction of the upper first premolars of 30patients (15 in the LPT group and 15in the control group). Paul Gjessing (PG)-segmented canine retraction springs were used for canine distalization. In the LPT group, the Biolux OrthoPulse™ (Biolux Research Ltd, Vancouver, Canada) intraoral device (wavelength 850 nm LED light and an energy density of 63 mW/cm2 [±13 mW/cm2]) was used for 5min per day over a period of 84days. For each patient, the diagnosis was based on standard orthodontic documentation with photographs, digital model casts, and cephalometric and panoramic radiographs. The anchorage loss, canine rotations, canine inclinations, and molar inclinations were also evaluated on plaster models obtained on days 0, 21, 42, 63, and 84. The models were measured by using 3Shape OrthoAnalyzer software (3Shape, Copenhagen, Denmark). Measurements were made by a researcher and a blinded clinician. For statistical comparison, a paired-samples t‑test and one-way analysis of variance (ANOVA) were used at the p < 0.05 level. The mean canine distalization rates were 1.36 mm/21days and 1.02 mm/21days in the LPT and control groups, respectively, and were statistically greater in the LPT group (p < 0.001). The amount of anchorage loss, canine rotations, canine inclinations and molar inclinations were not significantly different between the LPT and control groups at any of the timepoints. LPT has the potential to accelerate orthodontic tooth movement by 33%.

Artificial intelligence-based PET denoising could allow a two-fold reduction in [18F]FDG PET acquisition time in digital PET/CT

PurposeWe investigated whether artificial intelligence (AI)-based denoising halves PET acquisition time in digital PET/CT.MethodsOne hundred ninety-five patients referred for [18F]FDG PET/CT were prospectively included. Body PET acquisitions were performed in list mode. Original “PET90” (90 s/bed position) was compared to reconstructed ½-duration PET (45 s/bed position) with and without AI-denoising, “PET45AI and PET45”. Denoising was performed by SubtlePET™ using deep convolutional neural networks. Visual global image quality (IQ) 3-point scores and lesion detectability were evaluated. Lesion maximal and peak standardized uptake values using lean body mass (SULmax and SULpeak), metabolic volumes (MV), and liver SULmean were measured, including both standard and EARL1 (European Association of Nuclear Medicine Research Ltd) compliant SUL. Lesion-to-liver SUL ratios (LLR) and liver coefficients of variation (CVliv) were calculated.ResultsPET45 showed mediocre IQ (scored poor in 8% and moderate in 68%) and lesion concordance rate with PET90 (88.7%). In PET45AI, IQ scores were similar to PET90 (P = 0.80), good in 92% and moderate in 8% for both. The lesion concordance rate between PET90 and PET45AI was 836/856 (97.7%), with 7 lesions (0.8%) only detected in PET90 and 13 (1.5%) exclusively in PET45AI. Lesion EARL1 SULpeak was not significantly different between both PET (P = 0.09). Lesion standard SULpeak, standard and EARL1 SULmax, LLR and CVliv were lower in PET45AI than in PET90 (P < 0.0001), while lesion MV and liver SULmean were higher (P < 0.0001). Good to excellent intraclass correlation coefficients (ICC) between PET90 and PET45AI were observed for lesion SUL and MV (ICC ≥ 0.97) and for liver SULmean (ICC ≥ 0.87).ConclusionAI allows [18F]FDG PET duration in digital PET/CT to be halved, while restoring degraded ½-duration PET image quality. Future multicentric studies, including other PET radiopharmaceuticals, are warranted.

F18-FDG PET/CT imaging early predicts pathologic complete response to induction chemoimmunotherapy of locally advanced head and neck cancer: preliminary single-center analysis of the checkrad-cd8 trial

AimIn the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy.MethodsPatients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3–14 days before (pre-ICIT) and 21–28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu).ResultsThirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value.ConclusionFDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value.Trial registryClinicalTrials.gov identifier: NCT03426657.

Effectiveness of COVID-19 vaccine (Covaxin) against breakthrough SARS-CoV-2 infection in India

ABSTRACT India approved COVID-19 vaccine called Covaxin, developed by the Indian Council of Medical Research and Bharat Biotech Ltd. The primary objective of the study was to estimate the effectiveness of Covaxin in preventing breakthrough SARS-CoV-2 infection in healthcare workers (HCWs). A test-negative matched case-control study was conducted among HCWs of tertiary care hospital in Eastern India. Any HCW who tested positive for COVID-19 using RT-PCR during April and May 2021 was taken as the case. The HCWs who tested negative for COVID-19 by RT-PCR were considered as controls after matching with the date of testing and profession of the cases. Vaccination data were collected from the institution’s vaccine database and recall. In case of discrepancy, it was confirmed from the CoWIN portal (cowin.gov.in). The sample size was 670 participants (335 pairs). Conditional logistic regression models were used to calculate the adjusted odds ratio for breakthrough SARS-CoV-2 infection. Vaccine effectiveness was calculated using the following formula: VE = (1-aOR) × 100%. Sensitivity analysis was done for effectiveness of Covaxin, excluding Covishield vaccination. The mean age of participants was 29.1 years (SD = 7.1), and the majority were males (55.2%). Among the study participants, 60% were completely vaccinated, 18.51% were partially vaccinated, and 21.49% were unvaccinated. After adjusting for age, gender, type of household and past history of COVID-19 disease in conditional logistic models, the vaccine effectiveness was 22% (aOR 0.78, 95% CI: 0.52–1.17; p = .233). Sensitivity analysis with Covaxin showed an effectiveness of 29% (aOR 0.71, 95% CI: 0.47–1.08; p = .114) for preventing breakthrough SARS-CoV-2 infection.

Standardisation of conventional and advanced iterative reconstruction methods for Gallium-68 multi-centre PET-CT trials

PurposeTo assess the applicability of the Fluorine-18 performance specifications defined by EANM Research Ltd (EARL), in Gallium-68 multi-centre PET-CT trials using conventional (ordered subset expectation maximisation, OSEM) and advanced iterative reconstructions which include the systems’ point spread function (PSF) and a Bayesian penalised likelihood algorithm (BPL) commercially known as Q.CLEAR. The possibility of standardising the two advanced reconstruction methods was examined.MethodsThe NEMA image quality phantom was filled with Gallium-68 and scanned on a GE PET-CT system. PSF and BPL with varying post-reconstruction Gaussian filter width (2–6.4 mm) and penalisation factor (200–1200), respectively, were applied. The average peak-to-valley ratio from six profiles across each sphere was estimated to inspect any edge artefacts. Image noise was assessed using background variability and image roughness. Six GE and Siemens PET-CT scanners provided Gallium-68 images of the NEMA phantom using both conventional and advanced reconstructions from which the maximum, mean and peak recoveries were drawn. Fourteen patients underwent 68Ga-PSMA PET-CT imaging. BPL (200-1200) reconstructions of the data were compared against PSF smoothed with a 6.4-mm Gaussian filter.ResultsA Gaussian filter width of approximately 6 mm for PSF and a penalisation factor of 800 for BPL were needed to suppress the edge artefacts. In addition, those reconstructions provided the closest agreement between the two advanced iterative reconstructions and low noise levels with the background variability and the image roughness being lower than 7.5% and 11.5%, respectively. The recoveries for all methods generally performed at the lower limits of the EARL specifications, especially for the 13- and 10-mm spheres for which up to 27% (conventional) and 41% (advanced reconstructions) lower limits are suggested. The lesion standardised uptake values from the clinical data were significantly different between BPL and PSF smoothed with a Gaussian filter of 6.4 mm wide for all penalisation factors except for 800 and 1000.ConclusionIt is possible to standardise the advanced reconstruction methods with the reconstruction parameters being also sufficient for minimising the edge artefacts and noise in the images. For both conventional and advanced reconstructions, Gallium-68 specific recovery coefficient limits were required, especially for the smallest phantom spheres.

Comparison of Immunogenicity between the Proposed Pegfilgrastim Biosimilar MYL-1401H and Reference Pegfilgrastim

Introduction: Pegfilgrastim, a long-acting granulocyte colony-stimulating factor (G-CSF), is indicated for reduction of incidence of febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. Here, the immunogenicity data for MYL-1401H, a proposed biosimilar of pegfilgrastim, from the clinical studies will be presented.Methods: The efficacy, safety, and immunogenicity of MYL-1401H were investigated in 3 clinical studies, 2 in healthy volunteers (HV) and 1 in patients receiving chemotherapy. MYL-1401H-1001 was a 3-way crossover study comparing the pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2-mg dose of MYL-1401H with reference pegfilgrastim (Neulasta®) sourced from both the European Union (EU) and United States (US) in HV. MYL-1401H-1002 was a parallel-group study designed to compare the immunogenicity of MYL-1401H with US-pegfilgrastim at a repeated 6-mg dose in HV. MYL-1401H-3001 was a multicenter, randomized, double-blind, parallel-group equivalence study of MYL-1401H 6 mg vs EU-pegfilgrastim 6 mg in patients with breast cancer receiving chemotherapy for 6 cycles. The primary efficacy endpoint in MYL-1401H-3001 was duration of severe neutropenia in cycle 1, defined as days with absolute neutrophil count <0.5 × 109/L. A thorough assessment of immunogenicity was conducted across the 3 studies. The antidrug antibody (ADA; Covance, Chantilly, VA) analysis was performed using a validated, sensitive, and specific analytical method on the MesoScale Discovery® Platform (Rockville, MD). Serum samples were analyzed for the presence of ADA against MYL-1401H, EU-pegfilgrastim, and US-pegfilgrastim. Samples that resulted positive in the screening assay were further evaluated in a confirmatory assay. The samples confirmed as ADA positive were titrated to elucidate relative levels of the ADA response and further evaluated for domain characterization to determine if the antibodies were specifically directed against the polyethylene glycol (PEG) or the G-CSF domain of the molecule, or both. Samples confirmed as positive for ADA were analyzed for neutralizing antibodies (NAb; CIRION BioPharma Research) using a validated cell-based assay.Results: Overall, these studies demonstrated that the PK, PD, efficacy, and safety of MYL-1401H were equivalent to reference pegfilgrastim. Across all 3 studies, the proportions of subjects who were ADA positive before dosing were similar in the MYL-1401H (30/223; 13.5%) and EU-pegfilgrastim groups (16/139; 11.5%) and were lower in the US-pegfilgrastim group (4/97; 4.1%). Most (86.0%) of the subjects with ADA had antibodies that recognized the PEG domain, which may be attributable to exposure to PEG-related compounds in the environment as well as the highly sensitive nature of the assay, which can detect very low levels of antibodies. Treatment-induced impact on immunogenicity across the 3 studies was evaluated by analyzing the postdose ADA results excluding those subjects who were ADA positive at baseline (Table). Overall, the proportions of subjects with postdose treatment-induced ADA were similar in the MYL-1401H (20/192; 10.4%) and EU-pegfilgrastim groups (17/123; 13.8%), while they were higher in the US-pegfilgrastim group (28/93; 30.1%). Although the proportion of subjects with treatment-induced ADA was higher in the US-pegfilgrastim group, in most cases, the ADA recognized only the PEG moiety, the titers were low, and the antibodies were non-neutralizing. Two subjects (1 each in the MYL-1401H and EU-pegfilgrastim groups) had antibodies against the G-CSF moiety only. Two subjects were NAb positive in the MYL-1401H group, while none were NAb positive in either reference pegfilgrastim group. There was no evidence of loss of efficacy or severe treatment-induced immune-related adverse events in ADA- or NAb-positive subjects.Conclusion: Results in HV indicate that MYL-1401H does not induce either early or late immune response and has a low immunogenic potential, similar to that of EU- and US-pegfilgrastim, after repeated administration in a sensitive population without any confounding illness or immunosuppressive medications. Similarly, the immunogenic potentials of MYL-1401H and EU-pegfilgrastim are low in patients with breast cancer. Overall, MYL-1401H has an immunogenic profile similar to that of EU-pegfilgrastim and US-pegfilgrastim. [Display omitted] DisclosuresWaller:Mylan: Consultancy, Honoraria. Ranganna:Mylan Pharmaceuticals Inc: Employment. Pennella:Mylan: Employment. Mattano:HARP Pharma Consulting, LLC: Employment. Loa:Mylan Pharmaceuticals Inc: Employment. Donnelly:Mylan Pharmaceuticals Inc: Employment. Liu:Mylan Pharmaceuticals Inc: Employment. Watson:Covance: Employment. St-Jean:CIRION BioPharma Research Inc: Employment. Chatterjee:Biocon Research Ltd: Employment. Nayak:Biocon Research Ltd: Employment. Sengupta:Biocon Research Ltd: Employment. Kothekar:Biocon Research Ltd: Employment. Barve:Mylan Pharmaceuticals Inc: Employment.

Effect of light-emitting diode–mediated photobiomodulation on extraction space closure in adolescents and young adults: A split-mouth, randomized controlled trial

This split-mouth trial aimed to examine the effects of light-emitting diode (LED)-mediated photobiomodulation compared with no photobiomodulation on maxillary canine distalization. Twenty participants (10 males and 10 females; aged 11-20years) requiringbilateral extraction of maxillary first premolars were included from the Sydney Dental Hospital waiting list. After premolar extractions, leveling, and alignment, canines were retracted on 0.020-in stainless steel wires with coil springs delivering 150g of force to each side. Each patient's right side was randomly assigned to experimental or control using www.randomisation.com, and allocation concealment was performed with sequentially numbered, opaque, sealed envelopes. The experimental side received 850nm wavelength, 60mW/cm2 power, continuous LED with OrthoPulse device (Biolux Research Ltd, Vancouver, British Columbia, Canada) for 5min/d. For the control side, the device was blocked with opaque black film. Patients were reviewed at 4-week intervals for force reactivation and intraoral scanning over 12weeks. The primary outcome was the amount of tooth movement, and secondary outcomes were anchorage loss and canine rotation, all measured digitally. Blinding for study participants and the treating clinician was not possible; however, blinding was done for the measurements by deidentifying the digital scans. Linear mixed models were implemented for the data analysis. Nineteen participants concluded the study. Data analysis showed that the treatment×time interaction was not significant, suggesting no difference in space closure (unstandardized regression coefficient [b], 0.12; 95% confidence interval [CI], -0.05 to 0.29; P=0.17), canine rotation (b, 0.21; 95% CI, -0.82 to 1.25; P=0.69), and anchorage loss (b, -0.01, 95% CI, -0.28 to 0.26, P=0.94). No harms were noted. Daily 5-minute application of LED did not result in clinically meaningful differences during extraction space closure compared with no LED application. Australian New Zealand Clinical Trials Registry (ACTRN12616000652471). The protocol was not published before trial commencement. This research was funded by the Australian Society of Orthodontists Foundation for Research and Education.

18F-FDG PET/CT Scans Can Identify Sub-Groups of NSCLC Patients with High Glucose Uptake in the Majority of Their Tumor Lesions.

Background: Reprogrammed glucose metabolism is a hallmark of cancer making it an attractive therapeutic target, especially in cancers with high glucose uptake such as non-small cell lung cancer (NSCLC). Tools to select patients with high glucose uptake in the majority of tumor lesions are essential in the development of anti-cancer drugs targeting glucose metabolism. Type 2 diabetes mellitus (T2DM) patients may have tumors highly dependent on glucose uptake. Surprisingly, this has not been systematically studied. Therefore, we aimed to determine which patient and tumor characteristics, including concurrent T2DM, are related to high glucose uptake in the majority of tumor lesions in NSCLC patients as measured by 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) scans.Methods: Routine primary diagnostic 18F-FDG PET/CT scans of consecutive NSCLC patients were included. Mean standardized uptake value (SUVmean) of 18F-FDG was determined for all evaluable tumor lesions and corrected for serum glucose levels according to the European Association of Nuclear Medicine Research Ltd guidelines. Patient characteristics potentially determining degree of tumor lesion glucose uptake in the majority of tumor lesions per patient were investigated.Results: The cohort consisted of 102 patients, 28 with T2DM and 74 without T2DM. The median SUVmean per patient ranged from 0.8 to 35.2 (median 4.2). T2DM patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients (SUVmean 4.3 vs 2.8, P < 0.001 and SUVmean 5.4 vs 3.7, P = 0.009, respectively). However, in multivariable analysis, high tumor lesion glucose uptake was only independently determined by number of tumor lesions ≥1 mL per patient (odds ratio 0.8, 95% confidence interval 0.7-0.9).Conclusions: 18F-FDG PET/CT scans can identify sub-groups of NSCLC patients with high glucose uptake in the majority of their tumor lesions. T2DM patients had higher tumor lesion glucose uptake than non-diabetic patients. However, this was not independent of other factors such as the histological subtype and number of tumor lesions per patient.

Vaccinating Adolescents and Children Significantly Reduces Covid-19 Morbidity and Mortality Across All Ages: A Population-Based Modeling Study Using the UK as an Example

Background: Debate persists around the risk-benefit balance of vaccinating adolescents and children against Covid-19. Central to this debate is quantifying the contribution of adolescents and children to the transmission of SARS-CoV-2, and the potential impact of vaccinating these age groups.Methods: We developed a novel SEIR mathematical disease transmission model that quantifies the impact of different vaccination strategies on population-level SARS-CoV-2 infections and clinical outcomes. The model employs both age- and time-dependent social mixing patterns to capture the impact of changes in restrictions. The model was used to assess the impact of vaccinating adolescents and children on the natural history of the Covid-19 pandemic across all age groups, using the UK as an example.Results: The base case model demonstrates significant increases in Covid-19 disease burden in the UK following relaxation of restrictions from 19 July 2021, if vaccines are limited to those ≥18 years and vulnerable adolescents (≥12 years). This vaccination strategy would result in approximately 60% of new infections being in those Conclusions: This study demonstrates that vaccinating adolescents and children has the potential to play a vital role in reducing SARS-CoV-2 infections and subsequent Covid-19 morbidity and mortality across all ages. Our results have major global public health implications and provide valuable information to inform a potential pandemic exit strategy.Funding: Funding for this study was provided by Moderna, Inc.Declaration of Interest: TS, ARM and PM are employees of Health Economics and Outcomes Research Ltd., Cardiff, UK. Health Economics and Outcomes Research Ltd received fees from Moderna in relation to this study. MM is an employee of Moderna, Inc. CAT and POB are employees of Moderna, Inc. and hold Moderna stocks/stock options. ME and WDS have no conflicts of interest to declare.

Point-of-Care Inflammatory Phenotyping Predicts Clinical Outcome in COVID-19

Rationale: The COVID-19 pandemic has led to more than 445,000 deaths worldwide. There is an urgent need for effective treatment. Studies suggest that a hyper-inflammatory response is a major cause of disease severity and death. Using precision medicine to rapidly identify patients with COVID-19 with hyper-inflammation may be key for identify subgroups who may benefit from targeted immunomodulatory treatments. Methods: In combination with a diagnostic point-of-care test (POCT), we used a rapid multiplex cytokine assay to measure serum IL-6, IL-8, TNF-α, IL-1β, GM-CSF, IL-10, IL-33 and IFN-γ in 101 hospitalised patients with confirmed COVID-19 at admission to University Hospital Southampton. Demographic, clinical, laboratory and outcome data were collected for all patients. Findings: Age over 70 years was the strongest predictor of death (OR 28, 95% CI 5.94, 139.45). Cytokines IL-6, IL-8, TNF-α, IL-1β and IL-33 were significantly associated with adverse outcome in COVID-19. Clinical parameters at admission were predictive of poor outcome (AUROC 0.71), with addition of a combined cytokine panel significantly improving the predictability (AUROC 0.85). In those Interpretation: A combined cytokine panel improves the accuracy of the predictive value for adverse outcome beyond standard clinical data alone. Rapid identification of specific cytokines may help to stratify patients towards trials of specific immunomodulatory treatments to improve outcomes in COVID-19.Funding Statement: No external funding was received for this work. The parent study is supported by QIAGEN in the form of discounted equipment and consumables. They had no role in the study conception, design, data analysis or manuscript preparation.Declaration of Interests: Authors HB, AF, BS, NB, SP, FB, SW, NS, CMS, KJS and DC have no conflicts of interest to declare. Author TWC reports personal fees from BioMerieux and BioFire LLC, non-financial support from BioMerieux and BioFire LLC, personal fees from Synairgen research ltd, personal fees and other from Roche, personal fees from Cidara therapeutics, personal fees from Janssen , grants from NIHR, all outside the submitted work. Author TMAW reports personal fees and other from MMH, grants and personal fees from GSK, grants and personal fees from AZ, personal fees from BI, grants and personal fees from Synairgen, all outside the submitted work.Ethics Approval Statement: The study was approved by the South Central Hampshire A Research Ethics Committee: REC reference 20/SC/0138, on the 16th March 2020.

Clinical Impact of Molecular Point-of-Care Testing for Suspected COVID-19 in Hospital: A Prospective, Interventional, Non-Randomised, Controlled Study (COV-19POC)

Background: The management of the COVID-19 pandemic is hampered by the long delays associated with centralised laboratory PCR testing. In hospitals this leads to poor patient flow and nosocomial transmission. Rapid, accurate tests are therefore urgently needed for the next wave. Methods: We performed a prospective, interventional, non-randomised, controlled study of molecular point-of-care testing (POCT) in adults presenting to hospital with suspected COVID-19. Intervention group patients were tested using the QIAstat-Dx Respiratory SARS-CoV-2 Panel at the point-of-care and control patients were tested using laboratory PCR. The primary outcome was time to results. Secondary outcomes included infection control and diagnostic accuracy measures. Findings: 499 patients were tested by POCT and 555 control patients were tested using laboratory PCR. Median (IQR) time to results with POCT was 1.7 (1.6 to 1.9) hours versus 21.3 (16.0 to 27.9) hours in the control group (difference of 19.6 hours, 95%CI 19.0 to 20.3; pInterpretation: POCT was associated with large reductions in time to results and improvements in infection control measures, and had high diagnostic accuracy.Trial Registration: This study is registered ISRCTN:14966673 and has completed.Funding: University Hospitals Southampton NHS Foundation TrustDeclaration of Interests: TWC has received speaker fees, honoraria, travel reimbursement, and equipment and consumables free of charge for the purposes of research outside of this submitted study, from BioFire diagnostics LLC and BioMerieux. TWC has received consultancy fees from Synairgen research Ltd, Randox laboratories Ltd and Cidara therapeutics. He a member of an advisory board for Roche and a member of two independent data monitoring committees for trials sponsored by Roche. He has acted as the UK chief investigator for an IMP study sponsored by Janssen. All other authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: The study was approved by the South Central - Hampshire A Research Ethics Committee: REC reference 20/SC/0138, on the 16th March 2020.