Evaluating the Agreement between Oral, Armpit, and Ear Temperature Readings during Physical Activities in an Outdoor Setting.

Accurate body temperature measurement is essential for monitoring and managing safety during outdoor activities. Physical activities are an essential consideration for public health, with sports taking up an important proportion of these. Athletes' performances can be directly affected by body temperature fluctuations, with overheating or hypothermia posing serious health risks. Monitoring these temperatures allows coaches and medical staff to make decisions that enhance performance and safety. Traditional methods, like oral, axillary, and tympanic readings, are widely used, but face challenges during intense physical activities in real-world environments. This study evaluated the agreement, correlation, and interchangeability of oral, axillary, and tympanic temperature measurements in outdoor exercise conditions. Systems developed for specific placements might generate different sensor readouts. Conducted as an observational field study, it involved 21 adult participants (11 males and 10 females, average age 25.14 ± 5.80 years) that underwent the Yo-Yo intermittent recovery test protocol on an outdoor court. The main outcomes measured were the agreement and correlation between temperature readings from the three methods, both before and after exercise. The results indicate poor agreement between the measurement sites, with significant deviations observed post-exercise. Although the Spearman correlation coefficients showed consistent temperature changes post-exercise across all methods, the standard deviations in the pairwise comparisons exceeded 0.67 °C. This study concluded that widely used temperature measurement methods are challenging to use during outdoor exercises and should not be considered interchangeable. This variability, especially after exercise, underscores the need for further research using gold standard temperature measurement methods to determine the most suitable site for accurate readings. Care should thus be taken when temperature screening is done at scale using traditional methods, as each measurement site should be considered within its own right.

Porous versus solid shoulder implants in humeri of different bone densities: A finite element analysis.

Porous metallic prosthesis components can now be manufactured using additive manufacturing techniques, and may prove beneficial for promoting bony ingrowth, for accommodating drug delivery systems, and for reducing stress shielding. Using finite element modeling techniques, 36 scenarios (three porous stems, three bone densities, and four held arm positions) were analysed to assess the viability of porous humeral stems for use in total shoulder arthroplasty, and their resulting mechanobiological impact on the surrounding humerus bone. All three porous stems were predicted to experience stresses below the yield strength of Ti6Al4V (880 MPa) and to be capable of withstanding more than 10 million cycles of each loading scenario before failure. There was an indication that within an 80 mm region of the proximal humerus, there would be a reduction in bone resorption as stem porosity increased. Overall, this study shows promise that these porous structures are mechanically viable for incorporation into permanent shoulder prostheses to combat orthopedic infections.

Quantitative Magnetic Resonance Imaging of Lateral Compartment Articular Cartilage After Lateral Extra-articular Tenodesis.

BACKGROUND: Concerns have arisen that anterior cruciate ligament reconstruction (ACLR) with lateral extra-articular tenodesis (LET) may accelerate the development of posttraumatic osteoarthritis in the lateral compartment of the knee. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate whether the augmentation of ACLR with LET affects the quality of lateral compartment articular cartilage on magnetic resonance imaging (MRI) at 2 years postoperatively. We hypothesized that there would be no difference in T1rho and T2 relaxation times when comparing ACLR alone with ACLR + LET. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A consecutive subgroup of patients at the Fowler Kennedy Sport Medicine Clinic participating in the STABILITY 1 Study underwent bilateral 3-T MRI at 2 years after surgery. The primary outcome was T1rho and T2 relaxation times. Articular cartilage in the lateral compartment was manually segmented into 3 regions of the tibia (lateral tibia [LT]-1 to LT-3) and 5 regions of the femur (lateral femoral condyle [LFC]-1 to LFC-5). Analysis of covariance was used to compare relaxation times between groups, adjusted for lateral meniscal tears and treatment, cartilage and bone marrow lesions, contralateral relaxation times, and time since surgery. Semiquantitative MRI scores according to the Anterior Cruciate Ligament OsteoArthritis Score were compared between groups. Correlations were used to determine the association between secondary outcomes (including results of the International Knee Documentation Committee score, Knee injury and Osteoarthritis Outcome Score, Lower Extremity Functional Scale, 4-Item Pain Intensity Measure, hop tests, and isokinetic quadriceps and hamstring strength tests) and cartilage relaxation. RESULTS: A total of 95 participants (44 ACLR alone, 51 ACLR + LET) with a mean age of 18.8 years (61.1% female [58/95]) underwent 2-year MRI (range, 20-36 months). T1rho relaxation times were significantly elevated for the ACLR + LET group in LT-1 (37.3 ± 0.7 ms vs 34.1 ± 0.8 ms, respectively; P = .005) and LFC-2 (43.9 ± 0.9 ms vs 40.2 ± 1.0 ms, respectively; P = .008) compared with the ACLR alone group. T2 relaxation times were significantly elevated for the ACLR + LET group in LFC-1 (51.2 ± 0.7 ms vs 49.1 ± 0.7 ms, respectively; P = .03) and LFC-4 (45.9 ± 0.5 ms vs 44.2 ± 0.6 ms, respectively; P = .04) compared with the ACLR alone group. All effect sizes were small to medium. There was no difference in Anterior Cruciate Ligament OsteoArthritis Scores between groups (P = .99). Weak negative associations (rs = -0.27 to -0.22; P < .05) were found between relaxation times and quadriceps and hamstring strength in the anterolateral knee, while all other correlations were nonsignificant (P > .05). CONCLUSION: Increased relaxation times demonstrating small to medium effect sizes suggested early biochemical changes in articular cartilage of the anterolateral compartment in the ACLR + LET group compared with the ACLR alone group. Further evidence and long-term follow-up are needed to better understand the association between these results and the potential risk of the development of osteoarthritis in our patient cohort.

Detection and Characterization of Endplate Structural Defects on CT: A Diagnostic Accuracy Study.

STUDY DESIGN: Diagnostic test study. OBJECTIVE: To determine the reliability and validity or diagnostic accuracy of two previously described endplate structural defect (EPSD) assessment methods. SUMMARY OF BACKGROUND DATA: Studies of EPSD may further the understanding of pathoanatomical mechanisms underlying back pain. However, clinical imaging methods used to document EPSD have not been validated, leaving uncertainty about what the observations represent. METHODS: Using an evaluation manual, 418 endplates on CT sagittal slices obtained from 19 embalmed cadavers (9 men and 10 women, aged 62-91 y) were independently assessed by two experienced radiologists and a novice for EPSD using the two methods. The corresponding micro-CT (µCT) from the harvested T7-S1 spines were assessed by another independent rater with excellent intra-rater reliability (Kappa=0.96). RESULTS: Inter-rater reliability was good for presence (Kappa=0.60-0.69) and fair for specific phenotypes (Kappa=0.43-0.58) of EPSD. Erosion, for which the Brayda-Bruno classification lacked a category, was mainly (82.8%) classified as wavy/irregular, while many notched defects (n=15, 46.9%) and Schmorl's nodes (n=45, 79%) were recorded as focal defects using Feng's classification. When compared to µCT, endplate fractures (n=53) and corner defects (n=28) were routinely missed on CT. Endplates classified as wavy/irregular on CT corresponded to erosion (n=29, 21.2%), jagged defects (n=21, 15.3%), calcification (n=19, 13.9%), and other phenotypes on µCT. Some focal defects on CT represented endplate fractures (n=21, 27.6%) on µCT. Overall, with respect to the presence of an EPSD, there was a sensitivity of 70.9% and specificity of 79.1% using Feng's method, and 79.5% and 57.5% using Brayda-Bruno's. Poor to fair inter-rater reliability (k=0.26-0.47) was observed for defect dimensions. CONCLUSION: There was good inter-rater reliability and evidence of criterion validity supporting assessments of EPSD presence using both methods. However, neither method contained all needed EPSD phenotypes for optimal sensitivity, and specific phenotypes were often misclassified.

Cardiac resynchronization using fusion pacing during exercise.

INTRODUCTION: Fusion pacing requires correct timing of left ventricular pacing to right ventricular activation, although it is unclear whether this is maintained when atrioventricular (AV) conduction changes during exercise. We used cardiopulmonary exercise testing (CPET) to compare cardiac resynchronization therapy (CRT) using fusion pacing or fixed AV delays (AVD). METHODS: Patients 6 months post-CRT implant with PR intervals < 250 ms performed two CPET tests, using either the SyncAV™ algorithm or fixed AVD of 120 ms in a double-blinded, randomized, crossover study. All other programming was optimized to produce the narrowest QRS duration (QRSd) possible. RESULTS: Twenty patients (11 male, age 71 [65-77] years) were recruited. Fixed AVD and fusion programming resulted in similar narrowing of QRSd from intrinsic rhythm at rest (p = .85). Overall, there was no difference in peak oxygen consumption (V̇O2 PEAK , p = .19), oxygen consumption at anaerobic threshold (VT1, p = .42), or in the time to reach either V̇O2 PEAK (p = .81) or VT1 (p = .39). The BORG rating of perceived exertion was similar between groups. CPET performance was also analyzed comparing whichever programming gave the narrowest QRSd at rest (119 [96-136] vs. 134 [119-142] ms, p < .01). QRSd during exercise (p = .03), peak O2 pulse (mL/beat, a surrogate of stroke volume, p = .03), and cardiac efficiency (watts/mL/kg/min, p = .04) were significantly improved. CONCLUSION: Fusion pacing is maintained during exercise without impairing exercise capacity compared with fixed AVD. However, using whichever algorithm gives the narrowest QRSd at rest is associated with a narrower QRSd during exercise, higher peak stroke volume, and improved cardiac efficiency.

Exercise capacity following SARS-CoV-2 infection is related to changes in cardiovascular and lung function in military personnel.

BACKGROUND: Since the COVID-19 pandemic, post-COVID syndrome (persistent symptoms/complications lasting >12 weeks) continues to pose medical and economic challenges. In military personnel, where optimal fitness is crucial, prolonged limitations affecting their ability to perform duties has occupational and psychological implications, impacting deployability and retention. Research investigating post-COVID syndrome exercise capacity and cardiopulmonary effects in military personnel is limited. METHODS: UK military personnel were recruited from the Defence Medical Services COVID-19 Recovery Service. Participants were separated into healthy controls without prior SARS-CoV-2 infection (group one), and participants with prolonged symptoms (>12 weeks) after mild-moderate (community-treated) and severe (hospitalised) COVID-19 illness (group 2 and 3, respectively). Participants underwent cardiac magnetic resonance imaging (CMR) and spectroscopy, echocardiography, pulmonary function testing and cardiopulmonary exercise testing (CPET). RESULTS: 113 participants were recruited. When compared in ordered groups (one to three), CPET showed stepwise decreases in peak work, work at VT1 and VO2 max (all p < 0.01). There were stepwise decreases in FVC (p = 0.002), FEV1 (p = 0.005), TLC (p = 0.002), VA (p < 0.001), and DLCO (p < 0.002), and a stepwise increase in A-a gradient (p < 0.001). CMR showed stepwise decreases in LV/RV volumes, stroke volumes and LV mass (LVEDVi/RVEDVi p < 0.001; LVSV p = 0.003; RVSV p = 0.001; LV mass index p = 0.049). CONCLUSION: In an active military population, post-COVID syndrome is linked to subclinical changes in maximal exercise capacity. Alongside disease specific changes, many of these findings share the phenotype of deconditioning following prolonged illness or bedrest. Partitioning of the relative contribution of pathological changes from COVID-19 and deconditioning is challenging in post-COVID syndrome recovery.

Metal Organic Framework-Incorporated Three-Dimensional (3D) Bio-Printable Hydrogels to Facilitate Bone Repair: Preparation and In Vitro Bioactivity Analysis.

Hydrogels are three-dimensional (3D) water-swellable polymeric matrices that are used extensively in tissue engineering and drug delivery. Hydrogels can be conformed into any desirable shape using 3D bio-printing, making them suitable for personalized treatment. Among the different 3D bio-printing techniques, digital light processing (DLP)-based printing offers the advantage of quickly fabricating high resolution structures, reducing the chances of cell damage during the printing process. Here, we have used DLP to 3D bio-print biocompatible gelatin methacrylate (GelMA) scaffolds intended for bone repair. GelMA is biocompatible, biodegradable, has integrin binding motifs that promote cell adhesion, and can be crosslinked easily to form hydrogels. However, GelMA on its own is incapable of promoting bone repair and must be supplemented with pharmaceutical molecules or growth factors, which can be toxic or expensive. To overcome this limitation, we introduced zinc-based metal-organic framework (MOF) nanoparticles into GelMA that can promote osteogenic differentiation, providing safer and more affordable alternatives to traditional methods. Incorporation of this nanoparticle into GelMA hydrogel has demonstrated significant improvement across multiple aspects, including bio-printability, and favorable mechanical properties (showing a significant increase in the compressive modulus from 52.14 ± 19.42 kPa to 128.13 ± 19.46 kPa with the addition of ZIF-8 nanoparticles). The designed nanocomposite hydrogels can also sustain drug (vancomycin) release (maximum 87.52 ± 1.6% cumulative amount) and exhibit a remarkable ability to differentiate human adipose-derived mesenchymal stem cells toward the osteogenic lineage. Furthermore, the formulated MOF-integrated nanocomposite hydrogel offers the unique capability to coat metallic implants intended for bone healing. Overall, the remarkable printability and coating ability displayed by the nanocomposite hydrogel presents itself as a promising candidate for drug delivery, cell delivery and bone tissue engineering applications.

The "One-Step" approach for QT analysis increases the sensitivity of nonclinical QTc analysis.

Whether a compound prolongs cardiac repolarization independent of changes in beat rate is a critical question in drug research and development. Current practice is to resolve this in two steps. First, the QT interval is corrected for the influence of rate and then statistical significance is tested. There is renewed interest in improving the sensitivity of nonclinical corrected QT interval (QTc) assessment with modern studies having greater data density than previously utilized. The current analyses examine the effects of moxifloxacin or vehicle on the QT interval in nonhuman primates (NHPs) using a previously described one-step method. The primary end point is the statistical sensitivity of the assessment. Publications suggest that for a four animal crossover (4 × 4) in NHPs the minimal detectable difference (MDD) is greater than or equal to 10 ms, whereas in an eight animal crossover the MDD is ~6.5 ms. Using the one-step method, the MDD for the four animal NHP assessments was 3 ms. In addition, the one-step model accounted for day-to-day differences in the heart rate and QT-rate slope as well as drug-induced changes in these parameters. This method provides an increase in the sensitivity and reduces the number of animals necessary for detecting potential QT change and represents "best practice" in nonclinical QTc assessment in safety pharmacology studies.

Static compression and fatigue behavior of heat-treated selective laser melted titanium alloy (Ti6Al4V) gyroid cylinders.

Porous additively-manufactured structures could have a niche in orthopaedic implants, due to their potential to reduce stiffness (stress-shielding), improve bony ingrowth, and potential to house reservoirs of drug-eluting non-structural biomaterials. Computer aided design and finite element (FE) modelling plays an important role in the design of porous structured biomedical implants; however it is important to validate both their static and fatigue behaviours using experimental testing. This study compared the mechanical behaviors of titanium cylindrical gyroid structures of varying porosities using physical testing of additively manufactured prototypes and FE models. There was agreement in the measured and predicted relationships between porosity and apparent modulus of elasticity. As porosity increased (and wall thickness decreased), the structures failed at a lower number of cycles when loaded at the same percentage of their yield strengths. Calibration of the fatigue strength coefficient from a previously published value of 1586.5 MPa-1225 MPa greatly improved the fatigue life prediction accuracy for all the gyroid structures. Nevertheless, differences of up to 54% in the predicted versus experimental fatigue lives remained, which could be attributed to difficulties with how the precise time and location of failure is defined in the simulations, and/or minor differences in nominal and actual porosities. Although further calibration and validation should be explored, this study demonstrates that static and fatigue FE-modelling techniques could be used to aid in the design of porous prosthetics.

Thoracolumbar Vertebral Endplate Defect Morphology: A Descriptive Study of Human Cadaveric Spines Using Micro-Computed Tomography.

STUDY DESIGN: A descriptive, cross-sectional cadaver study. OBJECTIVE: This study aimed to provide a thorough depiction of vertebral endplate defects classified based on their morphologic features and reported with respect to size, location, and prevalence in the human cadaveric spines of older adults. SUMMARY OF BACKGROUND DATA: Back pain has been associated with vertebral endplate defects; however, findings have been inconsistent. This is partially due to miscommunication surrounding the classification of endplate defects observed using clinical imaging, and limited knowledge of the types of defects present on the endplate and their prevalence. A comprehensive study of vertebral endplates is needed to clarify types of structural defects, their character, and prevalence. MATERIALS AND METHODS: Using micro-computed tomography, 3-dimensional reconstructed images were created of 409 endplates from 19 cadaveric spines (9 men and 10 women; aged 62-91; T6-S1). Endplate defects were categorized based on their morphology, size, and location to investigate distribution patterns. RESULTS: Seven types of endplate defects were identified: Schmorl nodes, corner fracture or limbus vertebra, other fractures, erosion, jagged surface, calcification, and depressions. Defects were identified on 63.6% of endplates. Multiple defects were present on 19.1% of endplates. Fracture and erosion were the most common defect types. Defects were more common on the endplate cranial to the intervertebral disc and in male specimens ( P = 0.01). Defects were larger in the lumbar spine and the "total area of endplate defect" was larger on the cranial than the caudal endplate in the thoracic spine ( P < 0.05). CONCLUSION: This is the first study of which we are aware that provides a thorough depiction of the morphology and distribution of endplate defects across the entire lower thoracic and lumbar spine (T6-S1) using micro-computed tomography. Results support the presence of several distinct endplate defect phenotypes with different prevalence rates and provide a reference when considering endplate defects in the elderly.

Comparing the sensitivity of cross-over and parallel study designs for QTc assessment: An analysis based on a single large study of moxifloxacin in 48 nonhuman primates.

The cardiovascular safety pharmacology (SP) study conducted to satisfy ICH S7A and S7B has commonly used a cross-over study design where each animal receives all treatments. In an increasing number of cases, cross-over designs are not possible and parallel studies have to be used. These can seldom be as large as 8 animals/treatment to match an n = 8 cross-over. Animals in parallel designs receive only one treatment. Parallel studies will have a different sensitivity to detect changes. This sensitivity is a critical question in using nonclinical QTc evaluations to support an integrated proarrhythmic risk assessment under the newly released ICH E14/S7B Q&As. The current analysis used a study large enough (n = 48) to be analyzed both as a parallel and as a cross-over design to directly compare the performance of the two experimental designs coupled to different statistical models, while all other study conduct aspects were the same. A total of 48 nonhuman primates (NHP) received 2 different treatments twice: vehicle, moxifloxacin (80 mg/kg), vehicle, moxifloxacin (80 mg/kg). Post-dose QTc interval data were recorded for 48 h for each treatment. Data were analyzed using 12 animals randomly selected for each treatment in a parallel design or as an n = 48 animal cross-over study. Different statistical models were used. The primary endpoint was the residual deviation (sigma) from the models applied to hourly time intervals. The sigma was used to determine the minimal detectable difference (MDD) for the study design-statistical model combination. Two statistical models were applicable to either study design. They gave similar sigma and resulting MDD values. In cross-over designs, the individual animal identification (ID) can be used in the statistical model. This enabled the smallest MDD value. Simple statistical models for analysis were identified: Treatment + Baseline for parallel designs and Treatment + ID for cross-over designs. The statistical sensitivity of NHP parallel study designs is reasonable (MDD for n = 6 of 12.7 ms), and in combination with testing exposures higher than likely to be necessary in man could be used in an integrated risk assessment. Where sensitivity of the NHP in vivo QTc assessment is critical, the cross-over design enabled a higher sensitivity (MDD 12.2 ms for n = 4; 8 ms for n = 8).

Effects of risk factors on evoked pain patterns in rat models of experimental knee osteoarthritis.

Pain experiences in patients with knee osteoarthritis (OA) may be influenced differently by OA risk factors, reducing the translatability of preclinical research into the clinic. Our objective was to contrast evoked pain patterns after exposure to different OA risk factors including acute joint trauma, chronic instability, or obesity/metabolic syndrome using rat models of experimental knee OA. We tested longitudinal patterns of evoked pain behaviors (knee pressure pain threshold and hindpaw withdrawal threshold) in young male rats exposed to different OA-inducing risk factors including (1) nonsurgical joint trauma (impact-induced anterior cruciate ligament (ACL) rupture); (2) surgical joint destabilization (ACL + medial meniscotibial ligament transection); and (3) high fat/sucrose (HFS) diet-induced obesity. Histopathology for synovitis, cartilage damage, and subchondral bone morphology was performed. Pressure pain threshold was reduced (more pain) most, and earlier by joint trauma (Week 4-12) and HFS (Week 8-28) than by joint destabilization (Week 12). Hindpaw withdrawal threshold was reduced transiently after joint trauma (Week 4), with smaller and later reductions after joint destabilization (Week 12), but not with HFS. Synovial inflammation occurred at Week 4 after joint trauma and instability but only coincided with pain behaviors after joint trauma. Cartilage and bone histopathology were most severe after joint destabilization and least severe with HFS. The pattern, intensity, and timing of evoked pain behaviors varied due to OA risk factor exposure and were inconsistently associated with histopathological OA features. These findings may help to explain the challenges with translating preclinical OA pain research to multimorbid clinical OA contexts.

Induction Heating Triggers Antibiotic Release and Synergistic Bacterial Killing on Polymer-Coated Titanium Surfaces.

Infection is a major complication associated with orthopedic implants. It often involves the development of biofilms on metal substrates, which act as barriers to the host's immune system and systemic antibiotic treatment. The current standard of treatment is revision surgery, often involving the delivery of antibiotics through incorporation into bone cements. However, these materials exhibit sub-optimal antibiotic release kinetics and revision surgeries have drawbacks of high cost and recovery time. Herein, a new approach is presented using induction heating of a metal substrate, combined with an antibiotic-loaded poly(ester amide) coating undergoing a glass transition just above physiological temperature to enable thermally triggered antibiotic release. At normal physiological temperature, the coating provides a rifampicin depot for >100 days, while heating of the coating accelerates drug release, with >20% release over a 1-h induction heating cycle. Induction heating or antibiotic-loaded coating alone each reduce Staphylococcus aureus (S. aureus) viability and biofilm formation on Ti, but the combination causes synergistic killing of S. aureus as measured by crystal violet staining, determination of bacterial viability (>99.9% reduction), and fluorescence microscopy of bacteria on surfaces. Overall, these materials provide a promising platform enabling externally triggered antibiotic release to prevent and/or treat bacterial colonization of implants.

Cardiopulmonary, Functional, Cognitive and Mental Health Outcomes Post-COVID-19, Across the Range of Severity of Acute Illness, in a Physically Active, Working-Age Population.

BACKGROUND: The COVID-19 pandemic has led to significant morbidity and mortality, with the former impacting and limiting individuals requiring high physical fitness, including sportspeople and emergency services. METHODS: Observational cohort study of 4 groups: hospitalised, community illness with on-going symptoms (community-symptomatic), community illness now recovered (community-recovered) and comparison. A total of 113 participants (aged 39 ± 9, 86% male) were recruited: hospitalised (n = 35), community-symptomatic (n = 34), community-recovered (n = 18) and comparison (n = 26), approximately five months following acute illness. Participant outcome measures included cardiopulmonary imaging, submaximal and maximal exercise testing, pulmonary function, cognitive assessment, blood tests and questionnaires on mental health and function. RESULTS: Hospitalised and community-symptomatic groups were older (43 ± 9 and 37 ± 10, P = 0.003), with a higher body mass index (31 ± 4 and 29 ± 4, P < 0.001), and had worse mental health (anxiety, depression and post-traumatic stress), fatigue and quality of life scores. Hospitalised and community-symptomatic participants performed less well on sub-maximal and maximal exercise testing. Hospitalised individuals had impaired ventilatory efficiency (higher VE/V̇CO2 slope, 29.6 ± 5.1, P < 0.001), achieved less work at anaerobic threshold (70 ± 15, P < 0.001) and peak (231 ± 35, P < 0.001), and had a reduced forced vital capacity (4.7 ± 0.9, P = 0.004). Clinically significant abnormal cardiopulmonary imaging findings were present in 6% of hospitalised participants. Community-recovered individuals had no significant differences in outcomes to the comparison group. CONCLUSION: Symptomatically recovered individuals who suffered mild-moderate acute COVID-19 do not differ from an age-, sex- and job-role-matched comparison population five months post-illness. Individuals who were hospitalised or continue to suffer symptoms may require a specific comprehensive assessment prior to return to full physical activity.

Comparison of validity of standard nonclinical group size selection versus standard clinical group sizes for nonhuman primate QTc prolongation evaluation.

The number of animals used in a nonhuman primate (NHP) in vivo QTc assessment conducted as part of the safety pharmacology (SP) studies on a potential new drug is relatively small (4-8 subjects). The number is much smaller than the number of healthy volunteers in a conventional thorough QT (TQT) study (40-60 volunteers). How is it possible that such small studies could offer an equivalent sensitivity in an integrated nonclinical and clinical cardiac repolarization risk assessment? This study provided the opportunity to empirically demonstrate in a large number of NHPs the performance of a nonclinical evaluation at a similar size to a TQT study. By contrasting an analysis mimicking the sampling and aggregation of QTc interval data in a manner which is TQT-like with a more conventional SP-like analysis it was demonstrated that the SP-like analysis was more sensitive. In prospective power calculations 80% power at p = 0.05 can be achieved for a 5 ms QTc change with only n = 8 NHPs using the SP-like analysis and in a group of only 4 NHPs 80% power to detect 10 ms could be achieved. By contrast groups of 24 NHPs would be required to achieve 80% power to detect 5 ms using the TQT-like sampling and aggregation approach. Overall, this study has demonstrated that smaller safety pharmacology in vivo QTc assessments using all the available data in larger data aggregates can achieve sensitivity comparable to a human TQT study.

Exercise tolerance, fatigue, mental health, and employment status at 5 and 12 months following COVID-19 illness in a physically trained population.

Failure to recover following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may have a profound impact on individuals who participate in high-intensity/volume exercise as part of their occupation/recreation. The aim of this study was to describe the longitudinal cardiopulmonary exercise function, fatigue, and mental health status of military-trained individuals (up to 12-mo postinfection) who feel recovered, and those with persistent symptoms from two acute disease severity groups (hospitalized and community-managed), compared with an age-, sex-, and job role-matched control. Eighty-eight participants underwent cardiopulmonary functional tests at baseline (5 mo following acute illness) and 12 mo; 25 hospitalized with persistent symptoms (hospitalized-symptomatic), 6 hospitalized and recovered (hospitalized-recovered); 28 community-managed with persistent symptoms (community-symptomatic); 12 community-managed, now recovered (community-recovered), and 17 controls. Cardiopulmonary exercise function and mental health status were comparable between the 5 and 12-mo follow-up. At 12 mo, symptoms of fatigue (48% and 46%) and shortness of breath (SoB; 52% and 43%) remain high in hospitalized-symptomatic and community-symptomatic groups, respectively. At 12 mo, COVID-19-exposed participants had a reduced capacity for work at anaerobic threshold and at peak exercise levels of deconditioning persist, with many individuals struggling to return to strenuous activity. The prevalence considered "fully fit" at 12 mo was lowest in symptomatic groups (hospitalized-symptomatic, 4%; hospitalized-recovered, 50%; community-symptomatic, 18%; community-recovered, 82%; control, 82%) and 49% of COVID-19-exposed participants remained medically nondeployable within the British Armed Forces. For hospitalized and symptomatic individuals, cardiopulmonary exercise profiles are consistent with impaired metabolic efficiency and deconditioning at 12 mo postacute illness. The long-term deployability status of COVID-19-exposed military personnel is uncertain.NEW & NOTEWORTHY Subjective exercise limiting symptoms such as fatigue and shortness of breath reduce but remain prevalent in symptomatic groups. At 12 mo, COVID-19-exposed individuals still have a reduced capacity for work at the anaerobic threshold (which best predicts sustainable intensity), despite oxygen uptake comparable to controls. The prevalence of COVID-19-exposed individuals considered "medically non-deployable" remains high at 47%.

Reduced athletic performance post-COVID-19 is associated with reduced anaerobic threshold.

Detailed characterisation of cardiopulmonary limitations in patients post-COVID-19 is currently limited, particularly in elite athletes. A male elite distance runner in his late 30s experienced chest pain following confirmed COVID-19. He underwent cardiopulmonary exercise testing (CPET) at 5 months postacute illness. Subjective exercise tolerance was reduced compared with normal, he described inability to 'kick' (rapidly accelerate). His CPET was compared with an identical protocol 15 months prior to COVID-19. While supranormal maximal oxygen uptake was maintained (155% of peak predicted V̇O2) anaerobic threshold (AT), a better predictor of endurance performance, reduced from 84% to 71% predicted peak V̇O2 maximum. Likewise, fat oxidation at AT reduced by 21%, from 0.35 to 0.28 g/min. Focusing exclusively on V̇O2 maximum risks missing an impairment of oxidative metabolism. Reduced AT suggests a peripheral disorder of aerobic metabolism. This finding may result from virally mediated mitochondrial dysfunction beyond normal 'deconditioning', associated with impaired fat oxidation.

3D-printed large-area focused grid for scatter reduction in cone-beam CT.

BACKGROUND: Cone-beam computed tomography (CBCT) systems acquire volumetric data more efficiently than fan-beam or multislice CT, particularly when the anatomy of interest resides within the axial field-of-view of the detector and data can be acquired in one rotation. For such systems, scattered radiation remains a source of image quality degradation leading to increased noise, image artifacts, and CT number inaccuracies. PURPOSE: Recent advances in metal additive manufacturing allow the production of highly focused antiscatter grids (2D-ASGs) that can be used to reduce scatter intensity, while preserving primary radiation transmission. We present the first implementation of a large-area, 2D-ASG for flat-panel CBCT, including grid-line artifact removal and related improvements in image quality. METHODS: A 245 × 194 × 10 mm 2D-ASG was manufactured from chrome-cobalt alloy using laser powder-bed fusion (LPBF) (AM-400; Renishaw plc, New Mills Wotton-under-Edge, UK). The 2D-ASG had a square profile with a pitch of 9.09 lines/cm and 10:1 grid-ratio. The nominal 0.1 mm grid septa were focused to a 732 mm x-ray source to optimize primary x-ray transmission and reduce grid-line shadowing at the detector. Powder-bed fusion ensured the structural stability of the ASG with no need for additional interseptal support. The 2D-ASG was coupled to a 0.139-mm element pitch flat-panel detector (DRX 3543, Carestream Health) and proper alignment was confirmed by consistent grid-line shadow thickness across the whole detector array. A 154-mm diameter CBCT image-quality-assurance phantom was imaged using a rotary stage and a ceiling-mounted, x-ray unit (Proteus XR/a, GE Medical Systems, 80kVp, 0.5mAs). Grid-line artifacts were removed using a combination of exposure-dependent gain correction and spatial-frequency, Fourier filtering. Projections were reconstructed using a Parker-weighted, FDK algorithm and voxels were spatially averaged to 357 × 357 × 595 µm to improve the signal-to-noise characteristics of the CBCT reconstruction. Finally, in order to compare image quality with and without scatter, the phantom was scanned again under the same CBCT conditions but with no 2D-ASG. No additional antiscatter (i.e., air-gap, bowtie filtration) strategies were used to evaluate the effects in image quality caused by the 2D-ASG alone. RESULTS: The large-area, 2D-ASG prototype was successfully designed and manufactured using LPBF. CBCT image-quality improvements using the 2D-ASG included: an overall 14.5% CNR increase across the volume; up to 48.8% CNR increase for low-contrast inserts inside the contrast plate of the QA phantom; and a 65% reduction of cupping artifact in axial profiles of water-filled cross sections of the phantom. Advanced image processing strategies to remove grid line artifacts did not affect the spatial resolution or geometric accuracy of the system. CONCLUSIONS: LPBF can be used to manufacture highly efficient, 2D-focused ASGs that can be easily coupled to clinical, flat-panel detectors. The implementation of ASGs in CBCT leads to reduced scatter-related artifacts, improved CT number accuracy, and enhanced CNR with no increased equivalent dose to the patient. Further improvements to image quality might be achieved with a combination of scatter-correction algorithms and iterative-reconstruction strategies. Finally, clinical applications where other scatter removal strategies are unfeasible might now achieve superior soft-tissue visualization and quantitative capabilities.

Cost-effective micro-CT system for non-destructive testing of titanium 3D printed medical components.

Micro-CT imaging can be used as an effective method for non-destructive testing (NDT) of metal 3D printed parts-including titanium biomedical components fabricated using laser powder-bed-fusion (LPBF). Unfortunately, the cost of commercially available micro-CT scanners renders routine NDT for biomedical applications prohibitively expensive. This study describes the design, manufacturing, and implementation of a cost-effective scanner tailored for NDT of medium-size titanium 3D printed biomedical components. The main elements of the scanner; which include a low-energy (80 kVp) portable x-ray unit, and a low-cost lens-coupled detector; can be acquired with a budget less than $ 11000 USD. The low-cost detector system uses a rare-earth phosphor screen, lens-coupled to a dSLR camera (Nikon D800) in a front-lit tilted configuration. This strategy takes advantage of the improved light-sensitivity of modern full-frame CMOS camera sensors and minimizes source-to-detector distance to maximize x-ray flux. The imaging performance of the system is characterized using a comprehensive CT quality-assurance phantom, and two titanium 3D-printed test specimens. Results show that the cost-effective scanner can survey the porosity and cracks in titanium parts with thicknesses of up to 13 mm of solid metal. Quantitatively, the scanner produced geometrically stable reconstructions, with a voxel size of 118 µm, and noise levels under 55 HU. The cost-effective scanner was able to estimate the porosity of a 17 mm diameter titanium 3D-printed cylindrical lattice structure, with a 0.3% relative error. The proposed scanner will facilitate the implementation of titanium LPBF-printed components for biomedical applications by incorporating routine cost-effective NDT as part of the process control and validation steps of medical-device quality-management systems. By reducing the cost of the x-ray detector and shielding, the scan cost will be commensurate with the overall cost of the validated component.