Immunogenicity of COVID-19 vaccines in patients with follicular lymphoma receiving frontline chemoimmunotherapy.

Immune responses to primary COVID-19 vaccination were investigated in 58 patients with follicular lymphoma (FL) as part of the PETReA trial of frontline therapy (EudraCT 2016-004010-10). COVID-19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after cytoreductive treatment comprising rituximab (depletes B cells) and either bendamustine (depletes CD4+ T cells) or cyclophosphamide-based chemotherapy. Blood samples obtained after vaccine doses 1 and 2 (V1, V2) were analysed for antibodies and T cells reactive to the SARS-CoV-2 spike protein using the Abbott Architect and interferon-gamma ELISpot assays respectively. Compared to 149 healthy controls, patients with FL exhibited lower antibody but preserved T-cell responses. Within the FL cohort, multivariable analysis identified low pre-treatment serum IgA levels and V2 administration during induction or maintenance treatment as independent determinants of lower antibody and higher T-cell responses, and bendamustine and high/intermediate FLIPI-2 score as additional determinants of a lower antibody response. Several clinical scenarios were identified where dichotomous immune responses were estimated with >95% confidence based on combinations of predictive variables. In conclusion, the immunogenicity of COVID-19 vaccines in FL patients is influenced by multiple disease- and treatment-related factors, among which B-cell depletion showed differential effects on antibody and T-cell responses.

A Scoping Review of the Validity and Reliability of Smartphone Accelerometers When Collecting Kinematic Gait Data.

The aim of this scoping review is to evaluate and summarize the existing literature that considers the validity and/or reliability of smartphone accelerometer applications when compared to 'gold standard' kinematic data collection (for example, motion capture). An electronic keyword search was performed on three databases to identify appropriate research. This research was then examined for details of measures and methodology and general study characteristics to identify related themes. No restrictions were placed on the date of publication, type of smartphone, or participant demographics. In total, 21 papers were reviewed to synthesize themes and approaches used and to identify future research priorities. The validity and reliability of smartphone-based accelerometry data have been assessed against motion capture, pressure walkways, and IMUs as 'gold standard' technology and they have been found to be accurate and reliable. This suggests that smartphone accelerometers can provide a cheap and accurate alternative to gather kinematic data, which can be used in ecologically valid environments to potentially increase diversity in research participation. However, some studies suggest that body placement may affect the accuracy of the result, and that position data correlate better than actual acceleration values, which should be considered in any future implementation of smartphone technology. Future research comparing different capture frequencies and resulting noise, and different walking surfaces, would be useful.

Calculating the acoustic input impedance of a simplified brass instrument as an educational laboratory activity.

The concept of acoustic impedance is often difficult for students in introductory acoustics courses to make sense of, especially students without advanced mathematics backgrounds. This work summarizes a laboratory activity for students in a general education musical acoustics class where a simplified brass musical instrument is examined, focusing on how the geometry of the air column affects the input impedance of the instrument. Students are guided through making bore profile measurements for use in a computation of the input impedance. Options for making experimental measurements of the simplified instrument are explained. The laboratory activity was successfully used with students who reported their increased understanding of the acoustics of brass musical instruments.

How Is Jump Performance Affected in Male Athletes when Completed with a Visual Impairment?

SIGNIFICANCE: High-, long-, and triple-jump athletic events may need to consider whether it is appropriate to group vision-impaired athletes in the same classification with loss of different visual functions, and a greater emphasis may need to be placed on the visual field (VF) within the current classification system used. PURPOSE: Athletes with vision impairment are grouped, based on their visual function, into one of three different classes (B1, B2, and B3, with B1 being the most severe). Athletes in class B2 have loss in visual acuity (VA; range, 1.50 to 2.60 logMAR) or VF (constricted to a diameter of <10°). The current study investigated how loss of different visual function (VA or VF) within the same class impacts jumping performance, a fundamental component in long-, triple-, and high-jump athletic events. METHODS: Ten subelite male athletes (age, 21.6 ± 0.96 years; height, 178.8 ± 2.97 cm; mass, 82.2 ± 10.58 kg) with normal vision who participate in athletics were recruited. Participants completed drop jumps in four vision conditions: habitual vision condition (Full), VA no better than 1.60 logMAR (B2-VA), VF restricted to <10° (B2-VF), and VA no better than 1.30 logMAR (B3-VA). RESULTS: Meaningful differences were observed between Full and B2-VF conditions. After rebound, vertical velocity at take-off was highest in Full condition (2.84 ± 0.35 m · s-1; 95% confidence interval [CI], 2.68 to 2.99 m · s-1) and was lowest in B2-VF condition (20% reduction; 2.32 ± 0.29 m · s-1; 95% CI, 2.16 to 2.48 m · s-1). Peak vertical jump height was highest in Full (0.42 ± 0.10 m; 95% CI, 0.38 to 0.46 m) and reduced by 40% in B2-VF (0.28 ± 0.07 m; 95% CI, 0.24 to 0.32 m). Minimal differences were found between Full and B2-VA, or B3-VA conditions. CONCLUSIONS: Jump performance is compromised in athletes with simulated vision impairment. However, decrements in performance seem specific to those with severely constricted VF. Those with reduced VA (in B2-VA and B3-VA classes) seem to produce performance comparable to those with normal vision.

ConvNets for counting: Object detection of transient phenomena in steelpan drums.

We train an object detector built from convolutional neural networks to count interference fringes in elliptical antinode regions in frames of high-speed video recordings of transient oscillations in Caribbean steelpan drums, illuminated by electronic speckle pattern interferometry (ESPI). The annotations provided by our model aim to contribute to the understanding of time-dependent behavior in such drums by tracking the development of sympathetic vibration modes. The system is trained on a dataset of crowdsourced human-annotated images obtained from the Zooniverse Steelpan Vibrations Project. Due to the small number of human-annotated images and the ambiguity of the annotation task, we also evaluate the model on a large corpus of synthetic images whereby the properties have been matched to the real images by style transfer using a Generative Adversarial Network. Applying the model to thousands of unlabeled video frames, we measure oscillations consistent with audio recordings of these drum strikes. One unanticipated result is that sympathetic oscillations of higher-octave notes significantly precede the rise in sound intensity of the corresponding second harmonic tones; the mechanism responsible for this remains unidentified. This paper primarily concerns the development of the predictive model; further exploration of the steelpan images and deeper physical insights await its further application.

CD23 is a glycan-binding receptor in some mammalian species.

CD23, the low-affinity IgE receptor found on B lymphocytes and other cells, contains a C-terminal lectin-like domain that resembles C-type carbohydrate-recognition domains (CRDs) found in many glycan-binding receptors. In most mammalian species, the CD23 residues required to form a sugar-binding site are present, although binding of CD23 to IgE does not involve sugars. Solid-phase binding competition assays, glycoprotein blotting experiments, and glycan array analysis employing the lectin-like domains of cow and mouse CD23 demonstrate that they bind to mannose, GlcNAc, glucose, and fucose and to glycoproteins that bear these sugars in nonreducing terminal positions. Crystal structures of the cow CRD in the presence of α-methyl mannoside and GlcNAcß1-2Man reveal that a range of oligosaccharide ligands can be accommodated in an open binding site in which most interactions are with a single terminal sugar residue. Although mouse CD23 shows a pattern of monosaccharide and glycoprotein binding similar to cow CD23, the binding is weaker. In contrast, no sugar binding was observed in similar experiments with human CD23. The absence of sugar-binding activity correlates with accumulation of mutations in the gene for CD23 in the primate lineage leading to humans, resulting in loss of key sugar-binding residues. These results are consistent with a role for CD23 in many species as a receptor for potentially pathogenic microorganisms as well as IgE. However, the ability of CD23 to bind several different ligands varies between species, suggesting that it has distinct functions in different organisms.

The Nuclear Receptor HIZR-1 Uses Zinc as a Ligand to Mediate Homeostasis in Response to High Zinc.

Nuclear receptors were originally defined as endocrine sensors in humans, leading to the identification of the nuclear receptor superfamily. Despite intensive efforts, most nuclear receptors have no known ligand, suggesting new ligand classes remain to be discovered. Furthermore, nuclear receptors are encoded in the genomes of primitive organisms that lack endocrine signaling, suggesting the primordial function may have been environmental sensing. Here we describe a novel Caenorhabditis elegans nuclear receptor, HIZR-1, that is a high zinc sensor in an animal and the master regulator of high zinc homeostasis. The essential micronutrient zinc acts as a HIZR-1 ligand, and activated HIZR-1 increases transcription of genes that promote zinc efflux and storage. The results identify zinc as the first inorganic molecule to function as a physiological ligand for a nuclear receptor and direct environmental sensing as a novel function of nuclear receptors.

The relationship between the golf swing plane and ball impact characteristics using trajectory ellipse fitting.

The trajectory of the clubhead close to ball impact during the golf swing has previously been shown to be planar. However, the relationship between the plane orientation and the orientation characteristics of the clubhead at ball impact has yet to be defined. Fifty-two male golfers (27 high skilled, 25 intermediate skilled) hit 40 drives each in an indoor biomechanics laboratory. This study successfully fitted the trajectory of the clubhead near impact to an ellipse for each swing for players of different skill levels to help better explain this relationship. Additionally, the eccentricities of the ellipses were investigated for links to skill level. The trajectory of the clubhead was found to fit to an ellipse with RMSE of 1.2 mm. The eccentricity of the ellipse was found to be greater in the high-skilled golfers. The club path and angle of attack generated from the ellipse fitted clubhead trajectory were found to have a normalised bias-corrected RMSE of 2% and 3%, respectively. A set of "rule of thumb" values for the relationship between the club path, angle of attack and delivery plane angle was generated for use by coaches.

Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells.

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.

Evaluation of shaft angle to ball-to-target line as a predictor of horizontal delivery plane angle in the golf swing.

The shaft angle to the ball-to-target line at various points in the golf swing is used by coaches as an indication of the horizontal delivery plane angle (HPA). The aim of the current study was to understand to what degree this simplified method of using the shaft orientation can predict the orientation of the HPA. Fifty-two male golfers hit 40 drives each in an indoor biomechanics laboratory. Between-subject regression models were created for the relationship between the HPA and the shaft angle to the ball-to-target line at three different swing positions. Additionally, single subject regression models were created for each subject for the small variables. The only significant between-subjects regression model was for mid-downswing (Adjusted R2 = 89.5%, RMSE = 2.41°); however, this was deemed not accurate enough to distinguish differences between typical driver and wedge HPA. The only shaft position to have significant single-subject regression models for all participants was mid-downswing. The mean RMSE for those models was determined to be low enough to distinguish typical driver and wedge swing planes within individuals. Overall, the shaft angle was only deemed accurate enough to predict the HPA within individual subjects, and only for mid-downswing.

In vitro immunity: an overview of immunocompetent organ-on-chip models.

Impressive advances have been made to replicate human physiology in vitro over the last few years due to the growth of the organ-on-chip (OoC) field in both industrial and academic settings. OoCs are a type of microphysiological system (MPS) that imitates functional and dynamic aspects of native human organ biology on a microfluidic device. Organoids and organotypic models, ranging in their complexity from simple single-cell to complex multi-cell type constructs, are being incorporated into OoC microfluidic devices to better mimic human physiology. OoC technology has now progressed to the stage at which it has received official recognition by the Food and Drug Administration (FDA) for use as an alternative to standard procedures in drug development, such as animal studies and traditional in vitro assays. However, an area that is still lagging behind is the incorporation of the immune system, which is a critical element required to investigate human health and disease. In this review, we summarise the progress made to integrate human immunology into various OoC systems, specifically focusing on models related to organ barriers and lymphoid organs. These models utilise microfluidic devices that are either commercially available or custom-made. This review explores the difference between the use of innate and adaptive immune cells and their role for modelling organ-specific diseases in OoCs. Immunocompetent multi-OoC models are also highlighted and the extent to which they recapitulate systemic physiology is discussed. Together, the aim of this review is to describe the current state of immune-OoCs, the limitations and the future perspectives needed to improve the field.

An Organotypic Human Lymph Node Model Reveals the Importance of Fibroblastic Reticular Cells for Dendritic Cell Function.

BACKGROUND: Human lymph node (HuLN) models have emerged with invaluable potential for immunological research and therapeutic application given their fundamental role in human health and disease. While fibroblastic reticular cells (FRCs) are instrumental to HuLN functioning, their inclusion and recognition of importance for organotypic in vitro lymphoid models remain limited. METHODS: Here, we established an in vitro three-dimensional (3D) model in a collagen-fibrin hydrogel with primary FRCs and a dendritic cell (DC) cell line (MUTZ-3 DC). To study and characterise the cellular interactions seen in this 3D FRC-DC organotypic model compared to the native HuLN; flow cytometry, immunohistochemistry, immunofluorescence and cytokine/chemokine analysis were performed. RESULTS: FRCs were pivotal for survival, proliferation and localisation of MUTZ-3 DCs. Additionally, we found that CD1a expression was absent on MUTZ-3 DCs that developed in the presence of FRCs during cytokine-induced MUTZ-3 DC differentiation, which was also seen with primary monocyte-derived DCs (moDCs). This phenotype resembled HuLN-resident DCs, which we detected in primary HuLNs, and these CD1a- MUTZ-3 DCs induced T cell proliferation within a mixed leukocyte reaction (MLR), indicating a functional DC status. FRCs expressed podoplanin (PDPN), CD90 (Thy-1), CD146 (MCAM) and Gremlin-1, thereby resembling the DC supporting stromal cell subset identified in HuLNs. CONCLUSION: This 3D FRC-DC organotypic model highlights the influence and importance of FRCs for DC functioning in a more realistic HuLN microenvironment. As such, this work provides a starting point for the development of an in vitro HuLN.

Small molecule induced STING degradation facilitated by the HECT ligase HERC4.

Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its' involvement in a variety of diseases, STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here, we identify AK59 as a STING degrader leveraging HERC4, a HECT-domain E3 ligase. Additionally, our data reveals that AK59 is effective on the common pathological STING mutations, suggesting a potential clinical application of this mechanism. Thus, these findings introduce HERC4 to the fields of TPD and of compound-induced degradation of STING, suggesting potential therapeutic applications.

E-learning in a virtual science camp for urban youth.

The Virtual Science Camp (VSC) is a unique demonstration of synchronous e-learning developed by Mentoring in Medicine (MIM). This paper reports on a pilot offering during the summer of 2012 that taught advanced biological concepts, healthy living and health care career opportunities to medically underserved urban youth. Livestream's interactive video technology was used to engage a diverse audience of mostly high school students at remote sites in a new two week instructional program that provided custom course content free of charge over the internet. We describe the technical and program preparations undertaken, their implementation, the IT environment, a multi-faceted evaluation plan, the results of the experiment, and lessons learned.

Evaluating consistency of physical activity and exercise prescription in the UK for people with diabetes - a Delphi study.

Introduction: Increased physical activity is recommended as a cost-effective measure to tackle long-term management of people with diabetes, but research on interventions lacks consistency in terms of effective duration and modality. Methods: The aim of this study was to evaluate expert consensus on exercise and physical activity prescription via a three-round Delphi study conducted with 45 UK-based health and fitness professionals experienced in prescribing exercise or physical activity to people with diabetes. Results: The majority of items put forward to the panel reached consensus with 70% or above voting these items as important, but the details of the type, duration and/or modality of exercise or physical activity prescription within these items often contradicted each other, suggesting that patients are receiving inconsistent advice. The range of different exercise prescription found in this study suggests that patients are being given inconsistent and potentially confusing advice, which may affect their participation in exercise and long-term lifestyle change. Conclusion: More consistent promotion of advice from healthcare and fitness professionals may help with increasing physical activity in this participant group and achieving long term behavior change, reducing patient symptoms as well as reducing the cost to the National Health Service (NHS).

The global state of play: A study of the demographic characteristics of disability golfers.

BACKGROUND: Golf is a moderate-intensity physical activity that provides positive physical and mental health benefits. However, the inclusiveness of the sport for individuals with disabilities globally is unknown. OBJECTIVE: To characterize the demographics and disability characteristics of individuals engaging in disability golf globally. It was hypothesized that the majority of participants would be middle-aged, male, and from countries with higher gross domestic product, similar to the nondisabled population. DESIGN: Descriptive, cross-sectional analysis using European Disability Golf Association (EDGA) database. SETTING: Various international golf tournaments. PARTICIPANTS: Golfers (n = 1734) with disability from 44 countries registered with the EDGA (2017-2021). INTERVENTIONS: Not applicable. MAIN OUTCOMES: Descriptive analyses of frequencies, distributions, and means differences of demographic characteristics (age, gender, type of disability, level of handicap, golf cart use, and country of origin) of golfers with disability were performed. Data provided analysis of the association between number of participants and a country's gross domestic product (GDP). RESULTS: Individuals had a mean age of 52.5 (±15.6) years: 1589 (91.6%) male and 145 (8.4%) female. Twenty-three countries had female participation. The most commonly reported primary disability diagnoses were neurologic (24.8%), orthopedic (21.4%), and amputation below the knee (14.4%). Neurologic impairments (24.7%) were most common in men and orthopedic impairments (29.7%) were most common in women. Individuals with neurological impairments (27.4%) most frequently required golf carts to play. The GDP of a country had a positive correlation (r = 0.68) with the number of registered golfers with disability. CONCLUSION: Golf is played by individuals with a variety of disabilities and provides numerous benefits. However, there is an underrepresentation of youth, women, and individuals with certain impairments and from lower-income countries. These are the potential areas of opportunity to improve engagement and inclusiveness of golf.

Unclean Cooking Fuel Use and Slow Gait Speed Among Older Adults From 6 Countries.

BACKGROUND: Outdoor air pollution has been reported to be associated with frailty (including slow gait speed) in older adults. However, to date, no literature exists on the association between indoor air pollution (eg, unclean cooking fuel use) and gait speed. Therefore, we aimed to examine the cross-sectional association between unclean cooking fuel use and gait speed in a sample of older adults from 6 low- and middle-income countries (China, Ghana, India, Mexico, Russia, and South Africa). METHODS: Cross-sectional, nationally representative data from the World Health Organization Study on global AGEing and adult health were analyzed. Unclean cooking fuel use referred to the use of kerosene/paraffin, coal/charcoal, wood, agriculture/crop, animal dung, and shrubs/grass based on self-report. Slow gait speed referred to the slowest quintile based on height, age, and sex-stratified values. Multivariable logistic regression and meta-analysis were done to assess associations. RESULTS: Data on 14 585 individuals aged ≥65 years were analyzed (mean [standard deviation] age 72.6 [11.4] years; 45.0% males). Unclean cooking fuel use (vs clean cooking fuel use) was significantly associated with higher odds for slow gait speed (odds ratio = 1.45; 95% confidence interval: 1.14-1.85) based on a meta-analysis using country-wise estimates. The level of between-country heterogeneity was very low (I2 = 0%). CONCLUSIONS: Unclean cooking fuel use was associated with slower gait speed among older adults. Future studies of longitudinal design are warranted to provide insight into the underlying mechanisms and possible causality.

Synthesis of N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamides as new selective ligands for sigma receptors.

Novel benzofuran-2-carboxamide ligands, which are selective for sigma receptors, have been synthesized via a microwave-assisted Perkin rearrangement reaction and a modified Finkelstein halogen-exchange used to facilitate N-alkylation. The ligands synthesized are the 3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamides (KSCM-1, KSCM-5 and KSCM-11). The benzofuran-2-carboxamide structure was N-arylated and N-alkylated to include both N-phenyl and N-(3-(piperidin-1-yl)propyl substituents, respectively. These new carboxamides exhibit high affinity at the sigma-1 receptor with K(i) values ranging from 7.8 to 34nM. Ligand KSCM-1 with two methoxy substituents at C-5 and C-6 of the benzofuran ring, and K(i)=27.5nM at sigma-1 was found to be more selective for sigma-1 over sigma-2.

Expedited Synthesis of Benzofuran-2-Carboxylic Acids via Microwave-Assisted Perkin Rearrangement Reaction.

3-Halocoumarins are readily converted into benzofuran-2-carboxylic acids via a Perkin (coumarin-benzofuran ring contraction) rearrangement reaction. This rearrangement entails initial base catalyzed ring fission. The resulting phenoxide anion then attacks a vinyl halide to produce the final benzofuran moiety. We explored this reaction under microwave reaction conditions and were able to significantly reduce reaction times as well as obtain very high yields of a series of benzofuran-2-carboxylic acid derivatives.

Tracking transients in steelpan strikes using surveillance technology.

This paper presents advancements in tracking features in high-speed videos of Caribbean steelpans illuminated by electronic speckle pattern interferometry, made possible by incorporating robust computer vision libraries for object detection and image segmentation, and cleaning of the training dataset. Besides increasing the accuracy of fringe counts by 10% or more compared to previous work, this paper introduces a segmentation-regression map for the entire drum surface yielding interference fringe counts comparable to those obtained via object detection. Once trained, this model can count fringes for musical instruments not part of the training set, including those with non-elliptical antinode shapes.