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The Combination of an Oral Appliance and Supplemental Oxygen Markedly Improves Obstructive Sleep Apnea Severity: A Randomized Controlled Trial
No full textIntroduction: Obstructive sleep apnea (OSA) is challenging to treat due to limited tolerance of the leading therapy, continuous positive airway pressure. A leading second line therapy, oral appliances, are well tolerated but have limited efficacy. On the basis that oral appliance efficacy is lowest in patients with a high chemoreflex "loop gain", the current study tested the hypothesis that administration of supplemental oxygen (to lower loop gain) in combination with an oral appliance provides greater OSA treatment efficacy compared to oral appliance therapy alone.
Methods: In a multicentre randomized crossover trial, 41 patients with moderate-to-severe OSA (apnea-hypopnea index [AHI] >20 events/hr) underwent in-laboratory polysomnography to assess the impact of a night of supplemental oxygen (4 L/min), oral appliance, both therapies in combination, compared to sham (air) on AHI. For primary analysis, hypopneas were scored regardless of desaturation/arousal criteria. Mixed model analysis compared treatment efficacy (change in AHI from baseline) between combination therapy and oral appliance alone (primary outcome). Sensitivity analysis reported AHI changes using standard 3% desaturation or arousal criteria (AHI3pa). Key secondary outcomes were arousal index and visual analog scale for sleep quality (VASSQ); higher score reflects improved sleep (0-10 units).
Results: Of the 41 randomized patients (14F:27M, baseline AHI = 49 [29, 62] events/hr; median [interquartile range]), 38 completed all four interventions. Compared to sham, AHI was lowered with oxygen (−33% [CI: −46, −17]), oral appliances (−53% [−64, −41]), and the combination (−67% [−77, −57]): the combination provided a greater reduction compared to oral appliance alone (difference = −14% [−23, −4], P=0.009) confirming the study hypothesis. Sensitivity analysis using AHI3pa yielded a −73% change with the combination vs. sham (difference vs. oral appliance = −17% [−25, −7]). In secondary analysis, arousal index was lowered with oxygen (−19% [−28, −9]), oral appliances (−29% [−37, −20]), and the combination (−36% [−43, −27]; difference vs. oral appliance = −7% [−14, 2], P=0.11). VASSQ increased with oxygen (0.52 [−0.08, 1.1], borderline change), oral appliances (0.71 [0.11, 1.30]), and with the combination (0.98 [0.39, 1.58]; difference vs. oral appliance = 0.28 [−0.31, 0.86]).
Conclusion: In moderate-severe OSA, the combination of supplemental oxygen and oral appliance therapy provides a greater OSA treatment efficacy compared to oral appliances alone. Combining a loop gain intervention with oral appliances is a promising approach to markedly attenuate the severity of OSA
Carpal Kinematics in the Normal, Scapholunate Ligament Deficient, and Surgically Reconstructed Wrist
No full textThe objective of this study was to evaluate scaphoid, lunate and capitate kinematics after disruption to the primary and secondary scapholunate ligamentous stabilizers, and to assess the effectiveness of scapholunate ligament reconstruction in restoring carpal kinematics post-operatively. Seven upper extremities were harvested, and the scapholunate interosseous ligament (SLIL) was divided. Specimens were mounted onto a computer-controlled dynamic wrist simulator, and simulations of flexion-extension, radial-ulnar deviation, and dart-thrower's motion were undertaken by simulated force application to the wrist tendons. Three-dimensional kinematics of the scaphoid, lunate and capitate were measured using bi-plane X-ray fluoroscopy in the native and ligament deficient state. The SLIL was then reconstructed by either dorsal transarticular loop tenodesis (DTLT), or by the three-ligament tenodesis (3LT) technique, and re-evaluated. SLIL deficiency resulted in significant differences in carpal kinematics compared to that in the healthy wrist across all wrist motions (p < 0.05). The DTLT procedure corrected increased scaphoid ulnar deviation and pronation in the SLIL deficient wrist, but did not significantly improve scaphoid flexion or volar translation of the scaphoid. The 3LT reconstructive technique restored scaphoid flexion and ulnar deviation but did not correct pronation, the increased lunate extension, nor the volar and ulnar translation observed in the ligament deficient wrist. Three-dimensional scaphoid, lunate and capitate motion depends on SLIL integrity, with tears to this ligament resulting in pathological kinematics, which may be partially mitigated with DTLT and 3LT surgical reconstruction. These findings suggest that this surgical reconstruction of the SLIL may not mitigate long-term degenerative joint conditions at the wrist
Molecular Insights Into MR1-Mediated T Cell Immunity: Lessons Learned and Unanswered Questions
No full textThe major histocompatibility complex class-I related protein, MR1, is an evolutionarily conserved antigen presenting molecule that binds and displays organic metabolites to T cells, including mucosal associated invariant T (MAIT) cells and diverse MR1-restricted T cells (MR1T). Structural studies have elucidated how MR1 can accommodate a range of chemical scaffolds that arise from foreign, synthetic, and self-metabolites, although the full spectrum of metabolites that MR1 presents remains unclear. Presently, MAIT and MR1T cell recognition of MR1-antigen complexes represents a new immune recognition paradigm and is emerging as a critical player in protective immunity, aberrant immunity, tumor immunity, and tissue repair. Moreover, the limited allelic variation of MR1 makes it an attractive therapeutic target. This review will address the unique features and capability of the MR1 molecule to display several classes of small molecules for T cell surveillance. We will also address the molecular basis underlying MAIT and MR1T TCR recognition of MR1-binding ligands
DUEn: An Ensemble Framework Enhanced by Distribution-Free Uncertainty for Regression
No full textThe main objective of ensemble learning is to aggregate multiple models to better capture complex data distributions. Various ensemble techniques, including bagging and boosting, have been investigated and widely embraced in both research and practical applications. In this work, we enhance ensemble learning by incorporating distribution-free uncertainty inspired by conformal prediction. Conformal prediction allows us to quantify any model’s uncertainty rigorously with valid coverage guarantees under lenient assumptions of the data distribution. We propose a novel ensemble learning framework called Distribution-Free Uncertainty-Aware Ensemble Framework (DUEn) for regression tasks which uses the information from distribution-free uncertainty in the form of intervals to benefit final point predictions and makes outputs more accurate and robust. Moreover, we propose a weighted interval agreement approach that aggregates base learners considering the degrees of uncertainty of their predictions. Experiments conducted on multiple data sets from different domains illustrate that DUEn is capable of enhancing the accuracy of regression by effectively using data while considering each base learner’s distribution-free uncertainty
Underlying disease risk among patients with fatigue: a population-based cohort study in primary care
No full textBACKGROUND: Presenting to primary care with fatigue is associated with a wide range of conditions, including cancer, although their relative likelihood is unknown. AIM: To quantify associations between new-onset fatigue presentation and subsequent diagnosis of various diseases, including cancer. DESIGN AND SETTING: A cohort study of patients presenting in English primary care with new-onset fatigue during 2007-2017 (the fatigue group) compared with patients who presented without fatigue (the non-fatigue group), using Clinical Practice Research Datalink data linked to hospital episodes and national cancer registration data. METHOD: The excess short-term incidence of 237 diseases in patients who presented with fatigue compared with those who did not present with fatigue is described. Disease-specific 12-month risk by sex was modelled and the age-adjusted risk calculated. RESULTS: The study included 304 914 people in the fatigue group and 423 671 in the non-fatigue group. In total, 127 of 237 diseases studied were more common in men who presented with fatigue than in men who did not, and 151 were more common in women who presented with fatigue. Diseases that were most strongly associated with fatigue included: depression; respiratory tract infections; insomnia and sleep disturbances; and hypo/hyperthyroidism (women only). By age 80 years, cancer was the third most common disease and had the fourth highest absolute excess risk in men who presented with fatigue (fatigue group: 7.01%, 95% confidence interval [CI] = 6.54 to 7.51; non-fatigue group: 3.36%, 95% CI = 3.08 to 3.67; absolute excess risk 3.65%). In women, cancer remained relatively infrequent; by age 80 years it had the thirteenth highest excess risk in patients who presented with fatigue. CONCLUSION: This study ranked the likelihood of possible diagnoses in patients who presented with fatigue, to inform diagnostic guidelines and doctors' decisions. Age-specific findings support recommendations to prioritise cancer investigation in older men (aged ≥70 years) with fatigue, but not in women at any age, based solely on the presence of fatigue
Assessing Validity and Bias of Within-Person Variability in Affect and Personality
No full textWithin-person variability in affect (e.g., Neuroticism) and personality have been linked to well-being. These are measured either by asking people to report how variable they are or to give multiple reports on the construct and calculating a within-person standard deviation adjusted for confounding by the person-level mean. The two measures are weakly correlated with one another and the links of variability with well-being depend on which measure researchers use. Recent research suggests that people's repeated ratings may be biased by response styles. In a 7-day study (N = 399) with up to five measurements per day, we confirmed that the measures of variability lacked sufficient convergent validity to be used interchangeably. We found only 1 significant correlation (of 10) between variability in repeated ratings of affect or personality and variability in repeated ratings of a theoretically unrelated construct (i.e., features of images). There was very little evidence supporting the response styles hypothesis
Togaram1 is expressed in the neural tube and its absence causes neural tube closure defects
No full textNeural tube closure defect pathomechanisms in human embryonic development are poorly understood. Here we identified spina bifida patients expressing novel variants of the TOGARAM gene family. TOGARAM1 has been associated with the ciliopathy Joubert syndrome, but its connection to spina bifida and role in neural development is unknown. We show that Togaram1 is expressed in the neural tube and Togaram1 knockout mice have abnormal cilia, reduced sonic hedgehog (Shh) signaling, abnormal neural tube patterning, and display neural tube closure defects. Neural stem cells from Togaram1 knockout embryos showed reduced cilia and defects in Shh signaling. Overexpression in IMCD3 and HEK293 cells of TOGARAM1 carrying the variant found in the spina bifida patient resulted in cilia defect along with reduced pericentriolar material one (PCM1), a critical constituent of centriolar satellites involved in transporting proteins toward the centrosome and primary cilia. Our results demonstrate the role of TOGARAM1 in regulating Shh signaling during early neural development that is critical for neural tube closure and elucidates potential mechanisms whereby the ciliopathy-associated gene TOGARAM1 gives rise to spina bifida aperta in humans
Electric field promoted odontogenic differentiation of stem cells from apical papilla by remodelling cytoskeleton
No full textAIM: This study examined the impact of direct current electric fields (DCEFs) on the biological properties of stem cells derived from the apical papilla (SCAP) and further elucidated the underlying mechanisms involved in odontogenic differentiation induced by DCEFs stimulation. METHODOLOGY: The measurement of endogenous currents in wounded dentine was achieved using a non-invasive vibrating probe system. Two-dimensional (2D) and three-dimensional (3D) systems were developed to apply DCEFs of varying strengths. The migration direction and trajectories of SCAP within DCEFs were analysed using time-lapse imaging. Cell proliferation was assessed through Hoechst staining and the CCK-8 assay. Changes in cell morphology, arrangement, and polarization were examined using fluorescence staining. The odontogenic differentiation of SCAP in vitro was assessed using quantitative polymerase chain reaction (qPCR), western blot analysis, alkaline phosphatase staining, and Alizarin Red S staining. In vivo evaluation was conducted through Haematoxylin and eosin staining, immunohistochemistry staining, and Sirius Red staining after transplantation experiments. RESULTS: Injured dentine demonstrated a significantly increased outward current, and DCEFs facilitated the migration of SCAP towards the anode. DCEFs at a magnitude of 100 mV/mm promoted SCAP proliferation, whereas DCEFs at 200 mV/mm enhanced both polarization and odontogenic differentiation of SCAP. The application of cytoskeletal polymerization inhibitors mitigated the odontogenic differentiation induced by DCEFs. In vivo studies confirmed that DCEFs promoted the differentiation of SCAP into odontoblast-like cells in an orderly arrangement, as well as the formation of collagen fibres and dentine-like tissue. CONCLUSIONS: DCEFs of varying intensities exhibited an enhanced capacity for migration, proliferation, odontogenic differentiation, and polarization in SCAP. These findings provide substantial insights for the advancement of innovative therapeutic strategies targeting the repair and regeneration of immature permanent teeth and dentine damage
Access to dental care among individuals with intellectual and developmental disabilities in India: A scoping review
No full textINTRODUCTION: Individuals with intellectual and developmental disabilities (IDDs) face numerous challenges in accessing dental care. Despite difficulties, more evidence exploring difficulties among this cohort in India is needed. This study aims to conduct a scoping review of articles published in India exploring access to dental care among individuals with IDD. METHOD: We followed the Arksey O'Malley framework for scoping reviews and the PRISMA guidelines for reporting studies. Findings were analyzed based on Levesque's framework for access. RESULTS: Seventeen articles were collated from five databases. The perceived need for dental care was low, and dental visits were mainly need-based and infrequent. Knowledge regarding dental care did not translate to dental visits. Patient-related barriers were cost, transportation difficulties, fear, lack of dentist skills, patient behavior, and cooperation. From the providers' perspective, most dentists were willing to treat but noted infrastructural and knowledge-based limitations. CONCLUSION: Access to dental care was limited due to infrastructure constraints and a lack of dentist training. Caregivers and individuals with IDD did not prioritize dental health, faced communication barriers, and were afraid of dental procedures. It is important to improve preventive dental care and raise awareness among caregivers of individuals with IDD in India. Training dentists and incorporating special care dentistry into the standard dental curriculum will improve access
Measurement and modelling of human motion in the home setting using wearable sensors
No full text© 2025 Zhou FangMobility conditions such as stroke, Parkinson’s Disease and Osteoarthritis affect one in four people globally, impacting both physical and mental health. Traditional approaches for assessing joint function require that the patient make repeated visits to a specialist clinic, which is expensive and time consuming. In recent years, wearable sensors such as inertial measurement units (IMUs) have shown potential for measurement of human movement outside of the laboratory. However, existing computational algorithms that convert IMU data to quantitative joint motion are inadequate to support both accurate and user-friendly motion analysis. This thesis investigates the use of wearable sensors for human motion analysis during activities of daily living in the home setting and evaluates the kinematics and dynamics of the upper limb using musculoskeletal modelling. A systematic review was conducted to evaluate the accuracy of methods that convert IMU data to upper limb joint angles. The findings demonstrated that static or functional calibration tasks ought to be implemented for establishing joint axes of rotation, and scapular locators are necessary to address skin motion artefact in scapular motion tracking.
The first aim of this thesis was to develop and validate a novel method for quantifying shoulder joint angles using IMU data. This method was based on scapulohumeral regression modelling using data from healthy subjects and incorporated use of a scapular locator. It was found that accuracy of IMU-based humerothoracic and scapulothoracic was task dependent and varied across joint degrees of freedom (p<0.05). Humerothoracic elevation showed close agreement between IMUs and optoelectronic motion analysis across different tasks and speeds (RMS difference: 6.5 degrees), whereas larger discrepancies were observed for humerothoracic plane of elevation and axial rotation. Scapular motion measurement showed higher accuracy for in-plane scapular lateral rotation compared to out-of-plane protraction and posterior tilt, particularly for humeral elevation angles below 100 degrees. These results suggest that this method is effective for measuring shoulder kinematics during activities of daily living in healthy subjects.
Non-invasive estimation of muscle and joint reaction forces is typically achieved by computational modelling and measurement of joint kinematics. However, the sensitivity of musculoskeletal model force calculations to IMU motion measurement errors has not been explored to date. The second aim of this thesis was to evaluate shoulder muscle and joint reaction forces using IMU data and musculoskeletal modelling, and investigate the effect of task and speed on force evaluation accuracy. Task had a significant impact on the accuracy of IMU-based force estimates, with greater differences in muscle and joint reaction forces during flexion and abduction (p<0.05) due to increased soft tissue artifacts at high humeral elevations. Slower task speeds further impacted muscle force accuracy (p<0.05), attributed to the force-velocity properties of muscle, which amplify the effect of kinematic errors at lower velocities. Musculoskeletal model calculations of a muscle’s force are particularly sensitive to IMU motion measurement errors in the degree of freedom actuated by that muscle. These findings provided guidance in the use of IMU data in musculoskeletal modelling.
The ability to remotely monitor movement and assess mobility in the home setting has applications in identifying sedentary behaviour, supporting rehabilitation, fall prevention, and telemedicine. However, this environment presents unique challenges in measuring movement over extended periods due to the complexity of indoor settings and variability of daily activities. The third aim of this thesis was to develop a novel digital twin framework for indoor human monitoring that analyses and classifies kinematics during activities of daily living. An overall classification of 82.3% was achieved for 19 activities of daily living in the home. Individuals walked at different speeds within their home, with a faster speed and larger lower limb sagittal plane range of motion in the living room (1.00 +- 0.20 m/s) compared to the bathroom (0.78 +- 0.10 m/s) (p<0.05). Movements with distinctive patterns, such as tooth brushing and food chopping were classified with accuracies above 90%. Activities requiring a large range of joint motion were also identified, including hair combing which involved shoulder elevation over 120 degrees, and sit-to-stand which involved hip and knee flexion of approximately 75 degrees and 90 degrees, respectively. Reaching-related activities exhibited variations in shoulder joint motion across rooms due to different object layouts (p<0.05). The methodologies developed in this thesis will guide the use of IMUs over a range of applications, including telemedicine and remote monitoring, performance evaluation of athlete and military personnel, and the film and animation industries