An example of ventilatory limitation during cardiopulmonary exercise testing in a patient with COPD.

A 64-year-old obese gentleman attended for further evaluation of ongoing dyspnoea in the context of a previous diagnosis of moderate COPD treated with dual long-acting bronchodilators. A cardiopulmonary exercise test (CPET) was performed, which demonstrated reduced peak work and oxygen consumption with evidence of dynamic hyperinflation, abnormal gas exchange and ventilatory limitation despite cardiac reserve. The CPET clarified the physiological process underpinning the patient's dyspnoea and limiting the patient's activities. This, in turn, helped the clinician tailor the patient's management plan.

Contraceptive and pregnancy concerns in the UK during the first COVID-19 lockdown: A rapid study.

OBJECTIVES: COVID-19 resulted in significant disruption to sexual and reproductive health (SRH) services globally and the impact of this remains under explored. This study aimed to explore the impact of COVID-19 on SRH during the initial weeks of the first UK lockdown. DESIGN: This rapid study employed a cross-sectional anonymous survey design. Between 9th April and 4th May 2020, participants completed an online questionnaire around the impacts of COVID-19 on SRH. The survey was completed by 194 participants. The findings in this paper, report on data from closed and free text questions from 32% (n = 62) of the total sample who said they were able to get pregnant. RESULTS: Participants raised concerns around reduced access to, or a denial of, SRH services as well as reduced choice when such services were available. Participants felt their right to access SRH care was impinged and there were anxieties around the impact of COVID-19 on maternal and foetal health. CONCLUSIONS: The study contributes to a better understanding of the concerns, during the first 8 weeks of the UK lockdown, of those who could get pregnant. Policy makers and planners must ensure that SRH policy, that recognises the importance of bodily autonomy and rights, is central to pandemic planning and responses both in the UK and globally. Such policies should ensure the immediate implementation of protocols that protect SRH service delivery, alongside informing service users of both their right to access such care and how to do so. Further work is necessary with members from minority communities who are mostly absent from this study to explore if, and how, COVID-19 may have exacerbated already existing disparities.

Stress and strain in the contractile and cytoskeletal filaments of airway smooth muscle.

Stress and strain are omnipresent in the lung due to constant lung volume fluctuation associated with respiration, and they modulate the phenotype and function of all cells residing in the airways including the airway smooth muscle (ASM) cell. There is ample evidence that the ASM cell is very sensitive to its physical environment, and can alter its structure and/or function accordingly, resulting in either desired or undesired consequences. The forces that are either conferred to the ASM cell due to external stretching or generated inside the cell must be borne and transmitted inside the cytoskeleton (CSK). Thus, maintaining appropriate levels of stress and strain within the CSK is essential for maintaining normal function. Despite the importance, the mechanisms regulating/dysregulating ASM cytoskeletal filaments in response to stress and strain remained poorly understood until only recently. For example, it is now understood that ASM length and force are dynamically regulated, and both can adapt over a wide range of length, rendering ASM one of the most malleable living tissues. The malleability reflects the CSK's dynamic mechanical properties and plasticity, both of which strongly interact with the loading on the CSK, and all together ultimately determines airway narrowing in pathology. Here we review the latest advances in our understanding of stress and strain in ASM cells, including the organization of contractile and cytoskeletal filaments, range and adaptation of functional length, structural and functional changes of the cell in response to mechanical perturbation, ASM tone as a mediator of strain-induced responses, and the novel glassy dynamic behaviors of the CSK in relation to asthma pathophysiology.

Mechanisms of airway hyperresponsiveness in asthma.

Airway hyperresponsiveness (AHR) is a fundamental abnormality in asthma. There are many potential factors contributing to the excessive airway response demonstrable on airway challenge. These range from abnormalities of airway smooth muscle, airway remodelling and airway inflammation to abnormalities in the neural control of airway calibre. None of these by themselves fully explains the abnormalities seen on the dose response curves of the asthmatic. In this review, the main mechanisms are described, together with recent evidence providing a pathway by which a number of these mechanisms may interact to cause AHR through abnormality in ventilation distribution and airway closure. There is now evidence for a close relationship between ventilation heterogeneity and AHR which could be exploited clinically.

Activation time and material stiffness of sequential removable orthodontic appliances. Part 3: premolar extraction patients.

INTRODUCTION: The purpose of this study was to describe the movement of teeth adjacent to premolar extraction spaces during space closure with aligner appliances and then fixed appliances. METHODS: The sample included 24 subjects from a larger study investigating an aligner system. All subjects had at least 1 premolar extracted as part of treatment. Dental casts and panoramic radiographs were measured for tooth tipping adjacent to extraction spaces at 3 treatment points: T0, initial; T2, end of aligners; and T3, end of fixed appliances. Chart records were reviewed for information about time in treatment. RESULTS: Treatment with aligners resulted in significant tipping of the teeth adjacent to premolar extraction sites. When followed by fixed appliances, these teeth were significantly uprighted. Aligner treatment followed by treatment with fixed appliances took an average of 40 months. CONCLUSIONS: In premolar extraction patients treated with aligners, dental tipping occurs but can be corrected with fixed appliances. This dual modality treatment might require more time than treatment with fixed appliances alone.

In vitro and in vivo functional residual capacity comparisons between multiple-breath nitrogen washout devices.

Functional residual capacity (FRC) accuracy is essential for deriving multiple-breath nitrogen washout (MBNW) indices, and is the basis for device validation. Few studies have compared existing MBNW devices. We evaluated in vitro and in vivo FRC using two commercial MBNW devices, the Exhalyzer D (EM) and the EasyOne Pro LAB (ndd), and an in-house device (Woolcock in-house device, WIMR). FRC measurements were performed using a novel syringe-based lung model and in adults (20 healthy and nine with asthma), followed by plethysmography (FRCpleth). The data were analysed using device-specific software. Following the results seen with ndd, we also compared its standard clinical software (ndd v.2.00) with a recent upgrade (ndd v.2.01). WIMR and EM fulfilled formal in vitro FRC validation recommendations (>95% of FRC within 5% of known volume). Ndd v.2.00 underestimated in vitro FRC by >20%. Reanalysis using ndd v.2.01 reduced this to 11%, with 36% of measurements ≤5%. In vivo differences from FRCpleth (mean±sd) were 4.4±13.1%, 3.3±11.8%, -20.6±11% (p<0.0001) and -10.5±10.9% (p=0.005) using WIMR, EM, ndd v.2.00 and ndd v.2.01, respectively. Direct device comparison highlighted important differences in measurement accuracy. FRC discrepancies between devices were larger in vivo, compared to in vitro results; however, the pattern of difference was similar. These results represent progress in ongoing standardisation efforts.

FIZICS: fluorescent imaging zone identification system, a novel macro imaging system.

Constantly improving biological assay development continues to drive technological requirements. Recently, a specification was defined for capturing white light and fluorescent images of agar plates ranging in size from the NUNC Omni tray (96-well footprint, 128 x 85 mm) to the NUNC Bio Assay Dish (245 x 245 mm). An evaluation of commercially available products failed to identify any system capable of fluorescent macroimaging with discrete wavelength selection. To address the lack of a commercially available system, a custom imaging system was designed and constructed. This system provides the same capabilities of many commercially available systems with the added ability to fluorescently image up to a 245 x 245 mm area using wavelengths in the visible light spectrum.

On the terminology for describing the length-force relationship and its changes in airway smooth muscle.

The observation that the length-force relationship in airway smooth muscle can be shifted along the length axis by accommodating the muscle at different lengths has stimulated great interest. In light of the recent understanding of the dynamic nature of length-force relationship, many of our concepts regarding smooth muscle mechanical properties, including the notion that the muscle possesses a unique optimal length that correlates to maximal force generation, are likely to be incorrect. To facilitate accurate and efficient communication among scientists interested in the function of airway smooth muscle, a revised and collectively accepted nomenclature describing the adaptive and dynamic nature of the length-force relationship will be invaluable. Setting aside the issue of underlying mechanism, the purpose of this article is to define terminology that will aid investigators in describing observed phenomena. In particular, we recommend that the term "optimal length" (or any other term implying a unique length that correlates with maximal force generation) for airway smooth muscle be avoided. Instead, the in situ length or an arbitrary but clearly defined reference length should be used. We propose the usage of "length adaptation" to describe the phenomenon whereby the length-force curve of a muscle shifts along the length axis due to accommodation of the muscle at different lengths. We also discuss frequently used terms that do not have commonly accepted definitions that should be used cautiously.

Deep inspiration volume and the impaired reversal of bronchoconstriction in asthma.

It is unclear whether the failure to reverse bronchoconstriction with deep inspiration (DI) in asthma is due to reduced maximal dilatation of the DI. We compared the effect of different DI volumes on maximal dilatation and reversal of bronchoconstriction in nine asthmatics and ten non-asthmatics. During bronchoconstriction, subjects took DI to 40%, 70% and 100% inspiratory capacity, on separate days. Maximal dilatation was measured as respiratory system resistance (Rrs) at end-inspiration and residual dilatation as Rrs at end-expiration, both expressed as percent of Rrs at end-tidal expiration prior to DI. DI volume was positively associated with maximal dilatation in non-asthmatics (ANOVA p=0.055) and asthmatics (p=0.023). DI volume was positively associated with residual dilatation in non-asthmatics (p=0.004) but not in asthmatics (p=0.53). The degree of maximal dilatation independently predicted residual dilatation in non-asthmatics but not asthmatics. These findings suggest that the failure to reverse bronchoconstriction with DI in asthma is not due to reduced maximal dilatation, but rather due to increased airway narrowing during expiration.

Procedures to improve the repeatability of forced oscillation measurements in school-aged children.

Forced oscillation technique (FOT) parameters are less repeatable than spirometry, and the impact of technical factors, such as data acquisition and data filtering, are unknown. FOT was performed, in triplicate, on 48 children (8-11 years) and repeated two weeks later. We examined the separate effects of monitoring tidal volume (V(T)) prior to measurement and length of data acquisition on measurement repeatability. We compared the effects on repeatability of a filtering technique in which complete breaths containing respiratory artefact were rejected and statistical filters in which outlying data points were rejected. Within- and between-session repeatability of respiratory system resistance (Rrs) and reactance (Xrs) were assessed using coefficient of variation (CV) and intra-class correlation coefficient (ICC). Longer data acquisition reduced CV of Rrs and Xrs (60s vs. shorter durations, p ≤ 0.001). Monitoring V(T) reduced CV of Rrs (p = 0.05). Complete breath filtering improved CV and ICC for both Rrs and Xrs. The repeatability of FOT measurements can be improved by optimising data acquisition and filtering.

Disease-specific expression and regulation of CCAAT/enhancer-binding proteins in asthma and chronic obstructive pulmonary disease.

BACKGROUND: CCAAT/enhancer-binding proteins (C/EBPs) control cell proliferation; lack of C/EBPalpha correlates with increased proliferation of bronchial smooth muscle cells (BSMCs) of asthmatic patients. OBJECTIVE: We sought to assess disease-specific expression of C/EBPalpha, beta, delta, and epsilon and the effects of budesonide (10(-8) mol/L) and formoterol (10(-8) mol/L). METHODS: Expression and function of C/EBPalpha, beta, delta, and epsilon BSMCs of control subjects (n = 9), asthmatic patients (n = 12), and patients with chronic obstructive pulmonary disease (COPD; n = 10) were determined. RESULTS: The control group expressed C/EBPalpha, beta, delta, and epsilon, which were upregulated by serum (5%). Budesonide completely inhibited C/EBPalpha and beta expression; formoterol increased C/EBPalpha expression (2-fold). C/EBPdelta and epsilon expression were not affected by the drugs. The asthmatic group did not appropriately express C/EBPalpha. Basal levels of C/EBPbeta, delta, and epsilon were upregulated by serum (5%). Budesonide and formoterol increased C/EBPbeta levels (3.4-fold and 2.5-fold, respectively), leaving C/EBPalpha, delta, and epsilon levels unaffected. The COPD group normally expressed C/EBPalpha, beta, and epsilon, which were upregulated by serum treatment (5%). Basal levels of C/EBPdelta were downregulated by serum in 7 of 10 BSMC lines. Budesonide inhibited C/EBPalpha and beta expression, upregulated C/EBPdelta (3.2-fold), and had no effect on C/EBPepsilon. Formoterol upregulated C/EBPalpha expression (3-fold) but not the other C/EBPs. Protein analysis and electrophoretic mobility shift assay confirmed the disease-specific expression pattern of C/EBPalpha in asthmatic patients and C/EBPdelta in patients with COPD. CONCLUSIONS: The expression and regulation of C/EBPs in BSMCs of asthmatic patients and patients with COPD seems disease specific. Budesonide and formoterol modulate C/EBP expression in a drug- and disease-specific pattern. CLINICAL IMPLICATIONS: The data could provide a method to discriminate between asthma and COPD at an early disease stage.

Use of fusion imaging to localize an ectopic thoracic parathyroid adenoma.

We report the use of fused computed tomography and single photon emission computed tomography parathyroid (99m technetium)-sestamibi images to localize an ectopic parathyroid adenoma.

Activation time and material stiffness of sequential removable orthodontic appliances. Part 1: Ability to complete treatment.

Recent advances in technology have led to the availability of sequential removable orthodontic appliances (aligners) to move teeth in a stepwise fashion (Invisalign, Align Technology, Santa Clara, Calif). This study was undertaken to compare 2 distinctly different materials (hard and soft) and 2 activation frequencies (1 week and 2 weeks) for this technique. Fifty-one subjects, stratified by peer assessment rating (PAR) and need for extractions, were randomly assigned to a hard or a soft plastic appliance, and a 1-week or 2-week activation time. The primary endpoint was the completion of the initially prescribed series of aligners. Changing aligners every other week was more likely to lead to completion of the initial series of aligners than changing aligners weekly (37% vs 21%). No substantial difference in the completion rate was observed for the soft versus the hard appliance (27% vs. 32%). The completion rate was highest (46%) among patients with PAR scores less than 15 and no planned extractions, and lowest (0%) among subjects who had 2 or more premolars extracted. All who completed their initial series of aligners required an additional series of aligners or fixed appliances to achieve the original treatment goals. This exploratory study suggests that subjects with a 2-week activation regimen, no extractions, and a low PAR score are more likely to complete their initial series of aligners.

Activation time and material stiffness of sequential removable orthodontic appliances. Part 2: Dental improvements.

Fifty-one patients were enrolled in this study to explore the treatment effects of material stiffness and frequency of appliance change when using clear, sequential, removable appliances (aligners). Patients were stratified based on pretreatment peer assessment rating (PAR) scores and need for extractions. They were randomized into 4 treatment protocols: 1-week activation with soft material, 1-week activation with hard material, 2-week activation with soft material, and 2-week activation with hard material. Patients continued with their protocols until either the series of aligners was completed, or until it was determined that the aligner was not fitting well (study end point). Weighted PAR score and average incisor irregularity (AII) indexes were used to measure pretreatment and end-point study models, and average improvement was compared among the 4 groups. In addition to the evaluation of the 4 treatment groups, comparisons were made of the individual components of the PAR score to determine which occlusal components experienced the most correction with the aligners. The percentages and absolute extraction space closures were evaluated, and papillary bleeding scores before and during treatment were compared. Although no statistical difference was observed between the 4 treatment groups, a trend was noted with the 2-week frequency having a larger percentage of reduction in weighted PAR and AII scores, and greater extraction space closure. Anterior alignment was the most improved component, and buccal occlusion was the least improved. When analyzed by type of extraction, incisor extraction sites had a significantly greater percentage of closure than either maxillary or mandibular premolar extraction sites. A statistically significant decrease in mean average papillary bleeding score was found during treatment when compared with pretreatment scores, although this difference was not clinically significant.

A custom mandibular distraction device for the rat.

In the last several years, the rat model has been used as a reliable means of studying distraction osteogenesis (DO). This model has several benefits, including lower cost, the availability of molecular reagents for the rat, and the ability to perform a large number of operations in a short time. We have recently developed an external device that is custom-made for the rat mandible and secured at the mandibular ramus. The device consists of a Leone (Florence, Italy) jackscrew distraction assembly (0.2 mm per one-quarter turn), 2 Luhr L-shaped 0.8-mm five-hole microplates, and four 0.8-mm x 3-mm microscrews (Stryker-Leibinger Corp., Kalamazoo, MI) for fixation. Additionally, there is a methylmethacrylate block that is placed on the lingual surface of the angle of the mandible to support the posterior screws. Sterile surgical technique was used, and the same two surgeons performed all operations. To date, we have operated on 153 Sprague-Dawley rats. The procedure has been well tolerated by the animals. We had 17 postoperative deaths (11% mortality), largely as a result of anesthetic complications. There were no wound infections or dehiscence. A mandible fracture was noted in 6 rats (4%), which occurred at the time of device placement. There were no device dislodgments. Postmortem examination showed the device to be well positioned in all rats, with good callous formation at the distraction site. The rats surpassed their preoperative weight after an average of 9.2 days. These results compare favorably with those of other models currently in use. We have developed a device that is currently being used in the study of DO in the rat mandible. Our device is small in size, does not require wide undermining for its placement, and has had a low incidence of device dislodgment or infection. This model has shown great reproducibility and thus should be effective in its application for the histologic and biochemical investigation of DO in the rat.

Expression of connective tissue growth factor in asthmatic airway smooth muscle cells.

There is strong evidence to implicate transforming growth factor-beta in the remodeling that occurs in asthma, as levels are increased in bronchial lavage fluid and gene expression is increased in bronchial tissue. Transforming growth factor-beta is also known to increase the release of collagen from airway smooth muscle. Here we identify for the first time a possible mechanism for the effects of transforming growth factor-beta. Transforming growth factor-beta specifically induces mRNA and protein for connective tissue growth factor in airway smooth muscle, and moreover, we report that the connective tissue growth factor response is greater in airway smooth muscle cultured from patients with asthma compared with patients without asthma. This occurs at both the level of mRNA (37.53 +/- 11.62- and 13.59 +/- 3.12-fold increase at 24 hours compared with time 0, respectively, p < 0.02) and protein production (67.57 +/- 27.80- and 3.58 +/- 0.6-fold increase at 24 hours compared with time 0, respectively, p < 0.03). The differential connective tissue growth factor response to transforming growth factor-beta in asthmatic airway smooth muscle identifies a potential role for connective tissue growth factor in the remodeling that is characteristic of severe persistent asthma.