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Abstract Background Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with increased obesity, hyperandrogenism, and altered brown adipose tissue (BAT) thermogenesis. MicroRNAs play critical functions in brown adipocyte differentiation and maintenance. We aim to study the role of microRNA-21 (miR-21) in altered energy homeostasis and BAT thermogenesis in a PCOS mouse model of peripubertal androgen exposure. Methods Three-week-old miR-21 knockout (miR21KO) or wild-type (WT) female mice were treated with dihydrotestosterone (DHT) or vehicle for 90 days. Body composition was determined by EchoMRI. Energy expenditure (EE), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) were measured by indirect calorimetry. Androgen receptor (AR), and markers of adipogenesis, de novo lipogenesis, angiogenesis, extracellular matrix remodeling, and thermogenesis were quantified by RT-qPCR and/or Western-blot. Results MiR-21 ablation attenuated DHT-mediated increase in body weight while having no effect on fat or BAT mass. MiR-21 ablation attenuated DHT-mediated BAT AR upregulation. MiR-21 ablation did not alter EE; however, miR21KO DHT-treated mice have reduced VO2, VCO2, and RER. MiR-21 ablation reversed DHT-mediated decrease in food intake and increase in sleep time. MiR-21 ablation decreased some adipogenesis (Adipoq, Pparγ, and Cebpβ) and extracellular matrix remodeling (Mmp-9 and Timp-1) markers expression in DHT-treated mice. MiR-21 ablation abolished DHT-mediated increases in thermogenesis markers Cpt1a and Cpt1b, while decreasing CIDE-A expression. Conclusions Our findings suggest that BAT miR-21 may play a role in regulating DHT-mediated thermogenic dysfunction in PCOS. Modulation of BAT miR-21 levels could be a novel therapeutic approach for the treatment of PCOS-associated metabolic derangements.

Secretory leukocyte protease inhibitor (SLPI) is an important cationic protein involved in innate airway immunity and highly expressed in mucosal secretions, shown to target and inhibit neutrophil elastase (NE), cathepsin G and trypsin activity to limit proteolytic activity. In addition to the potent anti-protease activity, SLPI has been demonstrated to exert a direct anti-inflammatory effect, which is mediated via increased inhibition and competitive binding of NF-κB, regulating immune responses through limiting transcription of pro-inflammatory gene targets. In muco-obstructive lung disorders, such as Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF), there is an observed elevation in airway SLPI protein concentrations as a result of increased lung inflammation and disease progression. However, studies have identified COPD patients presenting with diminished SLPI concentrations. Furthermore, there is a decrease in SLPI concentrations through cleavage and subsequent inactivation by NE degradation in Pseudomonas aeruginosa infected people with CF (pwCF). These observations suggest reduced SLPI protein levels may contribute to the compromising of airway immunity indicating a potential role of decreased SLPI levels in the pathogenesis of muco-obstructive lung disease. The Beta Epithelial Na+ Channel transgenic (ENaC-Tg) mouse model phenotype exhibits characteristics which replicate the pathological features observed in conditions such as COPD and CF, including mucus accumulation, alterations in airway morphology and increased pulmonary inflammation. To evaluate the effect of SLPI in muco-obstructive pulmonary disease, ENaC-Tg mice were crossed with SLPI knock-out (SLPI-/-) mice, generating a ENaC-Tg/SLPI-/- colony to further investigate the role of SLPI in chronic lung disease and determine the effect of its ablation on disease pathogenesis.

Abstract A rich and complex temporal structure of variability in postural sway characterizes healthy and adaptable postural control. However, neurodegenerative disorders such as Parkinson’s disease, which often manifest as tremors, rigidity, and bradykinesia, disrupt this healthy variability. This study examined postural sway in young and older adults, including individuals with Parkinson’s disease, under different upright standing conditions to investigate the potential connection between the temporal structure of variability in postural sway and Parkinsonism. A novel and innovative method called oriented fractal scaling component analysis was employed. This method involves decomposing the two-dimensional center of pressure (CoP) planar trajectories to pinpoint the directions associated with minimal and maximal temporal correlations in postural sway. As a result, it facilitates a comprehensive assessment of the directional characteristics within the temporal structure of sway variability. The results demonstrated that healthy young adults control posture along two orthogonal directions closely aligned with the traditional anatomical anteroposterior (AP) and mediolateral (ML) axes. In contrast, older adults and individuals with Parkinson’s disease controlled posture along suborthogonal directions that significantly deviate from the AP and ML axes. These findings suggest that the altered temporal structure of sway variability is evident in individuals with Parkinson’s disease and underlies postural deficits, surpassing what can be explained solely by the natural aging process.

Dexterous postural control subtly complements movement variability with sensory correlations at many scales. The expressive poise of gymnasts exemplifies this lyrical punctuation of release with constraint, from coarse grain to fine scales. Dexterous postural control upon a 2D support surface might collapse the variation of center of pressure (CoP) to a relatively 1D orientation—a direction often oriented towards the focal point of a visual task. Sensory corrections in dexterous postural control might manifest in temporal correlations, specifically as fractional Brownian motions whose differences are more and less correlated with fractional Gaussian noises (fGns) with progressively larger and smaller Hurst exponent H. Traditional empirical work examines this arrangement of lower-dimensional compression of CoP along two orthogonal axes, anteroposterior (AP) and mediolateral (ML). Eyes-open and face-forward orientations cultivate greater variability along AP than ML axes, and the orthogonal distribution of spatial variability has so far gone hand in hand with an orthogonal distribution of H, for example, larger in AP and lower in ML. However, perturbing the orientation of task focus might destabilize the postural synergy away from its 1D distribution and homogenize the temporal correlations across the 2D support surface, resulting in narrower angles between the directions of the largest and smallest H. We used oriented fractal scaling component analysis (OFSCA) to investigate whether sensory corrections in postural control might thus become suborthogonal. OFSCA models raw 2D CoP trajectory by decomposing it in all directions along the 2D support surface and fits the directions with the largest and smallest H. We studied a sample of gymnasts in eyes-open and face-forward quiet posture, and results from OFSCA confirm that such posture exhibits the classic orthogonal distribution of temporal correlations. Head-turning resulted in a simultaneous decrease in this angle Δθ, which promptly reversed once gymnasts reoriented their heads forward. However, when vision was absent, there was only a discernible negative trend in Δθ, indicating a shift in the angle’s direction but not a statistically significant one. Thus, the narrowing of Δθ may signify an adaptive strategy in postural control. The swift recovery of Δθ upon returning to a forward-facing posture suggests that the temporary reduction is specific to head-turning and does not impose a lasting burden on postural control. Turning the head reduced the angle between these two orientations, facilitating the release of postural degrees of freedom towards a more uniform spread of the CoP across both dimensions of the support surface. The innovative aspect of this work is that it shows how fractality might serve as a control parameter of adaptive mechanisms of dexterous postural control.

Abstract Any reliable biomarker has to be specific, generalizable, and reproducible across individuals and contexts. The exact values of such a biomarker must represent similar health states in different individuals and at different times within the same individual to result in the minimum possible false-positive and false-negative rates. The application of standard cut-off points and risk scores across populations hinges upon the assumption of such generalizability. Such generalizability, in turn, hinges upon this condition that the phenomenon investigated by current statistical methods is ergodic, i.e., its statistical measures converge over individuals and time within the finite limit of observations. However, emerging evidence indicates that biological processes abound with nonergodicity, threatening this generalizability. Here, we present a solution for how to make generalizable inferences by deriving ergodic descriptions of nonergodic phenomena. For this aim, we proposed capturing the origin of ergodicity-breaking in many biological processes: cascade dynamics. To assess our hypotheses, we embraced the challenge of identifying reliable biomarkers for heart disease and stroke, which, despite being the leading cause of death worldwide and decades of research, lacks reliable biomarkers and risk stratification tools. We showed that raw R-R interval data and its common descriptors based on mean and variance are nonergodic and non-specific. On the other hand, the cascade-dynamical descriptors, the Hurst exponent encoding linear temporal correlations, and multifractal nonlinearity encoding nonlinear interactions across scales described the nonergodic heart rate variability more ergodically and were specific. This study inaugurates applying the critical concept of ergodicity in discovering and applying digital biomarkers of health and disease.

Evidence of multifractal structures has spread to a wider set of physiological time series supporting the intricate interplay of biological and psychological functioning. These dynamics manifest as random multiplicative cascades, embodying nonlinear relationships characterized by recurring division, branching, and aggregation processes implicating noise across successive generations. This investigation focuses on how well the diversity of multifractal properties can be specific to the type of cascade relationship between generation (i.e., multiplicative, additive, or a mixture) as well as to the type of noise (i.e., including additive white Gaussian noise, fractional Gaussian noise, and various amalgamations) among 15 distinct types of binomial cascade processes. Cross-correlation analysis of multifractal spectral features confirms that these features capture nuanced aspects of cascading processes with minimal redundancy. Principal component analysis using 13 distinct multifractal spectral features shows that different cascade processes can manifest multifractal evidence of nonlinearity for distinct reasons. This transparency of multifractal spectral features to underlying cascade dynamics becomes less amenable to machine-learning strategies. Fully connected neural networks struggled to classify the 15 distinct types of cascade processes based on the respective multifractal spectral features (45.5% accuracy) yet demonstrated improved accuracy when addressing single categories of cross-generation relationships, that is, additive (91.6%), multiplicative (75.4%), or additomultiplicative (70.6%). While traditional principal component analysis reveals distinct loadings attributed to individual noise processes, multiplicative relationships between generations effectively make the constituent noise processes less discernible to neural networks. Neural networks may lack sufficient hierarchical depth required to effectively distinguish among nonadditive cascading processes, recommending either elaborating multifractal geometry or using alternate architectures for machine-learning classification of cascades with multiplicative relationships.

Individuals with Parkinson’s disease exhibit tremors, rigidity, and bradykinesia, disrupting normal movement variability and resulting in postural instability. This comprehensive study aimed to investigate the link between the temporal structure of postural sway variability and Parkinsonism by analyzing multiple datasets from young and older adults, including individuals with Parkinson’s disease, across various task conditions. We used the Oriented Fractal Scaling Component Analysis (OFSCA), which identifies minimal and maximal long-range correlations within the center of pressure time series, allowing for detecting directional changes in postural sway variability. The objective was to uncover the primary directions along which individuals exerted control during the posture. The results, as anticipated, revealed that healthy adults predominantly exerted control along two orthogonal directions, closely aligned with the anteroposterior (AP) and mediolateral (ML) axes. In stark contrast, older adults and individuals with Parkinson’s disease exhibited control along suborthogonal directions that notably diverged from the AP and ML axes. While older adults and those with Parkinson’s disease demonstrated a similar reduction in the angle between these two control directions compared to healthy older adults, their reliance on this suborthogonal angle concerning endogenous fractal correlations exhibited significant differences from the healthy aging cohort. Importantly, individuals with Parkinson’s disease did not manifest the sensitivity to destabilizing task settings observed in their healthy counterparts, affirming the distinction between Parkinson’s disease and healthy aging.

Accounts of speech perception disagree on how listeners demonstrate perceptual constancy despite considerable variation in the speech signal due to speakers' coarticulation. According to the spectral contrast account, listeners' compensation for coarticulation (CfC) results from listeners perceiving the target-segment frequencies differently depending on the contrastive effects exerted by the preceding sound's frequencies. In this study, we reexamine a notable finding that listeners apparently demonstrate perceptual adjustments to coarticulation even when the identity of the speaker (i.e., the "source") changes midway between speech segments. We evaluated these apparent across-talker CfC effects on the rationale that such adjustments to coarticulation would likely be maladaptive for perceiving speech in multi-talker settings. In addition, we evaluated whether such cross-talker adaptations, if detected, were modulated by prior experience. We did so by manipulating the exposure phase of three groups of listeners by (a) merely exposing them to our stimuli (b) explicitly alerting them to talker change or (c) implicitly alerting them to this change. All groups then completed identical test blocks in which we assessed their CfC patterns in within- and across-talker conditions. Our results uniformly demonstrated that, while all three groups showed robust CfC shifts in the within-talker conditions, no such shifts were detected in the across-talker condition. Our results call into question a speaker-neutral explanation for CfC. Broadly, this demonstrates the need to carefully examine the perceptual demands placed on listeners in constrained experimental tasks and to evaluate whether the accounts that derive from such settings scale up to the demands of real-world listening.

IntroductionThe availability of quality primary health care (PHC) services in Nigeria is limited. The PHC system faces significant challenges and the improvement and expansion of PHC services is constrained by low government spending on health, especially on PHC. Out-of-pocket (OOP) expenditures dominate health spending in Nigeria and the reliance on OOP payments leads to financial burdens on the poorest and most vulnerable populations. To address these challenges, the Nigerian government has implemented several legislative and policy reforms, including the National Health Insurance Authority (NHIA) Act enacted in 2022 to make health insurance mandatory for all Nigerian citizens and residents. Our study aimed to determine the costs of providing PHC services at public health facilities in Kaduna and Kano, Nigeria. We compared the actual PHC service delivery costs to the normative costs of delivering the Minimum Service Package (MSP) in the two states.MethodsWe collected primary data from 50 health facilities (25 per state), including PHC facilities—health posts, health clinics, health centers—and general hospitals. Data on facility-level recurrent costs were collected retrospectively for 2019 to estimate economic costs from the provider’s perspective. Statewide actual costs were estimated by extrapolating the PHC cost estimates at sampled health facilities, while normative costs were derived using standard treatment protocols (STPs) and the populations requiring PHC services in each state.ResultsWe found that average actual PHC costs per capita at PHC facilities—where most PHC services should be provided according to government guidelines—ranged from US$ 18.9 to US$ 28 in Kaduna and US$ 15.9 to US$ 20.4 in Kano, depending on the estimation methods used. When also considering the costs of PHC services provided at general hospitals—where approximately a third of PHC services are delivered in both states—the actual per capita costs of PHC services ranged from US$ 20 to US$ 30.6 in Kaduna and US$ 17.8 to US$ 22 in Kano. All estimates of actual PHC costs per capita were markedly lower than the normative per capita costs of delivering quality PHC services to all those who need them, projected at US$ 44.9 in Kaduna and US$ 49.5 in Kano.DiscussionBridging this resource gap would require significant increases in expenditures on PHC in both states. These results can provide useful information for ongoing discussions on the implementation of the NHIA Act including the refinement of provider payment strategies to ensure that PHC providers are remunerated fairly and that they are incentivized to provide quality PHC services.

IntroductionThe Government of Ethiopia (GoE) has made significant progress in expanding access to primary health care (PHC) over the past 15 years. However, achieving national PHC targets for universal health coverage will require a significant increase in PHC financing. The purpose of this study was to generate cost evidence and provide recommendations to improve PHC efficiency.MethodsWe used the open access Primary Health Care Costing, Analysis, and Planning (PHC-CAP) Tool to estimate actual and normative recurrent PHC costs in nine Ethiopian regions. The findings on actual costs were based on primary data collected in 2018/19 from a sample of 20 health posts, 25 health centers, and eight primary hospitals. Three different extrapolation methods were used to estimate actual costs in the nine sampled regions. Normative costs were calculated based on standard treatment protocols (STPs), the population in need of the PHC services included in the Essential Health Services Package (EHSP) as per the targets outlined in the Health Sector Transformation Plan II (HSTP II), and the associated costs. PHC resource gaps were estimated by comparing actual cost estimates to normative costs.ResultsOn average, the total cost of PHC in the sampled facilities was US$ 11,532 (range: US$ 934–40,746) in health posts, US$ 254,340 (range: US$ 68,860–832,647) in health centers, and US$ 634,354 (range: US$ 505,208–970,720) in primary hospitals. The average actual PHC cost per capita in the nine sampled regions was US$ 4.7, US$ 15.0, or US$ 20.2 depending on the estimation method used. When compared to the normative cost of US$ 38.5 per capita, all these estimates of actual PHC expenditures were significantly lower, indicating a shortfall in the funding required to deliver an expanded package of high-quality services to a larger population in line with GoE targets.DiscussionThe study findings underscore the need for increased mobilization of PHC resources and identify opportunities to improve the efficiency of PHC services to meet the GoE’s PHC targets. The data from this study can be a critical input for ongoing PHC financing reforms undertaken by the GoE including transitioning woreda-level planning from input-based to program-based budgeting, revising community-based health insurance (CBHI) packages, reviewing exempted services, and implementing strategic purchasing approaches such as capitation and performance-based financing.

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFRL858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFRL858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.

Abstract Background The World Health Organization targeted trachoma for global elimination as a public health problem by 2030. Reaching elimination thresholds by the year 2030 in the Republic of South Sudan will be a considerable challenge, as the country currently has many counties considered hyper-endemic (> 30% trachomatous inflammation-follicular [TF]) that have yet to receive interventions. Evidence from randomized trials, modeling, and population-based surveys suggests that enhancements may be needed to the standard-of-care annual mass drug administration (MDA) to reach elimination thresholds in a timely manner within highly endemic areas. We describe a protocol for a study to determine the cost and community acceptability of enhanced antibiotic strategies for trachoma in South Sudan. Methods The Enhancing the A in SAFE (ETAS) study is a community randomized intervention costing and community acceptability study. Following a population-based trachoma prevalence survey in 1 county, 30 communities will be randomized 1:1 to receive 1 of 2 enhanced MDA interventions, with the remaining communities receiving standard-of-care annual MDA. The first intervention strategy will consist of a community-wide MDA followed by 2 rounds of targeted treatment to children ages 6 months to 9 years, 2 weeks and 4 weeks after the community MDA. The second strategy will consist of a community-wide biannual MDA approximately 6 to 8 months apart. The costing analysis will use a payer perspective and identify the total cost of the enhanced interventions and annual MDA. Community acceptability will be assessed through MDA coverage monitoring and mixed-methods research involving community stakeholders. A second trachoma-specific survey will be conducted 12 months following the original survey. Discussion ETAS has received ethical clearance and is expected to be conducted between 2022 and 2023. Results will be shared through subsequent manuscripts. The study’s results will provide information to trachoma programs on whether enhanced interventions are affordable and acceptable to communities. These results will further help in the design of future trachoma-specific antibiotic efficacy trials. Enhanced MDA approaches could help countries recover from delays caused by conflict or humanitarian emergencies and could also assist countries such as South Sudan in reaching trachoma elimination as a public health problem by 2030. Trial registration This trial was registered on December 1st, 2022 (clinicaltrails.org: NCT05634759).

Highlights 1. Androgen excess in PCOS model is associated with decreased markers of mitochondrial content in both subcutaneous and visceral white adipose tissue. 2. Androgen excess in PCOS model is associated with increased frequency of small adipocytes in subcutaneous white adipose tissue while decreasing frequency of small adipocytes in visceral white adipose tissue. 3. SGLT2 inhibition did not modify markers of mitochondrial content or oxidative stress in either subcutaneous or visceral white adipose tissue in PCOS model. 4. SGLT2 inhibition increased frequency of small adipocytes in both subcutaneous and visceral white adipose tissue in control rats; however, SGLT2 inhibition only increased frequency of small adipocytes in visceral white adipose tissue in PCOS model.

Introduction: The response of the brain to space radiation is an important concern for astronauts during space missions. Therefore, we assessed the response of the brain to 28Si ion irradiation (600 MeV/n), a heavy ion present in the space environment, on cognitive performance and whether the response is associated with altered DNA methylation in the hippocampus, a brain area important for cognitive performance.Methods: We determined the effects of 28Si ion irradiation on object recognition, 6-month-old mice irradiated with 28Si ions (600 MeV/n, 0.3, 0.6, and 0.9 Gy) and cognitively tested two weeks later. In addition, we determined if those effects were associated with alterations in hippocampal networks and/or hippocampal DNA methylation.Results: At 0.3 Gy, but not at 0.6 Gy or 0.9 Gy, 28Si ion irradiation impaired cognition that correlated with altered gene expression and 5 hmC profiles that mapped to specific gene ontology pathways. Comparing hippocampal DNA hydroxymethylation following proton, 56Fe ion, and 28Si ion irradiation revealed a general space radiation synaptic signature with 45 genes that are associated with profound phenotypes. The most significant categories were glutamatergic synapse and postsynaptic density.Discussion: The brain’s response to space irradiation involves novel excitatory synapse and postsynaptic remodeling.

When measuring physiological data, the central limit theorem typically implies a consistent variance, resulting in data that closely follow a Gaussian distribution. However, physiological measurements often deviate from this expectation, increasing variance due to nonlinear correlations across various scales. The challenge lies in testing these tails, which comprise only rare and extreme values. We introduce multiscale probability density function (PDF) analysis, a method that estimates this non-Gaussianity parameter for physiological fluctuations in each of multiple timescales. We gain valuable insights into the observed distributions with heavier tails and nonlinear correlations by exploring the relationship between non-Gaussianity and logarithmic scale. To maintain the fidelity of the original data, we incorporate an adaptive detrending filter into our multiscale PDF analysis. This filter effectively eliminates trends without distorting the distribution in a way that might risk artifactual signatures of non-Gaussianity. Additionally, we explain why multiscale PDF analysis is especially well suited for examining data that follow lognormal distributions. In the final stretch, we demonstrate how multiscale PDF analysis can provide fresh perspectives on heart rate variability and postural control. This innovative approach can facilitate diagnoses in health and disease while also deepening our comprehension of how constraints influence human physiological performance.

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by androgen excess, oligo/anovulation, and polycystic appearance of the ovaries. Women with PCOS have an increased prevalence of multiple cardiovascular risk factors such as insulin resistance, hypertension, renal injury, and obesity. Unfortunately, there is a lack of effective, evidence-based pharmacotherapeutics to target these cardiometabolic complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors provide cardiovascular protection in patients with and without type 2 diabetes mellitus. Although the exact mechanisms of how SGLT2 inhibitors confer cardiovascular protection remains unclear, numerous mechanistic hypotheses for this protection include modulation of the renin-angiotensin system and/or the sympathetic nervous system and improvement in mitochondrial function. Data from recent clinical trials and basic research show a potential role for SGLT2 inhibitors in treating obesity-associated cardiometabolic complications in PCOS. This narrative review discusses the mechanisms of the beneficial effect of SGLT2 inhibitors in cardiometabolic diseases in PCOS.

Walking exhibits stride-to-stride variations. Given ongoing perturbations, these variations critically support continuous adaptations between the goal-directed organism and its surroundings. Here, we report that stride-to-stride variations during self-paced overground walking show cascade-like intermittency-stride intervals become uneven because stride intervals of different sizes interact and do not simply balance each other. Moreover, even when synchronizing footfalls with visual cues with variable timing of presentation, asynchrony in the timings of the cue and footfall shows cascade-like intermittency. This evidence conflicts with theories about the sensorimotor control of walking, according to which internal predictive models correct asynchrony in the timings of the cue and footfall from one stride to the next on crossing thresholds leading to the risk of falling. Hence, models of the sensorimotor control of walking must account for stride-to-stride variations beyond the constraints of threshold-dependent predictive internal models.

It is widely established that gonadal hormones are fundamental to modulating and organizing the sex-specific nature of reproductive behaviors. Recently we proposed that context fear conditioning (CFC) may emerge in a sex-specific manner organized prior to the pubertal surge of gonadal hormones. Here we sought to determine the necessity of male and female gonadal hormones secreted at critical periods of development upon context fear learning. We tested the organizational hypothesis that neonatal and pubertal gonadal hormones play a permanent role in organizing contextual fear learning. We demonstrate that the postnatal absence of gonadal hormones by neonatal orchiectomy (oRX) in males and ovariectomy (oVX) in females resulted in an attenuation of CFC in adult males and an enhancement of CFC in adult females. In females, the gradual introduction of estrogen before conditioning partially rescued this effect. However, the decrease of CFC in adult males was not rescued by introducing testosterone before conditioning. Next, at a further point in development, preventing the pubertal surge of gonadal hormones by prepubertal oRX in males resulted in a reduction in adult CFC. In contrast, in females, prepubertal oVX did not alter adult CFC. However, the adult introduction of estrogen in prepubertal oVX rats reduced adult CFC. Lastly, the adult-specific deletion of gonadal hormones by adult oRX or oVX alone or replacement of testosterone or estrogen did not alter CFC. Consistent with our hypothesis, we provide initial evidence that gonadal hormones at early periods of development exert a vital role in the organization and development of CFC in male and female rats.

Background Increasing awareness of milder presentations of cystic fibrosis (CF) and greater interest in non-CF bronchiectasis are likely to lead to more CF screening by respiratory clinicians. As a result, adults who may not strictly fulfil CF diagnostic criteria yet display evidence of abnormal CF transmembrane conductance regulator (CFTR) function are being identified. The degree of agreement on diagnosis and care needs in these cases between CF clinicians remains unknown, and has implications for patient care, including access to CFTR modulator therapies. Methods We surveyed adult CF physicians in Canada, the USA, the UK and Ireland, and presented them with anonymised vignettes of adult patients referred for assessment of possible CF. Diagnostic inter-rater agreement over diagnosis, ease of classifying cases and appropriate follow-up was assessed using Krippendorff's reliability coefficient (α). Results Agreement over diagnosis (α=0.282), ease of classification (α= −0.01) and recommended follow-up (α=0.054) was weak. Clinician experience (>10 and 5–10 years versus

Abstract The SARS-CoV-2 pandemic has disrupted clinical trials worldwide. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has tracked clinical trial disruption by surveying its 58 trial sites across 17 European countries and collated information on measures to mitigate the impact of the pandemic and ensure trial continuity. Here, we present recommendations on how to reduce the risk of SARS-CoV-2 exposure to patients and trial staff by implementing remote trial visits where possible, using home assessments, video and phone calls, electronic consent, and home delivery of study drugs. We discuss the practicalities of remote source data verification, protocol amendments, changing trial site location, and staff absences and home working. We outline recommendations on how to protect trial outcomes, including home assessments, safety reporting, protocol deviations, and recruitment challenges. Finally, we discuss the importance of continued access to study drugs via extension trials for some patients. This guidance was co-created from the shared knowledge and experience of sites in our network and was re-distributed directly to all ECFS-CTN sites to help mitigate the impact of further waves of the SARS-CoV-2 pandemic. We will also use this guidance to assist companies, academia, and consortia with future protocol design and risk mitigation plans. This guidance can be applied to clinical trials in other diseases and could help sites that are not supported by clinical trial networks.

Neuronal identity dictates the position in an epithelium, and the ability to detect, process, and transmit specific signals to specified targets. Transcription factors (TFs) determine cellular identity via direct modulation of genetic transcription and recruiting chromatin modifiers. However, our understanding of the mechanisms that define neuronal identity and their magnitude remain a critical barrier to elucidate the etiology of congenital and neurodegenerative disorders. The rodent vomeronasal organ provides a unique system to examine in detail the molecular mechanisms underlying the differentiation and maturation of chemosensory neurons. Here, we demonstrated that the identity of postmitotic/maturing vomeronasal sensory neurons (VSNs), and vomeronasal-dependent behaviors can be reprogrammed through the rescue of Tfap2e/AP-2ε expression in the Tfap2eNull mice, and partially reprogrammed by inducing ectopic Tfap2e expression in mature apical VSNs. We suggest that the TF Tfap2e can reprogram VSNs bypassing cellular plasticity restrictions, and that it directly controls the expression of batteries of vomeronasal genes.

Anomalous diffusion in various complex systems abounds in nature and spans multiple space and time scales. Canonical characterization techniques that rely upon mean squared displacement break down for nonergodic processes, making it challenging to characterize anomalous diffusion from an individual time-series measurement. Nonergodicity reigns when the time-averaged mean square displacement differs from the ensemble-averaged mean squared displacement even in the limit of long measurement series. In these cases, the typical theoretical results for ensemble averages cannot be used to understand and interpret data acquired from time averages. The difficulty then lies in obtaining statistical descriptors of the measured diffusion process that are not nonergodic. We show that linear descriptors such as the standard deviation, coefficient of variation, and root mean square break ergodicity in proportion to nonergodicity in the diffusion process. In contrast, time series of descriptors addressing sequential structure and its potential nonlinearity: multifractality change in a time-independent way and fulfill the ergodic assumption, largely independent of the time series' nonergodicity. We show that these findings follow the multiplicative cascades underlying these diffusion processes. Adding fractal and multifractal descriptors to typical linear descriptors would improve the characterization of anomalous diffusion processes. Two particular points bear emphasis here. First, as an appropriate formalism for encoding the nonlinearity that might generate nonergodicity, multifractal modeling offers descriptors that can behave ergodically enough to meet the needs of linear modeling. Second, this capacity to describe nonergodic processes in ergodic terms offers the possibility that multifractal modeling could unify several disparate nonergodic diffusion processes into a common framework.

Summary: Here, we present a standardized protocol for isolation, maintenance, and polarization of the respiratory epithelial primary cells from patient samples acquired from nasal brushing, polyp specimens, or lung explants. This protocol generates a clearly defined polarized layer of epithelial cells on filters, with a good number of ciliated cells and a thin layer of mucus. We detail the steps for samples prepared from patients with cystic fibrosis as well as from subjects without cystic fibrosis. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Novel quinazolinones conjugated with indole acetamide (4a–c), ibuprofen (7a–e), or thioacetohydrazide (13a,b, and 14a-d) were designed to increase COX-2 selectivity. The three synthesised series exhibited superior COX-2 selectivity compared with the previously reported quinazolinones and their NSAID analogue and had equipotent COX-2 selectivity as celecoxib. Compared with celecoxib, 4 b, 7c, and 13 b showed similar anti-inflammatory activity in vivo, while 13 b and 14a showed superior inhibition of the inflammatory mediator nitric oxide, and 7 showed greater antioxidant potential in macrophages cells. Moreover, all selected compounds showed improved analgesic activity and 13 b completely abolished the pain response. Additionally, compound 4a showed anticancer activity in tested cell lines HCT116, HT29, and HCA7. Docking results were consistent with COX-1/2 enzyme assay results. In silico studies suggest their high oral bioavailability. The overall findings for compounds (4a,b, 7c, 13 b, and 14c) support their potential role as anti-inflammatory agents.

Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft.

Abstract Estradiol and testosterone are powerful steroid hormones that impact brain function in numerous ways. During development, these hormones can act to program the adult brain in a male or female direction. During adulthood, gonadal steroid hormones can activate or inhibit brain regions to modulate adult functions. Sex differences in behavioral and neuroendocrine (i.e., hypothalamic pituitary adrenal (HPA) axis) responses to stress arise as a result of these organizational and activational actions. The sex differences that are present in the HPA and behavioral responses to stress are particularly important considering their role in maintaining homeostasis. Furthermore, dysregulation of these systems can underlie the sex biases in risk for complex, stress-related diseases that are found in humans. Although many studies have explored the role of estrogen and estrogen receptors in mediating sex differences in stress-related behaviors and HPA function, much less consideration has been given to the role of androgens. While circulating androgens can act by binding and activating androgen receptors, they can also act by metabolism to estrogenic molecules to impact estrogen signaling in the brain and periphery. This review focuses on androgens as an important hormone for modulating the HPA axis and behaviors throughout life and for setting up sex differences in key stress regulatory systems that could impact risk for disease in adulthood. In particular, impacts of androgens on neuropeptide systems known to play key roles in HPA and behavioral responses to stress (corticotropin-releasing factor, vasopressin, and oxytocin) are discussed. A greater knowledge of androgen action in the brain is key to understanding the neurobiology of stress in both sexes.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes. Methods In this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis. Results Up to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0–18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7–35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4–17.8) (p≤0.001). SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency. Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF. Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function). Conclusion SARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s

Introduction This study aimed to determine the prevalence of diabetic kidney disease (DKD) and rapid renal function decline and to identify indices associated with this decline among adults attending a diabetes center in Northern Europe.Research design and methods This is a retrospective cohort study of 4606 patients who attended a diabetes center in Ireland between June 2012 and December 2016. Definition/staging of chronic kidney disease used the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 classification based on data from the most recently attended appointment. Relevant longitudinal trends and variabilities were derived from serial records prior to index visit. Rapid renal function decline was defined based on per cent and absolute rates of estimated glomerular filtration rate (eGFR) change. Multiple linear regression was used to explore the relationships between explanatory variables and per cent eGFR change.Results 42.0% (total), 23.4% (type 1 diabetes), 47.9% (type 2 diabetes) and 32.6% (other diabetes) had DKD. Rapid decline based on per cent change was more frequent in type 2 than in type 1 diabetes (32.8% vs 14.0%, p

Objectives Cystic fibrosis (CF) lung disease is characterised by mucus stasis, chronic infection and inflammation, causing progressive structural lung disease and eventual respiratory failure. CF airways are inhabited by an ecologically diverse polymicrobial environment with vast potential for interspecies interactions, which may be a contributing factor to disease progression. Pseudomonas aeruginosa and Aspergillus fumigatus are the most common bacterial and fungal species present in CF airways respectively and coinfection results in a worse disease phenotype. Methods In this review we examine existing expert knowledge of chronic co-infection with P. aeruginosa and A. fumigatus in CF patients. We summarise the mechanisms of interaction and evaluate the clinical and inflammatory impacts of this co-infection. Results P. aeruginosa inhibits A. fumigatus through multiple mechanisms: phenazine secretion, iron competition, quorum sensing and through diffusible small molecules. A. fumigatus reciprocates inhibition through gliotoxin release and phenotypic adaptations enabling evasion of P. aeruginosa inhibition. Volatile organic compounds secreted by P. aeruginosa stimulate A. fumigatus growth, while A. fumigatus stimulates P. aeruginosa production of cytotoxic elastase. Conclusion A complex bi-directional relationship exists between P. aeruginosa and A. fumigatus, exhibiting both mutually antagonistic and cooperative facets. Cross-sectional data indicate a worsened disease state in coinfected patients; however, robust longitudinal studies are required to derive causality and to determine whether interspecies interaction contributes to disease progression.

Background OligoG is a low molecular-weight alginate oligosaccharide that improves the viscoelastic properties of cystic fibrosis (CF) mucus and disrupts biofilms, thereby potentiating the activity of antimicrobial agents. The efficacy of inhaled OligoG was evaluated in adult patients with CF. Methods A randomised, double-blind, placebo-controlled multicentre crossover study was used to demonstrate safety and efficacy of inhaled dry powder OligoG. Subjects were randomly allocated to receive OligoG 1050 mg per day (10 capsules three times daily) or matching placebo for 28 days, with 28-day washout periods following each treatment period. The primary end-point was absolute change in percentage predicted forced expiratory volume in 1 s (FEV1) at the end of 28-day treatment. The intention-to-treat (ITT) population (n=65) was defined as randomised to treatment with at least one administration of study medication and post-dosing evaluation. Results In this study, 90 adult subjects were screened and 65 were randomised. Statistically significant improvement in FEV1 was not observed in the ITT population. Adverse events included nasopharyngitis, cough and pulmonary exacerbation. The number and proportions of patients with adverse events and serious adverse events were similar between OligoG and placebo group. Conclusions Inhalation of OligoG-dry powder over 28 days was safe in adult CF subjects. Statistically significant improvement of FEV1 was not reached. The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo. Post hoc exploratory analyses showed subgroup results that indicate that further studies of OligoG in this patient population are justified.

The advent of Cystic fibrosis transmembrane receptor (CFTR) modulators in 2012 was a critical event in the history of cystic fibrosis (CF) treatment. Unlike traditional therapies that target downstream effects of CFTR dysfunction, CFTR modulators aim to correct the underlying defect at the protein level. These genotype-specific therapies are now available for an increasing number of CF patients, transforming the way we view the condition from a life-limiting disease to one that can be effectively managed. Several studies have demonstrated the vast improvement CFTR modulators have on normalization of sweat chloride, CFTR function, clinical endpoints, and frequency of pulmonary exacerbation. However, their impact on other aspects of the disease, such as pathogenic burden and airway infection, remain under explored. Frequent airway infections as a result of increased susceptibility and impaired innate immune response are a serious problem within CF, often leading to accelerated decline in lung function and disease progression. Current evidence suggests that CFTR modulators are unable to eradicate pathogenic organisms in those with already established lung disease. However, this may not be the case for those with relatively low levels of disease progression and conserved microbial diversity, such as young patients. Furthermore, it remains unknown whether the restorative effects exerted by CFTR modulators extend to immune cells, such as phagocytes, which have the potential to modulate the response of people with CF (pwCF) to infection. Throughout this review, we look at the potential impact of CFTR modulators on airway infection in CF and their ability to shape impaired pulmonary defences to pathogens.

Vector autoregression (VAR) modeling allows probing bidirectional relationships in gender/sex development and may support hypothesis testing following multi-modal data collection. We show VAR in three lights: supporting a hypothesis, rejecting a hypothesis, and opening up new questions. To illustrate these capacities of VAR, we reanalyzed longitudinal data that recorded dyadic mother–infant interactions for 15 boys and 15 girls aged 3 to 11 months of age. We examined monthly counts of 15 infant behaviors and 13 maternal behaviors (Seifer et al., 1994). VAR models demonstrated that infant crawling predicted a subsequently close feedback loop from mothers of boys but a subsequently open-ended, branched response from mothers of girls. A different finding showed that boys’ standing independently predicted significant later increases of four maternal behaviors: rocking/jiggling, lifting, affectionate touching, and stimulation of infant gross-motor activity. In contrast, crawling by girls led mothers to later decrease the same maternal behaviors. Thus, VAR might allow us to identify how mothers respond differently during daily interactions depending on infant gender/sex. The present work intends to mainly showcase the VAR method in the specific context of the empirical study of gender/sex development.

The Disease Control Priorities (DCP) publications have pioneered new ways of thinking about investing in health. We agree with Norheim, that a useful first step to advance efforts to translate DCP’s global evidence into local health priorities, is to develop a clear Theory of Change (ToC). However, a ToC that aims to define how global evidence (DCP and others) can be used to inform national policy is too narrow an undertaking. We propose efforts should be directed towards developing a ToC to define how to support progressive institutional development to deliver on universal health coverage (UHC), putting the client at the center. Enhancing efforts to meet the new global health imperatives requires a shift in focus of attention to move radically from global to local. In order to achieve this we need to reorganize the nature of technical assistance (TA) along three major lines (1) examine and act to clarify the mandates and roles to be played by multilateral normative and convening agencies, (2) ensure detailed understanding of local institutions, their needs and their demands, and (3) provide TA over time and in trust with local counterparts. This last requirement implies the need for long-term local presence as well as an international network of expertise centers, to share scarce technical capabilities as well as to learn together across country engagements. Financing will need to be reorganized to incentivize and support demand-led capacity strengthening.

The susceptibility and the severity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with hyperandrogenism, obesity, and preexisting pulmonary, metabolic, renal, and cardiac conditions. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with obesity, hyperandrogenism, and cardiometabolic dysregulations. We analyzed cardiac, renal, circulatory, and urinary SARS-CoV-2 viral entry proteins (ACE2, TMPRSS2, TMPRSS4, furin, cathepsin L, and ADAM17) and androgen receptor (AR) expression, in a peripubertal androgen exposure model of PCOS. Peripubertal female mice were treated with dihydrotestosterone (DHT) and low (LFD) or high (HFD) fat diet for 90 days. HFD exacerbated DHT-induced increase in body weight, fat mass, and cardiac and renal hypertrophy. In the heart, DHT upregulated AR protein in both LFD and HFD, ACE2 in HFD, and ADAM17 in LFD. In the kidney, AR protein expression was upregulated by both DHT and HFD. Moreover, ACE2 and ADAM17 were upregulated by DHT in both diets. Renal TMPRSS2, furin, and cathepsin L were upregulated by DHT and differentially modulated by the diet. DHT upregulated urinary ACE2 in both diets, while neither treatment modified serum ACE2. Renal AR mRNA expression positively correlated with Ace2, Tmprss2, furin, cathepsin L, and ADAM17. Our findings suggest that women with PCOS could be a population with a high risk of COVID-19-associated cardiac and renal complications. Furthermore, our study suggests that weight loss by lifestyle modifications (i.e., diet) could potentially mitigate COVID-19-associated deleterious cardiorenal outcomes in women with PCOS.

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.

Objective: To examine the impact of a diabetes renal clinic (DRC) on renal functional and metabolic indices in adults who have diabetes mellitus (DM) and chronic kidney disease (CKD). Patients and Methods: All patients evaluated at a DRC in a single tertiary referral center from January 1, 2008, to December 31, 2012, were identified. Serial renal and metabolic indices from January 1, 2004, to December 31, 2014, were recorded, and trends over time were analyzed by linear mixed-effects models. Results: A total of 200 patients who had DM and CKD were identified and subdivided into 3 categories based on presumptive CKD etiology: 43 (21.5%) with type 1 DM (T1D) only, 127 (63.5%) with type 2 DM (T2D) only, and 30 (15.0%) with DM and an additional CKD etiology. Average annual absolute (mL/min per body surface area per year) and percentage (%/year) changes, respectively, in Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate before vs after first DRC attendance were: −1.59 vs −3.10 (P=.31) and −1.22 vs −9.39 (P=.06) for T1D; −5.64 vs −3.07 (P=.004) and −10.88 vs −9.94 (P=.70) for T2D; and −6.50 vs +0.91 (P

Background: The emergence of antimicrobial resistance globally has initiated the discovery of novel antibiotics and other antimicrobial substances. Many of these novel compounds may be found in phytochemicals, where these novel compounds are extremely difficult to redissolve for antimicrobial susceptibility testing, following extraction. The aim of this study was to examine the potential antimicrobial effects of the common solvents, dimethyl sulfoxide (DMSO) and N, N-dimethylformamide (DMF), which are commonly employed as solvents of novel antimicrobial substances, with the nontuberculous Mycobacterium and Mycobacterium abscessus. Methods: M. abscessus clinical isolates (n = 17 isolates) were examined for the antimicrobial effects of DMSO and DMF. McFarland 0.5 standards of each isolate were prepared individually on Columbia Blood agar onto which DMSO and DMF were added (10 μl) in the range neat (undiluted) – 10,000-fold (10−4) dilution and incubated. Zones of inhibition were recorded in mm. Results: DMSO and DMF had an inhibitory effect on M. abscessus (n = 17 clinical isolates). This inhibitory effect was avoided by diluting DMSO 10-fold and DMF 10,000-fold. Conclusion: Such data are important when employing these common solvents with molecules which are difficult to dissolve into solution, including conventional antibiotics, as well as novel antimicrobial agents, particularly in antimicrobial susceptibility studies. Investigators should therefore be aware of this inhibition and avoid working with these solvents at high concentration to avoid bacterial growth inhibition. The use of appropriate experimental controls is highly recommended in such circumstances to avoid the reporting of false-positive antimicrobial effects.

Background: Antimicrobial resistance (AMR) has rendered certain species of Mycobacterium difficult to treat clinically, particularly the nontuberculous Mycobacterium, Mycobacterium abscessus, in patients with cystic fibrosis (CF). Such patients are treated with several nonantibiotic medicines, which may have antimicrobial properties. Given the growing burden of AMR in M. abscessus, it is importtant to investigate the antimicrobial activity of all medicines used in the treatment of such patients. It was, therefore, the aim of this study to examine the antimicrobial activity of 10 nonantibiotic medicines used commonly in the treatment of CF. Methods: Antibiotic susceptibility studies were performed on human clinical isolates of M. abscessus (n = 16) including 11 smooth isolates, four rough isolates and one Reference isolate (NCTC 13031), against the following 10 nonantibiotic medicines:-aspirin (850 ug/ml), chlorphenamine (400 ug/ml), Creon (4000 international units/ml), cyclizine (50 mg/ml), DNase (1 μg/ml), hypertonic saline (NaCl) 7% (w/v), ibuprofen (44.4 mg/ml), lansoprazole (300 ug/ml), paracetamol (10 mg/ml), and prednisolone (500 ug/ml). Results: Of the 10 nonantibiotic drugs investigated, inhibition of M. abscessus was noted with chlorphenamine (400 ug/ml), cyclizine (50 mg/ml), ibuprofen (44.4 mg/ml) and lansoprazole (300 ug/ml), with no activity associated with aspirin (850 ug/ml), Creon (4000 international units/ml), DNase (1 μg/ml), hypertonic saline (NaCl) 7% (w/v), paracetamol (10 mg/ml), and prednisolone (500 ug/ml). The minimum inhibitory concentration (MIC) of cyclizine to M. abscessus (n = 6) ranged from 8.0 to 12.5 ug/ml, with a mean MIC, MIC50, and MIC90of 10.6, 10.0 and 12.5 ug/ml, respectively. Conclusion: This study identified that chlorphenamine, cyclizine, ibuprofen, and lansoprazole have in vitro antimycobacterial activity against clinical M. abscessus, isolated from patients with CF. Further studies should now examine potential antimicrobial synergy between these compounds and common conventional antimycobacterial antibiotics, including the macrolides and fluoroquinolones, to decide how best to exploit such positive interactions to reduce AMR burden and improve treatment regimens.

Movement coordination depends on directing our limbs to the right place and in the right time. Movement science can study this central requirement in the Fitts task that asks participants to touch each of two targets in alternation, as accurately and as fast as they can. The Fitts task is an experimental attempt to focus on how the movement system balances its attention to speed and to accuracy. This balance in the Fitts task exhibits a hierarchical organization according to which finer details (e.g., kinematics of single sweeps from one target to the other) change with relatively broader constraints of task parameters (e.g., distance between targets and width of targets). The present work seeks to test the hypothesis that this hierarchical organization of movement coordination reflects a multifractal tensegrity in which non-linear interactions across scale support stability. We collected movement series data during a easy variant of the Fitts task to apply just such a multifractal analysis with surrogate comparison to allow clearer test of non-linear interactions across scale. Furthermore, we test the role of visual feedback both in potential and in fact, i.e., by manipulating both whether experimenters instructed participants that they might potentially have to close their eyes during the task and whether participants actually closed their eyes halfway through the task. We predict that (1) non-linear interactions across scales in hand movement series will produce variability that will actually stabilize aiming in the Fitts task, reducing standard deviation of target contacts; (2) non-linear interactions across scales in head sway will stabilize aiming following the actual closing eyes; and (3) non-linear interactions across scales in head sway and in hand movements will interact to support stabilizing effects of expectation about closing eyes. In sum, this work attempts to make the case that the multifractal-tensegrity hypothesis supports more accurate aiming behavior in the Fitts task.

Ecological relationships between bacteria are important when considering variation in bacterial communities in humans, with such variation playing an important role in both health and disease. Using high-throughput sequence data of the 16S rRNA marker-gene, we analysed the prevalence of taxa in the airways of a number of health- and disease-associated cohorts and determined the main drivers of community variance and bacterial co-occurrence. A number of facultative and obligately anaerobic bacterial taxa are commonly associated with the upper airways, forming the main “core” microbiota, e.g. Streptococcus spp., Veillonella spp., Prevotella spp., Granulicatella spp. and Fusobacterium spp. Opportunistic pathogenic bacteria associated with chronic airways disease, such as Pseudomonas spp. (Pseudomonas aeruginosa), Burkholderia spp. (Burkholderia cepacia complex) and Haemophilus spp. (Haemophilus influenzae) demonstrated poor correlation with other members of their respective communities (ρ0.005), indicating probable independent acquisition and colonisation. Furthermore, our findings suggest that intra-genus variation between health and disease may affect community assemblies. Improved understanding of how bacteria assemble in time and space during health and disease will enable the future development of tailored treatment according to the patient's own signature microbiota, potentially providing benefit to patients suffering from airway diseases characterised by chronic infection.

Children with Attention-Deficit Hyperactivity Disorder (ADHD) struggle to perform a host of daily activities. Many of these involve forceful interaction with objects and thus implicate dynamic touch. Therefore, deficits in dynamic touch could underlie functional difficulties presented by ADHD children. We investigated whether performance on a dynamic touch task (length perception by wielding) differ between children with ADHD and age-matched controls. We further examined whether this difference could be explained by fractal temporal correlations (wielding dynamics). Forty-two children (ADHD: 21; typically developing: 21) wielded unseen wooden rods and reported their perceived length in the form of magnitude productions. The rods varied in the magnitude of the first principal moment of inertia (I1). Three-dimensional displacements of hand and rod positions were submitted to Detrended Fluctuation Analysis to estimate trial-by-trial temporal correlations. Children with ADHD reported shorter length for rods with higher I1 than their typically developing peers, indicative of reduced sensitivity to mechanical information supporting dynamic touch. Importantly, temporal correlations in wielding dynamics moderated children's usage of I1. This finding points to a role of exploratory movements in perceptual deficits presented by children with ADHD and, thus, should be considered a new potential target for interventions.

By definition, perception is a multisensory process that unfolds in time as a complex sequence of exploratory activities of the organism. In such a system perception and action are integrated, and multiple energy arrays are available simultaneously. Perception of affordances interweaves sensory and motor activities into meaningful behavior given task constraints. The present contribution offers insight into the manner in which perception and action usher the organism through competent functional apprehension of its surroundings. We propose that the tensegrity structure of the body, manifested via multifractality of exploratory bodily movements informs perception of affordances. The affordance of stand-on-ability of ground surfaces served as the experimental paradigm. Observers viewed a surface set to a discrete angle and attempted to match it haptically with a continuously adjustable surface occluded by a curtain, or felt an occluded surface set to a discrete angle then matched it visually with a continuously adjustable visible surface. The complex intertwining of perception and action was demonstrated by the interactions of multifractality of postural sway with multiple energy arrays, responses, and changing geometric task demands.

Reading research uses different tasks to investigate different levels of the reading process, such as word recognition, syntactic parsing, or semantic integration. It seems to be tacitly assumed that the underlying cognitive process that constitute reading are stable across those tasks. However, nothing is known about what happens when readers switch from one reading task to another. The stability assumptions of the reading process suggest that the cognitive system resolves this switching between two tasks quickly. Here, we present an alternative language-game hypothesis (LGH) of reading that begins by treating reading as a softly-assembled process and that assumes, instead of stability, context-sensitive flexibility of the reading process. LGH predicts that switching between two reading tasks leads to longer lasting phase-transition like patterns in the reading process. Using the nonlinear-dynamical tool of recurrence quantification analysis, we test these predictions by examining series of individual word reading times in self-paced reading tasks where native (L1) and second language readers (L2) transition between random word and ordered text reading tasks. We find consistent evidence for phase-transitions in the reading times when readers switch from ordered text to random-word reading, but we find mixed evidence when readers transition from random-word to ordered-text reading. In the latter case, L2 readers show moderately stronger signs for phase-transitions compared to L1 readers, suggesting that familiarity with a language influences whether and how such transitions occur. The results provide evidence for LGH and suggest that the cognitive processes underlying reading are not fully stable across tasks but exhibit soft-assembly in the interaction between task and reader characteristics.