Correction: Data-driven analyses of motor impairments in animal models of neurological disorders.

[This corrects the article DOI: 10.1371/journal.pbio.3000516.].

Data-driven analyses of motor impairments in animal models of neurological disorders.

Behavior provides important insights into neuronal processes. For example, analysis of reaching movements can give a reliable indication of the degree of impairment in neurological disorders such as stroke, Parkinson disease, or Huntington disease. The analysis of such movement abnormalities is notoriously difficult and requires a trained evaluator. Here, we show that a deep neural network is able to score behavioral impairments with expert accuracy in rodent models of stroke. The same network was also trained to successfully score movements in a variety of other behavioral tasks. The neural network also uncovered novel movement alterations related to stroke, which had higher predictive power of stroke volume than the movement components defined by human experts. Moreover, when the regression network was trained only on categorical information (control = 0; stroke = 1), it generated predictions with intermediate values between 0 and 1 that matched the human expert scores of stroke severity. The network thus offers a new data-driven approach to automatically derive ratings of motor impairments. Altogether, this network can provide a reliable neurological assessment and can assist the design of behavioral indices to diagnose and monitor neurological disorders.

Real-world Omalizumab and Mepolizumab treated difficult asthma phenotypes and their clinical outcomes.

BACKGROUND: Omalizumab and Mepolizumab are biologic drugs with proven efficacy in clinical trials. However, a better understanding of their real-world effectiveness in severe asthma management is needed. OBJECTIVES: To better understand the real-world effectiveness of Omalizumab and Mepolizumab, elucidate the clinical phenotypes of patients treated with these drugs, identify baseline characteristics associated with biologic response and assess the spectrum of responses to these medications. METHODS: Using real-world clinical data, we retrospectively phenotyped biologic naïve patients from the Wessex AsThma CoHort of difficult asthma (N = 478) commenced on Omalizumab (N = 105) or Mepolizumab (N = 62) compared to severe asthma patients not receiving biologics (SNB, N = 178). We also assessed multiple clinical endpoints and identified features associated with response. RESULTS: Compared to SNB, Omalizumab patients were younger, diagnosed with asthma earlier, and more likely to have rhinitis. Conversely, compared to SNB, Mepolizumab patients were predominantly older males, diagnosed with asthma later, and more likely to have nasal polyposis but less dysfunctional breathing. Both treatments reduced exacerbations, Acute Healthcare Encounters [AHE] (emergency department or hospital admissions), maintenance oral corticosteroid dose, and improved Asthma Control Questionnaire 6 (ACQ6) scores. Omalizumab response was independently associated with more baseline exacerbations (p = .024) but fewer AHE (p = .050) and absence of anxiety (p = .008). Lower baseline ACQ6 was independently associated with Mepolizumab response (p = .007). A composite group of non-responders demonstrated significantly more psychopathologies and worse baseline subjective disease compared to responder groups. CONCLUSIONS AND CLINICAL RELEVANCE: In a difficult asthma cohort, Omalizumab and Mepolizumab were used in distinct clinical phenotypes but were both multidimensionally efficacious. Certain baseline clinical characteristics were associated with poorer biologic responses, such as psychological co-morbidity, which may assist clinicians in biologic selection. These characteristics also emphasize the need for comprehensive approaches to support these patients.

Clinical evaluation of type 2 disease status in a real-world population of difficult to manage asthma using historic electronic healthcare records of blood eosinophil counts.

BACKGROUND: Blood eosinophil measurement is essential for the phenotypic characterization of patients with difficult asthma and in determining eligibility for anti-IL-5/IL-5Rα biological therapies. However, assessing such measures over limited time spans may not reveal the true underlying eosinophilic phenotype, as treatment, including daily oral corticosteroid therapy, suppresses eosinophilic inflammation and asthma is intrinsically variable. METHODS: We interrogated the electronic healthcare records of patients in the Wessex AsThma CoHort of difficult asthma (WATCH) study (UK). In 501 patients being evaluated in this tertiary care centre for difficult to control asthma, all requested full blood count test results in a 10-year retrospective period from the index WATCH assessment were investigated (n = 11,176). RESULTS: In 235 biological therapy-naïve participants who had 10 or more measures in this time period, 40.3% were eosinophilic (blood eosinophils ≥300 cells/µl) at WATCH enrolment whilst an additional 43.1%, though not eosinophilic at enrolment, demonstrated eosinophilia at least once in the preceding decade. Persistent eosinophilia was associated with worse post-bronchodilator airway obstruction and higher Fractional exhaled Nitric Oxide (FeNO). In contrast, the 16.6% of patients who never demonstrated eosinophilia at this blood eosinophil threshold showed preserved lung function and lower markers of Type 2 inflammation. CONCLUSIONS: This highlights the central role that type 2 inflammation, as indicated by blood eosinophilia, has in difficult asthma and suggests that longitudinal electronic healthcare record analysis can be an important tool in clinical asthma phenotyping, providing insight that may help understand disease progression and better guide more specific treatment approaches.

Triple differential cross-section measurements for electron-impact ionization of methane from a coplanar geometry to the perpendicular plane.

A new study of electron-impact single ionization of the HOMO 1t2 state of CH4 has been conducted at incident electron energies 20 eV and 40 eV above the ionization energy of the state. Triple differential cross sections were measured from a coplanar symmetric geometry, where scattered and ionized electrons were detected at equal angles, through to the perpendicular geometry where the outgoing electrons emerged orthogonal to the incident electron beam. At the lower energy, the electrons were detected with equal energies of 10 eV, whereas at the higher energy, data were obtained for equal energies of 20 eV and for unequal energies of 5 eV and 35 eV. The results are compared to a molecular 3-body distorted wave approximation that used a full averaging procedure to allow for the random orientation of the target, an orientation averaged molecular orbital model that averages the target wavefunction over all orientations prior to the collision, and a distorted wave Born approximation that does not include postcollisional interactions.

Triple differential cross sections for electron-impact ionization of methane at intermediate energy.

We report an experimental and theoretical investigation of electron-impact single ionization of the highest occupied molecular orbital 1t2 and the next highest occupied molecular orbital 2a1 states of CH4 at an incident electron energy of 250 eV. Triple differential cross sections measured in two different laboratories were compared with results calculated within the molecular 3-body distorted wave and generalized Sturmian function theoretical models. For ionization of the 1t2 state, the binary peak was observed to have a single maximum near the momentum transfer direction that evolved into a double peak for increasing projectile scattering angles, as has been seen for ionization of atomic p-states. A detailed investigation of this evolution was performed. As expected because of its s-type character, for ionization of the 2a1 state, only a single binary peak was observed. Overall, good agreement was found between experiment and theory.

Insights from Fragment Hit Binding Assays by Molecular Simulations.

Novel bioactive molecules can be rationally designed by growing and linking small fragments. Because fragments are fast and promiscuous, it is common to have contradictory hit results between different experimental screening techniques. Here, we simultaneously determine fragment binding poses, affinities, and kinetics on a focused library of 42 fragments against the serine protease factor Xa using multimillisecond molecular dynamics simulations. We predict experimental poses of 12 over 15 S1 crystal structures, and affinities are recovered for 4 out of 6. A kinetic map of protein cavities is computed in terms of on- and off-rates as well as insights into secondary ligand poses. The results suggest that the approach can be useful to recapitulate discordant fragment screening data.

Digital data repositories in chemistry and their integration with journals and electronic notebooks.

We discuss the concept of recasting the data-rich scientific journal article into two components, a narrative and separate data components, each of which is assigned a persistent digital object identifier. Doing so allows each of these components to exist in an environment optimized for purpose. We make use of a poorly-known feature of the handle system for assigning persistent identifiers that allows an individual data file from a larger file set to be retrieved according to its file name or its MIME type. The data objects allow facile visualization and retrieval for reuse of the data and facilitates other operations such as data mining. Examples from five recently published articles illustrate these concepts.

Developing and testing a produce prescription implementation blueprint to improve food security in a clinical setting: a pilot study protocol.

BACKGROUND: Food insecurity is common in the United States, especially in Rhode Island, where it affects up to 33% of residents. Food insecurity is associated with adverse health outcomes and disproportionally affects people from minoritized backgrounds. Produce prescription programs, in which healthcare providers write "prescriptions" for free or reduced cost vegetables, have been used to address food insecurity and diet-related chronic disease. Although there is growing evidence for the effectiveness of produce prescription programs in improving food security and diet quality, there have been few efforts to use implementation science methods to improve the adoption of these programs. METHODS: This two-phase pilot study will examine determinants and preliminary implementation and effectiveness outcomes for an existing produce prescription program. The existing program is funded by an Accountable Care Organization in Rhode Island and delivered in primary care practices. For the first phase, we conducted a formative evaluation, guided by the Consolidated Framework for Implementation Research 2.0, to assess barriers, facilitators, and existing implementation strategies for the produce prescription program. Responses from the formative evaluation were analyzed using a rapid qualitative analytic approach to yield a summary of existing barriers and facilitators. In the second phase, we presented our formative evaluation findings to a community advisory board consisting of primary care staff, Accountable Care Organization staff, and staff who source and deliver the vegetables. The community advisory board used this information to identify and refine a set of implementation strategies to support the adoption of the program via an implementation blueprint. Guided by the implementation blueprint, we will conduct a single-arm pilot study to assess implementation antecedents (i.e., feasibility, acceptability, appropriateness, implementation climate, implementation readiness), implementation outcomes (i.e., adoption), and preliminary program effectiveness (i.e., food and nutrition security). The first phase is complete, and the second phase is ongoing. DISCUSSION: This study will advance the existing literature on produce prescription programs by formally assessing implementation determinants and developing a tailored set of implementation strategies to address identified barriers. Results from this study will inform a future fully powered hybrid type 3 study that will use the tailored implementation strategies and assess implementation and effectiveness outcomes for a produce prescription program. TRIAL REGISTRATION: Clinical trials: NCT05941403 , Registered June 9, 2023.

Fatal epiglottic abscess after radiotherapy for laryngeal carcinoma.

Acute epiglottitis is a rare condition, especially in adults, largely owing to the widespread vaccination against Haemophilus influenzae. Traumatic epiglottitis as a result of thermal or caustic insults is documented. Epiglottic abscess formation is described as a sequela of epiglottitis in some cases. The development of epiglottic abscess from epiglottitis secondary to radiotherapy has previously been described in the literature; however, there are no reports of fatalities due to epiglottic abscess after radiotherapy. We present an unusual case of an adult sudden death due to epiglottic abscess formation subsequent to radiotherapy for laryngeal squamous cell carcinoma.

Measurement of Exhaled Volatile Organic Compounds as a Biomarker for Personalised Medicine: Assessment of Short-Term Repeatability in Severe Asthma.

The measurement of exhaled volatile organic compounds (VOCs) in exhaled breath (breathomics) represents an exciting biomarker matrix for airways disease, with early research indicating a sensitivity to airway inflammation. One of the key aspects to analytical validity for any clinical biomarker is an understanding of the short-term repeatability of measures. We collected exhaled breath samples on 5 consecutive days in 14 subjects with severe asthma who had undergone extensive clinical characterisation. Principal component analysis on VOC abundance across all breath samples revealed no variance due to the day of sampling. Samples from the same patients clustered together and there was some separation according to T2 inflammatory markers. The intra-subject and between-subject variability of each VOC was calculated across the 70 samples and identified 30.35% of VOCs to be erratic: variable between subjects but also variable in the same subject. Exclusion of these erratic VOCs from machine learning approaches revealed no apparent loss of structure to the underlying data or loss of relationship with salient clinical characteristics. Moreover, cluster evaluation by the silhouette coefficient indicates more distinct clustering. We are able to describe the short-term repeatability of breath samples in a severe asthma population and corroborate its sensitivity to airway inflammation. We also describe a novel variance-based feature selection tool that, when applied to larger clinical studies, could improve machine learning model predictions.

The Detrimental Clinical Associations of Anxiety and Depression with Difficult Asthma Outcomes.

Difficult asthma describes asthma in which comorbidities, inadequate treatment, suboptimal inhaler technique and/or poor adherence impede good asthma control. The association of anxiety and depression with difficult asthma outcomes (exacerbations, hospital admissions, asthma control, etc.) is unclear. This study assessed the clinical associations of anxiety and depression with difficult asthma outcomes in patients with a specialist diagnosis of difficult asthma. Using real-world data, we retrospectively phenotyped patients from the Wessex Asthma Cohort of Difficult Asthma (N = 441) using clinical diagnoses of anxiety and depression against those without anxiety or depression (controls). Additionally, we stratified patients by severity of psychological distress using the Hospital Anxiety and Depression Scale (HADS). We found that depression and/or anxiety were reported in 43.1% of subjects and were associated with worse disease-related questionnaire scores. Each psychological comorbidity group showed differential associations with difficult asthma outcomes. Anxiety alone (7.9%) was associated with dysfunctional breathing and more hospitalisations [anxiety, median (IQR): 0 (2) vs. controls: 0 (0)], while depression alone (11.6%) was associated with obesity and obstructive sleep apnoea. The dual anxiety and depression group (23.6%) displayed multimorbidity, worse asthma outcomes, female predominance and earlier asthma onset. Worse HADS-A scores in patients with anxiety were associated with worse subjective outcomes (questionnaire scores), while worse HADS-D scores in patients with depression were associated with worse objective (ICU admissions and maintenance oral corticosteroid requirements) and subjective outcomes. In conclusion, anxiety and depression are common in difficult asthma but exert differential detrimental effects. Difficult asthma patients with dual anxiety and depression experience worse asthma outcomes alongside worse measures of psychological distress. There is a severity-gradient association of HADS scores with worse difficult asthma outcomes. Collectively, our findings highlight the need for holistic, multidisciplinary approaches that promote early identification and management of anxiety and depression in difficult asthma patients.

Wikipedia: a key tool for global public health promotion.

The Internet has become an important health information resource for patients and the general public. Wikipedia, a collaboratively written Web-based encyclopedia, has become the dominant online reference work. It is usually among the top results of search engine queries, including when medical information is sought. Since April 2004, editors have formed a group called WikiProject Medicine to coordinate and discuss the English-language Wikipedia's medical content. This paper, written by members of the WikiProject Medicine, discusses the intricacies, strengths, and weaknesses of Wikipedia as a source of health information and compares it with other medical wikis. Medical professionals, their societies, patient groups, and institutions can help improve Wikipedia's health-related entries. Several examples of partnerships already show that there is enthusiasm to strengthen Wikipedia's biomedical content. Given its unique global reach, we believe its possibilities for use as a tool for worldwide health promotion are underestimated. We invite the medical community to join in editing Wikipedia, with the goal of providing people with free access to reliable, understandable, and up-to-date health information.

Digitally controlled laser frequency stabilization for a ring laser using saturated absorption.

A digital system for controlling the frequency of a continuous wave (CW) ring laser is described. The system utilizes Doppler-free absorption to steer the laser onto a resonance peak within a vapor cell and can hold the laser at this frequency for long periods of time using active feedback. The vapor cell is immersed in a sinusoidally varying magnetic field that produces a feedback signal by exploiting the Zeeman effect so that the laser frequency does not need to be dithered to achieve lock. A bias field can also be applied to adjust the frequency over several MHz while maintaining lock. This is advantageous for cold atom studies that require the laser to be red-detuned from resonance. Signals from the absorption cell and magnetic field are digitized and fed to a dedicated microcontroller that calculates and produces the feedback signal. The digital control system is described, and measurements are presented where the locked frequency is compared to data obtained from a commercial wavemeter. The locked frequency standard deviations ranged from 250 to 450 kHz within a 1 h period. The Allan deviations of the locked frequency had the best stability at a value of 6 × 10-11 in a 10 s averaging period. The locking system described here has application in experiments that require very stable laser frequency control and can also be used for regular recalibration of wavemeter parameters. The design can easily be adapted to control different CW laser systems and hence can be used for a range of atomic targets.

Joint ESCMID, FEMS, IDSA, ISID and SSI position paper on the fair handling of career breaks among physicians and scientists when assessing eligibility for early-career awards.

BACKGROUND: Though women increasingly make up the majority of medical-school and other science graduates, they remain a minority in academic biomedical settings, where they are less likely to hold leadership positions or be awarded research funding. A major factor is the career breaks that women disproportionately take to see to familial duties. They experience a related, but overlooked, hurdle upon their return: they are often too old to be eligible for 'early-career researcher' grants and 'career-development' awards, which are stepping stones to leadership positions in many institutions and which determine the demographics of their hierarchies for decades to come. Though age limits are imposed to protect young applicants from more experienced seniors, they have an unintended side effect of excluding returning workers, still disproportionately women, from the running. METHODS: In this joint effort by the European Society of Clinical Microbiology and Infectious Diseases, the Federation of European Microbiological Societies, the Infectious Disease Society of America, the International Society for Infectious Diseases and the Swiss Society for Infectious Diseases, we invited all European Congress of Clinical Microbiology and Infectious Diseases-affiliated medical societies and funding bodies to participate in a survey on current 'early-career' application restrictions and measures taken to provide protections for career breaks. RECOMMENDATIONS: The following simple consensus recommendations are geared to funding bodies, academic societies and other organizations for the fair handling of eligibility for early-career awards: 1. Apply a professional, not physiological, age limit to applicants. 2. State clearly in the award announcement that career breaks will be factored into applicants' evaluations such that: • Time absent is time extended: for every full-time equivalent of career break taken, the same full-time equivalent will be extended to the professional age limit. • Opportunity costs will also be taken into account: people who take career breaks risk additional opportunity costs, with work that they did before the career break often being forgotten or poorly documented, particularly in bibliometric accounting. Although there is no standardized metric to measure additional opportunity costs, organizations should (a) keep in mind their existence when judging applicants' submissions, and (b) note clearly in the award announcement that opportunity costs of career breaks are also taken into account. 3. State clearly that further considerations can be undertaken, using more individualized criteria that are specific to the applicant population and the award in question. The working group welcomes feedback so that these recommendations can be improved and updated as needed.

An experimental control system for electron spectrometers using Arduino and LabVIEW interfaces.

A modular, customizable, and low-cost experimental control system for electron spectrometers is described. LabVIEW is used to interface with a suite of Arduino-controlled power supplies, detectors, and stepper motors enabling a variety of different types of measurements to be performed. The structure of the LabVIEW control system and the general design of the Arduino-controlled modules are described. Examples of results from electron scattering and electron impact ionization experiments performed using this control system are presented.

Clinical characteristics, symptoms and outcomes of 1054 adults presenting to hospital with suspected COVID-19: A comparison of patients with and without SARS-CoV-2 infection.

OBJECTIVES: Most reports describing the characteristics of patients hospitalised with COVID-19 lack a comparator group. We compared clinical characteristics, symptoms, and outcomes of adults presenting to hospital during the pandemic first wave, who tested positive and negative for SARS-CoV-2. METHODS: Detailed patient data was obtained from a large, controlled, non-randomised trial of molecular point-of-care testing versus laboratory RT-PCR for SARS-CoV-2 in adults presenting to a large UK hospital with suspected COVID-19. RESULTS: 1054 patients were included: 352 (33.4%) tested positive and 702 (66.6%) negative. 13.4% (47/352) COVID-19-positive patients had COPD versus 18.7% (131/702) of COVID-19-negative patients (difference=5.3% [95%CI -9.7% to -0.5%], p = 0.0297). 5.7% (20/352) of COVID-19-positive patients were smokers versus 16.5% (116/702) of negative patients (difference=-10.8% [-14.4% to -7.0%], p = 0.0001). 70.5% (248/352) of COVID-19-positive patients were White-British versus 85.5% (600/702) of negative patients (difference=-15.0% [-20.5% to -9.7%], p<0.0001). 20.9% (39/187) of COVID-19-positive patients were healthcare workers versus 5.2% (15/287) of negative patients (p<0.0001). Anosmia was reported in 33.1% (47/142) versus 8.8% (19/216) of COVID-19-positive and negative patients respectively (p<0.0001). Non-SARS-CoV-2 respiratory viruses or atypical bacteria were detected in 2.5% (5/197) of COVID-19 patients versus 7.9% (24/302) of COVID-19-negative patients (p = 0.0109). Hospitalisation duration and 30-day-mortality were higher in COVID-19 patients and invasive ventilation was more frequent (11.1% vs 2.8%, p<0.0001), and longer (14.5 vs 4.7 days, p = 0.0015). CONCLUSIONS: There were substantial differences between patients with and without COVID-19 in terms of ethnicity, healthcare worker-status, comorbidities, symptoms, and outcomes. These data can inform healthcare planning for the next phase of the pandemic.

Patient perceived barriers to exercise and their clinical associations in difficult asthma.

BACKGROUND: Exercise is recommended in guidelines for asthma management and has beneficial effects on symptom control, inflammation and lung function in patients with sub-optimally controlled asthma. Despite this, physical activity levels in patients with difficult asthma are often impaired. Understanding the barriers to exercise in people with difficult asthma is crucial for increasing their activity, and in implementing successful, disease modifying, and holistic approaches to improve their health. METHODS: 62 Patients within the WATCH Difficult Asthma Cohort (Southampton, UK) completed an Exercise Therapy Burden Questionnaire (ETBQ). The results were analyzed with contemporaneous asthma-related data to determine relationships between perceived exercise barriers and asthma and comorbidity characteristics. RESULTS: Patients were reflective of a difficult asthma cohort, 66% were female, and 63% were atopic. They had a high BMI (median [inter-quartile range]) of 29.3 [25.5-36.2], age of 53.5 [38.75, 65.25], impaired spirometry with FEV1 73% predicted [59.5, 86.6%] and FEV/FVC ratio of 72 [56.5, 78.0] and poor symptom control, as defined by an Asthma Control Questionnaire (ACQ6) result of 2.4 [1.28, 3.2]. A high perceived barriers to exercise score was significantly correlated with increased asthma symptoms (r = 0.452, p < 0.0001), anxiety (r = 0.375, p = 0.005) and depression (r = 0.363, p = 0.008), poor quality of life (r = 0.345, p = 0.015) and number of rescue oral steroid courses in the past 12 months (r = 0.257, p = 0.048). Lung function, blood eosinophil count, FeNO, Njimegen and SNOT22 scores, BMI and hospitalisations in the previous year were not related to exercise perceptions. CONCLUSION: In difficult asthma, perceived barriers to exercise are related to symptom burden and psychological morbidity. Therefore, exercise interventions combined with psychological input such as CBT to restructure thought processes around these perceived barriers may be useful in facilitating adoption of exercise.

New Perspectives on Difficult Asthma; Sex and Age of Asthma-Onset Based Phenotypes.

BACKGROUND: Asthma is a diverse condition that differs with age and sex. However, it remains unclear how sex, age of asthma onset, and/or their interaction influence clinical expression of more problematic adult "difficult" asthma. OBJECTIVES: To better understand the clinical features of difficult asthma within a real-world clinical setting using novel phenotypic classification, stratifying subjects by sex and age of asthma onset. METHODS: Participants in a longitudinal difficult asthma clinical cohort study (Wessex AsThma CoHort of difficult asthma; WATCH), United Kingdom (n = 501), were stratified into 4 difficult asthma phenotypes based on sex and age of asthma onset (early <18 years or adult ≥18 years) and characterized in relation to clinical and pathophysiological features. RESULTS: The cohort had more female participants (65%) but had similar proportions of participants with early- or adult-onset disease. Early-onset female disease was commonest (35%), highly atopic, with good spirometry and strong associations with some physical comorbidities but highest psychophysiologic comorbidities. Adult-onset females also had considerable psychophysiologic comorbidities and highest obesity, and were least atopic. Amongst male subjects, proportionately more had adult-onset disease. Early-onset male disease was rarest (14%) but associated with worst lung function, high smoking, atopy, and fungal sensitization. Despite shortest disease duration, adult-onset males had highest use of maintenance oral corticosteroid, poor lung function, and highest fractional exhaled nitrogen oxide in spite of highest smoking prevalence. CONCLUSIONS: This study shows that sex, age of asthma onset, and their interactions influence different clinical manifestations of difficult asthma and identifies a greater risk for lung function loss and oral corticosteroid dependence associated with smoking in adult-onset male subjects.