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Project HERCULES has developed a natural history model (NHM) of disease progression in Duchenne muscular dystrophy (DMD) that comprises eight ordered health states (two ambulatory states, one transfer state indicating increased caregiver burden in which patients cannot walk/run 10m or rise from floor but can still support their own weight, and five non-ambulatory states). The current study used data from nine sources (clinical trial placebo arms, one real-world dataset, and three natural history datasets) to further characterize patients with DMD according to these health states. The study included 1,173 patients across 5,306‬ visits. Patients were on average older and exhibited worse ambulatory, pulmonary, upper limb, and cardiac functions with each successive health state. Mean±SE ages increased monotonically across health states, starting with 8.47±0.07 for early ambulatory, 10.86±0.13 for late ambulatory, 11.65±0.35 for transfer state, and ranging from 13.17±0.32 to 16.84±0.37 for the non-ambulatory states. North Star Ambulatory Assessment (NSAA) total score, which measures motor function and ranges from 34 (best) to 0 (worst), was 23.7 (interquartile range [IQR]: 20-30) for early ambulatory patients, 12.7 (IQR: 9-16) for late ambulatory patients, and 3.9 (IQR: 2-5) for transfer patients. Pulmonary function as measured by mean±SE of forced vital capacity percent predicted (FVC%p) was 94.5±0.8 for early ambulatory, 89.1±1.4 for late ambulatory, and 80.2±2.8 for transfer states, and decreased from 77.2±1.7 to 20.6±1.6 across the five non-ambulatory health states. In summary, these findings further characterize health states and their interpretation in economic modeling and decision-making in DMD management.

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the meaningfulness of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to 80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.

This study examined functional trajectories of subjects during the transition phase between ambulatory and non-ambulatory Duchenne muscular dystrophy (DMD) to inform clinical trial designs for new therapeutics. Ambulatory, pulmonary, and upper limb function leading up to loss of ambulation (LoA) and non-ambulatory measures following LoA were quantified; time ordering of pulmonary and upper limb milestones relative to LoA were determined; and the 10-second time threshold for 10-meter walk/run (10MWR) as a marker of approaching LOA was explored. Included in this analysis were 51 subjects aged between 7 and 18 years who experienced LoA during follow-up in the PRO-DMD-01 natural history study. Mean age at LoA was 12.7 (7.1-18.6) years. Mean annual rates of decline in forced vital capacity (FVC) 10 s, those with

PurposeBevacizumab-related imaging abnormality (BRIA), appearing as areas of restricted diffusion on magnetic resonance imaging (MRI) and representing atypical coagulative necrosis pathologically, has been observed in patients with brain tumors receiving radiotherapy and bevacizumab. We investigated the role of cumulative radiation dose in BRIA development in a voxel-wise analysis.MethodsPatients (n = 18) with BRIA were identified. All had high-grade gliomas or brain metastases treated with radiotherapy and bevacizumab. Areas of BRIA were segmented semi-automatically on diffusion-weighted MRI with apparent diffusion coefficient (ADC) images. To avoid confounding by possible tumor, hypoperfusion was confirmed with perfusion imaging. ADC images and radiation dose maps were co-registered to a high-resolution T1-weighted MRI and registration accuracy was verified. Voxel-wise normal tissue complication probability analyses were performed using a logistic model analyzing the relationship between cumulative voxel equivalent total dose in 2 Gy fractions (EQD2) and BRIA development at each voxel. Confidence intervals for regression model predictions were estimated with bootstrapping.ResultsAmong 18 patients, 39 brain tumors were treated. Patients received a median of 4.5 cycles of bevacizumab and 1-4 radiation courses prior to BRIA appearance. Most (64%) treated tumors overlapped with areas of BRIA. The median proportion of each BRIA region of interest volume overlapping with tumor was 98%. We found a dose-dependent association between cumulative voxel EQD2 and the relative probability of BRIA (β0 = -5.1, β1 = 0.03 Gy-1, γ = 1.3).ConclusionsBRIA is likely a radiation dose-dependent phenomenon in patients with brain tumors receiving bevacizumab and radiotherapy. The combination of radiation effects and tumor microenvironmental factors in potentiating BRIA in this population should be further investigated.

INTRODUCTION: The North Star Ambulatory Assessment (NSAA) tool is a key instrument for measuring clinical outcomes in patients with Duchenne muscular dystrophy (DMD). To gain a better understanding of the longitudinal utility of the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD treated with domagrozumab or placebo. METHODS: The NSAA exploratory analyses included assessment of individual skills gained/lost, total skills gained/lost, cumulative loss of function, and the impact of transient loss of function due to a temporary disability on NSAA total score (temporary zero score). RESULTS: There was no significant difference in the total number of NSAA skills gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p = 0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However, domagrozumab-treated patients were less likely to lose the ability to perform a NSAA item (hazard ratio 0.80, 95% confidence interval [CI]: 0.65-0.98, p = 0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores were changed to not obtainable (8 values from 7 patients), domagrozumab-treated patients scored higher on the NSAA total score versus placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1-3.9, p = 0.0359). CONCLUSIONS: These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as not obtainable for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test. CLINICALTRIALS.GOV IDENTIFIER: NCT02310763.

ObjectivesEmergency department (ED) health care personnel (HCP) are at risk of exposure to SARS-CoV-2. The objective of this study was to determine the attributable risk of SARS-CoV-2 infection from providing ED care, describe personal protective equipment use, and identify modifiable ED risk factors. We hypothesized that providing ED patient care increases the probability of acquiring SARS-CoV-2 infection.MethodsWe conducted a multicenter prospective cohort study of 1,673 ED physicians, advanced practice providers (APPs), nurses, and nonclinical staff at 20 U.S. centers over 20 weeks (May to December 2020; before vaccine availability) to detect a four-percentage point increased SARS-CoV-2 incidence among HCP related to direct patient care. Participants provided monthly nasal and serology specimens and weekly exposure and procedure information. We used multivariable regression and recursive partitioning to identify risk factors.ResultsOver 29,825 person-weeks, 75 participants (4.5%) acquired SARS-CoV-2 infection (31 were asymptomatic). Physicians/APPs (aOR 1.07; 95% CI 0.56-2.03) did not have higher risk of becoming infected compared to nonclinical staff, but nurses had a marginally increased risk (aOR 1.91; 95% CI 0.99-3.68). Over 99% of participants used CDC-recommended personal protective equipment (PPE), but PPE lapses occurred in 22.1% of person-weeks and 32.1% of SARS-CoV-2-infected patient intubations. The following factors were associated with infection: household SARS-CoV-2 exposure; hospital and community SARS-CoV-2 burden; community exposure; and mask non-use in public. SARS-CoV-2 intubation was not associated with infection (attributable risk fraction 13.8%; 95% CI -2.0-38.2%), and nor were PPE lapses.ConclusionsAmong unvaccinated U.S. ED HCP during the height of the pandemic, the risk of SARS-CoV-2 infection was similar in nonclinical staff and HCP engaged in direct patient care. Many identified risk factors were related to community exposures.

BackgroundReports on medium and long-term sequelae of SARS-CoV-2 infections largely lack quantification of incidence and relative risk. We describe the rationale and methods of the Innovative Support for Patients with SARS-CoV-2 Registry (INSPIRE) that combines patient-reported outcomes with data from digital health records to understand predictors and impacts of SARS-CoV-2 infection.MethodsINSPIRE is a prospective, multicenter, longitudinal study of individuals with symptoms of SARS-CoV-2 infection in eight regions across the US. Adults are eligible for enrollment if they are fluent in English or Spanish, reported symptoms suggestive of acute SARS-CoV-2 infection, and if they are within 42 days of having a SARS-CoV-2 viral test (i.e., nucleic acid amplification test or antigen test), regardless of test results. Recruitment occurs in-person, by phone or email, and through online advertisement. A secure online platform is used to facilitate the collation of consent-related materials, digital health records, and responses to self-administered surveys. Participants are followed for up to 18 months, with patient-reported outcomes collected every three months via survey and linked to concurrent digital health data; follow-up includes no in-person involvement. Our planned enrollment is 4,800 participants, including 2,400 SARS-CoV-2 positive and 2,400 SARS-CoV-2 negative participants (as a concurrent comparison group). These data will allow assessment of longitudinal outcomes from SARS-CoV-2 infection and comparison of the relative risk of outcomes in individuals with and without infection. Patient-reported outcomes include self-reported health function and status, as well as clinical outcomes including health system encounters and new diagnoses.ResultsParticipating sites obtained institutional review board approval. Enrollment and follow-up are ongoing.ConclusionsThis study will characterize medium and long-term sequelae of SARS-CoV-2 infection among a diverse population, predictors of sequelae, and their relative risk compared to persons with similar symptomatology but without SARS-CoV-2 infection. These data may inform clinical interventions for individuals with sequelae of SARS-CoV-2 infection.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens. METHODS: A list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists responses were collected using a modified Delphi approach. RESULTS: Among corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid. DISCUSSION: The options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects.

We develop fully glycosylated computational models of ACE2-Fc fusion proteins which are promising targets for a COVID-19 therapeutic. These models are tested in their interaction with a fragment of the receptor-binding domain (RBD) of the Spike Protein S of the SARS-CoV-2 virus, via atomistic molecular dynamics simulations. We see that some ACE2 glycans interact with the S fragments, and glycans are influencing the conformation of the ACE2 receptor. Additionally, we optimize algorithms for protein glycosylation modelling in order to expedite future model development. All models and algorithms are openly available.

The structured professional judgement (SPJ) approach was initially developed to support risk assessment and management decisions. The approach is now being adapted and applied to admission assessments for adult secure services. This systematic review aims to summarise the evidence for the effectiveness and acceptability of the SPJ approach in admission assessments of this kind. A comprehensive electronic search strategy was used to identify studies indexed in PubMed, PsycInfo, Medline and Cochrane Library (January 2007 –January 2024). Two search strategies included terms (and synonyms) for psychiatric patients (quantitative) or clinicians and clinicians' experiences (qualitative), structured professional judgement, admission, and secure services. Twelve quantitative articles (published 2007–2020) were identified. SPJ-informed guidance included were the DUNDRUM-1, DUNDRUM-2, DUNDRUM-3, DUNDRUM-4, and the HCR-20. While findings were variable, the overall pattern indicated that ratings suggestive of more problems were associated with increased likelihood of admission or movement to higher security levels. There is emerging evidence for the use of SPJ guidance to support admission decision-making. Specifically, it should be used as an adjunct to existing decision-making processes rather than as a replacement for those processes. Further research, both quantitative and qualitative, across a wider range of settings and populations is recommended. [ABSTRACT FROM AUTHOR]

Objective: To undertake a scoping review to identify methods and diagnostic levels used in determining unintentional, non-fire related carbon monoxide exposure. Design: Online databases and grey literature were searched from 1946 to 2023 identifying 80 papers where carbon monoxide levels were reported. Results: 80 papers were included; 71 research studies and 9 clinical guidelines. Four methods were described: blood carboxyhaemoglobin (arterial or venous blood analysis), carbon monoxide oximetry (SpO2), expired carbon monoxide, and ambient carbon monoxide sampling. Blood analysis methods predominated (60.0% of the papers). Multiple methods of measurement were used in 26 (32.5%) of the papers. Diagnostic levels for carboxyhaemoglobin were described in 54 (67.5%) papers, ranging between 2% and 15%. 26 (32.5%) papers reported diagnostic levels that were adjusted for the smoking status of the patient. Conclusions: Four methods were found for use in different settings. Variability in diagnostic thresholds impairs diagnostic accuracy. Agreement on standardised diagnostic levels is required to enable consistent diagnosis of unintentional, non-fire related carbon monoxide exposure. [ABSTRACT FROM AUTHOR]

Background: Treadmill belt perturbations have high clinical feasibility for use in perturbation-based training in older people, but their kinematic validity is unclear. This study examined the kinematic validity of treadmill belt accelerations as a surrogate for overground walkway trips during gait in older people. Methods: Thirty-eight community-dwelling older people were exposed to two unilateral belt accelerations (8 m s-2) whilst walking on a split-belt treadmill and two trips induced by a 14 cm trip-board whilst walking on a walkway with condition presentation randomised. Anteroposterior margin of stability (MoS), number of falls, and trunk and lower limb kinematics were quantified for the step prior and five recovery steps following the treadmill perturbations and the walkway trips which elicited elevating and lowering strategies. Findings: Rates of falls following the treadmill accelerations and walkway trips were 0% and 13.1%, respectively. MoS was similar during the first recovery step (P>0.05) but less negative during subsequent recovery steps following treadmill belt accelerations than walkway trips (P<0.01) regardless of recovery strategy. Excluding the first recovery step in the lowering strategy, recovery step lengths, toe clearance, maximum trunk, hip and knee angles (P<0.05) were smaller during recovery on the treadmill compared to the walkway. Interpretation: Destabilisation by treadmill belt accelerations quickly dissipated after only one recovery step but continued for multiple recovery steps following walkway trips. Smaller trunk displacement, step lengths, toe clearance and no falls on the treadmill indicate treadmill belt accelerations may not accurately simulate the biomechanical challenge of obstacle-induced trips in older people. [ABSTRACT FROM AUTHOR]

Nurse sharks (Ginglymostoma cirratum), especially juveniles, are often encountered by near-shore and shore-based recreational anglers and are suggested to exhibit minimal behavioral and physiological responses to capture, largely based on studies of adults using commercial or scientific fishing methods. To quantify the sub-lethal effects of recreational angling on juvenile nurse sharks, 27 individuals (across 31 angling events) were caught using hook-and-line fishing methods. Over a 30-min period, 4 blood samples were taken with variable time intervals between sampling (i.e., randomized ordering of an interval of 5, 10, and 15 min between each sampling event). Lactate increased by 611% (6.7 ± 2.17 mmol/L) on average over the 30-min fight, and significant relationships were identified between lactate and blood draw number, fight time, and temperature, with large effect sizes. Significant relationships were also detected between blood draw number, glucose, and hematocrit, while osmolality was only affected by fishing site. These results suggest juvenile nurse sharks may exhibit a greater physiological stress response when exposed to recreational angling than adults captured with other fishing methods. [ABSTRACT FROM AUTHOR]

Objective: Gestational diabetes mellitus (GDM) is a common medical complication of pregnancy that leads to adverse outcomes for both infants and pregnant people. Early detection and treatment can mitigate these negative outcomes. The COVID-19 pandemic strained healthcare and laboratory services, including GDM screening programs. Adapted GDM screening guidelines were introduced in many jurisdictions. This study examined changes in uptake, modality, and experiences of GDM screening in Ontario, Canada during the COVID-19 pandemic. Methods: This convergent mixed-method study involved a population-based retrospective cohort analysis of Ontario-based health administrative data to describe and compare gestational diabetes screening rates among 85,228 individuals with live, in-hospital births between January 1-March 31 before (2019) and during the COVID-19 pandemic (2021 and 2022). Descriptive analyses were conducted for GDM screening pathways aligning with usual and pandemic-adapted screening guidance. Qualitative descriptive interviews were conducted about experiences and decision-making of GDM screening with 43 Ontario residents who gave birth between May 2020 and December 2021. Data were integrated during the design and interpretation phases. Results: There were small but significant increases in GDM screening during the pandemic; likelihood of screening completion using any modality increased in 2021 and 2022 compared to 2019. Testing modality shifted; the alternate screening strategies introduced during COVID-19 were adopted by clinicians. Interview participants perceived GDM screening to be important and obligatory but accompanied by a degree of stress about potential COVID-19 exposure. Conclusion: Despite health system challenges experienced in Ontario during the COVID-19 pandemic, GDM screening rates increased in the study population, demonstrating the success of adapted GDM screening guidelines. Decisions about screening modalities were driven by clinician expertise, and interview participants were satisfied to provide informed consent to these recommendations. [ABSTRACT FROM AUTHOR]

Genome-wide CRISPR screens are an effective discovery tool for genes that underlie diverse cellular mechanisms that can be scored through cell fitness. Loss-of-function screens are particularly challenging compared to gain-of-function because of the limited dynamic range of decreased sgRNA sequence detection. Here we describe Guide-Only control CRISPR (GO-CRISPR), an improved loss-of-function screening workflow, and its companion software package, Toolset for the Ranked Analysis of GO-CRISPR Screens (TRACS). We demonstrate a typical GO-CRISPR workflow in a non-proliferative 3D spheroid model of dormant high grade serous ovarian cancer and demonstrate superior performance to standard screening methods. The unique integration of the pooled sgRNA library quality and guide-only controls allows TRACS to identify novel molecular pathways that were previously unidentified in tumor dormancy and undetectable to analysis packages that lack the guide only controls. Together, GO-CRISPR and TRACS can robustly improve the discovery of essential genes in challenging biological scenarios such as growth arrested cells. [ABSTRACT FROM AUTHOR]

The research-to-practice gap is a well-known phenomenon. The adoption of evidence into clinical practice needs to consider the complexity of the health care system and a multitude of contextual issues. Research evidence is usually a form of extrinsic motivation for practice change, but works best when it aligns with the intrinsic values of the system and the people in it. Health professionals tend to refer to internal, local policies, information sources and procedures more than external academic research evidence. This protocol paper describes a mixed-methods study with a quasi-experimental design that seeks to investigate how involvement in research might impact the uptake or implementation of recommendations arising from that research. Research evidence for the effectiveness and cost-effectiveness of mobilisation alarms for falls prevention will be disseminated at 36 hospital wards in Victoria, Australia. Eighteen of these wards will be sites where this research evidence was generated; another 18 wards will not have been involved in evidence generation. The uptake of research evidence will be measured across three time points using quantitative and qualitative data. Trial registration: This study has been registered with the Australian New Zealand Clinical Trials Registry: ACTRN12621000823875p. [ABSTRACT FROM AUTHOR]

E. coli Nissle (EcN) is a non-pathogenic probiotic bacterium of the Enterobacteriaceae family that has been used for over a century to promote general gut health. Despite the history of safe usage of EcN, concerns have been raised regarding the presence of the pks gene cluster, encoding the genotoxin colibactin, due to its association with colorectal cancer. Here, we sought to determine the effect of pks island removal on the in vitro and in vivo robustness and activity of EcN and EcN-derived strains. A deletion of the pks island (Δpks) was constructed in wild type and engineered strains of EcN using lambda red recombineering. Mass spectrometric measurement of N-myristoyl-D-asparagine, released during colibactin maturation, confirmed that the pks deletion abrogated colibactin production. Growth curves were comparable between Δpks strains and their isogenic parents, and wild type EcN displayed no competitive advantage to the Δpks strain in mixed culture. Deletion of pks also had no effect on the activity of strains engineered to degrade phenylalanine (SYNB1618 and SYNB1934) or oxalate (SYNB8802). Furthermore, 1:1 mixed dosing of wild type and Δpks EcN in preclinical mouse and nonhuman primate models demonstrated no competitive disadvantage for the Δpks strain with regards to transit time or colonization. Importantly, there was no significant difference on in vivo strain performance between the clinical-stage strain SYNB1934 and its isogenic Δpks variant with regards to recovery of the quantitative strain-specific biomarkers d5- trans-cinnamic acid, and d5-hippuric acid. Taken together, these data support that the pks island is dispensable for Synthetic Biotic fitness and activity in vivo and that its removal from engineered strains of EcN will not have a deleterious effect on strain efficacy.

The advent of micro-computed tomography (microCT) has provided significant advancement in our ability to generate clinically relevant assessments of lung health and disease in small animal models. As microCT use to generate outcomes analysis in pulmonary preclinical models has increased there have been substantial improvements in image quality and resolution, and data analysis software. However, there are limited published methods for standardized imaging and automated analysis available for investigators. Manual quantitative analysis of microCT images is complicated by the presence of inflammation and parenchymal disease. To improve the efficiency and limit user-associated bias, we have developed an automated pulmonary air and tissue segmentation (PATS) task list to segment lung air volume and lung tissue volume for quantitative analysis. We demonstrate the effective use of the PATS task list using four distinct methods for imaging, 1) in vivo respiration controlled scanning using a flexiVent, 2) longitudinal breath-gated in vivo scanning in resolving and non-resolving pulmonary disease initiated by lipopolysaccharide-, bleomycin-, and silica-exposure, 3) post-mortem imaging, and 4) ex vivo high-resolution scanning. The accuracy of the PATS task list was compared to manual segmentation. The use of these imaging techniques and automated quantification methodology across multiple models of lung injury and fibrosis demonstrates the broad applicability and adaptability of microCT to various lung diseases and small animal models and presents a significant advance in efficiency and standardization of preclinical microCT imaging and analysis for the field of pulmonary research.

PurposeBevacizumab-related imaging abnormality (BRIA), appearing as areas of restricted diffusion on magnetic resonance imaging (MRI) and representing atypical coagulative necrosis pathologically, has been observed in patients with brain tumors receiving radiotherapy and bevacizumab. We investigated the role of cumulative radiation dose in BRIA development in a voxel-wise analysis.MethodsPatients (n = 18) with BRIA were identified. All had high-grade gliomas or brain metastases treated with radiotherapy and bevacizumab. Areas of BRIA were segmented semi-automatically on diffusion-weighted MRI with apparent diffusion coefficient (ADC) images. To avoid confounding by possible tumor, hypoperfusion was confirmed with perfusion imaging. ADC images and radiation dose maps were co-registered to a high-resolution T1-weighted MRI and registration accuracy was verified. Voxel-wise normal tissue complication probability analyses were performed using a logistic model analyzing the relationship between cumulative voxel equivalent total dose in 2 Gy fractions (EQD2) and BRIA development at each voxel. Confidence intervals for regression model predictions were estimated with bootstrapping.ResultsAmong 18 patients, 39 brain tumors were treated. Patients received a median of 4.5 cycles of bevacizumab and 1-4 radiation courses prior to BRIA appearance. Most (64%) treated tumors overlapped with areas of BRIA. The median proportion of each BRIA region of interest volume overlapping with tumor was 98%. We found a dose-dependent association between cumulative voxel EQD2 and the relative probability of BRIA (β0 = -5.1, β1 = 0.03 Gy-1, γ = 1.3).ConclusionsBRIA is likely a radiation dose-dependent phenomenon in patients with brain tumors receiving bevacizumab and radiotherapy. The combination of radiation effects and tumor microenvironmental factors in potentiating BRIA in this population should be further investigated.

Burkholderia multivorans causes opportunistic pulmonary infections and is intrinsically resistant to many antibacterial compounds including the hydrophobic biocide triclosan. Chemical permeabilization of the Pseudomonas aeruginosa outer membrane affects sensitization to hydrophobic substances. The purpose of the present study was to determine if B. multivorans is similarly susceptive suggesting that outer membrane impermeability properties underlie triclosan resistance. Antibiograms and conventional macrobroth dilution bioassays were employed to establish baseline susceptibility levels to hydrophobic antibacterial compounds. Outer membrane permeabilizers compound 48/80, polymyxin B, polymyxin B-nonapeptide, and ethylenediaminetetraacetic acid were used in attempts to sensitize disparate B. multivorans isolates to the hydrophobic agents novobiocin and triclosan, and to potentiate partitioning of the hydrophobic fluorescent probe 1-N-phenylnapthylamine (NPN). The lipophilic agent resistance profiles for all B. multivorans strains were essentially the same as that of P. aeruginosa except that they were resistant to polymyxin B. Moreover, they resisted sensitization to hydrophobic compounds and remained inaccessible to NPN when treated with outer membrane permeabilizers. These data support the notion that while both phylogenetically-related organisms exhibit general intrinsic resistance properties to hydrophobic substances, the outer membrane of B. multivorans either resists permeabilization by chemical modification or sensitization is mitigated by a supplemental mechanism not present in P. aeruginosa.

Information about individual behaviour is collected regularly by organisations. This information has value to businesses, the government and third parties. It is not clear what value this personal data has to consumers themselves. Much of the modern economy is predicated on people sharing personal data, however if individuals value their privacy, they may choose to withhold this data unless the perceived benefits of sharing outweigh the perceived value of keeping the data private. One technique to assess how much individuals value their privacy is to ask them whether they might be willing to pay for an otherwise free service if paying allowed them to avoid sharing personal data. Our research extends previous work on factors affecting individuals' decisions about whether to share personal data. We take an experimental approach and focus on whether consumers place a positive value on protecting their data by examining their willingness to share personal data in a variety of data sharing environments. Using five evaluation techniques, we systematically investigate whether members of the public value keeping their personal data private. We show that the extent to which participants value protecting their information differs by data type, suggesting there is no simple function to assign a value for individual privacy. The majority of participants displayed remarkable consistency in their rankings of the importance of different types of data through a variety of elicitation procedures, a finding consistent with the existence of stable individual privacy preferences in protecting personal data. We discuss our findings in the context of research on the value of privacy and privacy preferences.

Objective To characterize the microbiota of the cerebrospinal fluid (CSF) from children with hydrocephalus at the time of initial surgical intervention. Study design CSF was obtained at initial surgical intervention. One aliquot was stored in skim milk-tryptone-glucose-glycerol (STGG) medium and the second was unprocessed; both were then stored at –70°C. Bacterial growth for CSF samples stored in STGG were subsequently characterized using aerobic and anaerobic culture on blood agar and MALDI-TOF sequencing. All unprocessed CSF samples underwent 16S quantitative polymerase chain reaction (qPCR) sequencing, and a subset underwent standard clinical microbiological culture. CSF with culture growth (either after storage in STGG or standard clinical) were further analyzed using whole-genome amplification sequencing (WGAS). Results 11/66 (17%) samples stored in STGG and 1/36 (3%) that underwent standard clinical microbiological culture demonstrated bacterial growth. Of the organisms present, 8 were common skin flora and 4 were potential pathogens; only 1 was also qPCR positive. WGAS findings and STGG culture findings were concordant for only 1 sample, identifying Staphylococcus epidermidis. No significant difference in time to second surgical intervention was observed between the STGG culture-positive and negative groups. Conclusion(s) Using high sensitivity methods, we detected the presence of bacteria in a subset of CSF samples at the time of first surgery. Therefore, the true presence of bacteria in CSF of children with hydrocephalus cannot be ruled out, though our findings may suggest these bacteria are contaminants or false positives of the detection methods. Regardless of origin, the detection of microbiota in the CSF of these children may not have any clinical significance.

BackgroundResearch suggests that the ingestion or aroma of rosemary enhances cognitive ability in both rodents and humans. However, how rosemary facilitates cognition and the precise therapeutic impacts on information processing remains unclear.Hypothesis/purposeThis pilot study used the temporal precision of event-related potentials (ERPs) to examine the cognitive-enhancing benefits of a rosemary drink. Neural markers of sustained attention were used as indices to explore whether rosemary facilitates concentration in general or the allocation of resources to task-relevant information only.Study design and methodsIn a between-subject design (rosemary vs water control drink), 48 adults performed a 3-stimulus visual oddball task. Participants differentiated between rare target stimuli (index of task-relevant attentional processes; P3b ERP) embedded in a train of frequent stimuli. The presentation of an infrequent novel stimulus was also included (index of task-irrelevant stimulus processing; P3a ERP). Throughout the session, electroencephalograms (EEG) were collected and time-locked to the presentation of the target (P3b) and novel (P3a) stimulus types.ResultsThe primary analyses revealed facilitation of the P3a in particular with a medium Cohen's effect size reported. The investigation of the P3b component, although less reliable, also had a medium effect. The subsidiary consideration of the association between behaviour and the ERPs provided a further level of explanation regarding the therapeutic effect of rosemary on cognition. Indeed, the pattern of associations was suggestive of strategy differences during the performance of the task across the treatment group., although these data should be treated with caution.ConclusionsThese pilot data provide critical insights into the utility of rosemary to facilitate different aspects of attention. In particular, data are consistent with rosemary providing additional attentional resources to enhance the processing of stimuli we encounter, irrespective of task relevance. Indeed, the enhancement of both P3a and P3b components following rosemary administration may indicate that the herb enhances the processing of all stimuli in the environment. We argue for the use of both behavioural and EEG methods to explore the therapeutic effects of herbal compounds.

[This corrects the article DOI: 10.1371/journal.pone.0233912.].

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.MethodsRECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.DiscussionRECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.RegistrationNCT05172024.

Background The effects of the COVID-19 pandemic have been more pronounced for socially disadvantaged populations. We sought to determine how access to SARS-CoV-2 testing and the likelihood of testing positive for COVID-19 were associated with demographic factors, socioeconomic status (SES) and social determinants of health (SDH) in three Canadian provinces. Methods An observational population-based cross-sectional study was conducted for the provinces of Ontario, Manitoba and New Brunswick between March 1, 2020 and April 27, 2021, using provincial health administrative data. After excluding residents of long-term care homes, those without current provincial health insurance and those who were tested for COVID-19 out of province, records from provincial healthcare administrative databases were reviewed for 16,900,661 healthcare users. Data was modelled separately for each province in accordance to a prespecified protocol and follow-up consultations among provincial statisticians and collaborators. We employed univariate and multivariate regression models to examine determinants of testing and test results. Results After adjustment for other variables, female sex and urban residency were positively associated with testing, while female sex was negatively associated with test positivity. In New Brunswick and Ontario, individuals living in higher income areas were more likely to be tested, whereas in Manitoba higher income was negatively associated with both testing and positivity. High ethnocultural composition was associated with lower testing rates. Both high ethnocultural composition and high situational vulnerability increased the odds of testing positive for SARS-CoV-2. Discussion We observed that multiple demographic, income and SDH factors were associated with SARS-CoV-2 testing and test positivity. Barriers to healthcare access identified in this study specifically relate to COVID-19 testing but may reflect broader inequities for certain at-risk groups.

ObjectivesPrediction of pediatric emergency department (PED) workload can allow for optimized allocation of resources to improve patient care and reduce physician burnout. A measure of PED workload is thus required, but to date no variable has been consistently used or could be validated against for this purpose. Billing codes, a variable assigned by physicians to reflect the complexity of medical decision making, have the potential to be a proxy measure of PED workload but must be assessed for reliability. In this study, we investigated how reliably billing codes are assigned by PED physicians, and factors that affect the inter-rater reliability of billing code assignment.MethodsA retrospective cross-sectional study was completed to determine the reliability of billing code assigned by physicians (n = 150) at a quaternary-level PED between January 2018 and December 2018. Clinical visit information was extracted from health records and presented to a billing auditor, who independently assigned a billing code-considered as the criterion standard. Inter-rater reliability was calculated to assess agreement between the physician-assigned versus billing auditor-assigned billing codes. Unadjusted and adjusted logistic regression models were used to assess the association between covariables of interest and inter-rater reliability.ResultsOverall, we found substantial inter-rater reliability (AC2 0.72 [95% CI 0.64-0.8]) between the billing codes assigned by physicians compared to those assigned by the billing auditor. Adjusted logistic regression models controlling for Pediatric Canadian Triage and Acuity scores, disposition, and time of day suggest that clinical trainee involvement is significantly associated with increased inter-rater reliability.ConclusionsOur work identified that there is substantial agreement between PED physician and a billing auditor assigned billing codes, and thus are reliably assigned by PED physicians. This is a crucial step in validating billing codes as a potential proxy measure of pediatric emergency physician workload.

ObjectiveSocio-emotional skills, including social competence and social cognition, form the basis for robust relationships and wellbeing. Despite their importance, these skills are poorly defined and measured, particularly in children with developmental vulnerabilities. As a consequence, targets for effective management and treatment remain unclear. We aimed to i) phenotype social competence and social cognition in typically developing children (TDC) and in children with neurodevelopmental or mental health disorders (clinical groups) and ii) establish the relationships between these child-direct measures and parent ratings of social competence and behavior.MethodUsing a multi-site, cross-sectional study design, we recruited 513 TDC and 136 children with neurodevelopmental (autism spectrum disorder [ASD], attention deficit hyperactivity disorder [ADHD]) or mental health (Anxiety Disorder [ANX]) diagnoses (age range 5-15 years). We administered the Paediatric Evaluation of Emotions, Relationships and Socialisation (PEERS) to children, and parents completed standardised questionnaires rating children's socio-emotional function.ResultsStandardised parent questionnaires revealed a global pattern of everyday socio-emotional impairment that was common to all clinical groups, while PEERS identified disorder-specific socio-cognitive profiles for children with ASD, ADHD and ANX. Compared to TDCs, children with ASD demonstrated global socio-cognitive impairment. Children with ADHD were impulsive, demonstrating difficulties managing speed accuracy trade-offs. Children with ANX exhibited slowed social decision-making, but otherwise intact skills.ConclusionsStandardized parent questionnaires of child socio-emotional function reveal differences between children with typical and atypical development, but do not yield disorder-specific, socio-emotional profiles. In contrast, findings from the PEERS objective assessment suggest that that ASD, ADHD and ANX are associated with distinct socio-cognitive phenotypes, to more accurately guide and target management and treatment of impaired social competence.

Marine reserves are implemented to achieve a variety of objectives, but are seldom rigorously evaluated to determine whether those objectives are met. In the rare cases when evaluations do take place, they typically focus on ecological indicators and ignore other relevant objectives such as socioeconomics and governance. And regardless of the objectives, the diversity of locations, monitoring protocols, and analysis approaches hinder the ability to compare results across case studies. Moreover, analysis and evaluation of reserves is generally conducted by outside researchers, not the reserve managers or users, plausibly thereby hindering effective local management and rapid response to change. We present a framework and tool, called MAREA, to overcome these challenges. Its purpose is to evaluate the extent to which any given reserve has achieved its stated objectives. MAREA provides specific guidance on data collection and formatting, and then conducts rigorous causal inference analysis based on data input by the user, providing real-time outputs about the effectiveness of the reserve. MAREAs ease of use, standardization of state-of-the-art inference methods, and ability to analyze marine reserve effectiveness across ecological, socioeconomic, and governance objectives could dramatically further our understanding and support of effective marine reserve management.

Background and objectives: Preterm birth (PTB) affects ~10% of births worldwide; however, most literature focused on short-term clinical outcomes, with much less focus on long-term socioeconomic outcomes after PTB. We examined associations between PTB and individuals' income, employment, and educational outcomes during early adulthood. Methods: We conducted a population-level matched cohort study including all live births in Canada between 1990 and 1996, followed until 2018. Outcomes included Employment income per year in 2018 CAD and employment between ages 18 and 28 years, postsecondary education enrollment (18–22 years), and maximum educational attainment at age 22–27 years. Mean differences and risk ratios (RR) and differences (RD) were estimated using generalized estimating equation regression models for economic outcomes and multinomial logistic regression models for educational outcomes. Results: Of 2.4 million births, 7% were born preterm (0.3%, 0.6%, 0.8%, and 5.4% born extremely preterm (24–27 weeks), very preterm (28–31 weeks), moderately preterm (32–33 weeks), and late preterm (34–36 weeks) respectively). After matching on baseline characteristics (e.g., sex, province of birth, and parental demographics) and adjusting for age and period effects, preterm-born individuals, on average, had $958 CAD less employment income per year (95% CI: $854-$1062), 6% lower income per year, than term-born individuals, and were 2.13% less likely to be employed (1.98–2.29%). PTB was also negatively associated with university enrollment (RR 0.93 (0.91–0.94) and graduation with a university degree (RR 0.95 (0.94–0.97)). Mean income differences for those born 24–27 weeks were -$5,463 CAD per year (17% lower), and adjusted RR were 0.55 for university enrollment and graduation. Conclusion: In this population-based study, preterm birth was associated with lower economic and educational achievements at least until the late twenties. The associations were stronger with decreasing GA at birth. Policymakers, clinicians, and parents should be aware that the socioeconomic impact of PTB is not limited to the early neonatal period but extends into adulthood. [ABSTRACT FROM AUTHOR]

Shunt infections are a common complication when treating hydrocephalus by cerebrospinal fluid (CSF) shunt placement. The source of infecting pathogens is not well understood. One hypothesis, which we explored here, is that microorganisms persist chronically in the host long before a symptomatic infection occurs and may be detectable in surgical events preceding infection. A cohort of 13 patients was selected, for which CSF samples were available from an infection episode and from a previous surgery event, which was either an initial shunt placement or a revision. Microbiota were analyzed both directly from CSF and from isolates cultured from CSF on aerobic and anaerobic media. The detection and identification of bacteria was done with high throughput DNA sequencing methods and mass spectrometry. The presence of bacteria was confirmed in 4 infection samples, of which 2 were after initial placement and 2 after revision surgery. Taxonomic identification was consistent with clinical microbiology laboratory results. Bacteria were not detected in any of the CSF samples collected at the time of the previous surgical events. While our findings do not provide direct evidence for long-term persistence of pathogens, they suggest the need for consideration of additional source material, such as biofilm and environmental swabs, and/or the use of more sensitive and specific analytical methods. [ABSTRACT FROM AUTHOR]

Serum metabolite profiling in Duchenne muscular dystrophy (DMD) may enable discovery of valuable molecular markers for disease progression and treatment response. Serum samples from 51 DMD patients from a natural history study and 22 age-matched healthy volunteers were profiled using liquid chromatography coupled to mass spectrometry (LC-MS) for discovery of novel circulating serum metabolites associated with DMD. Fourteen metabolites were found significantly altered (1% false discovery rate) in their levels between DMD patients and healthy controls while adjusting for age and study site and allowing for an interaction between disease status and age. Increased metabolites included arginine, creatine and unknown compounds at m/z of 357 and 312 while decreased metabolites included creatinine, androgen derivatives and other unknown yet to be identified compounds. Furthermore, the creatine to creatinine ratio is significantly associated with disease progression in DMD patients. This ratio sharply increased with age in DMD patients while it decreased with age in healthy controls. Overall, this study yielded promising metabolic signatures that could prove useful to monitor DMD disease progression and response to therapies in the future.

[This corrects the article DOI: 10.1371/journal.pone.0153461.].

IntroductionDiffusion Weighted Imaging (DWI), which is based on Echo Planar Imaging (EPI) protocols, is becoming increasingly important for neurosurgical applications. However, its use in this context is limited in part by significant spatial distortion inherent to EPI.MethodWe evaluated an efficient algorithm for EPI distortion correction (EPIC) across 814 DWI scans from 250 brain tumor patients and quantified the magnitude of geometric distortion for whole brain and multiple brain regions.ResultsEvaluation of the algorithm's performance revealed significantly higher mutual information between T1-weighted pre-contrast images and corrected b = 0 images than the uncorrected b = 0 images (p < 0.001). The distortion magnitude across all voxels revealed a median EPI distortion effect of 2.1 mm, ranging from 1.2 mm to 5.9 mm, the 5th and 95th percentile, respectively. Regions adjacent to bone-air interfaces, such as the orbitofrontal cortex, temporal poles, and brain stem, were the regions most severely affected by DWI distortion.ConclusionUsing EPIC to estimate the degree of distortion in 814 DWI brain tumor images enabled the creation of a topographic atlas of DWI distortion across the brain. The degree of displacement of tumors boundaries in uncorrected images is severe but can be corrected for using EPIC. Our results support the use of distortion correction to ensure accurate and careful application of DWI to neurosurgical practice.

Opioids targeting mu;μ (MOP) receptors produce analgesia in the peri-operative period and palliative care. They also produce side effects including respiratory depression, tolerance/dependence and addiction. The N/OFQ opioid receptor (NOP) also produces analgesia but is devoid of the major MOP side effects. Evidence exists for MOP-NOP interaction and mixed MOP-NOP ligands produce analgesia with reduced side effects. We have generated a HEKMOP/NOP human expression system and used bivalent MOP-NOP and fluorescent ligands to (i) probe for receptor interaction and (ii) consequences of that interaction. We used HEKMOP/NOP cells and two bivalent ligands; Dermorphin-N/OFQ (MOP agonist-NOP agonist; DeNO) and Dermorphin-UFP101 (MOP agonist-NOP antagonist; De101). We have determined receptor binding profiles, GTPγ[35S] binding, cAMP formation and ERK1/2 activation. We have also probed MOP and NOP receptor interactions in HEK cells and hippocampal neurones using the novel MOP fluorescent ligand, DermorphinATTO488 and the NOP fluorescent ligand N/OFQATTO594. In HEKMOP/NOP MOP ligands displaced NOP binding and NOP ligands displaced MOP binding. Using fluorescent probes in HEKMOP/NOP cells we demonstrated MOP-NOP probe overlap and a FRET signal indicating co-localisation. MOP-NOP were also co-localised in hippocampal tissue. In GTPγ[35S] and cAMP assays NOP stimulation shifted the response to MOP rightwards. At ERK1/2 the response to bivalent ligands generally peaked later. We provide evidence for MOP-NOP interaction in recombinant and native tissue. NOP activation reduces responsiveness of MOP activation; this was shown with conventional and bivalent ligands.

BackgroundReports on medium and long-term sequelae of SARS-CoV-2 infections largely lack quantification of incidence and relative risk. We describe the rationale and methods of the Innovative Support for Patients with SARS-CoV-2 Registry (INSPIRE) that combines patient-reported outcomes with data from digital health records to understand predictors and impacts of SARS-CoV-2 infection.MethodsINSPIRE is a prospective, multicenter, longitudinal study of individuals with symptoms of SARS-CoV-2 infection in eight regions across the US. Adults are eligible for enrollment if they are fluent in English or Spanish, reported symptoms suggestive of acute SARS-CoV-2 infection, and if they are within 42 days of having a SARS-CoV-2 viral test (i.e., nucleic acid amplification test or antigen test), regardless of test results. Recruitment occurs in-person, by phone or email, and through online advertisement. A secure online platform is used to facilitate the collation of consent-related materials, digital health records, and responses to self-administered surveys. Participants are followed for up to 18 months, with patient-reported outcomes collected every three months via survey and linked to concurrent digital health data; follow-up includes no in-person involvement. Our planned enrollment is 4,800 participants, including 2,400 SARS-CoV-2 positive and 2,400 SARS-CoV-2 negative participants (as a concurrent comparison group). These data will allow assessment of longitudinal outcomes from SARS-CoV-2 infection and comparison of the relative risk of outcomes in individuals with and without infection. Patient-reported outcomes include self-reported health function and status, as well as clinical outcomes including health system encounters and new diagnoses.ResultsParticipating sites obtained institutional review board approval. Enrollment and follow-up are ongoing.ConclusionsThis study will characterize medium and long-term sequelae of SARS-CoV-2 infection among a diverse population, predictors of sequelae, and their relative risk compared to persons with similar symptomatology but without SARS-CoV-2 infection. These data may inform clinical interventions for individuals with sequelae of SARS-CoV-2 infection.

Background The microbiome is an important and increasingly-studied mediator of organismal metabolism, although how the microbiome affects metabolism remains incompletely understood. Many investigators use antibiotics to experimentally perturb the microbiome. However, antibiotics have poorly understood yet profound off-target effects on behavior and diet, including food and water aversion, that can confound experiments and limit their applicability. We thus sought to determine the relative influence of microbiome modulation and off-target antibiotic effects on the behavior and metabolic activity of mice. Results Mice treated with oral antibiotics via drinking water exhibited significant weight loss in fat, liver, and muscle tissue. These mice also exhibited a reduction in water and food consumption, with marked variability across antibiotic regimens. While administration of bitter-tasting but antimicrobially-inert compounds caused a similar reduction in water consumption, this did not cause tissue weight loss or reduced food consumption. Mice administered intraperitoneal antibiotics (bypassing the gastrointestinal tract) exhibited reduced tissue weights and oral intake, comparable to the effects of oral antibiotics. Antibiotic-treated germ-free mice did not have reduced tissue weights, providing further evidence that direct microbiome modulation (rather than behavioral effects) mediates these metabolic changes. Conclusions While oral antibiotics cause profound effects on food and water consumption, antibiotic effects on organismal metabolism are primarily mediated by microbiome modulation. We demonstrate that tissue-specific weight loss following antibiotic administration is due primarily to microbiome effects rather than food and water aversion, and identify antibiotic regimens that effectively modulate gut microbiota while minimizing off-target behavioral effects.

IntroductionSmoking and chronic obstructive pulmonary disease (COPD) are associated with an increased risk of post-operative pulmonary complications (PPCs) following lung cancer resection. It remains unclear whether smoking cessation reduces this risk.MethodsRetrospective review of a large, prospectively collected database of over 1000 consecutive resections for lung cancer in a quaternary lung cancer centre over a 23-year period.ResultsOne thousand and thirteen patients underwent curative-intent lobectomy or pneumonectomy between 1995 and 2018. Three hundred and sixty-two patients (36%) were ex-smokers, 314 (31%) were current smokers and 111 (11%) were never smokers. A pre-operative diagnosis of COPD was present in 57% of current smokers, 57% of ex-smokers and 20% of never smokers. Just over 25% of patients experienced a PPC. PPCs were more frequent in current smokers compared to never smokers (27% vs 17%, p = 0.036), however, no difference was seen between current and ex-smokers (p = 0.412) or between never and ex-smokers (p = 0.113). Those with a diagnosis of COPD, independent of smoking status, had a higher frequency of both PPCs (65% vs 35%, pConclusionSmoking and COPD are both associated with a higher rate of PPCs post lung cancer resection. COPD, independent of smoking status, is also associated with an increased overall post-operative complication rate and length of hospital stay. An emphasis on COPD treatment optimisation, rather than smoking cessation in isolation, may help improve post-operative outcomes.

BackgroundMaintenance drugs are used to treat chronic conditions. Several classes of maintenance drugs have attracted attention because of their potential to affect susceptibility to and severity of COVID-19.MethodsUsing claims data on 20% random sample of Part D Medicare enrollees from April to December 2020, we identified patients diagnosed with COVID-19. Using a nested case-control design, non-COVID-19 controls were identified by 1:5 matching on age, race, sex, dual-eligibility status, and geographical region. We identified usage of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), statins, warfarin, direct factor Xa inhibitors, P2Y12 inhibitors, famotidine and hydroxychloroquine based on Medicare prescription claims data. Using extended Cox regression models with time-varying propensity score adjustment we examined the independent effect of each study drug on contracting COVID-19. For severity of COVID-19, we performed extended Cox regressions on all COVID-19 patients, using COVID-19-related hospitalization and all-cause mortality as outcomes. Covariates included gender, age, race, geographic region, low-income indicator, and co-morbidities. To compensate for indication bias related to the use of hydroxychloroquine for the prophylaxis or treatment of COVID-19, we censored patients who only started on hydroxychloroquine in 2020.ResultsUp to December 2020, our sample contained 374,229 Medicare patients over 65 who were diagnosed with COVID-19. Among the COVID-19 patients, 278,912 (74.6%) were on at least one study drug. The three most common study drugs among COVID-19 patients were statins 187,374 (50.1%), ACEI 97,843 (26.2%) and ARB 83,290 (22.3%). For all three outcomes (diagnosis, hospitalization and death), current users of ACEI, ARB, statins, warfarin, direct factor Xa inhibitors and P2Y12 inhibitors were associated with reduced risks, compared to never users. Famotidine did not show consistent significant effects. Hydroxychloroquine did not show significant effects after censoring of recent starters.ConclusionMaintenance use of ACEI, ARB, warfarin, statins, direct factor Xa inhibitors and P2Y12 inhibitors was associated with reduction in risk of acquiring COVID-19 and dying from it.

Background Whilst multidimensional assessment enables the detection of treatable traits in severe asthma and has the potential to improve patient outcomes, healthcare disparities exist, and little is known about the factors influencing optimal management in severe asthma. This study aimed to explore perceived barriers, and enablers to implementing personalised care in severe asthma, from the healthcare professionals’ perspective. Methods A descriptive, qualitative study involving a single focus group (n = 7) and semi-structured interviews (n = 33) with multidisciplinary healthcare professionals involved in severe asthma care was conducted. A hybrid thematic and content analysis was undertaken to identify themes, which were then deductively mapped to the Theoretical Domains Framework (TDF). Results Overall, three emergent themes were identified: (1) Barriers- (2) Enablers- to optimal management; (3) Desired model of care. Across all TDF domains, 6 constructs influenced development and implementation of optimal care: (1) belief about consequences, (2) environmental context and resources, (3) belief about capabilities, (4) social/professional role and identity, (5) goals and (6) knowledge. Conclusion Implementation of personalised care in severe asthma is complex and non-linear. The use of a theory-based approach effectively demonstrated how a variety of behaviours could be targeted to optimise and promote personalised care in different clinical setting.

Introduction Obesity is characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism, reducing fertility and increasing risk of pregnancy complications and birth defects. We termed this phenotype ‘Reprometabolic Syndrome’ and showed that it can be recapitulated by acute infusions of lipid/insulin into healthy, normal weight, eumenorrheic women. Herein, we examined the broader impact of hyperlipidemia and euglycemic hyperinsulinemia on anterior pituitary trophic hormones and their targets. Methods Serum FSH, LH, TSH, growth hormone (GH), prolactin (PRL), thyroid hormones (free T4, total T3), cortisol, IGF-1, adiponectin, leptin and creatinine were measured in a secondary analysis of an interventional crossover study of 12 normal weight cycling women who underwent saline and heparin (control) infusion, or a euglycemic insulin infusion with heparin and Intralipid® (lipid/insulin), between days 2–5 in sequential menstrual cycles. Results In contrast to the decrease in gonadotropins, FSH and LH, infusion of lipid/insulin had no significant effects on other trophic hormones; TSH, PRL or GH. Thyroid hormones (fT4 and total T3), cortisol, IGF-1, adiponectin and creatinine also did not differ between saline or lipid/insulin infusion conditions. Leptin increased in response to lipid/insulin (pConclusion Acute hyperlipidemia and hyperinsulinemia exerted differential, cell type specific effects on the hypothalamic-pituitary-gonadal, adrenal and thyroid axes. Elucidation of mechanisms underlying the selective modulation of pituitary trophic hormones, in response to changes in diet and metabolism, may facilitate therapeutic intervention in obesity-related neuroendocrine and reproductive dysfunction.

SARS-CoV-2 antibody tests have been marketed to diagnose previous SARS-CoV-2 infection and as a test of immune status. There is a lack of evidence on the performance and clinical utility of these tests. We aimed to carry out an evaluation of 14 point of care (POC) SARS-CoV-2 antibody tests. Serum from participants with previous RT-PCR (real-time polymerase chain reaction) confirmed SARS-CoV-2 infection and pre-pandemic serum controls were used to determine specificity and sensitivity of each POC device. Changes in sensitivity with increasing time from infection were determined on a cohort of study participants. Corresponding neutralising antibody status was measured to establish whether the detection of antibodies by the POC device correlated with immune status. Paired capillary and serum samples were collected to ascertain whether POC devices performed comparably on capillary samples. Sensitivity and specificity varied between the POC devices and in general did not meet the manufacturers' reported performance characteristics, which signifies the importance of independent evaluation of these tests. The sensitivity peaked at ≥20 days following onset of symptoms, however sensitivity of 3 of the POC devices evaluated at extended time points showed that sensitivity declined with time. This was particularly marked at >140 days post infection. This is relevant if the tests are to be used for sero-prevalence studies. Neutralising antibody data showed that positive antibody results on POC devices did not necessarily confer high neutralising antibody titres, and that these POC devices cannot be used to determine immune status to the SARS-CoV-2 virus. Comparison of paired serum and capillary results showed that there was a decline in sensitivity using capillary blood. This has implications in the utility of the tests as they are designed to be used on capillary blood by the general population.

The prevalence of patients who are Incapacitated with No Evident Advance Directives or Surrogates (INEADS) remains unknown because such data are not routinely captured in structured electronic health records. This study sought to develop and validate a natural language processing (NLP) algorithm to identify information related to being INEADS from clinical notes. We used a publicly available dataset of critical care patients from 2001 through 2012 at a United States academic medical center, which contained 418,393 relevant clinical notes for 23,904 adult admissions. We developed 17 subcategories indicating reduced or elevated potential for being INEADS, and created a vocabulary of terms and expressions within each. We used an NLP application to create a language model and expand these vocabularies. The NLP algorithm was validated against gold standard manual review of 300 notes and showed good performance overall (F-score = 0.83). More than 80% of admissions had notes containing information in at least one subcategory. Thirty percent (n = 7,134) contained at least one of five social subcategories indicating elevated potential for being INEADS, and

Covid-19 has been front and center in the global landscape since the beginning of 2020. In response, the scientific field has dedicated enormous amounts of resources to researching the virus and its effects. The number of times Covid-19 publications are being cited throughout the literature appears remarkably high but has not been directly compared to non-Covid-19 papers in the same journals over an extended period. In our study, we use Clarivate’s Web of Science—Science Citation Index Expanded™ database to identify Covid-19 papers published in 24 major scientific journals over a period of 24 months from January 1, 2020 to December 31, 2021. We conduct our search using keywords “Covid-19”, “coronavirus”, and “sars-cov-2” to locate publications with these words in the title. We then quantify the number of citations these papers have received and compare rates to non-Covid-19 papers in the same journals over the same timeframe. We find that, across 24 open-access and subscription-based scientific journals, Covid-19 papers published in the past 2 years currently have a median citation rate of 120.79 compared to 21.63 for non-Covid-19 papers. When negative binomial regression is used to minimize the influence of other variables such as article number variation and field of research, Covid-19 papers have still experienced more than 80% increase in citations relative to non-Covid-19 papers. These novel findings demonstrate that Covid-19 papers are being cited at remarkably higher rates than non-Covid-19 articles contained within the same journals. This suggests that journal impact factor, which is a product of the number of citations that recently published articles receive, will likely be drastically influenced by the number of Covid-19 papers that a journal has included within its pages in the previous years.